UICC Stage Grouping(except Thyroid & Nasopharynx)

Goals of Treatment:
Stage I-IVA   : Curative
Stage IV B-C : Palliative

Treatment modalities
Surgery and radiotherapy are the definitive therapies in the treatment of head and neck squamous cell carcinomas. Chemotherapy by itself is not a definitive treatment.

Surgery
It is used as a single modality in early disease (stage I & II). It is combined with post-operative adjuvant radiotherapy in advanced disease (stage III & IV). Wide excision of tumor in all dimensions with adequate margins and appropriate neck dissection is essential in local-regional control of disease.

Radiotherapy
External beam radiotherapy and / or brachytherapy are used either as a single modality or as a part of multi-modality treatment. Radiotherapy is used in 3 different settings
• Radical curative radiotherapy (Alone or in combination with chemotherapy)
• Post-operative adjuvant radiotherapy
• Palliative radiotherapy

Three Dimensional Conformal Radiotherapy (3-DCRT) and Intensity Modulated Radiation Therapy (IMRT) are useful advances in radiotherapy techniques that can be used in primary treatment with radiation therapy or for boost. These techniques allow for better sparing of adjacent critical structures like the spinal cord, parotids thereby enabling better tumor coverage and may help in dose escalation to the target volume.

Chemotherapy
It is usually used in combination with radiotherapy (sequential or concurrent. Current evidence favors concurrent administration of chemo radiotherapy). It has a role in organ / voice preservation (in laryngeal / hypo pharyngeal cancers) and in oropharyngeal cancers. In select patients chemotherapy can be used for palliating symptoms.

General guidelines for selecting a treatment modality:
• Stage I / II disease - Single modality (Surgery or RT)
• Stage III & IV disease - Combined modality
         * Surgery + Radiotherapy
         * Chemotherapy + radiotherapy
. Selection of modality depends on the subsite of cancer.
• When different modalities are available, the modality that gives maximum chance of cure should be used.
• When different modalities have similar results, a modality that gives better quality of life, with organ / voice preservation, functional and cosmetic results is preferred.

Surgery is preferred over radiotherapy as a single modality in
1. Sites where surgery is not morbid (cosmetically and functionally)
2. Lesions involving or close to bone - to prevent radionecrosis.
3. Young patients – possibility of a subsequent second primary
4. Sub mucous fibrosis

RT is preferred over surgery as a single modality, where
1. Severe impairment of function / cosmesis with surgery, e.g. base tongue, glottis.
2. Surgery is technically difficult with high morbidity and poor results e.g. nasopharyngeal carcinoma.
3. Patient refuses surgery / high risk of surgery

Criteria of Unresectability :
Primary disease: Adequate surgical clearance is not achievable
• Extensive InfraTemporal Fossa involvement
• Extensive involvement of base skull.
• Extensive soft tissue disease: skin edema/ ulceration.

Nodal Disease:
• Clinically fixed nodes.
• Infiltration of Internal /Common carotid artery.
• Extensive infiltration of prevertebral muscles, skull base.

Reconstruction options:
• Mucosal defects:

Small defect - local flap / SSG / leave raw
Large defect - Free flap/Pedicled flap (PMMC)

• Skeletal defect - free fibula /cadaveric bone graft /silastic /plate. Anterior or midline lesion- better reconstruction with free tissue transfer.
• Skin defect - local flap / free flap / deltopectoral flap / forehead flap / PMMC

Pathology report in Head & Neck specimens:
I. Gross Pathology :
        1. Morphology
        2. Location and extent of the tumour / lesion
        3. Tumour dimensions ( including tumour depth)
        4. Distance from the various margins of excision
        5. Nodal dissection
II. Microscopy :
        1. Histologic type
        2. Grade
        3. Extent of disease including depth of infiltration
        4. Presence / absence of perineural invasion
        5. Presence / Absence of lymphovascular invasion
        6. Bone / cartilage / skin / soft tissue involvement
        7. Margins of excision, submucosal spread, In-situ changes
        8. Nodal status - number and size of nodes, perinodal extension and level of                                 nodes.
        9. Type of margin
III. Miscellaneous features
        1. In RND / MND status of the internal jugular vein
        2. Presence of predisposing factors –leukoplakia, Submucous fibrosis.
        3. Dysplasia / in-situ elements
        4. In tongue specimens – microscopic tumour thickness.
        5. Larynx          - preepiglottic fat status
                                - paraglottic space status
                                - cartilage involvement

Indications for post operative radiotherapy
Primary :
• Large primary – T3 or T4
• Close or positive margins of excision
• Deep infiltrative tumour
• High grade tumour
• Lympho-vascular and perineural invasion

Lymph nodes :
• Bulky nodal disease N2 / N3
• Extra nodal extension
• Multiple level involvement

Indications for Brachytherapy (BRT):
* Accessible lesions
* Small (preferably < 3cm) tumours
* Lesions away from bone
* N0 nodal status
* Superficial lesions

Radical Radiotherapy:
Tumour suitable for brachytherapy
* T1-2 N0:Radical BRT : 60-70Gy Low Dose Rate 192 Iridium
    Or equivalent doses with fractionated high dose rate.
* T1-3 N0-1: External RT : 56-60Gy/ 28-30#/ 6 wks
                       Boost BRT : Low dose rate 192Iridium : 15-20Gy or
                       High Dose Rate : 14Gy in 4 fractions over 2 days (4-3-3-4 Gy)

Tumours not suitable for brachytherapy :
* T1-4 N0-2 : Concomitant Chemoradiation : 66-70Gy/33–35# /6-7 wks + concomitant weekly Cisplatinum, 30mg/m2 for 6-7 wks Or 3 weekly Cisplatinum, 100mg / m2 X 3 cycles
Or
* External RT : 66-70Gy/33-35# /6-7 wks (reducing fields)

Post-operative radiotherapy :
• Primary and nodal disease: 50-60 Gy/25-30 fr/5-6 weeks, using reducing fields.
                   - Site of residual disease, positive cut margins: 4-10 Gy Boost
• Trend towards the use of adjuvant post-operative concomitant CT + RT for patients with high risk factors.

Rehabilitation :
• Abstinence from tobacco/ alcohol
• Oral Hygiene
• Shoulder physiotherapy in all cases of neck dissections
• Bite guide prosthesis following mandibulectomy
• Jaw stretching exercises to prevent post-operative trismus
• Swallowing and speech rehabilitation

Follow up :
• Every two to three months for first 2 years.
• Six monthly for next 3 years.
• Annually thereafter.
On every follow up thorough head and neck examination for locoregional control, second primary tumour and late sequelae of treatment. Investigation only if indicated by symptoms and positive clinical findings.
• Serum T3 T4 TSH annually particularly for larynx patients.

1. Evaluation of the dose for postoperative radiation therapy of head and neck cancer: first report of a prospective randomized trial.
Peters LJ, Goepfert H, Ang KK, et al.
Int J Radiat Oncol Biol Phys 1993;26:3-11

PURPOSE: This study was designed to determine in a prospective randomized trial the optimal dose of conventionally fractionated postoperative radiotherapy for advanced head and neck cancer in relation to clinical and pathologic risk factors. METHODS AND MATERIALS: Between January 1983 and March 1991, 302 patients were enrolled on the study. This analysis is based on the first 240 patients entered through September 1989, of whom 221 (92%) had AJC Stage III or IV cancers of the oral cavity, oropharynx, hypopharynx, or larynx. The patients were stratified by postulated risk factors and randomized to one of three dose levels ranging between 52.2 Gy and 68.4 Gy, all given in daily doses of 1.8 Gy. Patients receiving > 57.6 Gy had a field reduction at this dose level such that boosts were only given to sites of increased risk. RESULTS: The overall crude and actuarial 2-year local-regional recurrence rates were 25.4% and 26%, respectively. Patients who received a dose of < or = 54 Gy had a significantly higher primary failure rate than those receiving > or = 57.6 Gy (p = 0.02). No significant dose response could be demonstrated above 57.6 Gy except for patients with extracapsular nodal disease in the neck in whom the recurrence rate was significantly higher at 57.6 Gy than at > or = 63 Gy. Analysis of prognostic factors predictive of local-regional recurrence showed that the only variable of independent significance was extracapsular nodal disease. However, clusters of two or more of the following risk factors were associated with a progressively increased risk of recurrence: oral cavity primary, mucosal margins close or positive, nerve invasion, > or = 2 positive lymph nodes, largest node > 3 cm, treatment delay greater than 6 weeks, and Zubrod performance status > or = 2. Moderate to severe complications of combined treatment occurred in 7.1% of patients; these were more frequent in patients who received > or = 63 Gy. CONCLUSION: With daily fractions of 1.7 Gy, a minimum tumor dose of 57.6 Gy to the whole operative bed should be delivered with a boost of 63 Gy being given to sites of increased risk, especially regions of the neck where extracapsular nodal disease is present. Treatment should be started as soon as possible after surgery. Dose escalation above 63 Gy at 1.8 Gy per day does not appear to improve the therapeutic ratio.

2. Postoperative radiation as adjuvant treatment for carcinoma of the oral cavity, larynx, and pharynx: preliminary report of a prospective randomized trial.
Kokal WA, Neifeld JP, Eisert D, et al.
J Surg Oncol 1988;38:71-6

A prospective randomized trial was performed in patients with advanced squamous cell carcinomas (SCC) of the oral cavity, larynx, and pharynx to examine the effect of adjuvant postoperative radiation therapy on locoregional recurrence and survival following “curative” resection. Fifty-one patients with stage III or IV SCC treated from 1981 through 1984 were randomized to receive either surgery alone (n = 27) or surgery with postoperative radiation (n = 24). Five patients were excluded from the study after randomization because of ineligibility or protocol violations. Overall recurrence rates of 55.6% and 36.8% were noted in the surgery and surgery with adjuvant radiotherapy arms, respectively (p = NS). This trend towards a higher recurrence rate in the surgery only arm was in part due to the development of lymph node metastases in the contralateral, nonoperated neck. Thus far, no significant differences in either locoregional or overall survival have been noted between the two treatment arms. In this preliminary analysis, adjuvant postoperative radiotherapy does not appear to improve disease-free or overall survival.

3. Randomized study of preoperative versus postoperative radiation therapy in advanced head and neck carcinoma : long-term follow-up of RTOG study 73-03.
Tupchong L, Scott CB, Blitzer PH, et al.
Int J Radiat Oncol Biol Phys 1991;20:21-8

This is a report of a 10-year median follow-up of a randomized, prospective study investigating the optimal sequencing of radiation therapy (RT) in relation to surgery for operable advanced head and neck cancer. In May 1973, the Radiation Therapy Oncology Group (RTOG) began a Phase III study of preoperative radiation therapy (50.0 Gy) versus postoperative radiation therapy (60.0 Gy) for supraglottic larynx and hypopharynx primaries. Of 277 evaluable patients, duration of follow-up is 9-15 years, with 7.6% patients lost to follow-up before 7 years. Loco-regional control was significantly better for 141 postoperative radiation therapy patients than for 136 preoperative radiation therapy patients (p = 0.04), but absolute survival was not affected (p = 0.15). When the analysis was restricted to supraglottic larynx primaries (60 postoperative radiation therapy patients versus 58 preoperative radiation therapy patients), the difference for loco-regional control was highly significant (p = .007), but not for survival (p = 0.18). In considering only supraglottic larynx, 78% of loco-regional failures occurred in the first 2 years. Thirty-one percent (18/58) of preoperative patients failed locally within 2 years versus 18% (11/60) of postoperative patients. After 2 years, distant metastases and second primaries became the predominant failure pattern, especially in postoperative radiation therapy patients. This shift in the late failure pattern along with the increased number of unrelated deaths negated any advantage in absolute survival for postoperative radiation therapy patients. The rates of severe surgical and radiation therapy complications were similar between the two arms. Because of an increased incidence of late distant metastases and secondary primaries, additional therapeutic intervention is required beyond surgery and postoperative irradiation to impact significantly upon survival.

4. A Radiation Therapy Oncology Group (RTOG) phase III randomized study to compare hyperfractionation and two variants of accelerated fractionation to standard fractionation radiotherapy for head and neck squamous cell carcinomas: first report of RTOG 9003.
Fu KK, Pajak TF, Trotti A, Jones CU et al.
Int J Radiat Oncol Biol Phys. 2000 Aug 1;48(1):7-16.

PURPOSE: The optimal fractionation schedule for radiotherapy of head and neck cancer has been controversial. The objective of this randomized trial was to test the efficacy of hyperfractionation and two types of accelerated fractionation individually against standard fractionation. METHODS AND MATERIALS: Patients with locally advanced head and neck cancer were randomly assigned to receive radiotherapy delivered with: 1) standard fractionation at 2 Gy/fraction/day, 5 days/week, to 70 Gy/35 fractions/7 weeks; 2) hyperfractionation at 1. 2 Gy/fraction, twice daily, 5 days/week to 81.6 Gy/68 fractions/7 weeks; 3) accelerated fractionation with split at 1.6 Gy/fraction, twice daily, 5 days/week, to 67.2 Gy/42 fractions/6 weeks including a 2-week rest after 38.4 Gy; or 4) accelerated fractionation with concomitant boost at 1.8 Gy/fraction/day, 5 days/week and 1.5 Gy/fraction/day to a boost field as a second daily treatment for the last 12 treatment days to 72 Gy/42 fractions/6 weeks. Of the 1113 patients entered, 1073 patients were analyzable for outcome. The median follow-up was 23 months for all analyzable patients and 41.2 months for patients alive. RESULTS: Patients treated with hyperfractionation and accelerated fractionation with concomitant boost had significantly better local-regional control (p = 0.045 and p = 0.050 respectively) than those treated with standard fractionation. There was also a trend toward improved disease-free survival (p = 0.067 and p = 0.054 respectively) although the difference in overall survival was not significant. Patients treated with accelerated fractionation with split had similar outcome to those treated with standard fractionation. All three altered fractionation groups had significantly greater acute side effects compared to standard fractionation. However, there was no significant increase of late effects. CONCLUSIONS: Hyperfractionation and accelerated fractionation with concomitant boost are more efficacious than standard fractionation for locally advanced head and neck cancer. Acute but not late effects are also increased.

5. Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma : three meta-analyses of updated individual data. MACH-NC Collaborative Group. Meta-Analysis of Chemotherapy on Head and Neck Cancer.
Pignon J, Bourhis J, Domenge C, et al.
Lancet 2000 18;355:949-55

BACKGROUND : Despite more than 70 randomised trials, the effect of chemotherapy on non-metastatic head and neck squamous-cell carcinoma remains uncertain. We did three meta-analyses of the impact of survival on chemotherapy added to locoregional treatment. METHODS : We updated data on all patients in randomized trials between 1965 and 1993. We included patients with carcinoma of the oropharynx, oral cavity, larynx, or hypopharynx. FINDINGS : The main meta-analysis of 63 trials (10,741 patients) of locoregional treatment with or without chemotherapy yielded a pooled hazard ratio of death of 0.90 (95% CI 0.85-0.94, p<0.0001), corresponding to an absolute survival benefit of 4% at 2 and 5 years in favour of chemotherapy. There was no significant benefit associated with adjuvant or neoadjuvant chemotherapy. Chemotherapy given concomitantly to radiotherapy gave significant benefits, but heterogeneity of the results prohibits firm conclusions. Meta-analysis of six trials (861 patients) comparing neoadjuvant chemotherapy plus radiotherapy with concomitant or alternating radiochemotherapy yielded a hazard ratio of 0.91 (0.79-1.06) in favour of concomitant or alternating radiochemotherapy. Three larynx-preservation trials (602 patients) compared radical surgery plus radiotherapy with neoadjuvant chemotherapy plus radiotherapy in responders or radical surgery and radiotherapy in non-responders. The hazard ratio of death in the chemotherapy arm as compared with the control arm was 1.19 (0.97-1.46). INTERPRETATION : Because the main meta-analysis showed only a small significant survival benefit in favour of chemotherapy, the routine use of chemotherapy is debatable. For larynx preservation, the non-significant negative effect of chemotherapy in the organ-preservation strategy indicates that this procedure must remain investigational.

6. Choosing a concomitant chemotherapy and radiotherapy regimen for squamous cell head and neck cancer : A systematic review of the published literature with subgroup analysis.
Browman GP, Hodson DI, et al.
Head Neck 2001;23:579-89

BACKGROUND: A systematic review was conducted to develop clinical recommendations for concomitant chemotherapy (CT) and radiotherapy (RT) in patients with locally advanced squamous cell head and neck cancer (SCHNC). METHODS: Results of published randomized controlled trials (RCTs) were pooled using Meta-analyst(0.988) software. RESULTS: A pooled analysis of 18 RCTs (20 comparisons) involving 3,192 patients detected a reduction in mortality for concomitant therapy compared with RT alone (odds ratio [OR], 0.62; 95% confidence interval [CI], 0.52-0.74; relative risk, 0.83; risk reduction, 11%; p < .00001). Platinum-based regimens involving 1,514 patients from nine trials (10 comparisons) were most effective (OR, 0.57; 95% CI, 0.46-0.71; p < .00001; risk reduction, 12%). Concomitant therapy produced more acute adverse effects than RT alone. CONCLUSION: Platinum-based concomitant CT and RT is superior to conventional RT alone in improving survival in locally advanced SCHNC. Subgroup analyses can be used to help in choosing the most appropriate concomitant regimen.

7. Postoperative Concurrent Radiotherapy and Chemotherapy for High-Risk Squamous-Cell Carcinoma of the Head and Neck
Cooper J S., M.D., Pajak T F., Ph.D., Forastiere A A., M.D.et al.
N Engl J Med 2004;350(19):1937-1944

Background Despite the use of resection and postoperative radiotherapy, high-risk squamous-cell carcinoma of the head and neck frequently recurs in the original tumor bed. We tested the hypothesis that concurrent postoperative administration of cisplatin and radiotherapy would improve the rate of local and regional control. Methods Between September 9, 1995, and April 28, 2000, 459 patients were enrolled. After undergoing total resection of all visible and palpable disease, 231 patients were randomly assigned to receive radiotherapy alone (60 to 66 Gy in 30 to 33 fractions over a period of 6 to 6.6 weeks) and 228 patients to receive the identical treatment plus concurrent cisplatin (100 mg per square meter of body-surface area intravenously on days 1, 22, and 43). Results After a median follow-up of 45.9 months, the rate of local and regional control was significantly higher in the combined-therapy group than in the group given radiotherapy alone (hazard ratio for local or regional recurrence, 0.61; 95 percent confidence interval, 0.41 to 0.91; P=0.01). The estimated two-year rate of local and regional control was 82 percent in the combined-therapy group, as compared with 72 percent in the radiotherapy group. Disease-free survival was significantly longer in the combined-therapy group than in the radiotherapy group (hazard ratio for disease or death, 0.78; 95 percent confidence interval, 0.61 to 0.99; P=0.04), but overall survival was not (hazard ratio for death, 0.84; 95 percent confidence interval, 0.65 to 1.09; P=0.19). The incidence of acute adverse effects of grade 3 or greater was 34 percent in the radiotherapy group and 77 percent in the combined-therapy group (P<0.001). Four patients who received combined therapy died as a direct result of the treatment. Conclusions Among high-risk patients with resected head and neck cancer, concurrent postoperative chemotherapy and radiotherapy significantly improve the rates of local and regional control and disease-free survival. However, the combined treatment is associated with a substantial increase in adverse effect.

8. Postoperative Irradiation with or without Concomitant Chemotherapy for Locally Advanced Head and Neck Cancer
Jacques Bernier, M.D., Ph.D., Christian Domenge, M.D., et al
N Engl J Med 2004;350(19):1945-1952

Background We compared concomitant cisplatin and irradiation with radiotherapy alone as adjuvant treatment for stage III or IV head and neck cancer. Methods After undergoing surgery with curative intent, 167 patients were randomly assigned to receive radiotherapy alone (66 Gy over a period of 6 1/2 weeks) and 167 to receive the same radiotherapy regimen combined with 100 mg of cisplatin per square meter of body-surface area on days 1, 22, and 43 of the radiotherapy regimen. Results After a median follow-up of 60 months, the rate of progression-free survival was significantly higher in the combined-therapy group than in the group given radiotherapy alone (P=0.04 by the log-rank test; hazard ratio for disease progression, 0.75; 95 percent confidence interval, 0.56 to 0.99), with 5-year Kaplan–Meier estimates of progression-free survival of 47 percent and 36 percent, respectively. The overall survival rate was also significantly higher in the combined-therapy group than in the radiotherapy group (P=0.02 by the log-rank test; hazard ratio for death, 0.70; 95 percent confidence interval, 0.52 to 0.95), with five-year Kaplan–Meier estimates of overall survival of 53 percent and 40 percent, respectively. The cumulative incidence of local or regional relapses was significantly lower in the combined-therapy group (P=0.007). The estimated five-year cumulative incidence of local or regional relapses (considering death from other causes as a competing risk) was 31 percent after radiotherapy and 18 percent after combined therapy. Severe (grade 3 or higher) adverse effects were more frequent after combined therapy (41 percent) than after radiotherapy (21 percent, P=0.001); the types of severe mucosal adverse effects were similar in the two groups, as was the incidence of late adverse effects. Conclusions Postoperative concurrent administration of high-dose cisplatin with radiotherapy is more efficacious than radiotherapy alone in patients with locally advanced head and neck cancer and does not cause an undue number of late complications.

9. Update of MACH-NC (Meta-Analysis of Chemotherapy in Head & Neck Cancer) database focused on concomitant chemoradiotherapy
J. Bourhis, C. Amand and J.-P. Pignon on behalf of the MACH-NC Collaborative Group
jco.org/cgi/content/abstract/22/14_suppl/5505

Background: The MACH-NC Group have previously shown (Lancet; 2000) that chemotherapy (CT) improved survival (4% at 5 years) in non metastatic head and neck squamous cell carcinoma (HNSCC) treated by loco-regional treatment (LRT), with an higher benefit (8%) with CT concomitant to radiotherapy (RT). However the relatively important heterogeneity of the results limited the conclusions and prompted the MACH-NC to further confirm the results, by adding to the data base the data from the randomized trials performed between 1994 and 2000. Methods: Updated individual data from HNSCC patients randomized to LRT versus LRT + CT between 1965 and 2000 were included in this meta-analysis. The logrank-test, stratified by trial, was used for comparison and the hazard ratio (HR) of death was calculated. Results: 24 new trials, most of them on concomitant CT, were included totalizing 87 trials and more than 16,000 patients. The overall pooled HR was 0.88 (p<.0001) with an absolute benefit for CT of 5% at 5-years, and a significant interaction (p<.0001) between CT timing (adjuvant, neoadjuvant or concomitant) and treatment. The following analyses concern only the 50 concomitant trials. For this group, the HR was 0.81 (p<.0001) with an absolute benefit of 8% at 5-years. The results were identical for the 1994–2000 trials and the 1965–1993 trials, but without significant heterogeneity in the recent group. Similar results were obtained in the trials with postoperative RT (HR=0.80), conventional RT (0.83) and altered fractionated RT (0.73). No significant difference was seen between mono-CT (0.84) and poly-CT (0.77). The magnitude of the benefit was higher (p<0.01) for platinum-based CT (0.75) than for other CT (0.86). There was a decreasing effect of CT with age (p=.01). Conclusions: The benefit of concomitant chemotherapy was confirmed and was similar with both definitive and postoperative radiotherapy. The final analysis will be presented at the meeting.

10. Investigation of relationship between change in locoregional control and change in overall survival in randomized controlled trials of modified radiotherapy in head-and-neck cancer
Jonathan C. Wadsley M.A., M.R.C.P., F.R.C.R.* and Søren M. Bentzen Ph.D., D.Sc.
Int J Radiat Oncol Biol Phys 2004;60(5):1405-1409

Purpose: To establish whether a relationship exists between improvement in locoregional control (LRC) and improvement in overall survival (OS) in trials of modified radiotherapy for head-and-neck cancer and to attempt to quantify the relationship. Methods and materials: A systematic review of the literature was performed for randomized controlled trials of radiotherapy for head-and-neck cancer involving the use of altered fractionation or hypoxic sensitizers. The changes in LRC at 2 years and OS at 5 years were recorded for each trial. Regression analysis was used to investigate the relationship between the two variables. Results: Nineteen relevant trials were identified. Fourteen reported sufficient data for analysis. Linear regression analysis showed a statistically significant correlation between LRC and OS with a slope of 0.67 (95% confidence interval, 0.38–0.96, p = 0.00017). Conclusions: We have demonstrated a relationship between a change in LRC and a change in OS in randomized trials of modified radiotherapy for head-and-neck cancer. A 10% improvement in the 2-year LRC is predicted to lead to a 6.7% improvement in the 5-year OS. This type of analysis may have applications in other tumor sites.

ORAL CAVITY

Specific Investigations:
• OPG for bone erosion.
• USG neck for clinically N0 neck when neck is to be observed or neck evaluation is difficult.
• CT scan/ MRI for suspected vascular / maxillary infiltration and extension of tumor in infratemporal fossa.
        - CT scan is preferred to assess early bone involvement, in midline lesions and            in sites as buccal mucosa, upper & lower alveolus, RMT & hard palate
        - MRI is preferred for tongue and floor of mouth lesions and for extension in            oropharynx or parapharyngeal space.
• PET(CT) scan for evaluation of post treatment residual/ recurrent disease.
• EUA for mapping of lesion.

TNM Staging (UICC, 2002)

LIP

T1, T2 Tumours: Surgery or RT
Primary:
Surgery: Wide excision
Radiotherapy: Radical Radiotherapy / Brachytherapy.

Nodes
N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) followed by FS, if positive nodes MND is required
N+: MND / RND

Note: Post op RT as per earlier guidelines.

T3, T4 Tumours: Surgery + Post operative RT/ CT-RT
Primary:
Surgery: Wide excision with marginal/ segmental / hemimandible resection if required with reconstruction.

Nodes
N0: SOHD followed by FS, if positive nodes MND is required
N+: MND / RND

Note: Bilateral neck needs to be addressed if the primary disease is in midline or extending across midline (including middle third mandible).
Post op RT/CT-RT as per earlier guidelines.

BUCCAL MUCOSA

T1, T2 Tumours:
Primary:
Surgery: wide excision +/- marginal mandibulectomy or margins.
Radiotherapy:Radical RT/ Brachytherapy.

Nodes
N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) followed by FS, if positive nodes, MND is required
N+: MND / RND
Note: Post op RT as per earlier guidelines.

T3, T4 Tumours:
Surgery + Post operative RT or CT-RT
Primary:
Surgery: Composite resection of the buccal mucosa with mandible or upper alveolus or overlying skin with reconstruction

Nodes
N0: SOHD followed by FS, if positive, nodes MND is required
N+: MND / RND
Note: Post op RT/ CT-RT as per earlier guidelines.

ORAL TONGUE & FLOOR OF MOUTH

T1, T2 Tumours:
Primary:
Surgery: Wide Excision Glossectomy / Hemiglossectomy
Radiotherapy: Radical RT/ Brachytherapy

Nodes
N0** Observe/ Elective MND (criteria listed below)#
N+ MND/ RND
Note: Post op RT/CT-RT as per earlier guidelines.

T3, T4 Tumours:
Surgery + Post operative Radiotherapy
Primary:
Surgery: Appropriate wide / total glossectomy with mandibular swing or pull through along with lingual plate / segmental / hemimandibular resection, if required (based on extent of involvement)

Nodes
N0: SOHD / MND / RND
N+: MND / RND
Note: Bilateral necks need to be addressed if the primary disease is in midline or extends across midline (including middle third mandible).
Post op RT/CT+RT as per guidelines.

** USG neck if decision to observe the N0 neck is made.
#Criteria for elective neck dissection
¨ Depth of infiltration > 3-4mm
¨ High grade tumour
¨ Expected poor follow up

LOWER ALVEOLUS & RETRO MOLAR TRIGONE

                       Mandible uninvolved or minimally involved
Primary:
Surgery: Wide Excision with marginal mandibulectomy (avoided in RMT disease, edentulous mandible, paramandibular disease, post radiotherapy)

Nodes
N0: Observe or SOHD (if cheek flap is raised, USG suspicious, thick tumour or poor follow up expected) followed by FS, if positive nodes MND is required
N+: MND / RND
Note: Post op RT as per earlier guidelines.

                                           Mandible grossly involved
Surgery + Post operative/ CT-RT
Primary:
Surgery: Wide Excision (cheek flap) with segmental/ hemi-mandible resection

Nodes
N0: SOHD followed by FS, if positive nodes, MND is required
N+: MND / RND.
Note: Bilateral necks needs to be addressed if the primary disease is in midline or extends across midline (including middle third mandible).
Post op RT/ CT-RT as per earlier guidelines.

UPPER ALVEOLUS & HARD PALATE

                                            Maxillary antrum not involved
Upper alveolectomy / Partial maxillectomy
Radical RT / Brachytherapy for selected early T1-2 Hard palate lesions

                                            Maxillary antrum involved
Orbital floor preserving total maxillectomy

Note: Neck needs to be addressed if the neck is clinically positive, if there is extension of the primary disease to the buccal mucosa or there is soft tissue infiltration or radiological suspicion of metastatic node.
Post operative RT/ CT-RT as per guidelines mentioned earlier.

Based on the size and composition of defect, the options are:
Mucosal defects –
• Leave raw
• Primary closure
• Split thickness skin graft (STSG)
• Mucosal grafts

Full thickness defects -
• Local Flaps- Abbe-Estlander’s flap, Gille’s Flap (for lip)
• Regional flaps - Tongue flap, Nasolabial flap, Facial artery myomucosal flap, , Masseter flap, Platysmal flap, , Forehead flap
• Distant Flaps- Pectoralis major myocutaneous flap, Deltopectoral flap, Latissimus dorsi myocutaneous flap
• Free Flaps- Radial forearm flap, Lateral arm flap, Antero-lateral thigh flap

Mandibular Defects
Anterior mandibular defect needs to be reconstructed by-
        . Free osteocutaneous flaps- Fibular osteocutaneous flap (preferred because         of long bone length, easy contouring and dual blood supply), Radial
        osteo-cutaneous flap,  Scapular osteocutaneous flap
        • Distant flaps- Pectoralis major msteocutaneous Flap, Latissimus dorsi         osteocutaneous flap, Trapezius osteocutaneous flap

Lateral mandibular defects may be reconstructed with adequate soft tissue replacement, complemented by proper use of guide bite prosthesis and appropriate post-operative isometric exercises.

Suggested reading:
1. de Visscher JG, Botke G, Schakenraad JA, et al. A comparison of results after radiotherapy and surgery for stage I squamous cell carcinoma of the lower lip.Head Neck 1999;21:526-30
2. Iyer SG, Pradhan SA, Pai PS, Patil S. Surgical treatment outcomes of localized squamous carcinoma of buccal mucosa. Head Neck. 2004 Oct;26(10):897-902.
3. Pathak KA, Agarwal R, Deshpande MS. Marginal mandibulectomy for lateral sulcus tumours. Eur J Surg Oncol. 2004 Sep;30(7):804-6.
4. Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for oral tongue cancer. Laryngoscope 2002; 112:616-25
5. Hicks WL Jr, North JH Jr, Loree TR, et al. Surgery as a single modality therapy for squamous cell carcinoma of the oral tongue. Am J Otolaryngol 1998: 19:24-8
6. Sessions DG, Spector GJ, Lenox J, et al. Analysis of treatment results for floor-of-mouth cancer. Laryngoscope 2000; 110:1764-72
7. Haddadin KJ, Soutar D, Oliver R, et al. Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection. Head Neck 1999;21:517-25
8. Fakih AR, Rao RS, Borges AM, et al. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue. Am J Surg 1989;158:309-13
9. Soo K C, Rpiro RH, King W, et al. Squamous carcinoma of the gums. Am J Surg 1998; 156:281-5
10. Totsuka Y, Usui Y, Tei K, et al. Mandibular involvement by squamous cell carcinoma of lower alveolus: analysis and comparative study of the histologic and radiologic features. Head Neck 1991;13:40-50.
11. Hidalgo DA: Fibula Free Flap mandibular reconstruction. Clin. Plast. Surg. 21:25, 1994.
12. Evans JF, Shah JP. Epidermoid carcinoma of the palate.
Am J Surg 1981;142:451-5
13. Kunkel M, Forster GJ, Reichert TE, Jeong JH, Benz P, Bartenstein P, Wagner W, Whiteside TL. Detection of recurrent oral squamous cell carcinoma by [18F]-2-fluorodeoxyglucose-positron emission tomography: implications for prognosis and patient management. Cancer. 2003 Nov15;98(10):2257-65.

1. A comparison of results after radiotherapy and surgery for stage I squamous cell carcinoma of the lower lip.
de Visscher JG, Botke G, Schakenraad JA, et al.
Head Neck 1999;21:526-30

BACKGROUND: Controversy still exists as to whether radiotherapy or surgery is the preferable therapeutic modality for stage I squamous cell carcinoma of the lower lip. Therefore, a retrospective study was undertaken to compare the results of both treatment modalities. METHODS: The results of 90 patients who received radiotherapy and 166 patients who underwent surgery as the primary form of treatment for their stage I primary squamous cell carcinoma of the lower lip were evaluated. Tumor size and histological grade of differentiation were assessed. RESULTS: Local control rates were the same with radiotherapy or surgery. Overall survival rates for both groups of patients were similar as well. Disease-free survival rates in the patients who underwent radiotherapy were significantly lower compared with the surgically treated group. This was due to a higher occurrence of regional metastases in the patients who received radiotherapy. Univariate analysis showed that irradiated patients had a statistically significant greater tumor size. The difference of histological differentiation between the groups was also statistically significant, the analysis showed that only tumor size carried significant independent prognostic information. CONCLUSIONS: The cure rates of stage I squamous cell carcinoma of the lower lip are favorable whether treated by radiotherapy or surgery, and local control rates are similar. The radiotherapeutic treated group showed an increased incidence of cervical metastases, which was due to the more advanced tumor size in these patients.

2. Surgical treatment outcomes of localized squamous carcinoma of buccal mucosa.
Iyer SG, Pradhan SA, Pai PS, Patil S. et al.
Head Neck. 2004 Oct;26(10):897-902.

BACKGROUND: The purpose of the study was to analyze the outcomes after surgical therapy (peroral wide excision) for early squamous carcinoma of the buccal mucosa. METHODS: This is a retrospective study of localized squamous carcinoma of the buccal mucosa treated with peroral wide excision at a major tertiary-care hospital. RESULTS: A total of 147 consecutive patients were analyzed. One hundred eight patients (73.5%) had no recurrence, whereas 18 (12.2%) had a local recurrence, 11 (7.5%) had regional metastasis, and 10 (6.8%) had locoregional recurrence over a median follow-up of 46 months. Most patients with local recurrences (15 patients, 83.3%) and regional metastases (eight patients, 72%) could be salvaged with treatment. In contrast, only four patients (40%) with locoregional recurrence could be salvaged. Most of the recurrences in this study group occurred within 2 years of primary treatment (29 [74%] of 39 patients). Three-year actuarial overall survival rate and disease-free survival rates were 91% and 77%, respectively. CONCLUSIONS: Peroral wide excision seems to be an adequate procedure for early squamous carcinoma of buccal mucosa. Histologic grade of the tumor emerged as the only prognostic factor of significance for recurrence in this study.

3. Marginal mandibulectomy for lateral sulcus tumours.
Pathak KA, Agarwal R, Deshpande MS.
Eur J Surg Oncol. 2004 Sep;30(7):804-6.

OBJECTIVE: To report a retrospective series of marginal mandibulectomy for cancers of oral cavity, with special reference to squamous cancers of gingival buccal complex. METHODS: Retrospective record review of 107 patients who underwent marginal mandibulectomy between 1994 and 2001. RESULTS: Eighty-three marginal mandibulectomies were done for gingivo-buccal complex cancers. Local failure rate was 16%. The 2-year and 5-year disease free survival rates were 69 and 60%, respectively. The local recurrence free survival at the end of 2 and 5 years were 79 and 70%, respectively. CONCLUSION: In carefully selected patients, marginal mandibulectomy is an oncologically safe.

4. Influence of bone invasion and extent of mandibular resection on local control of cancers of the oral cavity and oropharynx.
O'Brien CJ, Adams JR, McNeil EB, Taylor P, Laniewski P, Clifford A, Parker GD.
Int J Oral Maxillofac Surg. 2003 Oct;32(5):492-7.

The aim of this paper was to evaluate the influence of bone invasion on treatment outcome among patients with cancers of the oral cavity and oropharynx and to determine whether or not outcome was influenced by the extent of mandibular resection. A review of 127 prospectively documented patients who were treated with marginal or segmental resection for oral (n = 110) and oropharyngeal (n = 17) cancers was undertaken. There were 97 males and 30 females with a median age of 61 years. Clinical T stages were: T1 17 patients, T2 33, T3 22, T4 55. Median followup was 4 years. A total of 94 patients underwent marginal resections and 33 underwent segmental resections. Histological bone invasion was present in 17 patients (16%) in the marginal resection group and 21 patients (64%) in the segmental group (P<0.05). Soft tissue surgical margins were positive in 11 patients (12%) in the marginal group and in seven patients (21%) in the segmental group (P=not significant). Local control did not correlate significantly with T stage, the extent of mandibular resection or the presence of histological bone invasion, but was significantly influenced by positive soft tissue margins (P<0.01). Among patients with bone invasion, the local control rate was higher following segmental resection when compared to marginal resections (87% vs. 75%) but this was not statistically significant. Survival was significantly influenced by positive soft tissue margins but not bone invasion or the type of resection. We conclude that bone invasion alone did not predict for local control or survival rates among patients with oral and oropharyngeal cancers. Involved soft tissue margins were highly predictive of local recurrence and decreased survival. Conservative resection of the mandible is safe as long as marginal mandibulectomy does not lead to compromise of soft tissue margins. Segmental resection should be reserved for patients extensive bone invasion or those with limited invasion in a thin atrophic mandible.

5. Analysis of treatment results for oral tongue cancer.
Sessions DG, Spector GJ, Lenox J, et al.
Laryngoscope 2002;112:616-25

OBJECTIVE: The study reports the results of treatment of oral tongue cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 332 patients with oral tongue cancer treated in the Departments of Otolaryngology-Head and Neck Surgery and Radiation Therapy at Washington University School of Medicine (St. Louis, MO) from 1957 to 1996. METHODS: Patients with biopsy-proven squamous cell carcinoma of the oral tongue who were previously untreated and were treated with curative intent by one of five modalities and who were eligible for 5-year follow-up were included. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival rate (DSS) was 57% with death due to tumor in 43%. The 5-year cumulative disease-specific survival probability (CDSS) was 0.61 (Kaplan-Meier) with a mean of 17.5 years and a median of 30.1 years. The DSS by treatment modality included local resection (73%), composite resection (61%), radiation therapy (46%), local resection and radiation therapy (65%), and composite resection with radiation therapy (CR/RT) (44%). Overall, local resection had a significantly improved DSS and CR/RT had a decreased DSS that was related to the stage of disease being treated. In treating stage IV disease, CR/RT produced a more significantly improved CDSS than the other treatment modalities. Recurrence at the primary site was as common as recurrence in the neck. Eighty-nine percent of recurrences occurred within the first 60 months. Recurrence significantly decreased survival. DSS was significantly improved in patients with clear margins of resection. Metastasis to a distant site occurred in 9.6% of patients. Twenty-one percent of patients had second primary cancers, and 54% of these patients died of their second primary cancer. CONCLUSIONS: Significant improvement in DSS was seen in patients with clear margins, early stage grouping and clinical (pretreatment) tumor stage, and negative nodes. Significant decrease in DSS was seen in patients with close or involved margins, advanced stage grouping and clinical (pretreatment) tumor staging, positive clinical (pretreatment) node staging, and tumor recurrence. Obtaining clear margins of resection is crucial because it significantly affects survival. A minimum of 5 years of close monitoring is recommended because of the high incidence of second primary cancers.

6. Analysis of treatment results for floor-of-mouth cancer.
Sessions DG, Spector GJ, Lenox J, et al.
Laryngoscope 2000;110:1764-72

OBJECTIVE: This study reports the results of treating floor-of-mouth cancer with five different treatment modalities with long-term follow-up. STUDY DESIGN: Retrospective study of 280 patients with floor-of-mouth cancer treated in the Department of Otolaryngology-Head and Neck Surgery at Washington University Medical School (St. Louis, MO) from 1960 to 1994. METHODS: Patients with biopsy-proven squamous cell carcinoma of the floor of mouth who were previously untreated were treated with curative intent by one of five modalities and were all eligible for 5-year follow-up. The treatment modalities included local resection alone, composite resection alone (with neck dissection), radiation therapy alone, local resection with radiation therapy, and composite resection with radiation therapy. Multiple diagnostic, treatment, and follow-up parameters were studied using standard statistical analysis to determine statistical significance. RESULTS: The overall 5-year disease-specific survival (DSS) was 56% with death due to tumor in 44% of patients. The 5-year cumulative disease-specific survival (CDSS) was 0.61 (Kaplan-Meier probability) with a mean of 8.3 years and a median of 9.7 years. The DSS by treatment modality included local resection (76%), composite resection (63%), radiation therapy (43%), local resection with radiation therapy (61%), and composite resection with radiation therapy (55%). Overall, there was no significant difference in DSS by treatment modality. Recurrence at the primary site (41%) was the most common site of treatment failure. Nineteen percent of patients had recurrence in the neck. Eighty-eight percent of initial recurrences occurred within 60 months after the onset of treatment. Metastasis to a distant site occurred in 30% of patients. Twenty percent of these patients had second primary cancers, and 53% of these patients died of their second primary cancers. CONCLUSIONS: Significantly improved 5-year DSS was seen in the patients with clear margins, early clinical tumor stage, and negative nodes. Significantly decreased 5-year survival was seen in the patients with involved margins, advanced clinical tumor stage, positive nodes, and tumor recurrence. Patients with no clinically positive nodes (cNO) can be observed safely for regional nodal disease and subsequent positive nodes can be treated as they occur with no adverse affect on survival. Because of high recurrence rates at the primary site and neck, and an increased rate of both distant metastasis and the development of second primary cancers, patients should be monitored closely for a minimum of at least 5 years.

7. The prognostic implications of the surgical margin in oral squamous cell carcinoma.
Sutton DN, Brown JS, Rogers SN, Vaughan ED, Woolgar JA.
Int J Oral Maxillofac Surg. 2003 Feb;32(1):30-4.

The prime objective of tumour ablation in oral squamous cell carcinoma (OSCC) is the removal, with a 'margin' of normal tissue, of the whole tumour. Definition of what constitutes margin involvement varies. This study aims to examine the factors associated with close and involved surgical margins in the management of OSCC. A cohort of 200 consecutive patients with previously untreated OSCC provided the material for the study. Various clinical, operative and pathological parameters were related to the status of the surgical margin, as well as time to recurrence, and survival. Cox regression analysis of the survival was also undertaken. Of the 200 patients 107 (53.5%) had clear margins, 84 (42%) close and 9 (4.5%) involved. Poor correlation was found between the status of the surgical margin and clinical factors, but in contrast high correlation between histological indicators of aggressive disease and close or involved surgical margins. These results imply that close surgical margins in OSCC could be regarded as an indictor of aggressive disease.procedure to achieve good local control.

8. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity.
Kligerman J, Lima RA, Soares JR, et al.
Am J Surg 1994;168:391-4

BACKGROUND: Recent studies in patients with previously untreated T1 and T2 squamous cell carcinoma (SCC) of the tongue and floor of the mouth have shown a relationship between tumor thickness, neck metastasis, and survival. Our study was conducted to determine the indication of elective neck dissection in patients with early oral cavity SCC. PATIENTS AND METHODS: Sixty-seven patients were stratified by stage (T1 and T2 NO), and those in each stage were randomized to receive one of two types of treatment; resection alone (RA) or resection plus elective supraomohyoid neck dissection (RSOND). Fifty-two patients (78%) were men and 15 (22%) were women. The median age was 57 years old (range 34 to 95). RESULTS: Twenty-six (39%) patients had tumor in the floor of the mouth and 41 (61%), in the tongue. Using the criteria of the Union Internationale Contre le Cancer (UICC), 1987, we classified 31 tumors (46%) as T1 lesions and 36 (54%) as T2 lesions. Thirty patients had a tumor thickness < or = 4 mm and 37 had a tumor thickness > 4 mm. Thirty-three (49%) patients were treated with RA, and 34 patients (51%) were treated with RSOND. Seven (21%) patients of the RSOND group had occult cervical metastasis. There were recurrences in 14 (42%) patients of the RA group and 8 (24%) patients of the RSOND group. The disease-free survival rates at 3.5 years for RA and RSOND patients were 49%, and 72%, respectively. The impact of sex, age, site, cancer stage, and tumor thickness was assessed by the Mantel-Haenszel chi-square procedure. Later stage (P = 0.05) and increased tumor thickness (P = 0.005) were significantly associated with treatment failures. CONCLUSION: Neck dissection remains mandatory in the early stage of oral SCC, because of better survival rates compared to RA and the poor salvage rate. In particular, patients with tumor thickness > 4 mm treated with RSOND had significant benefit on disease-free survival.

9. Improved survival for patients with clinically T1/T2, N0 tongue tumors undergoing a prophylactic neck dissection.
Haddadin KJ, Soutar D, Oliver R, et al.
Head Neck 1999;21:517-25

BACKGROUND: Prophylactic surgical treatment of the neck in "early tongue tumors" is a controversial issue. METHODS: From a database of 226 patients with squamous cell carcinoma of the tongue treated at Canniesburn Hospital, Glasgow, U.K., between 1980 and 1996, a total of 137 patients with a minimum follow up of 24 months or until death were clinically identified as being T1/T2, N0 (UICC) when first seen. These patients were divided into three groups according to the management of the neck; 53 patients did not have a neck dissection at any time (NKD0), 47 patients underwent a synchronous neck dissection at the time of treatment of the primary (NKDS), and 37 patients subsequently required a metachronous neck dissection when lymph node metastasis became clinically apparent (NKDM). These three groups were compared with respect to age, sex, site, duration of symptoms, previous treatment (if any), initial treatment protocol, resection margin, type of neck dissection (if any), loco-regional recurrence, systemic escape, number of positive lymph nodes, and presence of extracapsular spread. Disease-related survival was calculated using Kaplan-Meier survival curves with logrank test and chi-square statistical analysis. RESULTS: The pT stage was upgraded to T3/4 in 3/53 patients (6%) of the NKD0 group, 11/47 patients (23%) of the NKDS group, and 2/37 patients (5%) of the NKDM group (p < 0.001). The 5-year determinate survival rates for the three groups were: NKD0 59.7%, NKDS 80.5%, NKDM 44.8%, and (NKD0 + NKDM) 53.6% with a statistically significant improvement in survival for NKDS vs NKDM (logrank 10.58, p = 0.001) and for NKDS vs (NKD0 + NKDM) (logrank 6.06, p = 0.014). The incidences of positive nodes in the NKDS and NKDM groups were 18/47 patients (38%) and 32/37 patients (86%) respectively. Neck positive patients in the NKDM group had a significantly greater number of positive nodes in comparison with N positive patients in the NKDS group (chi trend, p = 0.001), a higher incidence of extracapsular spread, 30/32 vs 9/18 (chi test, p < 0. 0001), and decreased survival. The incidence of occult cervical metastasis for the whole group was 41%. CONCLUSION: Patients with clinical T1/2, N0 tongue tumors who underwent a synchronous neck dissection had an improved survival outcome even though as a group they had a higher incidence of occult metastasis, relatively more T2 lesions, a worse pT stage, and had more posterior third lesions requiring more difficult initial surgery. Tongue tumors have a high incidence of subclinical nodal disease, which is less curable when it presents clinically. The information gleaned from the nodal status allows a more informed plan of adjuvant therapy.

10. Elective versus therapeutic neck dissection in early carcinoma of the oral tongue.
Fakih AR, Rao RS, Borges AM, et al.
Am J Surg 1989;158:309-13

A prospective, randomized trial was carried out to assess the value of elective versus therapeutic neck dissection in early squamous cell carcinoma of the oral tongue. Disease-free survival (median follow-up 20 months) was 52 percent versus 63 percent in patients who underwent hemiglossectomy alone and those who underwent hemiglossectomy and radical neck dissection, respectively (difference not statistically significant). Patients with a tumor depth of less than 4 mm did significantly better than those with a tumor depth of greater than 4 mm; they were also more likely to have uninvolved nodes at elective radical neck dissection compared with those with a tumor depth of greater than 4 mm. However, when the survival rates of patients in the two treatment groups were compared with respect to a tumor depth of 4 mm, there was no significant difference between the hemiglossectomy and the hemiglossectomy and radical neck dissection groups. A policy of interval elective radical neck dissection only in those with a tumor depth of greater than 4 mm may optimize cure rates and avoid neck dissection in those unlikely to develop neck recurrence.

11. Controlling advanced neck disease: efficacy of neck dissection and radiotherapy.
Richards BL, Spiro JD.
Laryngoscope 2000;110:1124-7

OBJECTIVE: Neck dissection remains the standard method of treating cervical metastasis from head and neck squamous cell carcinoma. In light of recent trends to modify the classic radical neck dissection (RND) for early neck disease, we reviewed our experience with radical and modified RND (MRND) plus radiotherapy as treatment for N2/N3 neck disease in head and neck squamous cell carcinoma. METHODS: We retrospectively reviewed our clinical records from July 1989 to June 1996 to identify 43 neck dissections in 39 patients who were found to have pathologically N2 or N3 neck disease treated primarily by neck dissection and postoperative radiotherapy. All patients had head and neck squamous cell carcinoma with a minimum follow-up of 24 months. RESULTS: Nine percent (4/43) of the dissected necks were pathologically N2a, 72% (31/43) were N2b, 7% (3/43) were N2c, and 12% (5/43) were N3. Of these, 28% (12/43) underwent a RND and 72% (31/43) underwent a MRND. The most common modification of RND was preservation of the spinal accessory nerve. All patients underwent postoperative radiotherapy with a mean dose of 55 Gy. Only 4 of 43 dissected necks had isolated treatment failure, for a regional control rate of 91%. CONCLUSIONS: The combination of RND or MRND and radiotherapy is highly effective in controlling neck disease in the absence of persistent or recurrent local disease. Also, in our experience, MRND appears to be as effective as RND in controlling even advanced neck disease, which supports preservation of the spinal accessory nerve whenever oncologically feasible.

12. Detection of recurrent oral squamous cell carcinoma by [18F]-2-fluorodeoxyglucose-positron emission tomography: implications for prognosis and patient management.
Kunkel M, Forster GJ, Reichert TE, Jeong JH, Benz P, Bartenstein P, Wagner W, Whiteside TL.
Cancer. 2003 Nov15;98(10):2257-65.

BACKGROUND: Patients with recurrent oral squamous cell carcinoma (OSCC) have a dismal prognosis and represent a therapeutic challenge. A positron emission tomography (PET) scan with [(18)F]-2-fluorodeoxyglucose [(18)F]FDG) can improve early cancer detection. The current study evaluates the prognostic value of [(18)F]FDG-PET scan in patients with recurrent OSCC. METHODS: The authors studied 97 patients with previously resected OSCC who were restaged by PET scanning. Of the 97 patients, 64 had no evidence of clinical disease and 33 were suspected of having disease by imaging, clinical findings, or pathologic evaluation. The median follow-up period was 35.4 months after a PET scan. The end points included disease recurrence, a disease recurrence-free period 6 months after a PET scan, or death. RESULTS: The overall sensitivity of a PET scan did not exceed 90% and its specificity varied from 67% for local disease recurrence/second primaries to 99% for lymph node metastasis. Increased [(18)F]FDG uptake predicted increased hazard of death (hazard ratio: 6.83; P = 0.00034) and proved to be a highly predictive marker of disease status. A significant association was established for incremental standardized uptake values and 3-year patient survival (P=0.0089), indicating that intense glucose metabolism in the tumor is a negative marker of survival in recurrent OSCC. Overall, survival was longer in patients with a negative rather than a positive PET scan (P<0.00001). CONCLUSIONS: PET scanning was found to be highly valuable for diagnosing OSCC recurrence in a postoperative setting. It provided prognostic information and played an important role in patient counseling and management.

Specific Investigations:
• Clinical evaluation including per-oral examination, indirect laryngoscopy and neck examination.
• Examination under general anaesthesia (EUA) for
          - extent of tumour,
          - biopsy
          - Assessment for operability (If surgery is contemplated).

    - MRI: investigation of choice for soft tissue extent.
    - CT scan: preferred in suspected bony erosion (mandible, pterygoid        plates, base skull)
    - PET-CT: for post-treatment residual or recurrent disease

Treatment options:
Stage I & II ( T1-2 N0 )
• Radical Radiotherapy : In most cases.
• Surgery: In selected cases eg. Lateralised lesion, infiltrative disease. (Criteria: Patient’s preference, institutional practice and complexity of procedure).

Stage III & IV
T1-2, N2-3
• Concomitant CT plus RT, followed by neck salvage if residual nodes or as a planned procedure.
• Split therapy: (In selected cases of large nodes with small radio-curable primary) Node mass excision followed by RT / CT+RT.

T3-4, N0, N+
• Concomitant CT plus RT : In most cases.
• Surgery: (if low peri-op risk & reasonable functional outcome) Composite resection + appropriate neck dissection + Post-operative radiotherapy
Note: Post-op RT / CT+RT as per general guidelines.

1. Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant radiochemotherapy in advanced-stage oropharynx carcinoma.
Denis F, Garaud P, Bardet E, Alfonsi M, et al.
J Clin Oncol. 2004 Jan 1;22(1):69-76.

PURPOSE: We report the 5-year survival and late toxicity results of a randomized clinical trial, which showed a 3-year improvement in overall survival and locoregional control of stage III or IV oropharynx carcinoma, using concomitant radiochemotherapy (arm B), compared with standard radiotherapy (arm A). PATIENTS AND METHODS: A total of 226 patients were entered onto a phase III multicenter randomized trial comparing radiotherapy alone (70 Gy in 35 fractions; arm A) with concomitant radiochemotherapy (70 Gy in 35 fractions with three cycles of a 4-day regimen comprising carboplatin and fluorouracil; arm B). Prognostic factors were evaluated by univariate and multivariate analysis. Five-year late toxicity was evaluated using National Cancer Institute Common Toxicity Criteria for neurological toxicity, hearing, taste, mandibula, and teeth damage, and Radiation Therapy Oncology Group toxicity criteria for skin, salivary gland, and mucosa. RESULTS: Five-year overall survival, specific disease-free survival, and locoregional control rates were 22% and 16% (log-rank P =.05), 27% and 15% (P =.01), and 48% and 25% (P =.002), in arm B and arm A, respectively. Stage IV, hemoglobin level lower than 125 g/L, and standard treatment were independent prognostic factors of short survival and locoregional failure by univariate and multivariate analysis. One or more grade 3 to 4 complications occurred in 56% of the patients in arm B, compared with 30% in arm A (P was not significant). CONCLUSION: Concomitant radiochemotherapy improved overall survival and locoregional control rates and does not statistically increase severe late morbidity. Anemia was the most important prognostic factor for survival in both arms.

2. Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.
Olmi P, Crispino S, Fallai C, Torri V, et al.
Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):78-92.

PURPOSE: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leucopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.

3. Randomized trial of neoadjuvant chemotherapy in oropharyngeal carcinoma. French Groupe d’Etude des Tumeurs de la Tete et du Cou (GETTEC).
Domenge C, Hill C, Lefebvre JL, De Raucourt D, et al.
Br J Cancer 2000;83:1594-8

The objective of the study was to evaluate the effect of neoadjuvant chemotherapy on the survival of patients with oropharyngeal cancer. Patients with a squamous cell carcinoma of the oropharynx for whom curative radiotherapy or surgery was considered feasible were entered in a multicentric randomized trial comparing neoadjuvant chemotherapy followed by loco-regional treatment to the same loco-regional treatment without chemotherapy. The loco-regional treatment consisted either of surgery plus plus radiotherapy or of radiotherapy alone. Three cycles of chemotherapy consisting of Cisplatin (100 mg/m2) on day 1 followed by a 24-hour i.v. infusion of fluorouracil (1000 mg/m2/day) for 5 days were delivered every 21 days. 2-3 weeks after the end of chemotherapy, local treatment was performed. The trial was conducted by the Groupe d’Etude des Tumeurs de la Tete Et du Cou (GETTEC). A total of 318 patients were enrolled in the study between 1986 and 1992. Overall survival was significantly better (P = 0.03) in the neoadjuvant chemotherapy group than in the control group, with a median survival of 5.1 years versus 3.3 years in the no chemotherapy group. The effect of neoadjuvant chemotherapy on event-free survival was smaller and of borderline significance (P = 0.11). Stratification of the results on the type of local treatment, surgery plus radiotherapy or radiotherapy alone, did not reveal any heterogeneity in the effect of chemotherapy.

4. Randomized trial of radiation therapy versus concomitant chemotherapy and radiation therapy for advanced-stage oropharynx carcinoma.
Calais G, Alfonsi M, Bardet E, et al.
J Natl Cancer Inst 1999;91:2081-6

BACKGROUND : We designed a randomized clinical trial to test whether the addition of three cycles of chemotherapy during standard radiation therapy would improve disease-free survival in patients with stages III and IV (i.e., advanced oropharynx carcinoma). METHODS : A total of 226 patients have been entered in a phase III multicenter, randomized trial comparing radiotherapy alone (arm A) with radiotherapy with concomitant chemotherapy (arm B). Radiotherapy was identical in the two arms, delivering, with conventional fractionation, 70 Gy in 35 fractions. In arm B, patients received during the period of radiotherapy three cycles of a 4-day regimen containing carboplatin (70 mg/m(2) per day) and 5-fluorouracil (600 mg/m(2) per day) by continuous infusion. The two arms were equally balanced with regard to age, sex, stage, performance status, histology, and primary tumor site. RESULTS : Radiotherapy compliance was similar in the two arms with respect to total dose, treatment duration, and treatment interruption. The rate of grades 3 and 4 mucositis was statistically significantly higher in arm B (71%; 95% confidence interval [CI] = 54%-85%) than in arm A (39%; 95% CI = 29%-56%). Skin toxicity was not different between the two arms. Hematologic toxicity was higher in arm B as measured by neutrophil count and hemoglobin level. Three-year overall actuarial survival and disease-free survival rates were, respectively, 51% (95% CI = 39%-68%) versus 31% (95% CI = 18%-49%) and 42% (95% CI = 30%-57%) versus 20% (95% CI = 10%-33%) for patients treated with combined modality versus radiation therapy alone (P =.02 and.04, respectively). The locoregional control rate was improved in arm B (66%; 95% CI = 51%-78%) versus arm A (42%; 95% CI = 31%-56%). CONCLUSION: The statistically significant improvement in overall survival that was obtained supports the use of concomitant chemotherapy as an adjunct to radiotherapy in the management of carcinoma of the oropharynx.

5. Prospective randomized trial comparing hyperfractionated versus conventional radiotherapy in stages III and IV oropharyngeal carcinoma.
Pinto LH, Canary PC, Araujo CM, et al.
Int J Radiat Oncol Biol Phys 1991;21:557-62

From April 1986 to May 1989, 112 patients seen at a single institution with previously untreated squamous cell oropharynx carcinoma, Stages III and IV, were randomly assigned to 66 Gy in 33 fractions of 2 Gy each (conventional RT) versus 70.4 Gy in 64 fractions of 1.1 Gy given twice a day with a minimal interfraction interval of 6 hours (hyperfractionated RT). The overall time for both arms was 6 1/2 weeks. Patients were stratified by site (base of the tongue vs others), T stage (T1/T2 vs T3 vs T4), N stage (N0/N1 vs N2 vs N3), and lymphnode size (less than 6 cm vs greater than 6 cm). As of January 1990, an analysis was performed in 98 patients (8 patients in the conventional arm and 6 in the hyperfractionation not included). The groups were balanced by age, performance status, stage, and site of the primary disease. The median follow-up time was 25 months. The probability of complete loco-regional response was 62% in the hyperfractionation arm and 52% for the conventional fractionation (p = 0.28). There was no difference in the control of lymphnodal disease (hyperfractionated = 55%, conventional = 57%; p = 0.92), but the disease control in the oropharynx only was significantly improved in the hyperfractionation arm (84% vs 64%, p = 0.02). Overall survival rate at 42 months was 27% for the hyperfractionation arm and 8% for the conventional (p = 0.03). Survival rates for hyperfractionated versus conventional RT were 40% versus 18% (p = 0.06), respectively, for Stage III patients and 16% versus 0% (p = 0.15), respectively, for Stage IV. There was significant improvement in survival in favor of the hyperfractionation arm in patients with lesions outside the base of the tongue (31% vs 15%, p = 0.02), for those with a 50-70% Karnofsky status (19% vs 0%, p = 0.006) and for patients with N0/N1 disease (38% vs 15%, p = 0.03). Acute toxicities were of similar magnitude, although both skin and mucosal reactions appeared earlier on the hyperfractionation scheme. To date, no differences in late toxicity have been observed. We conclude that in a subset group of patients with locally advanced carcinoma of the oropharynx, hyperfractionated radiotherapy appears to provide improved survival without adding to increased toxicity.

OTHER SELECT PUBLICATIONS :
* Tiwari RM, van Ardenne A, Leemans CR, et al. Advanced squamous cell carcinoma of the base of the tongue treated with surgery and post-operative radiotherapy. Eur J Surg Oncol. 2000;26:556-60.
* Gourin CG, Johnson JT. Surgical treatment of squamous cell carcinoma of the base of tongue. Head Neck. 2001; 23 (8) : 653-60.
* Robertson ML, Gleich LL, Barrett WL, et al. Base-of-tongue cancer: survival, function, and quality of life after external-beam irradiation and brachytherapy. Laryngoscope. 2001;111:1362-5.

LARYNX AND HYPOPHARYNX
Larynx:
• Supra-glottis: Epiglottis, Ary-epiglottic folds, Arytenoids, False cords, Ventricles.
• Glottis: True vocal cord with anterior & posterior commissure.
• Subglottis.

Hypopharynx:
• Pyriform sinus
• Post-cricoid region
• Posterior pharyngeal wall

Specific investigations before definitive treatment:
• Indirect laryngoscopy / Hopkins telescopy/flexible laryngoscopy : To access cord mobility and extent of mucosal disease.

• Barium swallow: To map the mucosal extent of disease. Post-cricoid involvement well seen.

• Direct laryngoscopy: To define the exact extent of the disease, assess areas not well seen on IDL/Hopkins namely anterior commissure; pyriform fossa and post-cricoid & obtain a biopsy.

• Microlaryngocsopy: for early cord lesions

• Imaging CT/MRI scan: Mandatory before conservative laryngectomy / laryngeal preservation therapy.
Gives information regarding:
      1- Extent of disease.
      2- Cartilage invasion.
      3- Extra-laryngeal spread.
      4- Para/Pre-epiglottic spaces.
      5- Tumor volume.
      6- Nodal disease.
                        * CT scan preferred for cartilage erosion.
                        * MRI preferred for soft tissue invasion.

• PET (CT) for evaluating post treatment residual or recurrent disease.

• Speech counseling.

TNM STAGING (UICC 2002)
PRIMARY TUMOR

TX – Primary tumor cannot be assessed.
T0 – No evidence of primary tumor.
Tis – Carcinoma in situ

Supraglottis

SUPRAGLOTTIS :
Surgery is preferred over radiotherapy in cases with
• large volume disease.
• Cartilage erosion.
• Bulky nodal disease.
• Gross pre epiglottis space involvement
• General condition not permitting concurrent chemoradiotherapy

Small primary (radiocurableT1-2) with large resectable disease (N2-3) may be considered for neck dissection with RT to primary and neck.

Note :
Post operative RT as per guidelines mentioned earlier

GLOTTIS

GLOTTIS

Stage III – T1-2 N1 / T3N0-1
• Concomitant CT+RT
• Surgery : Vertical Partial Laryngectomy/ Near-Total laryngectomy / Total laryngectomy + RT
• Radical radiotherapy in patients with low GC/poor performance status who might not tolerate CT+RT

Stage IV – T4a N0-1 / T1-4aN2-3
• Surgery : Near-Total laryngectomy / Total laryngectomy + RT
• Concomitant CT+RT
• Radical radiotherapy in patients with low GC/poor performance status who might not tolerate CT+RT

N0-1 nodes are managed with RT if the primary is treated with RT. If surgery is the primary treatment modified neck dissection for N1 nodes is recommended.

N2-3 nodes need MND/RND with Post-operative chemoradiotherapy. If radiotherapy is the primary treatment, neck dissection follows radiotherapy 4-6 weeks later if residual nodes persist, or electively irrespective of nodal status.

PYRIFORM FOSSA
T1-2 No,1
• Radical Radiotherapy
• Partial Laryngo-pharyngectomy
• Endoscopic laser resection in select cases.

T1-2 N2-3
• Concurrent CT+RT.
• Radical Radiotherapy Salvage surgery (Low GC - unable to tolerate CT+RT).
• Split Therapy - Neck dissection + Radical Radiotherapy to primary and neck.

T3-4, Any N
• Near-Total Laryngectomy /Total laryngectomy + Partial pharyngectomy + Post operative Radiotherapy.
• Reconstruction of defect depends on mucosal defect. If mucosa adequate – primary closure, if mucosa inadequate – patch PMMC or free radial forearm flap.
• Concurrent CT + RT.
• Radical radiotherapy salvage surgery (Low GC –unable to tolerate CT+RT).

Note :
• Post operative RT as per guidelines mentioned earlier
• Surgery is the treatment of choice in
         • Large volume disease
         • Bulky neck nodes
         • Cartilage erosion
         • Extensive soft tissue involvement

T3-4 Any N : Small volume disease
• Concurrent CT+RT.
• Radical Radiotherapy Salvage surgery (Low GC –unable to tolerate CT+RT

T3-4 Any N : Large volume disease
• Total laryngo-pharyngo-oesophagectomy with gastric pullup or Free jejunal flap or tube pectoralis myocutaneous flap and Post operative Radiotherapy.

Note :
1. Post operative RT as per guidelines mentioned earlier.
2. Surgery is the treatment of choice in
         • Large volume disease
         • Bulky neck nodes
         • Cartilage erosion
         • Extensive soft tissue involvement

1. LARYNGEAL PRESERVATION IN ADVANCED PYRIFORM SINUS CANCERS :
Larynx preservation in pyriform sinus cancer: preliminary results of a European Organization for Research and Treatment of Cancer phase III trial. EORTC Head and Neck Cancer Cooperative Group.
Lefebvre JL, Chevalier D, Luboinski B, et al.
J Natl Cancer Inst 1996;88:890-9

BACKGROUND: As a general rule, surgery whenever possible, followed by irradiation is considered to be the standard treatment for cancer of the hypopharynx, thus sacrificing natural speech. In most patients, surgery includes removal of the larynx. PURPOSE: A prospective, randomized phase III study was conducted by the European Organization for Research and Treatment of Cancer (EORTC) starting in 1990 to compare a larynx-preserving treatment (induction chemotherapy plus definitive, radiation therapy in patients who showed a complete response or surgery in those who did not respond) with conventional treatment (total laryngectomy with partial pharyngectomy, radical neck dissection, and postoperative irradiation) in previously untreated and operable patients with histologically proven squamous cell carcinomas of the pyriform sinus or aryepiglottic fold, but free of other cancers. METHODS: Patients were randomly assigned to one of two treatment arms: 1) immediate surgery with postoperative radiotherapy (50-70 Gy) or 2) induction chemotherapy (cisplatin [100 mg/m2] given as a bolus intravenous injection on day 1, followed by infusion of fluorouracil [1000 mg/m2 per day] on days 1-5). An endoscopic evaluation was performed after each cycle of chemotherapy. After two cycles, only partial and complete responders received a third cycle. Patients with a complete response after two or three cycles of chemotherapy were treated thereafter by irradiation (70 Gy); nonresponding patients underwent conventional surgery with postoperative radiation (50-70 Gy). Salvage surgery was also performed when patients relapsed after chemotherapy and irradiation. The trial was designed to test the equivalence of the two treatment arms; i.e., the induction chemotherapy treatment would be judged equivalent to immediate surgery if the relative risk of death for induction chemotherapy compared with immediate surgery was significantly less than 1.43 using a one-sided hypothesis test at the .05 level of significance. RESULTS: Two hundred two patients entered the trial and were randomly assigned; only 194 were eligible for treatment (94 in the immediate-surgery arm and 100 in the induction-chemotherapy arm). In the induction-chemotherapy arm, complete response was seen in 52 (54%) of 97 patients with local disease (primary tumor) and in 31 (51%) of 61 patients with regional disease (involvement of the neck). Treatment failures at local, regional, and second primary sites occurred at approximately the same frequencies in the immediate-surgery arm (12%, 19%, and 16%, respectively) and in the induction-chemotherapy arm (17%, 23%, and 13%, respectively). In contrast, there were fewer failures at distant sites in the induction-chemotherapy arm than in the immediate-surgery arm (25% versus 36%, respectively; P = .041). The median duration of survival was 25 months in the immediate-surgery arm and 44 months in the induction-chemotherapy arm and, since the observed hazard ratio was 0.86 (logrank test, P = .006), which was significantly less than 1.43, the two treatments were judged to be equivalent. The 3- and 5-year estimates of retaining a functional larynx in patients treated in the induction-chemotherapy arm were 42% (95% confidence interval = 31%-53%) and 35% (95% confidence interval = 22%-48%), respectively. CONCLUSIONS AND IMPLICATIONS: Larynx preservation without jeopardizing survival appears feasible in patients with cancer of the hypopharynx. On the basis of these observations, the EORTC has now accepted the use of induction chemotherapy followed by radiation as the new standard treatment in its future phase III larynx preservation trials.

1. Radiation therapy in T1-T2 glottic carcinoma: influence of various treatment parameters on local control/complications.
Dinshaw KA, Sharma V, Agarwal JP et al.
Int J Radiat Oncol Biol Phys 2000;48:723-35

PURPOSE : To evaluate the influence of various treatment parameters on local control as well as complications in T1 and T2 glottic carcinomas. METHODS AND MATERIALS : Between 1975 and 1989, 676 patients with early glottic carcinoma (460 T1 and 216 T2) received curative radiation with three different treatment regimens, as follows: Regimen 1-50 Gy/15 Fr/3 weeks (3.33 Gy/daily) for 192 patients; Regimen 2-60-62.5 Gy/24-25 Fr/5 weeks (2.5 Gy/daily) for 352 patients; and Regimen 3-55-60 Gy/25-30 Fr/5-6 weeks (2-2.25 Gy/daily) for 132 patients. RESULTS : The local control at 10 years was 82% and 57% for T1 and T2 lesions respectively (p = 0.0). For the T1N0M0 group, field size had significant impact on local control with both univariate (p = 0.05) and multivariate (p = 0.03) analysis. For T2N0M0, group field size (p = 0.03) as well as registration year (p = 0.016) were significant in univariate analysis whereas only field size remained significant on multivariate analysis. Persistent radiation edema was noted in 146 (22%) patients and was significantly worse with larger field size (p = 0.000) but not related to different treatment regimens. CONCLUSION : The shorter fractionation schedule had comparable local control, without increased complications in comparison to the protracted schedule and is best suited for a busy department.

2. Radiotherapy versus open surgery versus endolaryngeal surgery (with or without laser) for early laryngeal squamous cell cancer.
Dey P, Arnold D, Wight R, et al.
Cochrane Database Syst Rev 2002;(2):CD002027

BACKGROUND : Radiotherapy, open surgery and endolaryngeal excision (with or without laser) are all accepted modalities of treatment for early stage glottic cancer. Case series suggest that they confer similar survival advantage. Opinions on optimal therapy vary across disciplines and between countries. OBJECTIVES : To compare the effectiveness of open surgery, endolaryngeal excision (with or without laser) and radiotherapy in the management of early glottic laryngeal cancer SEARCH STRATEGY: Electronic search of MEDLINE (from 1966 to October 2000), EMBASE (from 1980 to October 2000), CINAHL (from 1982 to October 2000) and CancerLit (from 1963 to October 2000) databases and the Cochrane Controlled Trials Register. SELECTION CRITERIA : Randomised controlled trials (RCT) comparing open surgery, endolaryngeal resection and/or radiotherapy DATA COLLECTION AND ANALYSIS : Two reviewers independently assessed RCTs identified from the electronic searches for eligibility and methodological quality. All authors of the review discussed the results of these assessments. MAIN RESULTS : Only one RCT was identified which compared open surgery and radiotherapy among a substantial number of patients with early glottic laryngeal cancer. REVIEWER’S CONCLUSIONS : There is currently insufficient evidence to guide management decisions on the most effective treatment. Interpretation of the only large scale RCT comparing open surgery and radiotherapy in patients with early glottic cancer is limited because of concerns about the adequacy of treatment regimens and deficiencies in the reporting of the study design and analysis. Endolaryngeal resection of early glottic tumours is becoming more common and a well designed multicentre RCT is warranted.

1. Induction chemotherapy plus radiation compared with surgery plus radiation in patients with advanced laryngeal cancer. The Department of Veterans Affairs Laryngeal Cancer Study Group.
N Engl J Med 1991; 324 : 1685-90

BACKGROUND : We performed a prospective, randomized study in patients with previously untreated advanced (Stage III or IV) laryngeal squamous carcinoma to compare the results of induction chemotherapy followed by definitive radiation therapy with those of conventional laryngectomy and postoperative radiation. METHODS : Three hundred thirty-two patients were randomly assigned to receive either three cycles of chemotherapy (cisplatin and fluorouracil) and radiation therapy or surgery and radiation therapy. The clinical tumor response was assessed after two cycles of chemotherapy, and patients with a response received a third cycle followed by definitive radiation therapy (6600 to 7600 cGy). Patients in whom ther was no tumor response or who had locally recurrent cancers after chemotherapy and radiation therapy underwent salvage laryngectomy. RESULTS : After two cycles of chemotherapy, the clinical tumor response was complete in 31 percent of the patients and partial in 54 percent. After a median follow-up of 33 months, the estimated 2-year survival was 68 percent (95 percent confidence interval, 60 to 76 percent) for both treatment groups (P = 0.9846). Patterns of recurrence differed significantly between the two groups, with more local recurrences (P = 0.0005) and fewer distant metastases (P = 0.016) in the chemotherapy group than in the surgery group. A total of 59 patients in the chemotherapy group (36 percent) required total laryngectomy. The larynx was preserved in 64 percent of the patients overall and 64 percent of the patients who were alive and free of disease. CONCLUSIONS : These preliminary results suggest a new role for chemotherapy in patients with advanced laryngeal cancer and indicate that a treatment strategy involving induction chemotherapy and definitive radiation therapy can be effective in preserving the larynx in a high percentage of patients, without compromising overall survival.

2. Concurrent Chemotherapy and Radiotherapy for Organ Preservation in Advanced Laryngeal Cancer.
Arlene A. Forastiere, M.D., Helmuth Goepfert, M.D., Moshe Maor, M.D, et al
N Engl J Medicine 2003 ;349;2091-2098.

BACKGROUND: Induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy is the standard alternative to total laryngectomy for patients with locally advanced laryngeal cancer. The value of adding chemotherapy to radiotherapy and the optimal timing of chemotherapy are unknown. METHODS: We randomly assigned patients with locally advanced cancer of the larynx to one of three treatments: induction cisplatin plus fluorouracil followed by radiotherapy, radiotherapy with concurrent administration of cisplatin, or radiotherapy alone. The primary end point was preservation of the larynx. RESULTS: A total of 547 patients were randomly assigned to one of the three study groups. The median follow-up period was 3.8 years. At two years, the proportion of patients who had an intact larynx after radiotherapy with concurrent cisplatin (88 percent) differed significantly from the proportions in the groups given induction chemotherapy followed by radiotherapy (75 percent, P=0.005) or radiotherapy alone (70 percent, P<0.001). The rate of locoregional control was also significantly better with radiotherapy and concurrent cisplatin (78 percent, vs. 61 percent with induction cisplatin plus fluorouracil followed by radiotherapy and 56 percent with radiotherapy alone). Both of the chemotherapy-based regimens suppressed distant metastases and resulted in better disease-free survival than radiotherapy alone. However, overall survival rates were similar in all three groups. The rate of high-grade toxic effects was greater with the chemotherapy-based regimens (81percent with induction cisplatin plus fluorouracil followed by radiotherapy and 82 percent with radiotherapy with concurrent cisplatin, vs. 61 percent with radiotherapy alone).The mucosal toxicity of concurrent radiotherapy and cisplatin was nearly twice as frequent as the mucosal toxicity of the other two treatments during radiotherapy. CONCLUSIONS: In patients with laryngeal cancer, radiotherapy with concurrent administration of cisplatin is superior to induction chemotherapy followed by radiotherapy or radiotherapy alone for laryngeal preservation and locoregional control.

NASOPHARYNX

Specific Investigations before definitive treatment
        • Nasopharyngeal examination, endoscopy & biopsy
        • Chest X- ray
        • CT scan/ MRI including entire neck
        • Bone scan (optional), especially in WHO type III

Nasopharyngeal carcinoma differs from other head and neck squamous cell carcinomas in following aspects
• Classified into 3 types
a) WHO type I – Keratinising Sq. Ca
b) WHO type II – Non-keratinising Sq. Ca
c) WHO type III – Undiferrentiated carcinoma
• Radiosensitive tumours, even with large volume nodal disease respond well to radiotherapy.
• WHO type III (Undiferrentiated carcinoma) responds better than keratinising variety.
• Surgery has a very limited role as en bloc surgical resection of the primary tumour is difficult and severely morbid. Surgery is usually reserved for elective/ salvage of residual neck nodes.

Treatment options
T1 / Selected T2 N0 :
      • Radical Radiotherapy alone with or without Intraluminal Brachytherapy
      • IMRT or 3-DCRT maybe used when facilities are available.

T3-4 N0 / Any T N+
      • Concurrent chemoradiotherapy
      • Neo Adjuvant CT x 2 cycles + Concurrent CT + RT

Chemoradiotherapy Schedule for Undiferentiated Ca Nasopharynx:
Cisplatinum (33mg / m2 / day x 3 days) + Ifosfamide (2gm /m2 / day x 3 days) + Mesna rescue x 2 cycles followed by Concomitant weekly Cisplatinum (30 mg / m2) during radiotherapy(70Gy)

For bulky tumors at presentation, neo-adjuvant chemotherapy, followed by concurrent chemoradiotherapy may be tried though there is no evidence to suggest that it is superior to concurrent chemoradiotherapy.

Note :
• Role of surgery is minimal : No neck dissection upfront even for large nodes/ Neck dissection is reserved for palpable nodes persisting 8 weeks after radiotherapy and when the primary is controlled.
• Treatment of recurrence : Re-irradiation, surgery in selected cases.

1. Combined chemoradiation versus radiation therapy alone in locally advanced nasopharyngeal carcinoma: results of a meta-analysis of 1,528 patients from six randomized trials.
Am J Clin Oncol. 2002 Jun;25(3):219-23.
Huncharek M, Kupelnick B

It is currently unclear whether the addition of chemotherapy to standard radiation therapy improves clinical outcome in patients with locoregionally advanced nasopharyngeal cancer. A meta-analysis was performed to evaluate the impact of integrating chemotherapy with external beam radiation therapy in this clinical setting. Using previously described methods, a protocol was developed outlining a meta-analysis examining the influence of chemoradiation versus radiation alone (control arm) in locoregionally advanced nasopharyngeal carcinoma. The outcomes of interest were disease-free/progression-free and overall survival. Literature search techniques, study inclusion criteria, and statistical procedures were prospectively defined. Data from all available randomized controlled trials was pooled using a fixed effects model (Peto). Results were expressed as summary relative risks. Statistical tests for heterogeneity were performed. If statistical heterogeneity was demonstrated, sensitivity analyses were performed to evaluate possible sources of heterogeneity across the included studies. The literature search identified six randomized controlled trials enrolling more than 1,500 patients. All trials compared standard radical external beam radiation therapy (control arm) with radiation plus chemotherapy delivered either adjuvantly, neoadjuvantly, or concurrently with radiation. Pooling all six studies using disease-free/progression-free survival as the endpoint demonstrated that the addition of chemotherapy to radiation therapy increased disease-free/progression-free survival by 37% at 2 years, 40% at 3 years, and 34% at 4 years after treatment. Likewise, the summary relative risk for overall survival at 2 years after treatment with the addition of chemotherapy to the treatment regimen was 0.80 (0.63-1.02), reflecting a 20% increase in 2-year survival. This finding was marginally non-statistically significant. Three- and 4-year survival was increased by 19% and 21%, respectively, with the data for 4-year survival being statistically significant. The addition of chemotherapy to standard radical radiation therapy for locoregionally advanced nasopharyngeal cancer increases both disease-free/progression-free and overall survival by 19 to 40% at 2 to 4 years after treatment, depending on the endpoint of interest. Future trials are needed to confirm these results and determine the most effective regimen for integrating chemotherapy with radiation therapy in this setting.

2. Combined radiotherapy and chemotherapy for nasopharyngeal carcinoma.
Fu KK.
Semin Radiat Oncol 1998; 8 : 247-53

Among squamous cell carcinomas of the head and neck, nasopharyngeal carcinoma is probably the most radiosensitive and chemosensitive. It also has the highest incidence of distant metastasis. This article reviews the results of randomized trials of combined chemotherapy and radiotherapy for nasopharyngeal carcinoma to date. Induction chemotherapy with bleomycin, epirubicin, and cisplatin was shown to increase disease-free survival but not overall survival in a trial by the International Nasopharyngeal Cancer Study Group. Concurrent radiotherapy and cisplatin followed by adjuvant cisplatin and 5-fluorouracil infusion significantly decreased local, nodal, and distant failures and increased progression-free and overall survival in the Head and Neck Intergroup Trial. The toxicity of combined chemotherapy and radiotherapy, however, primarily acute toxicity, was significantly greater than that of radiotherapy alone. Further clinical trials using novel drugs, altered fractionation radiotherapy and chemotherapy dose schedules, new radiotherapy techniques, and other treatment modifiers are needed to further improve the therapeutic ratio.

3. Preliminary results of a randomized trial comparing neoadjuvant chemotherapy (cisplatin, epirubicin, bleomycin) plus radiotherapy vs. radiotherapy alone in stage IV(> or = N2, M0) undifferentiated nasopharyngeal carcinoma: a positive effect on progression-free survival. International Nasopharynx Cancer Study Group. VUMCA I trial.
Int J Radiat Oncol Biol Phys 1996; 35 : 463-9

PURPOSE : Our Phase II trial using bleomycin, epirubicin, and cisplatin (BEC) protocol in the treatment of loco-regionally advanced undifferentiated nasopharyngeal carcinoma (UCNT) patients has shown encouraging results with high objective response, disease-free survival, and overall survival rates. To establish the value of this BEC regimen as neoadjuvant chemotherapy, we initiated in 1989 a large international Phase III trial. It compares three cycles of BEC followed by radiotherapy to radiotherapy alone. METHODS AND MATERIALS : From November 1989 to October 1993, 339 patients with negative metastases workup, stratified by accrual center have been randomized, 168 to radiotherapy alone and 171 to chemotherapy plus radiotherapy. All patients characteristics were well balanced in both arms. There was a quality control/data verification by specialist panel (radiology, histology, radiotherapy, chemotherapy) and external policy board expert every 60-80 patients having completed treatment. RESULTS : With a median follow-up of 49 months (range: 23-70), despite an excess of treatment-related deaths in the neoadjuvant chemotherapy arm (8 vs. 1%), there is a significant difference in disease free survival favoring the chemotherapy arm (p < 0.01). The proportion of local and/or regional metastases was comparable in both arms. No difference in overall survival is seen but the numbers of events needed for analysis has not yet been reached. CONCLUSIONS : BEC type neoadjuvant chemotherapy has a significant impact in the natural history of UCNT. Further follow-up is needed to establish an eventual overall survival difference.

4. Chemoradiotherapy versus radiotherapy in patients with advanced nasopharyngealcancer: phase III randomized Intergroup study 0099.
Al-Sarraf M, LeBlanc M, Giri PG,et al.
J Clin Oncol 1998; 16 : 1310-7

PURPOSE : The Southwest Oncology Group (SWOG) coordinated an Intergroup studywith the participation of Radiation Therapy Oncology Group (RTOG), and EasternCooperative Oncology Group (ECOG). This randomized phase III trial compared chemoradiotherapy versus radiotherapy alone in patients with nasopharyngeal cancers. MATERIALS AND METHODS : Radiotherapy was administered in both arms: 1.8-to 2.0-Gy/d fractions Monday to Friday for 35 to 39 fractions for a total doseof 70 Gy. The investigational arm received chemotherapy with cisplatin 100 mg/m2on days 1, 22, and 43 during radiotherapy; postradiotherapy, chemotherapy with cisplatin 80 mg/m2 on day 1 and fluorouracil 1,000 mg/m2/d on days 1 to 4 was administered every 4 weeks for three courses. Patients were stratified by tumor stage, nodal stage, performance status, and histology. RESULTS : Of 193 patients registered, 147 (69 radiotherapy and 78 chemoradiotherapy) were eligible for primary analysis for survival and toxicity. The median progression-free survival (PFS) time was 15 months for eligible patients on the radiotherapy arm and was not reached for the chemo-radiotherapy group. The 3-year PFS rate was 24% versus 69%, respectively (P < .001). The median survival time was 34 months for the radiotherapy group and not reached for the chemo-radiotherapy group, and the 3-year survival rate was 47% versus 78%, respectively (P = .005). One hundred eighty-five patients were included in a secondary analysis for survival. The 3-year survival rate for patients randomized to radiotherapy was 46%, and for the chemoradiotherapy group was 76% (P < .001). CONCLUSION : We conclude that chemoradiotherapy is superior to radiotherapy alone for patients with advanced nasopharyngeal cancers with respect to PFS and overall survival.

5. Long-Term Survival After Cisplatin-Based Induction Chemotherapy and Radiotherapy for Nasopharyngeal Carcinoma: A Pooled Data Analysis of Two Phase III Trials
Daniel T.T. Chua , Jun Ma , Jonathan S.T. Sham *, Hai-Qiang Mai , Damon T.K. Choy, Ming-Huang Hong , Tai-Xiang Lu , and Hua-Qing Min
J Clin Oncol 2005;23(6): 1118-1124

Purpose: To evaluate the long-term outcome in patients with nasopharyngeal carcinoma (NPC) treated with induction chemotherapy and radiotherapy (CRT) versus radiotherapy alone (RT). Patients and Methods: The data from two phase III studies comparing CRT with RT in NPC were updated and pooled together for analysis. A total of 784 patients were included for analysis, with an equal number of patients in both arms. Induction chemotherapy consisted of two to three cycles of cisplatin, bleomycin, and fluorouracil, or cisplatin and epirubicin. RT was given to the nasopharynx and neck using megavoltage radiation (median dose, 70 Gy). The median follow-up time for surviving patients was 67 months. Analysis was based on intention to treat. Results: The addition of induction chemotherapy to RT was associated with a decrease in relapse by 14.3% and cancer-related deaths by 12.9% at 5 years. The 5-year relapse-free survival rate was 50.9% and 42.7% in the CRT and RT arm, respectively (P = .014), and the 5-year disease-specific survival rate was 63.5% and 58.1% in the CRT and RT arm, respectively (P = .029). The 5-year overall survival rate was 61.9% and 58.1% in CRT and RT arm, respectively (P = .092). The incidence of locoregional failure and distant metastases was reduced by 18.3% and 13.3% at 5 years, respectively, with induction chemotherapy. There was no significant difference in the treatment failure patterns between the two arms. Conclusion: The addition of cisplatin-based induction chemotherapy to RT was associated with a modest but significant decrease in relapse and improvement in disease-specific survival in advanced-stage NPC. However, there was no improvement in overall survival.

6. The Additional Value of Chemotherapy to Radiotherapy in Locally Advanced Nasopharyngeal Carcinoma: A Meta-Analysis of the Published Literature
J.A. Langendijk, Ch.R. Leemans, J. Buter, J. Berkhof, B.J. Slotman
J Clin Oncol 2004;22(22):4604-4612

PURPOSE: The purpose of this meta-analysis was to determine the additional value of neoadjuvant, concurrent, and/or adjuvant chemotherapy to radiation in the treatment of locally advanced nasopharyngeal carcinoma (NPC) with regard to the overall survival (OS) and the incidence of local-regional recurrences (LRR) and distant metastases (DM). PATIENTS AND METHODS: To be eligible, full published studies had to deal with biopsy-proven NPC and have patients randomly assigned to receive conventional radiotherapy (66 to 70 Gy in 7 weeks) or radiotherapy combined with chemotherapy. RESULTS: Ten randomized clinical studies were identified, including 2,450 patients. The pooled hazard ratio (HR) of death for all studies was 0.82 (95% CI, 0.71 to 0.95; P = .01) corresponding to an absolute survival benefit of 4% after 5 years. Three categories of trials were defined according to the sequence of chemotherapy, including neoadjuvant chemotherapy, at least concomitant chemoradiotherapy, and adjuvant chemotherapy. A significant interaction term (P = .02) was found among these three categories. The largest effect was found for concomitant chemotherapy, with a pooled HR of 0.48 (95% CI, 0.32 to 0.72), which corresponds to a survival benefit of 20% after 5 years. Comparable results were found for the incidence of LRR and DM. CONCLUSION: The results of this study indicate that concomitant chemotherapy in addition to radiation is probably the most effective way to improve OS in NPC.

NASAL CAVITY & PARANASAL SINUSES

Sites
• Nasal Cavity
• Maxilla
• Ethmoids
• Frontal Sinus
• Sphenoid

Investigations / Procedures
1. Biopsy
Punch / Endoscopic

2. Imaging (mandatory) to asses the extent of disease
Computed Tomography (CT) and / or Magnetic Resonance Imaging (MRI)
       * CT scan - preferred for osseous involvement, floor of anterior cranial fossa                           and orbital walls

       * MRI preferred for
              - Soft tissue extent
              - Intracranial extension
              - Perineural Spread
              - Differentiation between retained secretions and tumour tissue
              - Post surgery setting

3. Prosthetic / Dental Workup
Pre-operative dental impression for post-op prosthesis

Staging: TNM (UICC) 2002

Maxilla

Treatment Options
Nasal Cavity & Ethmoid sinus
Treatment of Primary:
T1, T2:
1. Surgery ± post-operative radiotherapy
       • Approaches-Midfacial degloving or Lateral rhinotomy or Endoscopic Transnasal
       • Medial maxillectomy with ethmoidal clearance may be adequate for localised           ethmoidal and nasal cavity tumors.
       • RT in case of margin positivity or perineural spread
2. Radical Radiotherapy preferred if surgical resection morbid

T3, T4a
Surgery + Adjuvant RT
       • Total Maxillectomy with ethmoidectomy
       • Combined Craniofacial approach for lesions reaching / involving the cribriform           plate.
       • Orbital exenteration if eye involved.

T4b
1. Palliative - RT or CT
Concurrent CTRT may be considered in patient with good performance status.

2. Resection in very select group with favourable histology with low biologically aggressive tumours for eg. Adenoid cystic carcinoma, basal cell carcinoma.

Treatment of Neck:
N0
Observe

N+
Appropriate neck dissection and post-operative radiotherapy to both necks.

MAXILLARY SINUS

Treatment of Primary:
T1, T2:
Surgery + Post-op Radiotherapy
            • Infrastructure maxillectomy
          • Maxillectomy with orbital plate preservation
          • RT in case of margin positivity or perineural spread

T3:
Surgery + Post op Radiotherapy
          • Total Maxillectomy with Ethmoidectomy
          • Orbital exenteration if eye involved.

T4a:
I. Combined craniofacial resection + Post op Radiotherapy

II. CT+RT in unresectable tumours

T4b:
I. Palliative - RT or CT
Concurrent CTRT may be considered in patient with extremely good performance status.

II. Resection in very select group with favourable histology tumours for eg. Adenoid cystic carcinoma, basal cell carcinoma.

Treatment of Neck:
N0 Observe
N+ Appropriate neck dissection and post-operative radiotherapy.

Criteria of Unresectibility
          • Gross infiltration of infratemporal fossa.
          • Pterygoplatine fissure involvement
          • Involvement of dura and intra-cerebral extension of squamous carcinoma.
          • Cavernous sinus involvement
          • Involvement of sphenoid.
          • Extensive soft tissue and skin infiltration.
          • Bilateral orbital involvement

Post- Maxillectomy Reconstruction:
          • Sling if orbital floor excised, to prevent post-op diplopia. Fascial sling                         preferred over muscle
          • Micro vascular Free tissue transfer for
                    1. Extensive skin and soft tissue defect
                    2.More than half of palatal loss
                    3. Orbit resection
                    4. Skull Base Reconstruction
          • Temporary obturator for 2 –3 months till complete contracture occurs.
          • Final maxillary prosthesis after 2-3 months

Follow up Policy : Follow up Imaging indicated when local examination with endoscope insufficient. MRI preferred over CT scan.

Suggested reading
• Schantz SP, Harrison LB, Forastiere AA: Tumors of the nasal cavity and paranasal sinuses, nasopharynx, oral cavity, and oropharynx. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 797-860.
• Goldenberg D, Golz A, Fradis M, et al.: Malignant tumors of the nose and paranasal sinuses: a retrospective review of 291 cases. Ear Nose Throat J 80 (4): 272-7, 2001. • Thawley SE, Panje WR, Batsakis JG, et al., eds.: Comprehensive Management of Head and Neck Tumors. 2nd ed. Philadelphia, Pa: WB Saunders, 1999.
• Perry C, Levine PA, Williamson BR, Cantrell RW: Preservation of the eye in paranasal sinus cancer surgery. Arch Otolaryngol Head Neck Surg 1988 Jun; 114(6): 632-4
• Som ML: Surgical management of carcinoma of the maxilla. Arch Otolaryngol 1974 Apr; 99(4): 270-3

Abstracts:

1. Malignant tumors of the nasal cavity and paranasal sinuses.
Katz TS, Mendenhall WM, Morris CG, Amdur RJ, Hinerman RW, Villaret DB.
Head Neck 2002 Sep;24(9):821-9

PURPOSE: To evaluate the role of radiation therapy in patients with nasal cavity and paranasal sinus tumors. MATERIALS AND METHODS: Between October 1964 and July 1998, 78 patients with malignant tumors of the nasal cavity (48 patients), ethmoid sinus (24 patients), sphenoid sinus (5 patients), or frontal sinus (1 patient) were treated with curative intent by radiation therapy alone or in the adjuvant setting. There were 25 squamous cell carcinomas, 14 undifferentiated carcinomas, 31 minor salivary gland tumors (adenocarcinoma, adenoid cystic carcinoma, and mucoepidermoid carcinoma), 8 esthesioneuroblastomas, and 1 transitional cell carcinoma. Forty-seven patients were treated with irradiation alone, 25 with surgery and postoperative irradiation, 2 with preoperative irradiation and surgery, and 4 with chemotherapy in combination with irradiation with or without surgery. RESULTS: The 5-year actuarial local control rate for stage I (limited to the site of origin; 22 patients) was 86%; for stage II (extension to adjacent sites (eg, adjacent sinuses, orbit, pterygomaxillary fossa, nasopharynx; 21 patients) was 65%; and for stage III (destruction of skull base or pterygoid plates, or intracranial extension; 35 patients) was 34%. The 5-year actuarial local control rate for patients receiving postoperative irradiation was 79% and for patients receiving irradiation alone was 49% (p=.05). The 5-, 10-, 15-, and 20-year ultimate local control rates for all 78 patients were 60%, 56%, 48%, and 48%, respectively. The 5-, 10-, 15-, and 20-year cause-specific survival rates for all 78 patients were 56%, 45%, 39%, and 39%, respectively. The 5-, 10-, 15-, and 20-year absolute survival rates for all 78 patients were 50%, 31%, 21%, and 16%, respectively. Of the 67 (86%) patients who were initially seen with node-negative disease, 39 (58%) received no elective neck treatment, and 28 (42%) received elective neck irradiation. Of the 39 patients who received no elective neck treatment, 33 (85%) did not experience recurrence in the neck compared with 25 (89%) of 28 patients who received elective neck irradiation. Most patients who received elective neck irradiation (57%) had stage III disease. Twenty-one (27%) of 78 patients had unilateral blindness develop secondary to radiation retinopathy or optic neuropathy; the complication was anticipated in most of these patients, because the ipsilateral eye was irradiated to a high dose. Four patients (5%) unexpectedly had bilateral blindness develop because of optic neuropathy. All four of these patients received irradiation alone. CONCLUSION: Surgery and postoperative radiation therapy may result in improved local control, absolute survival, and complications when compared with radiation therapy alone. Elective neck irradiation is probably unnecessary for patients with early-stage disease.

2. Nasal and paranasal sinus carcinoma: are we making progress? A series of 220 patients and a systematic review.
Dulguerov P, Jacobsen MS, Allal AS, Lehmann W, Calcaterra T.
Cancer 2001 Dec 15;92(12):3012-29

BACKGROUND: The authors reviewed treatment results in patients with nasal and paranasal sinus carcinoma from a large retrospective cohort and conducted a systematic literature review. METHODS: Two hundred twenty patients who were treated between 1975 and 1994 with a minimum follow-up of 4 years were reviewed retrospectively. A systematic review of published articles on patients with malignancies of the nasal and paranasal sinuses during the preceding 40 years was performed. RESULTS: The 5-year survival rate was 40%, and the local control rate was 59%. The 5-year actuarial survival rate was 63%, and the local control rate was 57%. Factors that were associated statistically with a worse prognosis, with results expressed as 5-year actuarial specific survival rates, included the following: 1) histology, with rates of 79% for patients with glandular carcinoma, 78% for patients with adenocarcinoma, 60% for patients with squamous cell carcinoma, and 40% for patients with undifferentiated carcinoma; 2) T classification, with rates of 91%, 64%, 72%, and 49% for patients with T1, T2, T3, and T4 tumors, respectively; 3) localization, with rates of 77% for patients with tumors of the nasal cavity, 62% for patients with tumors of the maxillary sinus, and 48% for patients with tumors of the ethmoid sinus; 4) treatment, with rates of 79% for patients who underwent surgery alone, 66% for patients who were treated with a combination of surgery and radiation, and 57% for patients who were treated exclusively with radiotherapy. Local extension factors that were associated with a worse prognosis included extension to the pterygomaxillary fossa, extension to the frontal and sphenoid sinuses, the erosion of the cribriform plate, and invasion of the dura. In the presence of an intraorbital invasion, enucleation was associated with better survival. In multivariate analysis, tumor histology, extension to the pterygomaxillary fossa, and invasion of the dura remained significant. Systematic review data demonstrated a progressive improvement of results for patients with squamous cell and glandular carcinoma, maxillary and ethmoid sinus primary tumors, and most treatment modalities. CONCLUSIONS: Progress in outcome for patients with nasal and paranasal carcinoma has been made during the last 40 years. These data may be used to make baseline comparisons for evaluating newer treatment strategies.

3. Surgical salvage after failed radiation for paranasal sinus malignancy.
Curran AJ, Gullane PJ, Waldron J, Irish J, Brown D, O'Sullivan B, Cummings B.
Laryngoscope 1998 Nov;108:1618-22

OBJECTIVE: To comment on the role of surgical salvage following failed initial treatment for paranasal sinus malignancy. DESIGN: A retrospective analysis of one hundred eighty patients treated at The Princess Margaret Hospital, Toronto, from 1976 to 1993. MATERIALS AND METHODS: Thirty-four of 95 patients (36%) who failed initial treatment underwent surgical salvage. Initial therapy in this group was radiation only (n = 27) and combined therapy (n = 7). Patient, tumor, and surgical data were recorded. There were 23 T4, three T3, six T2, and two T1 carcinomas. Survival, recurrence rates, and the influence of a variety of variables on outcome were analyzed. RESULTS: Two- and 5-year overall actuarial survival calculated from the date of diagnosis was 54% and 35%, respectively. Two- and 5-year overall actuarial survival calculated from the date of salvage surgery was 44% and 22%, respectively. Advanced age (P < .004), patients with T4 category disease (P < .04), and squamous cell carcinomas (P < .049) correlated with poorer outcome on univariate analysis. Local failure was the most common cause of death (n = 13; 65%). CONCLUSION: Salvage surgery has a limited role in the management of persistent or progressive disease following failure of initial treatment. Careful postradiation surveillance with endoscopic biopsy under general anesthesia and immediate surgical resection when appropriate may improve the salvage rate.

SALIVARY GLANDS
Specific Investigations prior to definitive treatment:
        • FNAC- Not mandatory, usually recommended when other pathology suspected             e.g. granulomatous infection and in cases of malignancy when facial nerve             may have to be sacrificed.
        • CT scan- Whenever bony infiltration or skull base infiltration is suspected
        • MRI - Investigation of choice for deep lobe involvement, facial nerve                    involvement, intra-cranial extension and recurrent tumors.

Treatment :

Primary Tumor :
• Parotid:
        - Superficial parotidectomy is minimal surgical procedure.
        - Adequate parotidectomy for small adenomas in the tail of the parotid
        - Total parotidectomy – in cases with
                            - Deep lobe tumors
                            - High grade tumors
                            - Positive margin following a superficial Parotidectomy
        - Total Parotidectomy with the excision of facial nerve
                             - when the nerve is involved by the tumor.
       -Radical parotidectomy - when tumor involves
                             - Skin
                             - Infra-temporal fossa
                             - Mandible
                             - Petrous bone.

Note: Facial nerve is spared if there is clearly identifiable plane between it and the tumor, else sacrificed, not to leave behind residual disease

• Submandibular gand - excision of the submandibular gland + MND
• Minor salivary gland tumors - excision with a cuff of normal tissue ( adequate margins).
• Management of Neck: N0 neck -Level II nodal sampling-FS-MND
N+ neck - MND/RND

Adjuvant RT- Indications are as follows [1,2,3]
1. T3/T4 cancers
2. Close or positive margins
3. Lymph node metastasis
4. Adenoid cystic carcinoma
5. High or intermediate grade tumors
6. Deep lobe tumors
7. Pre op facial nerve paralysis
8. Lymphatic or vascular invasion or peri-neural involvement
9. Recurrent tumors

• Radical RT for unresectable primary. Fast neutron beam radiation therapy or accelerated hyperfractionated photon beam schedules have been shown to be effective in the treatment of inoperable, unresectable, and recurrent tumors. [4, 5,6]

References:
1. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.
2. Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.
3. Sessions RB, Harrison LB, Forastiere AA: Tumors of the salivary glands and paragangliomas. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2001, pp 886-906.
4. Buchholz TA, Laramore GE, Griffin BR, et al.: The role of fast neutron radiation therapy in the management of advanced salivary gland malignant neoplasms. Cancer 69 (11): 2779-88, 1992.
5. Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
6. Laramore GE, Krall JM, Griffin TW, Duncan W, Richter MP, Saroja KR, Maor MH, Davis LW.Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40.

1. Surgery for major salivary gland cancer
Witt RL
Oncol Clin N Am. 2004 Jan;13(1):113-127

Major salivary gland cancers are rare, with many histologic types and subtypes.The tumor stage at presentation will dictate the need for imaging,FNA, and facial nerve monitoring. Immunohistochemistry has enhanced diagnosis. In addition, precise attention to surgical landmarks and technique will reduce complications. Tumor stage, histologic type, tumor grade,surgical margin, facial nerve dysfunction, perineural involvement, extra-parenchymal spread, and nodal metastasis are factors influencing the indication for neck dissection, postoperative radiation therapy, and survival rate.

2. Management of malignant sublingual salivary gland tumors.
Ferlito A, Rinaldo A, Shaha AR, Pellitteri PK, Bradley PJ,.
Oral Oncol. 2004 Jan;40(1):2-5.

The majority of tumors of the sublingual gland are malignant, with adenoid cystic carcinoma and mucoepidermoid carcinoma being the most frequent. Many other malignant tumor types have also been reported. The sublingual gland anatomically is not a unit organ and while it is described anatomically as being confined to the anterior floor of the mouth, salivary tissue may be located laterally along the submandibular duct and posterior floor of the mouth. Diagnosis should be suspected when any thickening or raised lesion presents in this area and a biopsy performed to confirm malignancy before planning further treatment. Surgery is the treatment of choice, and should include an en-block resection of the anterior floor of mouth as a minimum, and may include a portion of mandible, as well as a supraomohyoid neck dissection. Adjuvant radiotherapy should be considered in most of the patients after surgical excision.

3. Salivary gland neoplasms.
Day TA, Deveikis J, Gillespie MB, Joe JK et al.
Curr Treat Options Oncol. 2004 Feb;5(1):11-26

Treatment and cure of salivary gland neoplasms requires surgical intervention in most cases. For parotid neoplasms, the most common surgical procedure performed is the superficial parotidectomy with facial nerve preservation. Postoperative radiation therapy is indicated in high-grade salivary gland malignancies and malignancies with increased risk of locoregional recurrence. Primary radiation, including neutron beam techniques, may play a role in certain histologic types or nonoperative candidates. Chemotherapy has yet to result in improvements in survival or quality of life in the treatment of salivary gland malignancy. Advances in radiation therapy techniques, including intensity-modulated radiation therapy, provide opportunities for reduced morbidity.

4. Salivary neoplasms: overview of a 35-year experience with 2,807 patients.
Spiro RH.
Head and Neck Surgery 1986; 8 : 177-184

We have reviewed a 35-year experience with 2,807 patients treated for salivary tumors which arose in the parotid gland (1,695 patients; 70%), submandibular gland (235 patients; 8%), and seromucinous glands of the upper aerodigestive tract (607 patients; 22%). Pleomorphic adenomas comprised 45% of the total, most of which occurred in the parotid gland. The clinical findings and the distribution of patients according to the histology and the site of origin are summarized. Treatment was surgical and the resection was conservative when possible, depending upon the extent of the tumor. The impact of site, histology, grade, and tumor stage on the results is shown.

5. Malignant parotid tumors: prognostic factors and optimum treatment..
Theriault C, Fitzpatrick PJ
American Journal of Clinical Oncology 1986; 9 : 510-516

A retrospective study of 271 patients with parotid carcinoma seen between 1958 and 1980 is reported. Among these were 64 (24%) mucoepidermoid tumors (all degrees of differentiation), 50 (18%) adenocarcinomas, 40 (15%) malignant mixed tumors, 39 (14%) adenoid cystic carcinomas, 37 (14%) undifferentiated, 21 (8%) acinic, and 20 (7%) squamous cell carcinomas. The proportion of advanced (T3T4) to early (T1T2) tumors was 1.7:1. At diagnosis, 42 (15%) patients had regional metastases. An analysis for prognostic factors showed that the histology, tumor stage, regional metastases (No vs. N+), age, and damage to the facial nerve all influence cause-specific survival. After multivariate analysis the tumor size and the presence of regional metastases were the two most significant factors (p less than 0.0001 and 0.004). The prognostic characteristics were similar for the 67 (25%) patients treated by surgery and for the 169 (62%) patients treated with surgery and postoperative radiotherapy. Patients treated with combined therapy had a 10-year relapse-free rate of 62% compared to 22% for those treated by surgery alone (p = 0.0005).

6. Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council.
Laramore GE, Krall JM, Griffin TW et al
Int J Radiat Oncol Biol Phys. 1993 Sep 30;27(2):235-40.

To compare the efficacy of fast neutron radiotherapy versus conventional photon and/or electron radiotherapy for unresectable, malignant salivary gland tumors a randomized clinical trial comparing was sponsored by the Radiation Therapy Oncology Group in the United States and the Medical Research Council in Great Britain. METHODS AND MATERIALS: Eligibility criteria included either inoperable primary or recurrent major or minor salivary gland tumors. Patients were stratified by surgical status (primary vs. recurrent), tumor size (less than or greater than 5 cm), and histology (squamous or malignant mixed versus other). After a total of 32 patients were entered onto this study, it appeared that the group receiving fast neutron radiotherapy had a significantly improved local/regional control rate and also a borderline improvement in survival and the study was stopped earlier than planned for ethical reasons. Twenty-five patients were study-eligible and analyzable. RESULTS: Ten-year follow-up data for this study is presented. On an actuarial basis, there continues to be a statistically-significant p = 0.009) but there is no improvement in overall survival (15% vs. 25%, p = n.s.). Patterns of failure are analyzed and it is shown that distant metastases account for the majority of failures on the neutron arm and local/regional failures account for the majority of failures on the photon arm. Long-term, treatment-related morbidity is analyzed and while the incidence of morbidity graded "severe" was greater on the neutron arm, there was no significant difference in "life-threatening" complications. This work is placed in the context of other series of malignant salivary gland tumors treated with definitive radiotherapy. CONCLUSIONS: Fast neutron radiotherapy appears to be the treatment-of-choice for patients with inoperable primary of recurrent malignant salivary gland tumors.

Specific Investigations prior to definitive treatment:
1. FNAC
2. Serum Calcitonin (In suspected case of Medullary thyroid carcinoma)
3. USG neck for the initial work-up of a solitary thyroid nodule and in follow-up.
4. CT scan of Neck (if tracheal / vascular infiltration suspected) in differentiated thyroid cancer
5. CT Scan of Neck and Mediastinum- in Medullary carcinoma to assess nodal involvement..
6. Chest X-Ray
7. PET-CT Scan:
            - Raised thyroglobulin and disease not located
            - Raised calcitonin and disease not located.

STAGING (UICC -2002) (Thyroid cancer is the only cancer where age and histology are incorporated in the staging)

Primary tumor (T)
[Note: All categories may be subdivided into (a) solitary tumor or (b) multifocal tumor (the largest determines the classification).]
TX: Primary tumor cannot be assessed
T0: No evidence of primary tumor
T1: Tumor 2 cm or less in greatest dimension, limited to the thyroid
T2: Tumor more than 2 cm but not more than 4 cm in greatest dimension, limited to the thyroid
T3: Tumor more than 4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues)
T4a: Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve
T4b: Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels

All anaplastic carcinomas are considered T4 tumors.

T4a: Intrathyroidal anaplastic carcinoma— surgically resectable
T4b: Extrathyroidal anaplastic carcinoma— surgically unresectable

Regional lymph nodes ( N )

Regional lymph nodes are the central compartment, lateral cervical, and upper mediastinal lymph nodes.
NX: Regional lymph nodes cannot be assessed
N0: No regional lymph node metastasis
N1: Regional lymph node metastasis
      N1a: Metastasis to level VI (pretracheal, paratracheal, and prelaryngeal /       Delphian lymph nodes)
      N1b: Metastasis to unilateral or bilateral cervical or superior mediastinal lymph nodes

Distant metastases (M)
MX: Distant metastasis cannot be assessed
M0: No distant metastasis
M1: Distant metastasis

UICC stage groupings
Separate stage groupings are recommended for papillary or follicular, medullary, and anaplastic (undifferentiated) carcinoma.

Papillary or follicular thyroid cancer
Younger than 45 years
• Stage I - Any T, any N, M0
• Stage II - Any T, any N, M1

Age 45 years and older
• Stage I T1, N0, M0
• Stage II T2, N0, M0
• Stage III T3, N0, M0, T1, N1a, M0 , T2, N1a, M0, T3, N1a, M0
• Stage IVA T4a, N0, M0, T4a, N1a, M0, T1, N1b, M0, T2, N1b, M0, T3, N1b, M0, T4a, N1b, M0
• Stage IVB T4b, any N, M0
• Stage IVC Any T, any N, M1

Medullary thyroid cancer
• Stage I T1, N0, M0
• Stage II T2, N0, M0
• Stage III T3, N0, M0 , T1, N1a, M0 , T2, N1a, M0, T3, N1a, M0
• Stage IVA T4a, N0, M0 , T4a, N1a, M0 , T1, N1b, M0, T2, N1b, M0, T3, N1b, M0, T4a, N1b, M0
• Stage IVB T4b, any N, M0
• Stage IVC Any T, any N, M1

Anaplastic thyroid cancer
All anaplastic carcinomas are considered stage IV.
• Stage IVA - T4a, any N, M0
• Stage IVB T4b, any N, M0
• Stage IVC Any T, any N, M1

Risk Stratification: There are several risk stratification criteria such as AGES, AMES, MACIS etc. The broad consensus from all of them are as follows-

Treatment of Differentiated Thyroid Cancers :
Surgery forms the mainstay of treatment in all stages of differentiated thyroid cancers including metastatic cancer. The extent of surgery depends upon the risk categorization of the patient.

Low Risk Patient - Hemithyroidectomy

High Risk Patients- Total Thyroidectomy

Management of lymph nodes :
• Central compartment clearance (removal of glands along the recurrent laryngeal nerve) and ipsilateral nodal sampling ? FS ? MND.
• MND (Type II or III) for positive lymph nodes.
• RND (rarely required) if large nodes infiltrating surrounding structure

Other treatment modalities :
• Surgery : For orthopaedic stabilisation / cord compression.
• External radiotherapy : Limited role, indications are
- Surgically unresectable disease not responding to I 131
- Gross residual disease,
- poor uptake on post-op scan.
• Chemotherapy – No role.

Treatment of Medullary Thyroid Carcinoma (MTC) :
There are two types of MTC
• Sporadic type
• Familial type – associated with Multiple Endocrine Neoplasia (MEN) IIA, IIB and familial non-MEN MTC

Indications to investigate for familial MTC :
• Young age
• Bilateral / multicentric disease
• Clinical features of familial MTC
• Family history of MTC or other tumours associated with MEN

Investigations for suspected familial MTC :
• S. Ca, S. phosphate and S. PTH for parathyroid tumours
• USG abdomen, Urinary VMA

Metastatic work-up for all MTCs :
• Chest X-ray
• USG abdomen
• Bone scan

Treatment for MTC :
• Surgery : Total thyroidectomy with central compartment clearance (dissection of nodes from Hyoid to Innominate vessels and Laterally from carotid to carotid) +/- MND
• Radiotherapy used only for palliation in advanced unresectable disease. Adjuvant RT following an R+ resection is recommended.
• No role of chemotherapy.

Treatment of anaplastic thyroid carcinoma :
Operable (very uncommon) :
Total Thyroidectomy

Inoperable :
Palliative Adriamycin based CT+ RT

FOLLOW UP POLICY:

Papillary / follicular carcinoma:
• Oral thyroxine (T4) supplementation to keep TSH low (0.5-5 mIU/ml if no residual disease and 0.1 mIU/ml if residual disease present);
• Oral calcium supplementation if hypo-calcemia present.
• S. Thyroglobulin, Chest X-ray, Diagnostic whole body scan according to risk category.

Medullary Thyroid cancers:
• Serum Calcitonin
        Serum Calcitonin normal : Observe
        Serum Calcitonin raised : Imaging to detect recurrence

• Operable recurrence detected : Surgery
• Inoperable Recurrence detected :
- If patient is symptomatic and debulking not morbid- Palliative surgery
- Palliative Radiotherapy
- Symptomatic treatment.

• No recurrence detected: Observe only

Selected Readings:
1. Sanders LE, Cady B: Differentiated thyroid cancer: reexamination of risk groups and outcome of treatment. Arch Surg 133 (4): 419-25, 1998.
2. Mazzaferri EL: Treating differentiated thyroid carcinoma: where do we draw the line? Mayo Clin Proc 66 (1): 105-11, 1991.
3. Staunton MD: Thyroid cancer: a multivariate analysis on influence of treatment on long-term survival. Eur J Surg Oncol 20 (6): 613-21, 1994.
4. Mazzaferri EL, Jhiang SM: Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med 97 (5): 418-28, 1994.
5. Shah JP, Loree TR, Dharker D, et al.: Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg 164 (6): 658-61, 1992.
6. Andersen PE, Kinsella J, Loree TR, et al.: Differentiated carcinoma of the thyroid with extrathyroidal extension. Am J Surg 170 (5): 467-70, 1995.

1. An expanded view of risk-group definition in differentiated thyroid carcinoma.
Cady B, Rossi R.
Surgery 1988; 104 : 947-53

There continues to be controversy about every aspect of management of differentiated thyroid carcinoma. In an age-based risk group previously described, low-risk patients made up 62% of cases and had a death rate of only 1%. Recent reports from the Mayo Clinic have expanded the concept of the low-risk group to include 86% of all cases with a 2% death rate by utilizing several anatomic and pathologic criteria of risk. We offer here another multifactorial system for the identification of low-risk patients who made up 89.4% of all patient seen between 1961 and 1980 and who have a death rate of only 1.8%. The resultant high-risk group constitutes 11% of cases but carries a 46% mortality rate. The risk-group definition is completely clinical and is based on age, presence of distant metastases, and the size and extent of primary cancer. It can be used confidently at the operating table to select conservative succeeding decades analyzed, from 1941 to 1980, the effectiveness of this clinical categorization has increased substantially in separating patients at high and low risk, so that a mortality rate ratio of 26:1 now exists between high- and low-risk groups, respectively.

2. Ipsilateral lobectomy versus bilateral lobar resection in papillary thyroid carcinoma: a retrospective analysis of surgical outcome using a novel prognostic scoring system.
Hay ID, Grant CS, Taylor WF, et al.
Surgery 1987; 102 : 1088-95

From a multivariate analysis of more than 14,200 patient-years’ experience with papillary thyroid carcinoma (PTC), we devised a prognostic scoring system based on patient age, tumor grade, extent, and size (AGES). This scoring system can identify patients at increased risk of PTC mortality and was employed as an adjustment variable for analyzing the role of different types of surgical treatment in 860 PTC patients. Cancer mortality at 25 years in patients with an AGES score of 3.99 or less was 1% after ipsilateral lobectomy (n = 131) and 2% after bilateral resection (n = 603), whether subtotal or total (p = 0.15). Of patients with an AGES score of 4 or more, those who underwent lobectomy alone (n = 30) had a mortality rate from PTC at 25 years of 65%, while those undergoing bilateral resection (n = 86) had a lower rate of 35% (p = 0.06). For patients at minimal risk (score of 3.99 or less) of PTC death, no improvement in survival was demonstrable when patients underwent more than ipsilateral lobectomy. However, in a subgroup (score of 4 or more) identified to be at significant risk of PTC death, the survival after bilateral resection was much higher than after ipsilateral lobectomy alone. In neither the “minimal” nor the “higher” risk subgroup was PTC survival significantly improved by the performance of total thyroidectomy.

3. Addition of nuclear DNA content to the AMES risk-group classification for papillary thyroid cancer.
Pasieka JL, Zedenius J, Auer G, et al.
Surgery 1992; 112 : 1154-9

BACKGROUND : The purpose of this study was to prospectively assess whether nuclear DNA content added prognostic value to existing risk factors in patients with papillary thyroid cancer. METHODS : Nuclear DNA content was measured both on the fine needle aspiration material and the surgical specimen in 73 patients with primary or recurrent papillary thyroid cancer. We modified the existing age of patient, presence of distant metastases, extent and size of the tumor (AMES) risk-group classification to include DNA ploidy with AMES (DAMES). Patients with euploid tumors that were AMES low risk were considered to be DAMES low risk; patients with euploid tumors that were AMES high risk became intermediate risk, and patients with aneuploid tumors that were AMES high risk became DAMES high risk. RESULTS : Forty-eight patients were in the DAMES low-risk group. Recurrences and/or distant metastases developed in only four (8%) of these patients. Twenty-two patients were in the DAMES intermediate-risk group. Twelve (55%) of the intermediate-risk group had residual, recurrent, or distant metastatic disease, with one death from cancer at 120 months. Three patients were in the DAMES high-risk group. Distant metastases developed in all three patients, who died within 24 months from thyroid cancer. A statistically significant difference existed in the development of recurrence/metastases or death from cancer in the DAMES high-risk group compared with the other risk groups combined. CONCLUSIONS : Nuclear DNA content adds prognostic value to the existing AMES risk-group classification. Because DNA analysis on fine needle aspiration correlated well with the surgical specimen DNA analysis, this modified classification can be used perioperatively to further individualize the treatment of patients with papillary thyroid cancer.

4. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989.
Hay ID, Bergstralh EJ, Goellner JR, et al.
Surgery 1993; 114 : 1050-7

BACKGROUND : Multivariate analyses in papillary thyroid carcinoma (PTC) have shown that age, tumor size, local invasion and distant metastasis are independent predictive variables. This study attempted to define a reliable prognostic scoring system for predicting PTC mortality rates with 15 candidate variables that included completeness of primary tumor resection but excluded histologic grade and DNA ploidy. METHODS : The study group comprised 1779 patients with PTC (followed up for > 26,000 patient-years), divided by treatment dates into 1940 to 1964 (n = 764) and 1965 to 1989 (n = 1015). Cox model analysis and stepwise variable selection led to a prognostic model initially derived from the training set (n = 764). The initial prognostic score was thereafter validated externally with the later (1965 to 1989) “test” data set. RESULTS : The final model included five variables abbreviated by metastasis, age, completeness of resection, invasion, and size (MACIS). The final prognostic score was defined as MACIS = 3.1 (if aged < or = 39 years) or 0.08 x age (if aged > or = 40 years), + 0.3 x tumor size (in centimeters), +1 (if incompletely resected), +1 (if locally invasive), +3 (if distant metastases present). Twenty-year cause-specific survival rates for patients with MACIS less than 6, 6 to 6.99, 7 to 7.99, and 8+ were 99%, 89%, 56%, and 24%, respectively (p < 0.0001). CONCLUSIONS : Because the five variables needed for MACIS scoring are readily available after primary operation, such a prognostic system could have widespread applicability in assessment of PTC.

5. Low-risk differentiated thyroid cancer: the need for selective treatment.
Shaha AR, Shah JP, Loree TR.
Ann Surg Oncol 1997; 4 : 328-33

BACKGROUND : The well recognized prognostic factors in differentiated carcinoma of the thyroid are age, grade, extracapsular extension, distant metastasis, and size of the tumor. Based on these prognostic factors, we have divided patients into low-, intermediate-, and high-risk categories. Clearly, there are significant differences in these three groups. This article analyzes in depth our data on low-risk thyroid cancer patients. METHODS: A retrospective review of 1,038 patients with differentiated carcinoma of the thyroid was undertaken. Various prognostic factors and risk groups were analyzed. Univariate and multivariate analyses were performed, and the survival curves were plotted by the Kaplan-Meier method. The inclusion criteria for the low-risk group were age younger than 45 years, tumors < 4 cm in size, low-grade histology, absence of distant metastasis, and absence of extrathyroidal extension. There were 465 patients in the low-risk group. Four hundred three patients had papillary and 62 patients had follicular thyroid cancer. There were 120 male and 354 female patients. Two hundred seventy-eight patients (60%) presented with clinically apparent lymph node metastasis. RESULTS: With a median follow-up of 20 years, the 10- and 20-year survival in this select group was 99%. The local, regional, and distant recurrence rates were 5, 9, and 2% in this series. The analysis of the data showed statistical difference in local recurrence rate between partial lobectomy and total lobectomy (27 vs. 4%; p = 0.005). There was no statistical difference in local recurrence rate between total lobectomy compared with total thyroidectomy (4 vs. 1%; p = 0.10). The overall failure rate between partial lobectomy and total thyroidectomy (27 vs. 8%) was statistically significant (p = 0.04). There was no statistical difference in the overall failure rate between total lobectomy and total thyroidectomy (13 vs. 8%; p = 0.06). There was no survival difference between various histologies or nodal status. CONCLUSIONS: Patients with low-risk tumors have excellent long-term survival. Nodulectomy or partial lobectomy should be avoided. The intraoperative decisions regarding the extent of thyroidectomy should be based on gross clinical findings and risk group analysis.

6. Current approaches and perspectives in the therapy of medullary thyroid carcinoma.
Vitale G, Caraglia M, Ciccarelli A, et al.
Cancer 2001; 91 : 1797-808

BACKGROUND: Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor derived from parafollicular cells. At present, surgery is the most important treatment for MTC. METHODS : We describe the current approaches of MTC treatment (surgery, chemotherapy, radiation therapy, and biologic therapy). RESULTS: MTC is currently approached surgically in the main part through total thyroidectomy and compartment-oriented microdissection of cervicomediastinal lymph nodes. Substitutive l-thyroxine administration together with close clinical monitoring and the measurement of basal and stimulated serum calcitonin are subsequently performed. Radiotherapy and chemotherapy play a marginal role in advanced MTC. Recently, it has been found that somatostatin analogs and type I interferon are able to control the neuroendocrine symptoms induced by advanced MTC and that they provide clinical benefit by improving the lifestyle of these patients. CONCLUSION : Although these agents are poorly active in inducing a shrinkage in tumor mass, the combined use of different biologic agents and cytotoxic drugs needs to be explored in advanced MTC. However, at present, surgery is the only curative treatment for MTC. Copyright 2001 American Cancer Society.

7. Prognostic factors in patients with differentiated thyroid carcinoma.
Steinmuller T, Klupp J, Rayes N, Ulrich F, Jonas S, Graf KJ, Neuhaus P Eur J Surg 2000;166:29-33.

Thyroid cancers are a heterogenous group of disorders. The treatment is based on evidence available from retrospective studies as there are no prospective trials available. It is impossible to perform a prospective randomised trial as the number of cases required will be enormous and considering the indolent nature of the disease a prolonged follow up is required. For differentiated cancers the treatment is guided by risk stratification criteria. Loboisthumectomy for the low-risk group, and total/near-total thyroidectomy for the high-risk, intermidiate risk and for cases with lymph node metastases is recommended. No role of prophylactic neck dissection. Anterolateral neck dissection or MND is recommended for clinically palpable nodal metastasis. Post – operative 131I treatment is mandatory in the high and intermidiate risk group where complete removal of the thyroid gland is achieved. Surgery is the mainstay in the treatment of medullary cancers and external radiotherapy is reserved for palliation in advanced and unresectable recurrent cases. Anaplastic cancers are treated with palliative intent.

OTHER SELECT PUBLICATIONS:
- Shaha AR, Loree TR, Shah JP. Prognostic factors and risk group analysis in follicular carcinoma of the thyroid. Surgery 1995 Dec;118:1131-6; discussion 1136-8
- Steinmuller T, Klupp J, Rayes N, Ulrich F, Jonas S, Graf KJ, Neuhaus P. Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg 2000;166:29-33