Nodal Stations: The cervix is drained by preureteral, postureteral, and uterosacral routes into the following first station nodes: parametrial, internal (obturator - hypogastric), external iliac, presacral, and common iliac. Para-aortic nodes are second station and are considered metastases.

Metastatic sites: The most common sites of distant spread include the aortic and mediastinal nodes, the lungs and skeleton.

Pretreatment Evaluation:
1. Complete physical and gynecological examination
2. CBC, Biochemistry and urine analysis, Chest X ray
3. Ultrasonography or CT Scan / MRI of abdomen and pelvis
4. Biopsy- punch, knife, colposcopy guided or conization
5. Cystoscopy / Barium enema / sigmoidoscopy / IVU - if bladder, rectal or ureteric involvement is suspected

Rules for Classification: FIGO GUIDELINES
(International Federation of Gynecology and Obstetrics. Benedet JL, Odicino F, Maisonneuve P et al. Caricinoma of the cervix uteri. J Epidemiol Biostat 2001;6(1):5-44.)

Clinical-diagnostic staging: Staging of cervical cancer is based on clinical evaluation; therefore, careful clinical examination should be performed in all cases, preferably by an experienced examiner and under anaesthesia. The clinical staging must not be changed because of subsequent findings. When there is doubt as to which stage a particular cancer should be allocated, the earlier stage is mandatory. The following examinations are permitted: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton. Suspected bladder or rectal involvement should be confirmed by biopsy and histologic evidence. Conization or amputation of the cervix is regarded as a clinical examination. Invasive cancers so identified are to be included in the reports. Findings of optional examinations, e.g. lymphangiography, arteriography, venography, laparoscopy, ultrasound, CT scan and MRI, are of value for planning therapy but, because these are not generally available and the interpretation of results is variable, the findings of such studies should not be the basis for changing the clinical staging. Fine needle aspiration (FNA) of scan-detected suspicious lymph nodes may be helpful in treatment planning.

Postsurgical treatment -pathologic staging: In cases treated by surgical procedures, the pathologist's findings in the removed tissues can be the basis for extremely accurate statements on the extent of disease. The findings should not be allowed to change the clinical staging, but should be recorded in the manner described for the pathologic staging of disease. The TNM nomenclature is appropriate for this purpose. Infrequently it happens that hysterectomy is carried out in the presence of unsuspected extensive invasive cervical carcinoma. Such cases cannot be clinically staged or included in therapeutic statistics, but it is desirable that they be reported separately. As in all gynaecological cancers, staging is determined at the time of the primary diagnosis and cannot be altered, even at recurrence. Only if the rules for clinical staging are strictly observed will it be possible to compare results among clinics and by differing modes of therapy.

Staging classification
Stage 0 comprises those cases with full-thickness involvement of the epithelium with atypical cells but with no signs of invasion into the stroma. The diagnosis of both Stage la1 and la2 should be based on microscopic examination of removed tissue, preferably a cone biopsy, which must include the entire lesion. The depth of invasion should not be > 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. The second dimension, the horizontal spread, must not exceed 7 mm. Vascular space involvement, either venous or lymphatic, should not alter the staging, but should be specifically recorded because it may affect treatment decisions in the future. Larger lesions should be staged as Ib. As a rule, it is impossible to clinically estimate if a cancer of the cervix has extended to the corpus. Extension to the corpus should therefore be disregarded. A patient with a growth fixed to the pelvic wall by a short and indurated, but not nodular, parametrium should be allotted to Stage IIB. It is impossible, at clinical examination, to decide whether a smooth and indurated parametrium is truly cancerous, or only inflammatory. Therefore, the case should be placed in Stage III only if the parametrium is nodular to the pelvic wall or if the growth itself extends to the pelvic wall. The presence of hydronephrosis or non functioning kidney resulting from stenosis of the ureter by cancer permits a case to be allotted to Stage III even if, according to other findings, the case should be allotted to Stage I or Stage II. The presence of bullous edema, as such, should not permit a case to be allotted to Stage IV. Ridges and furrows into the bladder wall should be interpreted as signs of submucous involvement of the bladder if they remain fixed to the growth at rectovaginal examination. Finding malignant cells in cytologic washings from the urinary bladder requires further histological confirmation in order to be considered for Stage IVA.

Regional Lymph Nodes (N)
• NX – Regional lymph nodes cannot be assessed
• N0 – No regional lymph node metastasis
• N1 – Regional lymph node metastasis

Distant Metastasis (M)
• MX – Distant metastasis cannot be assessed
• M0 – No distant metastasis;
• M1 – Distant metastasis.

Histopathologic types
- Cervical intraepithelial neoplasia, Grade III
- Squamous cell carcinoma in situ
- Squamous Carcinoma :Keratinizing,Nonkeratinizing& Verrucous
- Adenocarcinoma in situ
- Adenocarcinoma in situ, endocervical type
- Endometrioid adenocarcinoma
- Clear cell adenocarcinoma
- Adenosquamous carcinoma
- Adenoid cystic carcinoma
- Small cell carcinoma
- Undifferentiated carcinoma

FIGO Staging of Carcinoma of Cervix (1994)
(To be done jointly by Gynaecologic Surgical and Radiation Oncologists and may have to be supplemented by EUA)

Note: The depth of invasion should not be more than 5 mm taken from the base of the epithelium, either surface or glandular, from which it originates. The depth of invasion is defined as the measurement of the tumour from the epithelial-stromal junction of the adjacent most superficial epithelial papilla to the deepest point of invasion. Vascular space involvement, venous or lymphatic, does not affect classification.
Note: The presence of bullous edema is not sufficient to classify a tumour as T4.

Carcinoma of the Cervix Uteri – Stage Grouping

TREATMENT OPTIONS

Stage 0 Cervical Cancer (Carcinoma in situ)
Extent of the disease is the most important factor in the treatment decision. The other factors that also influence the treatment decision include age of the patient, fertility preservation and other medical conditions.

Ectocervical lesions:
          - Loop electrosurgical excision procedure (LEEP).
          - Laser therapy
          - Conization.
          - Cryotherapy

Endocervical canal involved:
          - Laser or cold-knife conization may be used for selected patients to preserve              the uterus and avoid radiation therapy and/or more extensive surgery.
          - Total abdominal or vaginal hysterectomy is an accepted therapy for the              post-reproductive age group and is particularly indicated when the              neoplastic process extends to the inner cone margin.
          - For medically inoperable patients, a single intracavitary insertion to a dose              of 80 Gy vaginal surface dose may be used[1]. Grade B Recommendation

STAGE IA
Stage IA1 : Micro-invasive (diagnosed only under microscopy), no greater than 3 mm depth and no wider than 7 mm.
The treatment options are:
- Conization
- Total Abdominal Hysterectomy
- Brachytherapy

Conization : In patients with lA1 disease if no vascular or lymphatic channel invasion is noted, and the margins of the cone are negative, conization alone may be appropriate in patients wishing to preserve fertility[2]. Grade B Recommendation.

Total hysterectomy (abdominal or vaginal): In patients with lA1 lesion with no vascular or lymphatic emboli, the frequency of lymph node involvement is very low and hence lymph node dissection is not required. Ovaries can be preserved in young women[2]. Grade B Recommendation.

Intracavitary Bracyhtherapy alone: In lA1 lesions if no capillary lymphatic space invasion is noted, the frequency of lymph node involvement is sufficiently low that external beam radiation is not required. One or 2 intraravitary insertions may be considered up to a dose of 100-125 Gy vaginal surface dose in women who are not fit for surgery[1].

Stage IA2 : 3.1-5.0 mm below the basement membrane (BM) and <7 mm in transverse dimension. The treatment options are:
- Radical hysterectomy (type II) with pelvic node dissection
- Radiation Therapy

Radical hysterectomy (type II) with pelvic node dissection: Has been recommended[3] because of a reported risk of lymph node metastasis of up to 10% However, a study suggests that the rate of lymph node involvement in this group of patients may be much lower and questions whether conservative therapy might be adequate for patients believed to have no residual disease following conization[4]. Radical hysterectomy with node dissection may also be considered for patients where the depth of tumor invasion was uncertain due to invasive tumor at the cone margins. Grade C Recommendation.

If fertility is desired, options are:

Radiation Therapy : Radical intracavitary radiotherapy or intracavitary plus external pelvic irradiation may be considered in women who are not fit for surgery1.

STAGE IB and IIA
Similar cure rates are obtained with surgical and radiotherapeutic treatment approach for stage IB squamous carcinoma of the cervix[5]. The choice between initial surgical or radiotherapeutic management depends upon the age of the patient, desire to preserve ovarian function, co-morbid conditions, associated gynaecological conditions requiring surgery, facilities and expertise available and patents wish.
Grade A Recommendation.

Stage IB1: The treatment options are:
- Radical hysterectomy (type III) with pelvic node dissection
- Radical Radiation Therapy

Radical hysterectomy and bilateral pelvic lymphadenectomy.

Radiation therapy: External-beam pelvic irradiation combined with intracavitary applications, which together delivers the dose of equivalent to 80Gy to point A.

Stage IB2 and IIA:
The treatment options include
          - Radical hysterectomy (Type III) and bilateral pelvic lymphadenectomy               +/- Adjuvant therapy
          - Radical Radiation therapy (External plus intracavitary).
          - Radiation therapy plus chemotherapy

Radical hysterectomy (type III) and bilateral pelvic lymphadenectomy involves removal of entire uterus, upper third vagina, bilateral parametria, uterosacral, utero-vesical ligaments and bilateral pelvic lymph nodes. Bilateral salpino-ooperectomy is discretionary.

Adjuvant therapy after Radical Surgery
High Risk: Lymph node metastases, +ve surgical margins, parametrial extension.
Adjuvant chemoradiation therapy with external pelvic radiation therapy with concurrent weekly cisplatin chemotherapy is recommended if any one of the above factor is seen on final histopathology. The risk of recurrence after radical surgery is increased with the presence of positive nodes, positive parametria, or positive surgical margins. Adjuvant concurrent chemoradiation (using 5FU + Cisplatin or Cisplatin alone) improves survival compared with pelvic irradiation alone in such patients[6] Grade A Recommendation.

Intermediate Risk: Deep invasion of cervical stroma, lymphovascular space invasion, tumor size >4 cm.
Adjuvant radiation therapy is recommended if at least two of the above factors are seen on final histopathology. Risk of recurrence is also increased in those with uninvolved nodes but large tumour volume, capillary-like space (CLS) involvement, and outer one-third invasion of the cervical stroma. Adjuvant whole pelvic irradiation reduces the local failure rate and improves progression-free survival compared with patients treated with surgery alone[7]. Grade A Recommendation.

Low risk: All other patients with none of the above-mentioned risk factors (High & Intermediate).
No adjuvant therapy recommended.

Radical Radiation Therapy

A combination of external-beam pelvic irradiation covering the uterus, parametria and pelvic nodes and intracavitary irradiation primarily for the central disease is used. The aim is to deliver a dose equivalent of 80Gy to point A.

External Radiation: Using conventional fractionation, a dose of 40-50 Gy in 20-25 fractions over a period of 4-5 weeks is recommended. Use of four-field beam arrangement, corner shields and a special midline block (after 20Gy), helps in reducing the dose to rectum, bladder and small bowel during external radiation.

Intracavitary Brachytherapy: Brachytherapy plays a very important role in obtaining high cure rates with minimum complications. A good intracavitary insertion delivers a very high radiation dose to the cervix, upper vagina and medial parametria without exceeding the tolerance doses for rectum and bladder. The randomized trials comparing low dose rate (LDR) with high dose rate (HDR) brachytherapy in carcinoma cervix have shown that the two modalities are comparable in terms of local control and survival[8-11]. Thus, either LDR or HDR brachytherapy may be used, taking into account the availability of equipment and other logistics of treatment delivery. HDR brachytherapy can be done as a day procedure in contrast to approximately 20 hours of continuous LDR treatment requiring overnight inpatient stay. However, due to radiobiological considerations, 5 applications of HDR are required in contrast to 2 applications of LDR (for stage I and II) to maintain low complication rates. HDR is being increasingly used now as the control rates are comparable and the toxicity is slightly less. Grade A recommendation.

LDR: Two Intracavitary Application (ICA), the first application in the second week of external radiation while the second is delivered just after completion of external radiation. The dose in each application is 30 Gy to point A.

HDR: Five weekly intracavitary applications of 7 Gy to point A each, starting from second week of external radiation.

Radiotherapy with Concurrent Chemotherapy
Five randomized phase III trials of radical RT alone versus concurrent cisplatin-based chemotherapy and RT, and their meta-analysis have shown an absolute benefit in overall survival and Progression free survival with chemoradiotherapy in patients with stage IB2 to IVA disease as well as high risk patients after hysterectomy[12-19]. While these trials vary somewhat in terms of heterogeneity in data, stage of disease, sub optimal doses of radiation, non-uniform usage for chemotherapeutic drugs and different schedules and doses of cisplatin, nevertheless demonstrate significant survival benefit for this combined approach. The risk of death from cervical cancer was decreased by 30% to 50% by concurrent chemo-radiation. Based on these results, NCI has recommended that ‘strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer especially in early stage disease’.
However the most recent trial[20] did not find any additional survival benefit of concurrent weekly cisplatin. The major criticism of this study was that nearly 2/3rds of the patients with CT+RT had low hemoglobin, which was not corrected during radiation. Regardless, the authors stressed that careful attention to RT details is more important for achieving optimum outcome.
While chemoradiotherapy is perhaps the new standard of care, it is worth remembering that these results were obtained in a trial setting, in women from affluent countries who had better nutritional or performance status and renal parameters as compared to the majority of our patients from lower socioeconomic status and with more advanced disease. Therefore in women with doubtful compliance or tolerance to combined modality treatment, radical radiotherapy alone without compromising the doses and duration can still be considered as the gold standard treatment approach.

STAGE IIB, IIIA and IIIB
Radiotherapy remains the mainstay of treatment for advanced stages. Platinum based concomitant chemo-radiation improves survival and the pros and cons of this approach have been discussed earlier. Both the Cochrane and Canadian meta-analysis have to a large extent tried to address the role of concomitant chemo-radiation, but in all these trials carcinoma cervix Stage III accounted for only 30-35% and moreover evaluation with optimal radiation schedules and comparison of late toxicities still remains unanswered. Grade A recommendation.

Radiation therapy :

Stage IIB : The technique and doses of external and intracavitary radiation are same as described for Stage IB.

Stage IIIA : The dose of external beam radiation therapy is 50Gy to the whole pelvis over 5 weeks with 2Gy fractionation. Whenever possible, a midline block should be used after 40Gy. An LDR Intracavitary application with tandem and ovoids to a dose of 30Gy to point A is recommended. Patients, in whom standard ICA is not feasible due to residual disease extending below upper third vagina, intracavitary application using tandem and cylinders to a dose of 15 - 25 Gy to point A (depending on rectal dose) is recommended.

Stage IIIB : The dose of external beam radiation therapy is 50Gy to the whole pelvis over 5 weeks with 2 Gy fractionation. Whenever possible, a midline block should be used after 40 Gy. Intracavitary application with Low dose rate (one application of 30 Gy to point A) or High dose rate (3 applications of 7Gy to point A each every week, starting from 3rd or 4th week of external radiation) is recommended.

Stage IVA :
The management of patients with stage IVA disease (invasion of bladder and/or rectum) has to be individualized, taking into account the extent of bladder / rectal involvement, parametrial infiltration, renal function and patients performance status.The treatment options include:

         - Pelvic Exenteration
         - Neoadjuvant chemotherapy or concurrent chemoradiotherapy
         - Palliative Radiotherapy

Surgical Exenteration : Selected patients of stage IV, with no or minimal parametrial invasion may be treated with primary exenterative surgery, the extent of which (anterior, posterior or total) would depend on the extent of the lesion.

Neoadjuvant chemotherapy or concurrent chemoradiotherapy
Selected patients with good general and renal status and not suitable for surgical exenteration can be treated with this approach with radical intent.

Palliative Radiotherapy: The majority of stage IVA patients has poor general condition and extensive local disease in our setting and are best treated with palliative radiation therapy alone. A short palliative regime of 30 Gy in 10 fractions over two weeks or 30 Gy / 3# / 60 days (10 Gy / every month x 3#) is generally used and in few patients who respond very well, this is followed by intracavitary application.

Stage IVB
No standard chemotherapy regimen is proven in patients with stage IVB cervical cancer. Various single agent chemotherapy drugs have been used with varying response rates in phase I and II studies (cisplatin+ ifosphomide or cisplatin+paclitaxel). Radiation therapy can be used for palliation of central disease or symptomatic distant metastasis. The role of systemic therapy is discussed later with recurrent disease.

Para-Aortic nodes: Extended field radiation therapy has been reported to produce long term disease control in women with microscopic or small volume (<2cm) lower para-aortic nodes (below L3) with acceptable complications rates when radiation dose was not exceeded beyond 50 Gy and the lymphadenectomy was performed by extraperitoneal rather than transperitoneal route[21,22]. In the RTOG randomised trial reported recently23, the 10 year overall survival was improved from 44% with pelvic radiation to 55% with pelvic plus prophylactic para-aortic radiation in 367 women with stage IB1 and IIA disease. Grade 4 and 5 radiation toxicities at 10 years however increased from 4% to 8% with para-aortic irradiation. Patients with positive common iliac or para aortic nodes may be treated by extended field radiation with or without chemotherapy. Grade C Recommendation.

Management of patients who relapse after primary treatment :
Treatment decisions should be based on the performance status of the patient, the site of recurrence and/or metastases, the extent of metastatic disease and the prior treatment.

Therapeutic options for local relapse after Primary Surgery
Relapse in the pelvis following primary surgery may be treated by either radical radiation or pelvic exenteration. Radical irradiation (+/concurrent chemotherapy) may cure a substantial proportion of those with isolated pelvic failure after primary surgery. Radiation dose and volume should be tailored to the extent of disease. 50 Gy in 25# @ 1.8 Gy per day should be delivered to microscopic disease and using field reductions 64 to 66 Gy should be delivered to the gross tumour volume.
Where disease is metastatic or recurrent in the pelvis after failure of primary therapy and not curable, a trial of chemotherapy with palliative intent or symptomatic care is indicated. Cisplatin is the single most active agent for the treatment of cervical cancer.
The expected median time to progression or death is three to seven months.

Local Recurrence after Primary Radiotherapy Selected patients with resectable recurrences should be considered for pelvic Exenteration. The only potentially curative treatment after primary irradiation is pelvic exenteration. Patients should be selected carefully; those with resectable central recurrences that involve the bladder and/or rectum without evidence of intraperitoneal or extra pelvic spread and who have a dissectable tumour-free space along the pelvic sidewall are potentially suitable. The triad of unilateral leg edema, sciatic pain and ureteral obstruction almost always indicates unresectable disease on the pelvic sidewall, and palliative measures are indicated. This surgery should be undertaken only in centres with facilities and expertise for this surgery available and only by teams who have the experience and commitment to look after the long-term rehabilitation of these patients. The prognosis is better for patients with a disease-free interval greater than six months, a recurrence 3 cm or less in diameter, and no sidewall fixation. The five-year survival for patients selected for treatment with pelvic exenteration is in the order of 30 – 60% and the operative mortality should be < 10%. In carefully selected patients, a radical hysterectomy may be performed. Suitable patients are mainly those whose central tumour is not more than 2 cm in diameter. Grade C Recommendation.

Systemic CT in Stage IVB or Recurrent Metastatic Disease

Distant Metastases : Should be treated with a palliative intent with chemotherapy or radiotherapy or symptomatic & supportive care only. Symptoms of recurrent / metastatic cervical cancer may include pain, leg swelling, anorexia, vaginal bleeding, cachexia and psychological problems among others. The coordinated efforts of a team of professionals are optimal; this may include gynaecologic oncologists, radiation and medical oncologists, palliative care physicians, specialised nursing staff, psychologists, and possibly stomal therapists. Relief of pain and other symptoms, along with comprehensive support for the patient and her family, are paramount.
Local treatment with radiation therapy is indicated to sites of symptomatic involvement in patients with metastatic disease for alleviation of symptoms including pain arising from skeletal metastases, enlarged paraaortic or supraclavicular nodes, and symptoms associated with cerebral metastases. In view of the shortened life expectancy of patients with metastatic cervical cancer, palliative radiotherapy should be given via larger fractions over shorter periods of time than conventional radical courses of treatment.

The Evidence for Cervix Cancer Screening in India

An estimated number of 4,70,000 new cases of cervix cancer are diagnosed each year worldwide. Over 80% of the cases occur in developing countries where, in many regions, it is the most common cancer among women. Around 27% of the cases occur in India from where 1,26,000 new cases are diagnosed annually and over 71,000 deaths due to cervix cancer are reported each year. Cervix cancers ranges from 15.2% to 50.7% of all female cancers in different parts of the country and the age adjusted incidence rates range from 17.2 to 30.7 per 1,00,000. Over 80% of the cases report for treatment in fairly advanced stages of the disease.

Although, cervical cancer control by early detection and treatment is one of the priorities of the National Cancer Control Programme (NCCP) of India, no organised screening programmes are currently existent. The objective of cervical cancer screening should be to reduce cervical cancer incidence and mortality by detecting and treating precancerous lesions. Conventional cytology is the most widely used screening test worldwide and has been effective in reducing the incidence of and mortality from cervical cancer in developed countries. Cytology, however, has been less successful and largely ineffective in reducing the cervical cancer burden in low resource setting countries that have implemented it. National consultations on cervical cancer control have concluded that cytology screening is not feasible in India in the foreseeable future in view of technical, financial and manpower constraints. In this context, visual inspection and HPV testing strategies have been evaluated as an alternative to cytology in India. Let us examine whether and what level of evidence we currently have for cervix cancer screening in India.

Four methods of visual screening have been investigated in India

1) Naked eye inspection without acetic acid application (downstaging/DVI)
2) Naked eye inspection after application of 3-5% acetic acid (VIA)
3) VIA using magnification devices (VIAM)
4) Naked eye inspection after the application of Lugol's iodine (VILI)

Downstaging has been shown to have a poor sensitivity and specificity to detect cervical neoplasia, particularly precancerous lesions, and is no longer considered as a suitable screening test for cervical neoplasia. Eleven cross-sectional studies, using a common protocol, involving 56,939 women aged 25-65 years were conducted in India and in 5 sub-Saharan African countries, as part of IARC collaborative studies, to evaluate the accuracy of VIA and VILI testing by health workers. The VIA and VILI test positivity rates were 16.1% and 16.4% respectively. 1,063 women were diagnosed with CIN 2-3 in the study. The pooled sensitivity, specificity, positive and negative predictive values for VIA were 76.8%, 85.5%, 9.4%, and 99.5%, respectively. The values were 91.7%, 85.4%, 10.9%, and 99.8%, respectively for VILI. The range of sensitivity and specificity for VIA was 56.1-93.9% and 74.2-93.8%, respectively between studies, and was 76.0-97.0 % and 73.0-91.3% for VILI. VILI had a significantly higher sensitivity than VIA in detecting CIN 2-3 lesions, but specificity was similar. Results from the Indian studies indicate that low-level magnification (VIAM) did not improve the performance of VIA.

The accuracy of conventional cervical cytology was evaluated in a multi-centre cross-sectional study involving 22,663 women in India[24]. The test positivity rates of cytology were 8.8% at atypical squamous cells of uncertain significance (ASCUS), 6.2% at low-grade squamous intraepithelial lesion (LSIL) and 1.8% at high-grade squamous intraepithelial lesion (HSIL) thresholds. The pooled sensitivity, specificity, positive and negative predictive values for detecting CIN 2-3 lesions at ASCUS threshold were: 64.5%, 92.3%, 11.8% and 99.4% respectively. The corresponding values at LSIL threshold were: 58.0%, 94.9%, 15.2% and 99.3% and at the HSIL threshold were: 45.4%, 99.2%, 46.3% and 99.1%. The sensitivity varied between 37.8 - 81.3% at ASCUS, 28.9-76.9% at LSIL and 24.4-72.3% at HSIL thresholds. A significantly low sensitivity was observed in women aged 25-39 years (P<0.001). Findings from this and other studies emphasize the importance of sustained efforts in improving sampling of cells, preparation and reading of cytological specimens and clinical judgment are essential to achieve concurrently high sensitivity and specificity.

The finding that persistent infection with one or more of 15 types of human papillomavirus (HPV) as the necessary cause for cervical neoplasia has led to the evaluation of the role of HPV testing in screening. The accuracy of HPV testing by Hybrid capture II (HC II) method in detecting CIN 2-3 lesions was evaluated in 4 cross-sectional studies involving 18,085 women in India.24 The sensitivity of HPV testing for detecting CIN 2-3 lesions varied from 45.7% to 80.9% across the study sites; the specificity varied from 91.7% to 94.6% and the positive predictive value from 6.7% to 13.7%. Although HPV testing is a promising approach, a large range in sensitivity was observed in studies in India, possibly due to variations in the quality of specimen collection, and reference standards. A higher sensitivity was associated with the centre performing the test well. Further developments in terms of better reproducibility, lesser cost and lesser sophistication are vital for HPV testing to be feasible and effective in low-resource settings.

The efficacy of a single round of VIA screening on cervical cancer incidence and mortality is being investigated in a cluster randomised trial in Dindigul District, south India[25]. The findings from this study indicate that a VIA screening programme is feasible, safe and acceptable to a population in rural settings, and it leads to early detection of cervical neoplasia.

The impact of screening by visual inspection with acetic acid (VIA), cytology, or HPV testing on cervical cancer incidence and mortality and their cost-effectiveness are investigated in a cluster randomized controlled trial in Osmanabad district, India.26 142,701 women aged 30-59 years were randomized into 4 clusters for a single round of screening by trained midwives with either VIA, cytology, HPV testing or to a control group. All laboratory tests were done locally. Of the eligible women, 72-74% were screened. Test positivity rates were 14.0% for VIA, 7.0% for cytology and 10.4% for HPV. The detection rate of high-grade lesions was similar in all intervention arms (0.7% for VIA, 1.0% for cytology and 0.9% for HPV testing) (p=0.06). While the detection rate for VIA dropped to 0.5% with declining test positivity during the course of the study, it remained constant for cytology and HPV testing. Over 85% of women with high-grade lesions received treatment. The results show that a high level of participation and good quality cytology can be achieved in low-resource settings. VIA is a useful alternative, but requires careful monitoring. Detection rates obtained by HPV testing were similar to cytology, despite higher investments.

A cluster randomized controlled trial involving 152,000 socio-economically disadvantaged women aged 35-64 years at entry, from the slums of Mumbai is on-going since 1997 to evaluate the efficacy of clinical breast examination and VIA by trained primary health workers at 2 year intervals, to a total of 4 screening rounds, in reducing mortality from breast and cervical cancers, as compared to a control group who received one round of health education (on risk factors, prevention, signs and symptoms, early detection and treatment of breast, cervical and oral cancers) at recruitment. This study has demonstrated the feasibility of conducting organised screening programmes for cervix cancer screening in terms of excellent participation rates (over 70% at first round and 68% at second round of screening), good compliance to diagnostic confirmation (over 80%), good compliance to treatment (over 80%).

As of current knowledge and evidence base we can say that the visual tests have a better sensitivity than Cytology and HPV. The specificity of the visual tests is however lower. The visual tests are therefore not suitable as stand-alone screening tools for cervix cancer. The visual tests can be considered for primary screening /triaging if the screening positives can be followed-up with cytology and or HPV testing to complete the screening process. One should also bear in mind that the visual screening tests depend heavily on the training and skills of the test providers and hence the test characteristics can vary significantly in different situations and with different levels of test providers.

1. Radiotherapy alone for medically inoperable carcinoma of the cervix: stage IA and carcinoma in situ.
Grigsby PW, Perez CA.
Int J Radiat Oncol Biol Phys 1991; 21 :375-8

The objective of this study was to define the role of radiotherapy alone for medically inoperable patients with Carcinoma in Situ (CIS) and Stage IA carcinoma of the uterine cervix. At the Mallinckrodt Institute of Radiology, Radiation Oncology Center from January 1959 through December 1986 21 patients with CIS and 34 with Stage IA were treated. All patents had histologically proven disease. The average age was 56 years for CIS and 51 years for Stage IA patients. Therapy for patients with CIS consisted of a single intracavitary insertion with a uterine tandem and colpostats. The average radiation doses were 4612 cGy to point A, 9541 cGy to the surface of the cervix, and 5123 milligram-hours (mgh). Radiotherapy for Stage IA tumors was delivered with intracavitary irradiation alone in 13 (average doses were 5571 cGy to point A, 10,430 cGy vaginal surface dose, and 6488 mgh). The other 21 patients were treated with external beam and intracavitary irradiation. The average whole pelvis dose was 1443 cGy with an additional 2354 cGy boost to the parametria with a midline stepwedge shield. The average intracavitary doses were 5200 cGy to point A, 10234 cGy to the vaginal surface, and 6293 mgh. None of the patients with CIS developed recurrent disease and none had severe sequelae of therapy. Only one patient with Stage IA developed recurrent disease in the pelvis. None developed metastatic disease. The severe complication rate was 5.9% (2134) for Stage IA and only occurred in those receiving intracavitary irradiation and external beam irradiation. We conclude that irradiation consisting of intracavitary implants alone is excellent treatment for patients with medically inoperable Stage IA and CIS of the cervix.

2. Microinvasive carcinoma of the cervix.
Sevin BU, Nadji M, Averette HE, Hilsenbeck S, Smith D, Lampe B.
Cancer 1992; 70 : 2121-8

BACKGROUND : Microinvasive carcinoma of the cervix (MIC) has been poorly defined in the past and is still a focus of persistent controversy. In 1985, the International Federation of Gynecology and Obstetrics (FIGO) defined Stage IA as “preclinical invasive carcinoma, diagnosed by microscopy only,” subdividing it into Stage IA1 or “minimal microscopic stromal invasion,” and Stage IA2 or “tumor with invasive component 5 mm or less in depth taken from the base of the epithelium and 7 mm or less in horizontal spread.” In 1974, the Society of Gynecologic Oncologists SGO) defined MIC as any lesion with a depth of invasion of 3 mm or less from the base of the epithelium, without lymphatic or vascular space invasion. METHODS : To assess the risk of lymph node metastasis and treatment failures, pathologic material and clinical data on 370 patients with Stage I carcinoma of the cervix, who were treated by radical hysterectomy and pelvic-aortic node dissection, were reviewed. Histopathologic analysis of tumors was based on a uniform formal, including measurement of the maximum depth of invasion, the width and length of the horizontal tumor spread, invasive growth pattern, cell type, tumor grade, and lymphatic or vascular space involvement. RESULTS : Of the 370 patients, 110 had a depth of invasion of 5 mm or less. Of these, 54 patents fulfilled the SGO definition of MIC; 42, the new FIGO Stage IA2 definition; and 27, both definitions. None of the patients with MIC, as defined by either the SGO or the new FIGO Stage IA2, had lymph node metastases or tumor recurrence. These data support the conclusion that MIC, defined by either the SGO or FIGO definitions, have a low risk for lymph node metastasis or recurrent carcinoma. A review of the literature indicated a recurrence rate for Stage IA2 of 4.2%. In addition to depth of invasion, lymph vascular space invasion is a better predictor of lymph node metastasis and recurrence than the surface dimension. CONCLUSIONS : The authors recommend adoption of the SGO definition of MIC. Patients with a depth of invasion of 3 mm or less without lymph vascular space invasion safely can be treated conservatively.

3. Early invasive carcinoma of the cervix.
Jones WB, Mercer GO, Lewis JL, Rubin SC, Hoskins WI.
Gynecol Oncol 1993; 51 : 26-32

Ninety-two patients with early invasive carcinoma of the cervix (5 mm or less) treated between July 1977 and June 1990 are reviewed, Eighty patents had squamous cell carcinomas and 12 had adenocarcinomas. The diagnosis was established by conization in 77 of 92 (83.6%) patients. Thirty-six patients (39%) had a depth of stromal invasion of 1 mm or less, 32 patients (35%) between 1 and 3 mm, and 24 patients (26%) between 3 and 5 mm. Forty-four patients were treated with radical hysterectomy and bilateral pelvic lymphadenectomy (RHND). None of these patients had positive lymph nodes. Thirty-three patients were treated with conservative hysterectomy (CH), 4 with modified radical hysterectomy, and 2 with trachelectomy. Six patients received radiotherapy. Three patients were treated by conization only. Two patients developed in situ carcinoma (CIS) of the vagina 12 months after CH for lesions on conization that invaded less than I mm. In both cases the cone margins were positive, and in one a microscopic focus of CIS of the cervix was present at the resection margin of the hysterectomy specimen. A third patient developed an invasive lesion of the vagina 25 months after CH for a lesion that invaded 2.5 mm in a cone whose margins were not specified, but the hysterectomy margins were clear. All 3 patients were successfully retreated, The remaining patients are free of disease for a median follow-up of 51 months. The results of the study indicate that CH is adequate therapy for patients in whom the diagnosis of early invasive cervical cancer is established by conization with free margins and the depth of invasion is 3 mm or less. Although only 1 of 24 patients with invasion > 3 mm but < or = 5 mm had a CH, pathologic findings in 18 patients who had RHND suggest that CH would have been sufficient for these since there were no instances of spread to nodes or parametrium.

4. Early invasive carcinoma of the cervix (3 to 5 mm invasion): risk factors and prognosis. A Gynecologic Oncology Group study.
Creasman WT, Zaino RJ, Major FJ, Di Saia PJ, Hatch KD, Homesley HD.
Am J Obstet Gynecol 1998; 178: 62-5.

OBJECTIVE : Our purpose was to evaluate the risk factors and prognosis in patients with stage IA squamous cell carcinoma of the cervix and 3 to 5 mm of invasion. STUDY DESIGN : From 1981 to 1984 the Gynecologic Oncology Group conducted a prospective clinicopathologic study of patients with stage I carcinoma of the cervix. A selective study group that was previously defined and reported included patients with squamous cell carcinoma of the cervix who were treated with radical hysterectomy and pelvic lymphadenectomy and who had disease confined to the uterus, with or without microscopically positive lymph nodes. RESULTS : One hundred eighty-eight patients had invasion of 3, 4, or 5 mm as determined by central pathology review. Patients who satisfied the 3 to 5 mm invasion definition of the current stage IA2 classification of the International Federation of Gynecology and Obstetrics (1995) are the subject of this report CONCLUSIONS : Patients with stage IA2 carcinoma of the cervix who have 3 to 5 mm of invasion present on conization with no invasion in the hysterectomy specimen are at very low risk for lymph node metastases, recurrences, or death caused by cancer.

5. Randomised study of radical surgery versus radiotherapy for stage Ib-lla cervical cancer.
Landoni F, Maneo A, Colombo A et al.
Lancet 1997; 350 : 535-40

BACKGROUND : Stage lb and Ila cervical carcinoma can be cured by radical surgery or radiotherapy. These two procedures are equally effective, but differ in associated morbidity and type of complications. In this prospective randomised trial of radiotherapy versus surgery, our aim was to assess the 5-year survival and the rate and pattern of complications and recurrences associated with each treatment. METHODS : Between September, 1986, and December, 1991,469 women with newly diagnosed stage lb and Ila cervical carcinoma were referred to our institute. 343 eligible patients were randomised: 172 to surgery and 171 to radical radiotherapy. Adjuvant radiotherapy was delivered after surgery for women with surgical stage pT2b or greater, less than 3 mm of safe cervical stroma, cut-through, or positive nodes. The primary outcome measures were 5-year survival and the rate of complications. The analysis of survival and recurrence was by intention to treat and analysis of complications was by treatment delivered. FINDINGS : 170 patients in the surgery group and 167 in the radiotherapy group were included in the intention-to-treat analysis; scheduled treatment was delivered to 169 and 158 women, respectively, 62 of 114 women with cervical diameters of 4 cm or smaller and 46 of 55 with diameters larger than 4 cm received adjuvant therapy, After a median follow-up of 87 (range 57120) months, 5-year over all and disease-free survival were identical in the surgery and radiotherapy groups (83% and 74%, respectively, for both groups), 86 women developed recurrent disease: 42 (25%) in the surgery group and 44 (26%) in the radiotherapy group. Significant factors for survival in univariate and multivariate analyses were: cervical diameter, positive lymphangiography, and adeno-carcinomatous histotype. 48 (28%) surgery group patients had severe morbidity compared with 19 (12%) radiotherapy group patients (p=0.0004). INTERPRETATION : There is no treatment of choice for early-stage cervical carcinoma in terms of overall or disease-free survival. The combination of surgery and radiotherapy has the worst morbidity, especially urological complications. The optimum therapy for each patient should take account of clinical factors such as menopausal status, age, medical illness, histological type, and cervical diameter to yield the best cure with minimum complications.

6. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix.
Peters WA, Liu PY, Barrett RJ et al.
Clin. Oncol 2000; 18 (8): 1606-13.

PURPOSE: To determine whether the addition of cisplatin-based chemotherapy (CT) to pelvic radiation therapy (RT) will improve the survival of early-stage, high-risk patients with cervical carcinoma. PATIENTS AND METHODS : Patients with clinical stage IA(2), IIB, and IIA carcinoma of the cervix, initially treated with radical hysterectomy and pelvic lymphadenectomy, and who had positive pelvic lymph nodes and/or positive margins and/or microscopic involvement of the parametrium were eligible for this study. Patients were randomized to receive RT or RT + CT Patients in each group received 49.3 GY RT in 29 fractions to a standard pelvic field. Chemotherapy consisted of bolus cisplatin 70 mg/m2 and a 96-hour infusion of fluorouracil 1,000 mg/m(2)/d every 3 weeks for four cycles, with the first and second cycles given concurrent to RT RESULTS: Between 1991 and 1996, 268 patients were entered onto the study. Two hundred forty-three patients were assessable (127 RT + CT patients and 116 RT patients), Progression-free and overall survival are significantly improved in the patients receiving CT. The hazard ratios for progression-free survival and overall survival in the RT only arm versus the RT + CT arm are 2.01 (P=.003) and 1.96 (P=.007), respectively. The projected progression-free survivals at 4 years is 63% with RT and 80% with RT + CT. The projected overall survival rate at 4 years is 71 % with RT and 81 % with RT + CT Grades 3 and 4 hematologic and gastrointestinal toxicity were more frequent in the RT + CT group. CONCLUSION: The addition of concurrent cisplatin-based CT to RT significantly improves progression-free and overall survival for high-risk, early-stage patients who undergo radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix.

7. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study
Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ.
Gynecol Oncol. 1999 May;73(2):177-83.

OBJECTIVE: The objective of this study was to evaluate the benefits and risk of adjuvant pelvic radiotherapy aimed at reducing recurrence in women with Stage IB cervical cancer treated by radical hysterectomy and pelvic lymphadenectomy. METHODS: Two hundred seventy-seven eligible patients were entered with at least two of the following risk factors: >1/3 stromal invasion, capillary lymphatic space involvement, and large clinical tumor diameter. Of 277 patients, 137 were randomized to pelvic radiotherapy (RT) and 140 to no further treatment (NFT). RESULTS: Twenty-one (15%) in the RT group and 39 (28%) in the NFT group had a cancer recurrence, 18 of whom were vaginal/pelvic in the RT and 27 in the NFT group. In the RT group, of 18 (13%) who died, 15 died of cancer. In the NFT group, of the 30 (21%) who died, 25 died from cancer. Life table analysis indicated a statistically significant (47%) reduction in risk of recurrence (relative risk = 0.53, P = 0.008, one-tail) among the RT group, with recurrence-free rates at 2 years of 88% versus 79% for the RT and NFT groups, respectively. Severe or life-threatening (Gynecologic Oncology Group grade 3 or 4) urologic adverse effects occurred in 4 (3.1%) in the RT group and 2 (1.4%) in the NFT group; 3 (2.3%) and 1 (0.7%) hematologic; 4 (3.1%) and 0 gastrointestinal (GI); and 1 (0.8%) and 0 neurologic, respectively. One patient's death was attributable to grade 4 GI adverse effects. CONCLUSIONS: Adjuvant pelvic radiotherapy following radical surgery reduces the number of recurrences in women with Stage IB cervical cancer at the cost of 6% grade 3/4 adverse events versus 2.1% in the NFT group.

8. Low dose rate vs. high dose rate brachytherapy in the treatment of carcinoma of the uterine cervix : a clinical trial.
Patel FD, Sharma SC, Negi PS, Choshal S, Gupta BD.
Int J Radial Oncol Biol Phys 1994; 28: 335-9

PURPOSE : This study is a prospective randomized clinical trial undertaken at our center to compare low dose rate versus high dose rate intracavitary brachytherapy for the treatment of carcinoma uterine cervix. METHODS AND MATERIALS : From June 1986 to June 1989, 482 patients with previously untreated invasive squamous call carcinoma of the uterine cervix were entered into the study. After an initial clinical examination and investigative work-up the patients were staged according to FIGO staging system. Depending upon the stage of the disease, the size of the local growth and the local cervical anatomy, the patients were divided into two main groups. In group I patients, the predominant treatment was by intracavitary therapy and in group II patients, the predominant therapy was by external beam radiation. In both the groups at the time of intracavity brachytherapy the patients were alternately randomized to receive either low dose rate or high dose rate brachytherapy. There were thus two hundred forty-six patients in the low dose rate group and two hundred thirty-six patents in the high dose rate group. The patients were analyzed for local control, 5 years survival and late radiation morbidity. RESULTS : Stage for stage the local control rates in the low dose rate group and high dose rate group were similar. The overall local control achieved in the low dose rate group was 79.7% as compared to 75.8% in the high dose rate group. The 5 years survival figures in the low dose rate and high dose rate group were also comparable. In Stage I, it was 73% for low dose rate patients and 78% for high dose rate patients, for Stage II it was 62% and 64% respectively and for Stage III patients it was 50% and 43%. The only statistically significant difference was found in the incidence of overall rectal complications which was 19.9% for the low dose rate group as compared to only 6.4% for the high dose rate group. However, the more severe grade 3-4 complications were not significantly different between the two groups (2.4% vs. 0.4%, respectively). The bladder morbidity in both the groups was similar. CONCLUSION : Thus high dose rate intracavitary brachytherapy is an equally good alternative to conventional low dose rate brachytherapy in the treatment of carcinoma of the uterine cervix.

9. HDR and MDR intracavitary treatment for carcinoma of the uterine cervix. A prospective randomized study.
el-Baradie M, Inoue T, Murayama S et al.
Strahlenther Onkol 1997; 173 : 155-62

AIM : Treatment of carcinoma of the uterine cervix by remote afterloading brachytherapy has been accompanied with new isotopes having dose rates different from the classical low-dose rate (LDR) radium source. The dose rate conversion factor from LDR to high-dose rate (HDR) found to be around 0.54 in most studies. As regards medium-dose rate (MDR) brachytherapy, the published data are very few and the experience is still short. In this study the experience of Osaka University Hospital with micro-HDR-Selectron and Selectron-MDR, as a preliminary report of the clinical trial, is presented. PATIENTS AND METHOD : From August 1991 through April 1993, a total of 45 patients with carcinoma of the uterine cervix were randomly allocated to either microSelectron-HDR or Selectron-MDR at the Osaka University Hospital. As regards HDR, dose to point A was adjusted to 32 Gy (for stages I and II). 30 Gy/4 fractions, and 22.5 Gy/3 fractions, for stages 111, and IV, respectively. The corresponding values in case of MDR were 35.6, 34 Gy/4 fractions, and 25.5 Gy/3 fractions. External irradiation, according to the stage, was the same in the 2 groups. Nucletron Planning System (NPS) was used for pre-treatment dose calculation at point A, rectal and bladder wall. The dose rate at point A ranged from 24 to 75.6 cGy/min for the HDR group, while for the MDR group ranged among 174.8 to 229.6 cGy/h. RESULTS : The 3-year survival and loco-regional control rates for both modalities were nearly equivalent (62% and 67% for HDR and 68% and 74% for MDR). The cumulative rectal and bladder complication rates were the same in both groups (29% at 3 years), with only 1 patient (MDR-group) developed grade 3 rectal and bladder complication. In this study, point A dose rate correction factor from LDR to HDR was 0.53 and 0.6 from LDR to MDR. CONCLUSIONS : From the previous reports from Osaka University Medical School, as well as others, HDR was proposed as an alternative to LDR brachytherapy for treatment of carcinoma of the uterine cervix. In this report, Selectron-MDR was nearly equivalent to the microSelectron-HDR as regards survival and loco-regional control rates as well as radiation-induced complication. This is a preliminary report, and the study still needs larger number of patients, and longer follow-up period.

10. High-dose-rate versus low-dose-rate intracavitary therapy for carcinoma of the uterine cervix: a randomized trial.
Hareyama M, Sakata K, Oouchi A et al.
Cancer 2002; 94 :117-24

BACKGROUND : This was a prospective randomized clinical trial undertaken at our institution to compare low-dose-rate (LDR) intracavitary radiation therapy versus high-dose-rate (HDR) intracavitary radiation therapy for the treatment of cervical carcinoma. METHODS : From January 1984 to December 1997, a total of 132 patients with Stage II or IIIB of invasive carcinoma of the uterine cervix were entered into this randomized study. Treatment arm by HDR or LDR was allocated according to the month of each patient's birth. External irradiation consisted of whole pelvis irradiation and pelvic irradiation. Doses of external irradiation for both groups were identical. The authors used 0.588 as the conversion factor of total intracavitary dose from LDR to HDR. RESULTS : The 5-year disease specific survival rates of Stage II and III patients treated with HDR were 69% and 51 % whereas those with LDR were 87% and 60%, respectively. The 5-year pelvic recurrence free survival rates of Stage II and III patients treated with HDR were 89% and 73% whereas those with LDR were 100% and 70%, respectively. There was no significant difference in disease specific survival or pelvic recurrence free survival rates between HDR and LDR. The actuarial complication rate (Radiation Therapy Oncology Group Grade 3,4, or 5) at 5 years was 10% in the HDR group and 13% in the LDR group, and the difference between the HDR and LDR groups was not statistically significant. CONCLUSIONS : The pelvic control or actuarial complication rates were comparable between HDR and LDR treatment. The difference between the disease specific survival rates for HDR and LDR was not statistically significant for Stage II or III, although in Stage II, patients treated with LDR appeared to have a better survival rate than those treated with HDR.

11. High-dose-rate brachytherapy may be radiobiologically superior to low-dose rate due to slow repair of late-responding normal tissue cells.
Orton.CG.
Int J Radiat Oncol Biol Phys. 2001 Jan 1;49(1):183-9.

BACKGROUND AND PURPOSE: Recent analysis of morbidity for patients treated with the continuous hyperfractionated accelerated radiotherapy (CHART) regimen demonstrates that repair half-times for late-reacting normal tissue cells are of the order of 4-5 h, which is considerably longer than previously believed. This would reduce repair of these tissue cells during a course of low-dose rate (LDR) brachytherapy, but have no effect at high-dose-rate (HDR), where there is no repair during, and full repair between fractions, regardless of repair half-time. The effect this has upon radiobiologic comparison of LDR and HDR is the topic of this paper. METHODS AND MATERIALS: The linear-quadratic (L-Q) model is used to compare late-effect biologically effective doses (BEDs) of LDR and HDR, for constant BED (tumor). The effects of dose rate (for LDR), fractionation (for HDR), and geometrical sparing of normal tissues are all considered. Repair half-times observed in the CHART study are used to investigate the potential impact of long repair times on the comparison of LDR and HDR. RESULTS: It is demonstrated that, for a repair half-time of 1.5 h for tumor cells, if the half-time for repair of late-reacting normal tissue cells exceeds about 2.5 h, LDR becomes radiobiologically inferior to HDR. Even with the least HDR-favorable combinations of parameters, HDR at over about 5 Gy/fraction ought to be radiobiologically superior to LDR at 0.5 Gy/h, so long as the time between HDR fractions is long compared to the repair half time. It is also shown that any geometrical sparing of normal tissues will benefit HDR more than LDR. CONCLUSION: The previously held belief that LDR must be inherently superior radiobiologically to HDR is wrong if the long repair times demonstrated in the recent CHART study are applicable to other late-reacting normal tissues. This could explain why HDR has been so successful in clinical practice, especially for the treatment of cervical cancer, despite previous convictions of radiobiologic inferiority of this modality.

12. Concomitant chemotherapy and radiation therapy for cancer of the uterine cervix.
Green J, Kirwan J, Tierney J et al.
Cochrane Database Syst Rev 2001; (4): CDO02225

Background : The National Cancer Institute (USA) alert in February 1999 stated that concomitant chemoradiotherapy should be considered for all patients with cervical cancer, based on evidence from five randomized controlled trials. Objectives : To review all known randomized clinical controlled trials (RCTS) comparing concomitant chemotherapy and radiation therapy with radiotherapy for locally advanced cervical cancer. Search strategy : We searched electronic databases, trials registers and reference lists of published trial reports and review articles were also searched. Selection criteria : This review includes RCTs in cervical cancer comparing concomitant chemoradiation with radiotherapy. In the experimental arm, further adjuvant chemotherapy was allowable. Hydroxyurea was considered inactive and allowable. Trials using radiosensitisers or radioprotectors in the experimental arm were excluded. Data collection and analysis : Two authors reviewed trials for inclusion and extracted data, For meta-analyses of time-to-event outcomes (survival, progression-free survival), a hazard ratio (HR) was extracted or estimated from trial reports, where possible. Only overall rates of local and distant recurrence were presented in many reports so only an odds ratios (OR) of recurrence rates could be calculated, which takes no account of time to recurrence or censoring. The HRs and ORs for individual trials were combined across all trials, using the fixed effect model. Few trials reported acute toxicity adequately. Data were therefore grouped and the number of toxic events was used to calculate a single OR for each site and grade. Late toxicity was rarely described so could only be reviewed qualitatively. Main results : Nineteen trials (17 published, two unpublished) were identified including 4580 patients, although due to patient exclusion and differential reporting 62 -to 78% were available for the analyses. The review strongly suggests chemoradiation improves overall survival and progression free survival, whether or not platinum was used with absolute benefits of 12% and 16% respectively. There was, however, statistical heterogeneity for these outcomes There was some evidence that the effect was greater in trials including a high proportion of stage I and II patients. Chemoradiation also showed significant benefit for both local and distant recurrence. Haematological and gastrointestinal toxicity was significantly greater in the concomitant chemoradiation group. Details of late morbidity were sparse. Reviewers Conclusions: Concomitant chemoradiation appears to improve overall survival and progression-free survival in locally advanced cervical cancer. It also reduces local and distant recurrence suggesting Concomitant chemotherapy may afford cytotoxic and sensitisation effects. Some acute toxicity is increased, but data on long-term side effects were sparse.

13. Survival and recurrence after concomitant chemotherapy and radiotherapy for cancer of the uterine cervix: a systematic review and meta-analysis.
Green JA, Kirwan JM, Tierney JF et al.
Lancet 2001; 358 : 781-6

BACKGROUND : The US National Cancer Institute alert in February, 1999, stated that concomitant chemotherapy and radiotherapy should be considered for all patients with cervical cancer. Our aim was to review the effects of chemoradiotherapy on overall and progression-free survival, local and distant control, and acute and late toxicity in patients with cervical cancer. METHODS : With the methodology of the Cochrane Collaboration, we did a systematic review of all known randomised controlled trials done between 1981 and 2000 (17 published, two unpublished) of chemoradiation for cervical cancer. FINDINGS: The trials included 4580 randomised patients, and 2865-3611 patients (62-78%) were available for analysis. Cisplatin was the most common agent used. The findings suggest that chemoradiation improves overall survival (hazard ratio 0.71, p<0.0001), whether platinum was used (0.70, p<0.0001) or not (0.81, p=0.20). A greater beneficial effect was seen in trials that included a high proportion of stage I and 11 patients (p=0.009). An improvement in progression-free survival was also seen with chemoradiation (0.61, p<0.0001). Thus, the absolute benefit in progression-free and overall survival was 16% (95% Cl 13-19) and 12% (8-16), respectively. A significant benefit of chemoradiation on both local (odds ratio 0.61, p<0.0001) and distant recurrence (0.57, p<0.0001) was also recorded. Grade 3 or 4 haematological (odds ratio 1.49-8.60) and gastrointestinal (2.22) toxicities were significantly greater in the concomitant chemoradiation group than the control group. There was insufficient data to establish whether late toxicity was increased in the concomitant chemoradiation group. INTERPRETATION: Concomitant chemotherapy and radiotherapy improves overall and progression-free survival and reduces local and distant recurrence in selected patients with cervical cancer, which may give a cytotoxic and sensitisation effect.

14. Randomized comparison of fluorouracil plus cisplatin versus hydroxyurea as an adjunct to radiation therapy in stage llB-IVA carcinoma of the cervix with negative para-aortic lymph nodes : a Gynecologic Oncology Group and Southwest Oncology Group study.
Whitney CW, Sause W, Bundy BN et al.
J Clin Oncol 1999; 17: 1339-48

PURPOSE : In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS : All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS: Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P=.033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P=.018). CONCLUSION: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

15. Pelvic radiation with concurrent chemotherapy compared with pelvic and para-aortic radiation for high-risk cervical cancer.
Morris M, Eifel PJ, Lu J et al.
N Engl J Med 1999; 340: 1137-43

BACKGROUND AND METHODS : We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or Ila with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. RESULTS : Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. CONCLUSIONS : The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.

16. Concurrent cisplatin-based radiotherapy and chemotherapy for locally advanced cervical cancer.
Rose PG, Bundy BN, Ha Watkins EB et al.
N Engl J Med 1999; 340: 1144-53

BACKGROUND AND METHODS: On behalf of the Gynecologic Oncology Group, we performed a randomized trial of radiotherapy in combination with three concurrent chemotherapy regimens - cisplatin alone; cisplatin, fluorouracil, and hydroxyurea; and hydroxyurea alone - in patients with locally advanced cervical cancer. Women with primary untreated invasive squamous-cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix of stage IIB, III, or IVA, without involvement of the para-aortic lymph nodes, were enrolled. The patients had to have a leukocyte count of at least 3000 per cubic millimeter, a platelet count of at least 100,000 per cubic millimeter, a serum creatinine level no higher than 2 mg per deciliter (177 micromol per liter), and adequate hepatic function. All patients received external-beam radiotherapy according to a strict protocol. Patients were randomly assigned to receive one of three chemotherapy regimens: 40 mg of cisplatin per square meter of body-surface area per week for six weeks (group 1); 50 mg of cisplatin per square meter on days 1 and 29, followed by 4 g of fluorouracil per square meter given as a 96-hour infusion on days 1 and 29, and 2 g of oral hydroxyurea per square meter twice weekly for six weeks (group 2); or 3 g of oral hydroxyurea per square meter twice weekly for six weeks (group 3). RESULTS : The analysis included 526 women. The median duration of follow-up was 35 months. Both groups that received cisplatin had a higher rate of progression-free survival than the group that received hydroxyurea alone (P<0.001 for both comparisons). The relative risks of progression of disease or death were 0.57 (95 percent confidence interval, 0.42 to 0.78) in group 1 and 0.55 (95 percent confidence interval, 0.40 to 0.75) in group 2, as compared with group 3. The overall survival rate was significantly higher in groups 1 and 2 than in group 3, with relative risks of death of 0.61 (95 percent confidence interval, 0.44 to 0.85) and 0.58 (95 percent confidence interval, 0.41 to 0.81), respectively. CONCLUSIONS: Regimens of radiotherapy and chemotherapy that contain cisplatin improve the rates of survival and progression-free survival among women with locally advanced cervical cancer.

17. Cisplatin, radiation, and adjuvant hysterectomy compared with radiation and adjuvant hysterectomy for bulky stage IB cervical carcinoma.
Keys HM, Bundy BN, Stehman FB et al.
N Engl J Med 1999; 340: 1154-61

BACKGROUND : Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer. METHODS : Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement, The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later. RESULTS: The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent). CONCLUSIONS: Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.

18. Concurrent cisplatin-based chemotherapy plus radiotherapy for cervical cancer--a meta-analysis.
Lukka H, Hirte H, Fyles A, Thomas G, Elit L, Johnston M, Fung MF, Browman G;
Clin Oncol (R Coll Radiol). 2002 Jun;14 (3):203-12.

PURPOSE: To evaluate the role of concurrent cisplatin plus radiotherapy in the treatment of cervical cancer. METHODS: A systematic review of randomized trials of cisplatin administered concurrently with external beam radiotherapy versus radiotherapy without cisplatin for cervical cancer was combined with a meta-analysis of results abstracted from published reports of the trials. RESULTS: Pooled survival rates from eight randomized trials that evaluated the role of cisplatin, alone or in combination with other chemotherapy agents, administered concurrently with external beam radiotherapy to patients with cervical cancer demonstrated a statistically significant effect in favour of cisplatin-based chemotherapy plus radiotherapy compared with radiotherapy without cisplatin (relative risk [RR] of death, 0.74; 95% confidence interval [CI], 0.64 to 0.86). The pooled RR of death among the six trials that enrolled only women with locally advanced cervical cancer was 0.78 (95% CI, 0.67 to 0.90). The pooled relative risk for the two trials in high-risk early-stage disease also demonstrated a statistically significant benefit for the addition of cisplatin-based chemotherapy to radiotherapy (RR=0.56; 95% CI, 0.41 to 0.77). CONCLUSION: This meta-analysis confirms that treatment with concurrent cisplatin-based chemotherapy plus radiotherapy improves overall survival over various controls in women with locally advanced cervical cancer, large stage IB tumours (prior to surgery) and high-risk early-stage disease (following surgery). The variation in control treatments and the quality of their delivery among the randomized trials makes interpretation difficult. Nonetheless, the meta-analysis supports the use of concurrent cisplatin with radical radiotherapy in the treatment of cervical cancer.

19. Improved treatment for cervical cancer-concurrent chemotherapy and radiotherapy.
Thomas GM.
N Engl J Med 1999;340:1198-200. [Editorial]

Despite screening programs, approximately 14,000 cases of invasive cervical cancer are diagnosed annually in the United States. In approximately half these cases, locally advanced disease is present at the time of diagnosis. In developing countries, the disease is usually advanced by the time of diagnosis, the prevalence is much higher, and cervical cancer is the principal cause of death due to cancer in women. Pelvic radiation has been the standard, definitive therapy for advanced disease. With this treatment, the overall five-year survival rate is approximately 65 percent, but it ranges from 15 to 80 percent, depending on the extent of the disease. The main cause of death among women with cervical cancer is uncontrolled disease within the pelvis. Although increasing the dose of radiation improves the control of pelvic disease, the dose that can be delivered is limited by the severe late complications of the treatment.
There have been no substantial improvements in the treatment of cervical cancer since the advent of megavoltage irradiation in the 1950s. Many attempts have been made to improve the outcome of radiotherapy, but none of these have been successful. As a result, strategies involving combination therapy, especially the concurrent use of chemotherapy with radiotherapy, have been considered. The administration of chemotherapy concurrently with radiotherapy has theoretical advantages over the use of radiotherapy alone. The two treatments may interact to increase the killing of tumor cells without delaying the course of radiotherapy or protracting the overall treatment time, which may accelerate the proliferation of tumor cells. Theoretically, chemotherapy may act synergistically with radiotherapy by inhibiting the repair of radiation-induced damage, promoting the synchronization of cells into a radiation-sensitive phase of the cell cycle, initiating proliferation in nonproliferating cells, and reducing the fraction of hypoxic cells that are resistant to radiation. Chemotherapy may also independently increase the rate of death of tumor cells. Nevertheless, since the doses of chemotherapeutic drugs that are administered concurrently with radiation are less than the usual amounts used for solid tumors, it is not likely that such treatment will affect any distant metastases that may be present.
Since the 1980s, many phase 1–2 studies have established that treatment with cisplatin, fluorouracil, and mitomycin can safely be combined with pelvic irradiation. Since the rate of complete response expected with the use of radiotherapy alone is high, whether there is any incremental benefit from the added chemotherapy could not be assessed in phase 2 studies. Answers to this question have now come from phase 3 trials of this strategy. Three large randomized studies by Keys et al, Rose et al, and Morris et al appear in this issue of the Journal, and a fourth was published elsewhere. The promising results of the three studies in the Journal and the preliminary results of other trials prompted the National Cancer Institute to issue a rare clinical announcement that “strong consideration should be given to the incorporation of concurrent cisplatin-based chemotherapy with radiation therapy in women who require radiation therapy for treatment of cervical cancer”.
Why did the National Cancer Institute make this recommendation? One reason is the well-conducted study by Keys et al for the Gynecologic Oncology Group, which compared radiotherapy alone with a regimen of six weeks of cisplatin and pelvic irradiation given concurrently in 369 patients with node-negative bulky stage IIB cervical cancer. The combined regimen was well tolerated and did not increase the median treatment time, which was 50 days in both groups. The concurrent use of cisplatin and radiation in this particular stage of cervical cancer significantly improved control of pelvic disease and prolonged survival. The second reason is the study by Rose et al of women with more advanced stages of cervical cancer. Rose et al. assessed data on 526 women with stage IIB, III, or IVA cervical cancer who were randomly assigned to receive radiotherapy concomitantly with one of three chemotherapy regimens: weekly cisplatin; two courses of a three-drug combination consisting of hydroxyurea, cisplatin, and fluorouracil; or twice-weekly hydroxyurea. Almost half the patients in this study had disease involving the pelvic wall (stage IIIB) or the bladder (stage IVA).
The progression-free survival rates at 24 months were significantly higher in the two groups that received cisplatin (67 percent and 64 percent) than in the group that received hydroxyurea (47 percent). Because there was less toxicity with cisplatin alone than with the three-drug regimen, the former is probably the preferable regimen to use in combination with radiotherapy. The results of this study send a clear message that it is time to abandon the use of hydroxyurea, which has never been widely accepted as a treatment for cervical cancer.
Keys et al. used a somewhat low dose of radiation, and Rose et al. not only used a relatively low total dose of radiation but also had a protracted treatment time (median, 63 days). Even though neither of the studies included a group that was given radiation alone at a dose and within an interval that are considered optimal, there is no doubt that adding cisplatin-containing chemotherapy to the various regimens of radiotherapy that were used was beneficial. Nevertheless, doubt remains about the magnitude of the benefit that might have accrued by adding chemotherapy to an optimal regimen of radiotherapy.
The third reason for the optimistic bulletin from the National Cancer Institute is the study by Morris et al, which involved 388 women with a spectrum of advanced disease ranging from bulky stage IB through stage IVA. The women were assigned to receive either three cycles of cisplatin and fluorouracil in combination with pelvic radiation or irradiation of the pelvis and para-aortic lymph nodes alone. Morris et al. used a higher dose of radiation and a somewhat shorter overall treatment time than Rose et al. (median, 58 days vs. 63 days). The addition of chemotherapy improved the control of pelvic disease and significantly increased overall survival rates (73 percent, as compared with 58 percent with the use of irradiation alone).
It is unclear whether the results of this study are applicable to all stages of cervical cancer, since only 30 percent of the patients had stage III or IVA disease. The study by Rose et al. offers the only available evidence of the benefit of combined therapy in women with stage III or IVA cervical cancer, and that applies only to a special group of women without involvement of lymph nodes outside the pelvis. Confirmatory data are required, particularly those of the now completed study by the National Cancer Institute of Canada, which compared concurrent treatment with cisplatin and radiation with an optimal dose of radiation, and those of the Gynecologic Oncology Group study of women with advanced disease, which compared cisplatin and fluorouracil with hydroxyurea alone.
The results of these five trials, show similar reductions in the risk of death from cervical cancer and similar absolute improvements in survival. These results are supported by the findings in comparable studies of other solid tumors and squamous-cell cancers of the head and neck.
Currently available data do not allow conclusions to be drawn as to which drugs or regimens are optimal in the treatment of cervical cancer. Until further data become available, it is reasonable to suggest that cisplatin-based chemotherapy - most likely consisting of weekly cisplatin should be given concurrently with radiotherapy. One must also keep in mind that the reported improvements in survival are associated only with concurrent chemotherapy and not with neoadjuvant chemotherapy (chemotherapy given before or after radiotherapy). Eight of nine large published studies of cervical cancer and a meta-analysis of 31 randomized trials of head and neck cancer revealed no significant benefit for the latter strategy.

20. Phase III trial comparing radical radiotherapy with and without cisplatin chemotherapy in patients with advanced squamous cell cancer of the cervix.
Pearcey R, Brundage M, Drouin P et al.
J Clin Oncol 2002; 20: 966-72

PURPOSE : To test the hypothesis that cisplatin (CDDP) administered concurrently with standard radiotherapy (RT) would improve pelvic control and survival in patients with advanced squamous cell cancer of the cervix. PATIENTS AND METHODS : A total of 259 patients with International Federation of Gynecology and Obstetrics stage IB to IVA squamous cell cervical cancer with central disease greater-than-or-equal 5 cm or histologically confirmed pelvic lymph node involvement were randomized to receive RT (external-beam RT plus brachytherapy) plus weekly CDDP chemotherapy - 40 mg/m2 (arm 1) or the same RT without chemotherapy (arm 2). RESULTS : A total of 253 patients were available for analysis. Median follow-up was 82 months. No significant difference was found in progression-free survival (P =.33). No significant difference in 3 and 5 year survival rates was found (69% v 66% and 62% v 58%, respectively; P=42). The hazard ratio for survival (arm 2 to arm 1) was 1.10 (95% confidence interval, 0.75 to 1.62). CONCLUSION : This study did not show a benefit to either pelvic control or survival by adding concurrent weekly CDDP chemotherapy in a dose of 40 mg/m2 to radical RT as given in this trial. Careful attention to RT details is important for achieving optimum outcome for patients with this disease.

21. Extended field irradiation for carcinoma of the uterine cervix with positive periaortic nodes.
Vigliotti AP, Wen BC, Hussey DH et al.
Int J Radiat Oncol Biol Phys 1992; 23 : 501-9

Forty-three patients were treated with extended field irradiation for periaortic metastasis from carcinoma of the uterine cervix (FIGO stages IB-lV). Twelve patients (28%) remained continuously free of disease to the time of analysis or death from intercurrent disease, 20 (46%) had persistent cancer within the pelvis, 11 (26%) had persistent periaortic disease, and 23 (53%) developed distant metastasis. The actuarial 5-year survival rate was 32%. The results correlated well with the periaortic tumor burden at the time of irradiation. None of 19 patients (0%) with microscopic or small (less than 2 cm) periaortic disease had periaortic failures, compared to 29% (4/14) of those with moderate-sized (2-5 cm) disease and 70% (7/10) of those with massive (greater than 5 cm) periaortic metastasis. Similarly, the 5-year survival rates were 50% (6/ 12) with microscopic disease, 33% (2/6) with small gross disease, 23% (3/13) with moderate-sized disease, and 0% (0/10) with massive periaortic metastases. Only 10% (1/10) of patients whose tumor extended to the L 1-2 level survived 5 years, compared with 31% (9/29) of those whose disease extended no higher than the L 3-4 level. The periaortic failure rates correlated to some extent with the dose delivered through extended fields, although the difference was not statistically significant. Only 8% (1/13) of those who had undergone extraperitoneal lymphadenectomies developed small bowel complications, compared with 25% (7/29) of those who had transperitoneal lymphadenectomies. The incidence of small bowel obstruction was 8% (1/13) following periaortic doses of 4000-4500 cGy, 10% (1/10) after 5000 cGy, and 32% (6/19) after approximately 5500 cGy. From this, we concluded that the subset of patients who would benefit most from extended field irradiation are those in whom the residual disease in the periaortic area measures less than 2 cm in size at the time of treatment, whose disease extends no higher than L3, and whose cancer within the pelvis has a reasonable chance of control with standard radiation therapy techniques.

22. Cervical carcinoma metastatic to para-aortic nodes: extended field radiation therapy with concomitant 5-fluorouracil and cisplatin chemotherapy: a Gynecologic Oncology Group study.
Varia MA, Bundy BN, Deppe G, Mannel R, Averette HE, Rose PG, Connelly.P.
Int J Radiat Oncol Biol Phys. 1998 Dec 1; 42 (5):1015-23.

PURPOSE: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma. METHODS AND MATERIALS: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I--14, Stage II--40, Stage III--27, Stage IVA--5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5. RESULTS: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3-4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I--50%, Stage II--39%, and Stage III/IVA--38%. CONCLUSIONS: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.

23. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages lIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20.
Rotman M, Pajak TK, Choi K et al.
JAMA 1995; 274:387-93

OBJECTIVES : To investigate whether irradiation to the standard pelvic field only improves the response rate and survival in comparison with pelvic plus para-aortic irradiation in patients with high-risk cervical carcinoma, and to investigate patterns of failure and treatment-related toxicity. DESIGN: Randomized controlled trial from November 1979 to October 1986, with stratification by histology, para-aortic nodal status, and International Federation of Gynecology and Obstetrics (FIGO) stage. SETTING : Radiation Therapy Oncology Group (RTOG) multicenter clinical trial. PATIENTS : A total of 367 patients with FIGO stage IB or IIA primary cervical cancers measuring 4 cm or greater in lateral diameter or with FIGO stage IIB cervical cancers were randomized to RTOG protocol 7920 to receive either standard pelvic only irradiation or pelvic plus para-aortic irradiation. INTERVENTION : Pelvic only irradiation consisted of a midplane pelvic dose of 40 to 50 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. Pelvic plus para-aortic irradiation delivered 44 to 45 Gy in 4.5 to 6.5 weeks with daily fractions of 1.6 to 1.8 Gy for 5 d/wk. A total dose of 4000 to 5000 mg/h of radium equivalent or 30 to 40 Gy was provided by intracavitary brachytherapy to point A. MAIN OUTCOME MEASURES : Response rate, overall and disease-free survival, patterns of failure, and treatment-related toxicities. RESULTS : Ten-year overall survival was 44% for the pelvic only irradiation arm and 55% for the pelvic plus para-aortic irradiation am (P=.02). Cumulative incidence of death due to cervical cancer was estimated as significantly higher in the pelvic only arm at 10 years (P=.01). Disease-free survival was similar in both arms; 40% for the pelvic only arm and 42% for the pelvic plus para-aortic arm. Locoregional failures were similar at 10 years for both arms (pelvic only, 35%; pelvic plus para-aortic, 31 %; P=.44). In complete responders, the patterns of locoregional failures were the same for both arms, but there was a lower cumulative incidence for first distant failure in the pelvic plus para-aortic irradiation arm (P=.053). Survival following first failure was significantly higher in the pelvic plus para-aortic arm (P=.007). A higher percentage of local failures were salvaged long-term on the pelvic plus para-aortic arm compared with the pelvic only arm (25% vs 8%). The cumulative incidence of grade 4 and 5 toxicities at 10 years in the pelvic plus para-aortic arm was 8%, compared with 4% in the pelvic only arm (P=.06). The death rate due to radiotherapy complications was higher in the pelvic plus para-aortic arm (four [2%] of 170) compared with the pelvic only arm (one [1%] of 167) (P=.38). The proportion of deaths due to radiotherapy complications in the pelvic plus para-aortic arm was higher than in the pelvic only arm (four [6%] of 67 vs one [1 %] of 85; P=.24). If the patient had abdominal surgery prior to para-aortic irradiation, the estimated cumulative incidence of grade 4 and 5 complications was 11 %, compared with 2% in the pelvic only arm. CONCLUSIONS : The statistically significant difference in overall survival at 10 years for the pelvic plus para-aortic irradiation arm, without a difference in disease-free survival, can be explained by the following two factors: (1) a lower incidence of distant failure in complete responders and (2) a better salvage in the complete responders who later failed locally.

24. Accuracy of conventional cytology: Results from a ulticentre screening study in India
Sankaranarayanan R, Somanathan T, Sharma A, Roy C, Shastri S, Mahé C, Muwonge R, Fontanière B, for the multicentre study group on cervical cancer early detection in India
J Med Screen 2004; 11: 77-84.

OBJECTIVE: We conducted a multi-centre cross-sectional study in India to evaluate the accuracy of conventional cytology to detect high-grade squamous intraepithelial lesions (HSIL). SETTING: Cross-sectional studies in Jaipur, Kolkata, Mumbai and Trivandrum, India, during 1999-2003. METHODS: A common protocol and questionnaire were used to test 22,663 women aged 25-65 years with conventional cytology in five cross-sectional studies. Three thresholds were used to define test positivity: atypical squamous cells of uncertain significance (ASCUS), low-grade squamous intra-epithelial lesion (LSIL), or HSIL. All screened women were investigated with colposcopy, and biopsies were taken when necessary. The reference standard for final disease status was histology or negative colposcopy. Data from the studies were pooled to evaluate the test characteristics for the detection of histologically confirmed HSIL. RESULTS: The test positivity rates of cytology were 8.8% at ASCUS, 6.2% at LSIL and 1.8% at HSIL thresholds, and 355 women had histologically confirmed HSIL while 74 had invasive cancer. The pooled sensitivity, specificity, positive and negative predictive values at ASCUS threshold were 64.5%, 92.3%, 11.8% and 99.4% respectively. The corresponding values at LSIL threshold were 58.0%, 94.9%, 15.2% and 99.3%, while at the HSIL threshold they were 45.4%, 99.2%, 46.3% and 99.1%. The sensitivity varied between 37.8-81.3% at ASCUS, 28.9-76.9% at LSIL and 24.4-72.3% at HSIL thresholds. A significantly low sensitivity was observed in women aged 25-39 years (p<0.001). The wide variation in sensitivity across study sites persisted even after age standardisation. CONCLUSION: The sensitivity of cytology varied widely between the study sites. Findings from our study and other reviews indicate that sustained efforts in improving sampling, preparation and reading of cytological specimens and improvements in clinical judgement are essential to achieve concurrently high sensitivity and specificity.

25. Initial results from a randomised trial of cervical visual screening in rural South India
Sankaranarayanan R, Rajkumar R, Theresa R, Esmy P.O, Mahe C, Bagyalakshmi KR, Thara S, Frappart L, Lucas E, Muwonge R, Shanthakumari S, Jeevan D, Subbarao TM, Parkin DM, Cherian J.
Int J Cancer 2004; 109:461-467.

The impact of a single round of screening of visual inspection with acetic acid (VIA) on cervical cancer incidence and mortality was investigated in a cluster randomized trial in south India. Women 30-59 years of age in 113 clusters in Dindigul District were randomized to VIA screening (57 clusters, 48,225 women) by nurses and to a control group (56 clusters, 30,167 women). 30,577 eligible women were screened between May 2000 and April 2003; 2,939 (9.6%) screen-positive women were investigated with colposcopy by nurses and 2,777 (9.1%) women had biopsy. CIN 1 was diagnosed in 1,778 women, CIN 2-3 lesions were found in 222, and there were 69 screen detected invasive cervical cancers. The detection rates of lesions per 1,000 screened women were 58.2 for CIN 1, 7.3 for CIN 2-3, and 2.3 for invasive cancer. The detection rate of high-grade lesions in our study was 2-3-fold higher than those observed in repeatedly screened populations in developed countries. 71% of women with CIN 1 and 80% of those with CIN 2-3 lesions accepted cryotherapy provided by nurses and surgical treatment by mid-level clinicians. Overall, 97 and 34 incident cervical cancer cases were observed in the intervention and control arms, respectively. The intervention arm accrued 124,144 person years and the control arm accrued 90,172 during the study period. The age standardized cervical cancer incidence rates were 92.4/100,000 person-years in the intervention and 43.1/100,000 in the control arms. In the screened arm, 35.0% of cases were in Stage I as opposed to none in the control arm. The preliminary findings from our study indicate that not only is a VIA-based screening programme feasible, safe and acceptable to a population in rural settings, it also results in early detection of cervical neoplasia