|
|
A.
Osteosarcoma
Osteosarcoma selected abstracts
B. Ewing’s Sarcoma
Ewing’s Sarcoma selected
abstracts
C. Soft Tissue Sarcoma
Soft Tissue Sarcoma selected
abstracts |
EVIDENCE
BASED MANAGEMENT FOR
osteosarcoma
|
|
A
– Documentation of exact extent of primary tumor
Clinical examination, X-ray, MRI (MRI has become the premier
imaging modality for the evaluation of musculoskeletal tumors
because of its excellent soft tissue contrast, its sensitivity
to bone marrow and soft tissue edema, and its multiple imaging
planes).
B – Pathological confirmation of diagnosis by biopsy
A needle biopsy can often confirm the diagnosis. If tissue
is inadequate or diagnosis uncertain an open biopsy is indicated.
The closed needle biopsy technique has proven to be an extremely
effective means of procuring representative tissue, is associated
with low morbidity, and avoids many of the potential complications
of biopsy. If limb-sparing surgery is contemplated, the biopsy
should be performed by the surgeon who will do the definitive
operation, since incision placement is crucial.
C- Classification , Staging and biochemical investigations
CT chest, Bone scan, S. Alkaline phosphatase, S. LDH
The World Health Organization’s histologic classification
of bone tumors separates the osteosarcomas into central (medullary)
and surface (peripheral) tumors and recognizes a number of
subtypes within each group.
Central
(Medullary)
-
Conventional central osteosarcoma.
- Telangiectatic
osteosarcoma.
- Intraosseous well-differentiated (low-grade) osteosarcoma.
- Small cell osteosarcoma.
Surface (Peripheral)
- Parosteal (juxtacortical) well-differentiated (low-grade)
osteosarcoma.
- Periosteal osteosarcoma: low-grade to intermediate-grade
osteosarcoma.
- High-grade surface osteosarcoma
|
UICC/
AJCC TNM staging system
T- Primary tumor
TX
-Primary tumor cannot be assessed
T0
- No evidence of primary tumor
T1
- Tumor 8 cm or less in greatest dimension
T2
- Tumor more than 8 cm in greatest dimension
T3
- Discontinuous tumors in the primary bone site
N- Regional Lymph Nodes
NX
- Regional lymph nodes cannot be assessed
N0
- No regional lymph node metastasis
N1
- Regional lymph node metastasis
M - Distant metastasis
MX
– Distant metastasis cannot be assessed
M0
- No distant metastasis
M1
- Distant metastasis
M1a
- Lung
M1b
- Other distant metastasis |
Stage
grouping
| StageIA |
T1 |
No |
Mo |
G1,
2 |
Low
grade |
| StageIB |
T2 |
No |
Mo |
G1,
2 |
Low
grade |
| StageIIA |
T1 |
No |
Mo |
G3,
4 |
High
grade |
| StageIIB |
T2 |
No |
Mo |
G3,
4 |
High
grade |
| StageIII |
T3 |
No |
Mo |
Any
G |
|
| StageIVA |
Any
T |
No |
Any
M |
Any
G |
|
| StageIVB |
Any
T |
N1 |
Any
M |
Any
G |
|
| |
Any
T |
Any
N |
M1b |
Any
G |
|
|
The
common staging system followed is the simple Musulo Skeletal
Tumor Society staging system as devised by Enneking
| Stage |
Grade |
Site |
| IA |
Low
(G1) |
Intracompartmental
(T1) |
| IB |
Low
(G1) |
Extracompartmental
(T2) |
| IIA |
High
(G2) |
Intracompartmental
(T1) |
| IIB |
High
(G2) |
Extracompartmental
(T2) |
| III |
Any
(G) |
Any
(T) |
| |
Regional
or distant metastasis |
|
|
D
– Chemotherapy
Chemotherapy constitutes a fundamental initial approach to
the management of osteosarcoma and, if effective, an important
prognostic determinant. (Level II, Grade A)
Neoadjuvant chemotherapy in OGS is the norm and seems to offer
following advantages:
-
enhancement of limb sparing surgery
- provision of a window time during which customized endoprosthetic
devices could be made
- delivery of early systemic treatment against micro-metastasis
- tailoring of the postoperative chemotherapy based on the
primary tumor response.
With the possible exception of the first two, these advantages
are no longer true. There is no significant difference in
disease free survival with neoadjuvant chemotherapy in comparison
with standard adjuvant chemotherapy. (Level II,Grade A)
Chemotherapy is multiagent and drugs used include : Adriamycin
(as a continuous infusion), Ifosfamide, Etoposide, Cisplatinum
and Methotrexate, Non methotrexate based regimes offer similar
survivals to methotrexate based regimes in operable, non-metastatic
osteosarcoma. (level II,
Grade B)
The strategy of salvaging poor responders with alternative
agents has not been proven to be beneficial. (Level III, Grade
B)
Chemotherapy for certain histologic subtypes
Round cell osteosarcoma
Round cell osteosarcoma is a definite reproducible histologic
entity. Treatment should be based on a protocol for osteosarcoma.
It seems reasonable to treat tumors with spindling small cells
on a protocol for OGS. When matrix production is definite,
these tumors should also be treated on a protocol for OGS.
If the tumor cells are small, round and uniform and matrix
production is questionable, it probably is best to treat it
as Ewing’s sarcoma.
|
Parosteal
osteosarcoma :
Wide surgical excision alone is adequate treatment for patients
with conventional parosteal osteosarcoma. Recognition of dedifferentiated
areas on histopathology should prompt the addition of chemotherapy
to optimize patient outcome.
Periosteal osteosarcoma :
Periosteal osteosarcoma is a low-grade to intermediate-grade
osteosarcoma and receives the same chemotherapy as conventional
osteosarcoma.
MFH of bone :
Neoadjuvant chemotherapy is as effective in high-grade MFH of
bone as in high-grade OGS. In terms of histologic response to
primary chemotherapy, MFH has a lower chemosensitivity than
osteosarcoma. Nevertheless, the two tumors have similar prognoses
when treated with similar chemotherapy regimens. MFH of bone
also shows a significant correlation between histologic response
to chemotherapy and prognosis.
E – Local control
There is no difference in overall survival between patients
treated by amputation and those treated with a limb-sparing
procedure.
(Level III, Grade A)
The type of surgery required for complete ablation of the primary
tumor depends on a number of factors that must be evaluated
on an individual basis. Limb-sparing procedures should be planned
only when the preoperative staging indicates that it is possible
to achieve wide surgical margins. A pathologic fracture noted
at diagnosis or during preoperative chemotherapy does not preclude
limb salvage surgery if wide surgical margins can be achieved.
(Level III, Grade A)
Factors that directly influence the development of a local recurrence
are the quality of the surgical margins and local response to
preoperative chemotherapy. If the pathologic examination of
the surgical specimen shows inadequate margins, especially if
the histologic response to preoperative chemotherapy is poor.
an immediate amputation should be considered. (Level III, Grade
C). |
In
patients who refuse surgery or present with unresectable disease
radiotherapy after effective induction chemotherapy may help
in improve local control. (Level IV, Grade B).
F – Histopathology report and its importance
The specimen is evaluated for margins of surgical resection.
Response to chemotherapy is noted based on percentage necrosis
of tumor cells. For patients who receive chemotherapy prior
to surgery, the degree of tumor necrosis observed postoperatively
is highly predictive of disease-free survival, local recurrence,
and overall survival. Patients showing 90% and greater necrosis
in the resected tumor specimen have a better outcome than patients
with a poorer histologic response. (Level III, Grade A)
Histopathology grading :
Grade I – upto 50% necrosis
Grade II – 50 - 89 % necrosis
Grade III – 90 - 99% necrosis
Grade IV – 100% necrosis (no viable tumor)
An ideal pathology report should include
- Type of specimen received with entire gross description
- A numerical list of the various sections submitted for histological
examination
- Histological diagnosis with grade of tumor where applicable
- The exact anatomical location of the soft tissue or bone tumor
- The extent of the tumor with respect to the various cut margins
and also with respect to skin and bone including involvement
of cortex, periosteum, muscle, subcutaneous fat, joint capsule
and articular cartilage
- Evidence of angiolymphatic invasion, perineural invasion,
lymph node invasion
- Status of cut margins of bone, skin, soft tissue, neurovascular
cut margins
- Comments on response to chemotherapy with percentage of necrosis
|
G
– Follow up schedule
Patient is followed up at 3 monthly interval for the first 2
years, 6 monthly intervals for next 3 years and annually thereafter.
At every follow up, S. Alkaline phosphatase, X ray of the local
part & chest radiograph is done. A CT scan of the chest
and a bone scan is done at 6 monthly intervals for the first
2 years and annually for the next 3 years.
(Currently there is inadequate evidence to suggest that intensive
follow up with early detection of recurrent disease would significantly
impact on survival).
H- Metastatic / Recurrent disease
Preoperative chemotherapy followed by surgical ablation of the
primary tumor and resection of metastatic disease. (Level III,
Grade A)
This is followed by postoperative combination chemotherapy.
All patients should receive intensive multiagent chemotherapy
whether or not the primary and metastatic lesions are surgically
resectable. Even if an adequate response has been achieved through
chemotherapy, resection of any pulmonary nodule is indicated,
even if the nodule has shrunk dramatically.
Patients with a longer relapse-free interval have a significantly
better post-relapse survival than those with a shorter relapse-free
interval. The surgically-treated patients have a better post-relapse
survival probability. The ability to achieve a complete resection
of recurrent disease is the most important prognostic factor
at first relapse. The prognosis is poor for patients who develop
bone metastases. The postrelapse outcome of patients who have
a local recurrence is worse than that for patients who relapse
with metastases alone. |
OSTEOSARCOMA
-
Investigations
|
Prognostic
significance of serum alkaline phosphatase in osteosarcoma of
the extremity treated with neoadjuvant chemotherapy : recent
experience at Rizzoli Institute.
Bacci G, Longhi A, Ferrari S et al.
Oncol Rep. 2002, Jan.-Feb.; 9(1):171-5.
Abstract : In 560 patients with high-gra de osteosarcoma of
the extremity treated with 5 different protocols of neoadjuvant
chemotherapy at a single institution between 1983 and 1995,
the pre-treatment serum alkaline phosphatase (SAP) was examined
to evaluate whether the enzyme levels had a clinical value in
predicting the course of the disease. SAP was normal in 302
(54%) patients and high in 258 (46%). High levels of SAP was
observed significantly and independently more frequently in
male patients over 14-years-old, and in tumours larger than
150 ml and of osteoblastic subtypes. The 5-year event-free survival
(EFS) and overall survival (OS) for all patients were respectively
60 and 68%. With multivariate analysis only two factors were
independently correlated with the 5-year EFS: SAP levels (p=0.002)
and the grade of chemotherapy-induced necrosis (p=0.0001). The
authors conclude that in planning randomized clinical trials
of neoadjuvant treatment for osteosarcoma, patients should be
stratified according to SAP levels, and that when tailoring
the aggressiveness of postoperative chemotherapy to the risk
of relapse, in addition to the histologic response to preoperative
treatment, the SAP levels should also be considered. |
EFFICACY
OF MRI AS A DIAGNOSTIC AND STAGING MODALITY
Radiographic imaging of musculoskeletal neoplasia.
Sanders TG, Parsons TW 3rd.,
Cancer Control. 2001 May-Jun.; 8(3): 221-31
BACKGROUND : Imaging is an integral part of the diagnosis, staging
and evaluation of outcomes for bone and soft-tissue neoplasms.
Each of the available imaging tools has a different role. METHODS
: The authors reviewed the efficacy of the current imaging modalities
in the diagnosis, staging, and follow-up of patients with musculoskeletal
neoplasia. RESULTS : Plain-film radiography remains the gold
standard in the differential diagnosis of bone lesions. Bone
scintigraphy is an excellent screening modality, and computed
tomography is especially useful in evaluating lesions of the
axial skeleton. The superior soft-tissue resolution and multiplanar
capabilities achieved with magnetic resonance imaging, however,
has replaced the need for CT scans in many cases. CONCLUSIONS
: The technological advances seen in recent years in all areas
of imaging have improved the capabilities of these modalities
to assist in the diagnosis, definition of tumor extent, and
accurate staging of musculoskeletal tumors.
|
|
OSTEOSARCOMA
-
Chemotherapy
|
ADJUVANT
vs NEOADJUVANT CHEMOTHERAPY
Presurgical chemotherapy compared with immediate surgery and
adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric
Oncology Group Study POG-8651.
Goorin AM, Schwartzentruber DJ, Devidas M et al.
Pediatric Oncology Group. J Clin Oncol. 2003 Apr. 15;21 (8):1574-80
PURPOSE : Successful therapeutic interventions to prevent disease
progression in patients with nonmetastatic osteosarcoma have
included surgery with adjuvant chemotherapy. Presurgical chemotherapy
has been advocated for these patients because of putative improvement
in event-free survival (EFS). The advantages of presurgical
chemotherapy include early administration of systemic chemotherapy,
shrinkage of primary tumor, and pathologic identification of
risk groups. The theoretic disadvantage is that it exposes a
large tumor burden to marginally effective chemotherapy. The
contribution of chemotherapy and surgery timing has not been
tested rigorously. PATIENTS AND METHODS : Between 1986 and 1993,
we conducted a prospective trial in patients with nonmetastatic
osteosarcoma who were assigned randomly to immediate surgery
or presurgical chemotherapy. Except for the timing of surgery
(week 0 or 10), patients received 44 weeks of identical combination
chemotherapy that included high-dose methotrexate with leucovorin
rescue, doxorubicin, cisplatin, bleomycin, cyclophosphamide,
and dactinomycin. RESULTS : One hundred six patients were enrolled
onto this study. Six were excluded from analysis. Of the remaining
100 patients, 45 were randomly assigned to immediate chemotherapy,
and 55 were randomly assigned to immediate surgery. Sixty-seven
patients remain disease-free. At 5 years, the projected EFS
+/- SE is 65% +/- 6% (69% +/- 8% for immediate surgery and 61%
+/- 8% for presurgical chemotherapy; P =.8). The treatment arms
had similar incidence of limb salvage (55% for immediate surgery
and 50% for presurgical chemotherapy). CONCLUSION : Chemotherapy
was effective in both treatment groups. There was no advantage
in EFS for patients given presurgical chemotherapy.
|
IS
NON METHOTREXATE BASED THERAPY EFFECTIVE ?
Randomised trial of two regimens of chemotherapy in operable
osteosarcoma : a study of the European Osteosarcoma Intergroup.
Souhami RL, Craft AW, Van der Eijken JW et al.
Lancet. 1997 Sep. 27;350(9082):900-1.
BACKGROUND : A previous trial by the European Osteosarcoma Intergroup
(EOI) suggested that a short intensive chemotherapy regimen
with doxorubicin and cisplatin might produce survival of operable,
non-metastatic osteosarcoma similar to that obtained with complex
and longer-duration drug regimens based on the widely used T10
multi-drug protocol. We undertook a randomised multicentre trial
to compare these two approaches. METHODS : 407 patients with
operable, non-metastatic osteosarcoma were randomly assigned
the two-drug regimen (six cycles [18 weeks] of doxorubicin 25
mg/m2 on days 1-3 and cisplatin 100 mg/m2 on day 1) or a multi-drug
regimen (preoperatively vincristine, high-dose methotrexate,
and doxorubicin; postoperatively bleomycin, cyclophosphamide,
dactinomycin, vincristine, methotrexate, doxorubicin, and cisplatin;
this protocol took 44 weeks). Surgery was scheduled for week
9 for the two-drug group and week 7 for the multi-drug group.
Analyses of survival and progression-free survival were by intention
to treat. FINDINGS : Of 407 randomised patients, 391 were eligible
and have been followed up for at least 4 years (median 5-6 years).
Toxic effects were qualitatively similar with the two regimens.
However, 188 (94%) of 199 patients completed the six cycles
of two-drug treatment, whereas only 97 (51%) of 192 completed
18 or more of the 20 cycles of the multi-drug regimen. The proportion
showing a good histopathological response (> 90% tumour necrosis)
to preoperative chemotherapy was about 29% with both regimens
and was strongly predictive of survival. Overall survival was
65% at 3 years and 55% at 5 years in both groups (hazard ratio
0.94 [95% CI 0.69-1.27]). Progression-free survival at 5 years
was 44% in both groups (hazard ratio 1.01 [0.77-1.33]). INTERPRETATION
: We found no difference in survival between the two-drug
and multi-drug regimens in operable, non-metastatic osteosarcoma.
The two-drug regimen is shorter in duration and better tolerated,
and is therefore the preferred treatment. However, 5-year survival
is still unsatisfactory and new approaches to treatment, such
as dose intensification, are needed to improve results. |
DO
YOU NEED TO CHANGE CHEMOTHERAPY BASED ON PRE OPERATIVE RESPONSE
?
Chemotherapy for nonmetastatic osteogenic sarcoma: the Memorial
Sloan-Kettering experience.
Meyers PA, Heller G, Healey J, et al.
Journal of Clinical Oncology 10(1): 5-15, 1992.
Purpose : Adjuvant chemotherapy improves disease-free survival
(DFS) for patients with osteogenic sarcoma (OS). We reviewed
our experience with OS to determine prognostic factors, the
role of preoperative chemotherapy and subsequent histologic
response, and the role of salvage chemotherapy after poor initial
response. Methods : From 1975 to 1984, we saw 279 patients with
previously untreated OS without metastasis. All patients received
intensive chemotherapy and underwent surgical resection of primary
tumor. Chemotherapy included high-dose methotrexate; Adriamycin
(doxorubicin; Adria Laboratories, Columbus, OH); and bleomycin,
cyclophosphamide, and dactinomycin (BCD). Selected patients
also received cisplatin. Results : DFS was not affected by use
of preoperative chemotherapy versus immediate surgery, by use
of limb-sparing surgery versus amputation, age, sex, or dose
intensity of chemotherapy. DFS did correlate with serum lactate
dehydrogenase (LDH), alkaline phosphatase, primary tumor site,
race, and histologic response to preoperative chemotherapy.
There was no difference in DFS for patients with a poor histologic
response who did or did not receive cisplatin, although patients
who did receive cisplatin had a longer time to relapse. The
5-year DFS was 76% for patients aged less than or equal to 21
years who had extremity primary tumor and were treated with
the T10 protocol. Conclusions : Intensive chemotherapy can achieve
DFS for a high proportion of patients with OS. Although it is
a powerful predictor of DFS, histologic response to preoperative
chemotherapy cannot be assessed at diagnosis. We have not
shown an ability to salvage patients with an unfavorable response.
We need to increase the proportion of patients with a favorable
response, identify the patients who will have an unfavorable
response, and develop novel treatments to salvage poor responders. |
Primary
chemotherapy and delayed surgery (neoadjuvant chemotherapy)
for osteosarcoma of the extremities. The Istituto Rizzoli Experience
in 127 patients treated preoperatively with intravenous methotrexate
(high versus moderate doses) and intraarterial cisplatin.
Bacci G, Picci P, Ruggieri P et al.
Cancer. 1990 Jun. 1;65(11):2539-53.
Abstract : Between March 1983 and June 1986 127 patients with
localized osteosarcoma of the extremity were treated with neoadjuvant
chemotherapy. Preoperative chemotherapy consisted of two cycles
of methotrexate (MTX) (high or moderate doses) followed by 6
days by cisplatin (CDP). Surgery was an amputation or a rotation
plasty, or a limb salvage. Necrosis was good in 52% of cases,
fair in 36%, and poor in 12%. Postoperative chemotherapy consisted
of Adriamycin (doxorubicin [ADM]) and bleomycin (BCD) for poor
responders; and ADM, MTX, and CDP for fair responders. Good
responders were treated as fair responders or with only MTX
and CDP. At a 47-month follow-up, 66 patients remained continuously
disease free and 61 patients developed metastases. Six of these
patients had also a local recurrence. According to the grade
of necrosis, the cumulative disease-free probability at 5 years
was 67% for good responders, 42% for fair responders, and for
poor responders 10% at 45 months. According to the doses of
MTX, survival at 5 years was 58% for patients who received high
doses and 42% for patients treated with moderate doses. No differences
in the rate of survivors were observed between amputated patients
and patients treated with limb salvage. The authors conclude
that (1) a limb salvage procedure is possible in about 70% of
cases and as safe as demolitive surgery, if adequate surgical
margins are achieved; (2) good responders have a better prognosis
than fair and poor responders if postoperative chemotherapy
is sufficiently prolonged and also includes ADM; (3) a different
postoperative chemotherapy for poor responders did not improve
their prognosis; and (4) a multidrug regimen using high
doses of MTX is probably more effective than moderate doses. |
DOES
DOSE INTENSIFICATION BEYOND STANDARD DOSES AFFECT SURVIVAL ?
Intensification of preoperative chemotherapy for osteogenic
sarcoma: results of the Memorial Sloan-Kettering (T12) protocol.
Meyers PA, Gorlick R, Heller G et al.
J Clin Oncol. 1998 Jul;16(7):2452-8.
PURPOSE : It has been observed previously in osteosarcoma (OS)
that the degree of necrosis of the resected primary tumor following
a period of preoperative chemotherapy is predictive of subsequent
event-free survival (EFS). The aim of this study was to determine
if more intensive preoperative chemotherapy would increase the
proportion of patients with a good histologic response and improve
EFS. PATIENTS AND METHODS : Seventy-three patients with OS were
treated at Memorial-Sloan Kettering Cancer Center (MSKCC) on
the T12 protocol between 1986 and 1993. Patients were randomized
between therapy based on the T10 protocol and therapy with more
intensive preoperative chemotherapy. The more intensive preoperative
regimen consisted of two courses of cisplatin (CDDP) and doxorubicin
(DOX) in addition to the usual preoperative regimen of high-dose
methotrexate (HD MTX) and bleomycin, cyclophosphamide, and dactinomycin
(BCD). RESULTS : The regimen with more intensive preoperative
chemotherapy achieved a modest increase in the proportion of
patients with a good histologic response (44% with a grade III
or IV histologic response v 37% in the control arm, 33% with
grade IV histologic response v 13% in the control arm). EFS
continued to correlate with histologic response. The actuarial
5-year EFS in patients with localized disease was 78% for the
regimen with more intensive preoperative chemotherapy and 73%
for the control arm. CONCLUSION : Despite modest increases
in the proportion of patients with good histologic response
with intensified preoperative chemotherapy, no improvement in
EFS was observed. |
SMALL
CELL OSTEOSARCOMA OF BONE - WHAT CHEMOTHERAPY?
Small cell osteosarcoma of bone. Review of 72 cases.
Nakajima H, Sim FH, Bond JR et al.
Cancer 1997 Jun. 1;79(11):2095-106.
BACKGROUND : Small cell osteosarcoma of bone is a rare form
of osteosarcoma, with an incidence rate of 1.3%. This tumor
must be differentiated from other small cell malignancies because
of treatment considerations, particularly patient response to
chemotherapy. METHODS: Clinicopathologic findings in 72 cases
(22 from Mayo Clinic files and 50 from consultation files) of
small cell osteosarcoma of bone were studied. RESULTS: The femur
was the most common bone involved, although the tumor was found
in all portions of the skeleton. Radiographic features (available
in 35 cases) suggested a diagnosis of osteosarcoma in 20 cases,
Ewing’s sarcoma or lymphoma in 14 cases, and giant cell
tumor in 1 case. Histologically, there were four types according
to the predominant cell size and cytologic features. Osteoid
production was identified in all tumors. Complete treatment
and follow-up data were available for 45 cases. Generally, in
those cases without surgical treatment, greater than 60% of
patients died of disease within 2 years. If the surgical procedure
was associated with a marginal tumor margin, the prognosis was
poor. In the 30 patients with wide or radical surgical margins,
at last follow-up 13 were alive with no evidence of disease,
2 were alive with disease, and 15 died of disease at 5 months
to 13.1 years after diagnosis. In 16 of 22 Mayo Clinic patients,
excluding those who presented with metastasis, the cumulative
5-year survival rate was 28.9%. Median survival time in patients
who had surgery with additional chemotherapy was 13.4 years,
compared with 1.4 years in patients who underwent surgery alone
(P = 0.17). CONCLUSIONS : Small cell osteosarcoma is a definite
reproducible histologic entity. Treatment should be based on
a protocol for osteosarcoma. |
IS
CHEMOTHERAPY IN MALIGNANT FIBROUS HISTIOCYTOMA NECESSARY ?
Neoadjuvant chemotherapy in malignant fibrous histiocytoma of
bone and in osteosarcoma located in the extremities : analogies
and differences between the two tumors.
Picci P, Bacci G, Ferrari S, et al.
Annals of Oncology 8(11): 1107-1115, 1997.
Background : Malignant fibrous histiocytoma (MFH) is a rare
bone tumor usually treated like osteosarcoma. Studies on analogies
and differences between the two tumors have seldom been reported.
Patients and Methods : Between March 1982 and December 1994,
51 patients with high-grade MFH of bone and 390 with high-grade
osteosarcoma were treated with the same regimen of neoadjuvant
chemotherapy. All of the tumors in both groups were located
in the limbs. Preoperative chemotherapy was performed according
to three different, successively activated, regimens consisting
of MTX/CDP intraarterially, MTX/CDP/ADM, and MTX/CDP/ADM//IFO.
Results : The rate of limb salvage was the same in both the
MFH (92%) and osteosarcoma (85%) patients. MFH showed a statistically
significantly lower rate of good histologic response, 90% or
more tumor necrosis (27% vs. 67%, P=0.00001) for all three regimens.
Despite this low chemosensitivity, the disease-free survivals
of the two neoplasms were similar (67% vs. 65%). Conclusions
: In terms of histologic response to primary chemotherapy,
MFH has a lower chemosensitivity than osteosarcoma. Nevertheless,
the two tumors have similar prognoses when treated with chemotherapy
regimens based on MTX, CDP, ADM and IFO. |
|
OSTEOSARCOMA
-
Surgery
|
|
DOES
LIMB SALVAGE COMPROMISE SURVIVAL ?
HOW IMPORTANT IS ADEQUATE LOCAL CONTROL ?
PROGNOSTIC SIGNIFICANCE OF HISTOPATHOLOGIC RESPONSE FOR LOCAL
CONTROL AND OVERALL SURVIVAL
Surgical outcomes in osteosarcoma.
Grimer RJ, Taminiau AM, Cannon SR et al.
J Bone Joint Surg Br. 2002 Apr;84(3):395-400.
Abstract : From the European Osteosarcoma Intergroup study
202 patients were assessed with respect to their surgical
treatment. Although treated in three different centres the
survival of the three groups was identical (57% at five years).
Two of the centres had rates of limb salvage of 85% and 83%,
respectively, while the third had a rate of 49%. The corresponding
risks of local recurrence were 13.3%, 6.8% and 2.5%, with
all local recurrences arising in limbs with attempted limb
salvage. Local recurrence was closely related to the adequacy
of the margins of excision and to the chemotherapeutic response.
Patients who had undergone limb-salvage surgery and who developed
local recurrence still had a better survival than those who
had primary amputation (37% v 31% survival at five years).
Of patients who relapsed, 31% of those with local recurrence
alone were cured by further treatment, as compared with only
10% of those with metastases. Limb-salvage surgery with
effective chemotherapy remains the optimum treatment for osteosarcoma.
Risk factors for local recurrences after limb-salvage surgery
for high-grade osteosarcoma of the extremities.
Picci P, Sangiorgi L, Bahamonde L et al.
Ann Oncol. 1997 Sep;8(9):899-903.
BACKGROUND : Improvements in preoperative staging as well
as in chemotherapeutic regimens have made limb-salvage surgery
a reliable modality of treatment for high-grade osteosarcomas
of the extremities, with local recurrences in most series
of less than 10% after this type of surgery. The quality of
surgical margins and local response to preoperative chemotherapy
are known to be the most significant factors in recurrence
[1, 8-10, 12], and complications related to the biopsy procedure
may also be a significant factor. The study reported here
comprised a histopathological analysis of our recurrent cases
as part of an effort to identify the impact of each of the
factors cited above. MATERIALS AND METHODS : Five hundred
fourteen cases of high-grade, non-multicentric osteosarcoma
of the extremities were treated at the Istituto Ortopedico
Rizzoli between March 1983 and August 1991. In this study
we analyzed 23 cases of local recurrence in patients with
classic osteosarcoma who underwent limb-salvage procedures.
RESULTS : In 15 cases we found correlation between the site
of local recurrence and the site where the margins were less
than wide. In five cases the recurrence was secondary to complications
of the biopsy procedure (hematoma, delayed healing). In one
case we suspect a previously undetected skip lesion. In the
remaining two cases no clear explanation was found for the
recurrence. There was also a statistically significant difference
in the time of appearance of recurrences related to the tumor
response to chemotherapy. CONCLUSIONS : For only two cases
of recurrence was there no clear explanation. In one we suspect
an undetected skip metastasis, and in the other there were
certain factors which may have increased its risk of recurrence
(non diagnostic trochar biopsy followed by an incisional biopsy,
fair tumor necrosis, recurrence in a ‘problem’
anatomical site, i.e., the popliteal space). In the remaining
cases the following factors were found to be directly related
to the development of a local recurrence: a) the quality of
the surgical margins, b) site of the biopsy as well as complications
related to the biopsy procedure, c) local response to preoperative
chemotherapy.
Pulmonary metastases of stage IIB extremity osteosarcoma
and subsequent pulmonary metastases.
Ward WG, Mikaelian K, Dorey F et al.
Journal of Clinical Oncology 12(9): 1849-1858,1994.
Purpose : This study investigated prognostic factors in nonmetastatic
high-grade extremity osteosarcoma and the prognosis following
resection of subsequent pulmonary metastases, with emphasis
on the effect of chemotherapy-induced tumor necrosis. Patients
and Methods : We reviewed 111 consecutive patients with high-grade
nonmetastatic extremity osteosarcoma treated with preoperative
chemotherapy and surgical resection, with additional review
of 36 patients who had subsequent pulmonary metastases resected.
Results : The overall 5-year survival rate was 53%. In resected
primary tumors, tumor-free resection margin (P<.001) and
increasing chemotherapy-induced tumor necrosis (> 90% threshold,
P<.003) correlated with increased metastasis-free survival.
Relative risk factors for metastases were as follows : tumor-containing
resection margin (most likely to metastasize); poor response
to preoperative chemotherapy and/or lack of postoperative
chemotherapy (next worse prognosis); and excellent response
to preoperative chemotherapy (>or=90% necrosis) combined
with postoperative chemotherapy (best prognosis). The 5-year
survival rate following pulmonary metastasis resection was
23%, whereas a 0% 4-year survival rate followed development
of bony metastases (P<.001). The extent of tumor necrosis
in resected pulmonary metastases did not affect prognosis.
Survival was best in patients with three or fewer pulmonary
nodules (P<.048), four or fewer recurrent pulmonary nodules
(P<.047), unilateral pulmonary metastases (P<.037),
or longer intervals between primary tumor resection and metastases
(P<.082). Conclusion : Intensive preoperative and postoperative
chemotherapy combined with complete resection of both primary
and metastatic pulmonary osteosarcomas is justified, with
a goal of 100% tumor necrosis and excision. Although current
treatment regimens allow effective salvage therapy for a few
patients with pulmonary metastases, more effective systemic
treatment is needed.
The effect of local recurrence on survival in resected
osteosarcoma.
Weeden S, Grimer RJ, Cannon SR et al.
European Journal of Cancer 37(1): 39-46, 2001.
Abstract : The aim of this study was to assess the effect
of local recurrence on survival in primary osteosarcoma. 559
patients entered into two randomised trials of the European
Osteosarcoma Intergroup who received surgery for primary operable
high-grade osteosarcoma of the extremities were included in
this analysis. Proportional hazards modelling techniques were
used to assess the relative importance of sex, age, site,
surgery performed and local recurrence. The last of these
was considered as a time-dependent covariate. 42/559 (8%)
patients had a local recurrence. In the multivariate analysis,
local recurrence was found to greatly increase the risk of
death (hazard ratio (HR)=5.10, 95% confidence interval (CI)
3.51-7.41). Site and surgery performed also had a significant
influence within this model. Using the technique of landmark
analysis, with thelandmark
time set at 18 months, local recurrence alone had a significant
influence on survival (HR=4.60, 95% CI 2.80-7.57). Local
recurrence is an indicator of poorer survival for patients
with operable primary osteosarcoma.
Osteosarcoma of the limb. Amputation or limb salvage in
patients treated by neoadjuvant chemotherapy.
Bacci G, Ferrari S, Lari S et al.
J Bone Joint Surg Br. 2002 Jan;84(1):88-92.
Abstract : We have studied 560 patients with osteosarcoma
of a limb, who had been treated by neoadjuvant chemotherapy,
in order to analyse the incidence of systemic and local recurrence
according to the type of surgery undertaken. Of these, 465patients
had a limb-salvage procedure and 95 amputation or rotationplasty.
At a median follow-up of 10.5 years there had been 225 recurrences.
The five-year disease-free survival and overall survival rates
were 60.5% and 68.5%, respectively, with no significant difference
between patients undergoing amputation and patients undergoing
resection. The incidence of local recurrence was the same
for patients treated by either amputation or limb salvage
and correlated significantly with the margins of surgical
excision and the histological response to chemotherapy. The
outcome for patients with local recurrence was significantly
worse than those who had recurrent disease with metastases
only.We conclude that limb-salvage procedures are relatively
safe in osteosarcoma treated with neo-adjuvant chemotherapy.
They should, however only be performed in institutions where
the margins of surgical excision and the histological response
to chemotherapy can be accurately assessed. If the margins
are inadequate and the histological response to chemotherapy
is poor an immediate amputation should be considered.
PATHOLOGIC
FRACTURE IN OSTEOSARCOMA - LIMB SALVAGE IS POSSIBLE
Pathologic fracture in osteosarcoma : prognostic importance
and treatment implications.
Scully SP, Ghert MA, Zurakowski D et al.
J Bone Joint Surg Am.2002,Jan.;84-A(1):49-57
BACKGROUND : The presence of a pathologic fracture in an osteosarcoma
has been considered a poor prognostic factor and an indication
for immediate amputation. The purpose of the present study
was to determine, in the current era of neoadjuvant chemotherapy,
whether a pathologic fracture in an osteosarcoma has prognostic
importance and whether limb salvage can be safely performed
in such patients without compromising clinical outcome. METHODS
: In a cooperative effort of the Musculoskeletal Tumor Society,
members from eight institutions provided retrospective data
on fifty-two patients with osteosarcoma who had a pathologic
fracture and on fifty-five patients with osteosarcoma who
had not had a pathologic fracture and had been followed for
at least two years or until disease recurrence, metastasis,
or death. The two groups were matched for patient age and
tumor location. Outcomes examined were survival and local
recurrence. A subgroup analysis was performed to assess differences
in outcome within the group with the pathologic fracture.
RESULTS : The five-year estimated survival rates were 55%
for the group with a pathologic fracture and 77% for the group
without a fracture (p=0.02). The rate of survival without
a local recurrence at five years was 75% for the group with
a fracture and 96% for the group without a fracture (p=0.007).
In the group with a fracture, seven (23%) of the thirty patients
managed with limb salvage and four (18%) of the twenty-two
managed with an amputation had a local recurrence (p=0.75).
Eleven (37%) of the thirty patients with a fracture who were
managed with limb salvage and ten (45%) of the twenty-two
patients with a fracture who were managed with an amputation
died of the disease (p=0.50). Five patients underwent open
reduction and internal fixation followed by limb-salvage surgery.
Two of them had a local recurrence and died at an average
of eight months postoperatively. The remaining three patients
were alive at an average of 6.1 years postoperatively. Local
disease control and the survival of these patients were not
significantly different from those for the thirty-three patients
who were treated with nonoperative immobilization of the fracture
followed by limb-salvage surgery. CONCLUSIONS : Patients with
osteosarcoma who present with a pathologic fracture or sustain
one during preoperative chemotherapy have an increased risk
of local recurrence and a decreased rate of survival compared
with patients who have not sustained a pathologic fracture.
The performance of a limb-salvage procedure in carefully
selected patients with a pathologic fracture does not significantly
increase the risk of local recurrence or death. Factors
predictive of improved outcome, such as the response to chemotherapy
and union of the fracture, should be taken into account when
limb salvage is being considered.
Nonmetastatic osteosarcoma of the extremity with pathologic
fracture at presentation: local and systemic control by amputation
or limb salvage after preoperative chemotherapy.
Bacci G, Ferrari S, Longhi A et al.
Acta Orthop Scand. 2003 Aug;74(4):449-54.
Abstract : To determine whether a pathologic fracture in osteosarcoma
of long bones has prognostic importance, and limb salvage
can be safely performed in such cases, we reviewed the surgical
treatment and oncologic results in 46 patients with nonmetastatic
osteosarcoma of the extremity and pathologic fracture at presentation
who had been treated in our Institution with neoadjuvant chemotherapy,
between 1983 and 1999. Neoadjuvant chemotherapy was given
according to 6 consecutive protocols. Surgery consisted of
limb salvage (34 patients), amputation (11 patients) and rotationplasty
(1 patient). The average follow-up was 11 (3-20) years. 28
patients remained continuously disease-free, 17 patients relapsed
and 1 died of chemotherapy-related toxicity. Despite the high
rate of limb salvage, only 2 local failures occurred, 1 after
amputation and 1 after limb salvage. The 5-year disease-free
survival and overall survival rates were 59% and 65%, respectively,
with no differences between amputated and resected patients.
These results are similar to those obtained in 689 contemporary
patients having an osteosarcoma without a pathologic fracture
treated in our Institution, and using the same protocols for
chemotherapy. We conclude that with neoadjuvant chemotherapy,
osteosarcoma patients presenting with a pathologic fracture
can be surgically treated like those with no fracture, and
that limb salvage procedures do not increase the risk of local
recurrence or death of these patients.
|
DO
YOU NEED TO BE AGGRESSIVE SURGICALLY IN METASTATIC AND RECURRENT
DISEASE ?
Osteosarcoma recurrences in pediatric patients previously
treated with intensive chemotherapy.
Tabone MD, Kalifa C, Rodary C, et al.
Journal of Clinical Oncology 12(12): 2614-2620, 1994.
Purpose and Methods : Between January 1981 and June 1993, 137
children and adolescents were each treated at the Institut Gustave
Roussy for an initially nonmetastatic osteosarcoma of the extremities.
We report the retrospective analysis of 42 cases of recurrence
that occurred in this population. Results:The median interval
between the diagnosis of the primary osteosarcoma and the first
recurrence was 21 months (range, 5 to 60). The site of the first
recurrence was limited to the lung in 20 patients, the bone
in seven patients, was local in six patients, and was confined
to soft tissue in one patient. In eight patients, the first
recurrence affected multiple sites. Subsequent recurrences often
involved unusual or multiple sites. Management of recurrences
included surgery and/or various regimens of second-line chemotherapy,
and in one case involved high-dose chemotherapy followed by
autologous bone marrow transplantation. Overall survival and
event-free survival were, respectively, 36% and 27% at 36 months.
At present, 13 patients are alive without evidence of disease.
Response of the primary tumor to preoperative chemotherapy,
the time between the diagnosis and the first recurrence, and
the number of metastatic lesions did not correlate with survival.
The survival rate is better in patients with a local or a pulmonary
first recurrence. Conclusion : The most important prognostic
indicator at first recurrence seems to be the possible complete
resection of disease. Patients not amenable to surgery and patients
with a second or a third recurrence have a poor prognosis. The
potential benefit of more aggressive treatments such as high-dose
chemotherapy and autologous bone marrow transplantation should
be investigated for these patients. |
Osteogenic
sarcoma of the extremity with detectable lung metastases at
presentation. Results of treatment of 23 patients with chemotherapy
followed by simultaneous resection of primary and metastatic
lesions.
Bacci G, Mercuri M, Briccoli A et al.
Cancer. 1997 Jan 15;79(2):245-54.
BACKGROUND : In the past 20 years, it has been demonstrated
that the combination of surgery and chemotherapy improves the
prognosis for patients with osteosarcoma of the extremity without
detectable metastases at presentation. By contrast, the efficacy
of chemotherapy coupled with aggressive surgery has not yet
been well established for patients with metastatic disease at
diagnosis. The current study evaluates the efficacy of chemotherapy
associated with simultaneous surgery of primary and metastatic
lesions in patients presenting with osteosarcoma of the extremity
with lung metastases. METHODS : Patients with lung metastases
originating from an osteosarcoma of the extremity received chemotherapy
(high dose methotrexate, cisplatin, doxorubicin, and ifosfamide)
followed by simultaneous resection of primary and metastatic
lesions and additional chemotherapy. RESULTS : Between January
1993 and June 1995, 23 patients entered the study. After primary
chemotherapy, lung metastases disappeared in three patients,
whereas in four patients they remained surgically unresectable.
All seven patients received surgical treatment of the primary
tumor only. In the remaining 16 patients, a simultaneous resection
of the primary and metastatic tumors was performed after chemotherapy.
The resection of metastatic lesions resulted in a complete remission
in 15 patients and an incomplete remission in 1 patient. All
five patients who never achieved tumor free status died within
a few months. Of the 18 patients who achieved radiologic remission
at a 30-month follow-up (range, 14-50 months), 10 (55.5%) remained
continuously free of disease, 7 relapsed with new metastases,
and 1 died of toxicity. In 13 of the 18 patients who underwent
a complete simultaneous resection of the primary and the metastatic
lesions, or whose pulmonary metastases disappeared after chemotherapy,
a strong correlation was found between degree of necrosis of
the primary tumor and of the metastatic tumor. CONCLUSIONS :
In patients presenting with osteosarcoma of the extremity
with lung metastases, the combination of aggressive chemotherapy
with simultaneous resection of the primary and metastatic lesions
improves traditionally negative outcomes. The strong correlation
found between the histologic response of the primary and metastatic
tumors supports the strategy, largely used currently in the
neoadjuvant treatment of osteosarcoma, of tailoring postoperative
chemotherapy on the basis of the histologic response of the
primary tumor to preoperative chemotherapy. |
EVIDENCE
BASED MANAGEMENT FOR
Ewing’s sarcoma / pnet
|
A
– Documentation of exact extent of primary tumor
Clinical examination, X-ray, MRI (MRI has become the premier
imaging modality for the evaluation of musculoskeletal tumors
because of its excellent soft tissue contrast, its sensitivity
to bone marrow and soft tissue edema, and its multiple imaging
planes).
B – Pathological confirmation of diagnosis by biopsy
A needle biopsy can often confirm the diagnosis. If tissue is
inadequate or diagnosis uncertain an open biopsy is indicated.
The closed needle biopsy technique has proven to be an extremely
effective means of procuring representative tissue, is associated
with low morbidity, and avoids many of the potential complications
of biopsy. If limb-sparing surgery is contemplated, the biopsy
should be performed by the surgeon who will do the definitive
operation, since incision placement is crucial.
Traditionally a major distinction has been made between classical
Ewing’s sarcoma (which shows minimal evidence of differentiation)
and PNET (which shows evidence of neural differentiation). The
degree of neural differentiation does not influence outcome.
C- Staging and biochemical investigations
CT chest, bone scan, bone marrow studies, Serum LDH.
Localized : For Ewing’s tumor of bone, the tumor is defined
as localized when, by clinical and imaging techniques, it has
not spread beyond the primary site or regional lymph nodes.
There may be contiguous extension into adjacent soft tissue.
Extraosseous Ewing’s has been grouped using the rhabdomyosarcoma
staging system shown below:
Group
I : Completely excised.
Group
II : Microscopic residual.
Group
III : Gross residual.
Metastatic : These tumors have spread to distant sites, most
commonly lung, bone, and/or bone marrow. Lymph node and, in
particular, central nervous system metastases are less common.
By other staging systems in common use, this is stage 4 or group
IV.
D – Chemotherapy
Induction chemotherapy Ô Local control (Surgery and/ Radiotherapy)
- Maintenance chemotherapy is the usual sequence.
Chemotherapy is multiagent and drugs used include: Vincristine
(given weekly), Ifosfamide, Etoposide, Cyclophosphamide, Adriamycin
and Actinomycin-D.
After induction chemotherapy (generally between 9-12 weeks)
patient is evaluated for local treatment.
E – Local control
Local control can be achieved by surgery and/or radiation. Surgery
is generally the preferred approach if the lesion is resectable.
(Level III,
Grade A)
Adequate surgical margins significantly affect the outcome &
hence whenever it is feasible wide/radical resection is indicated.
(Level III, Grade A)
Radiation therapy should be employed for patients who do not
have a surgical option that preserves function and should be
used for patients whose tumors have been excised but with inadequate
margins. (Level III, Grade A)
|
|
|
The
radiation dose is adjusted depending upon the extent of residual
disease after the initial surgical procedure. No radiation therapy
is recommended for those who have no evidence of microscopic
residual disease following surgical resection. (Level III, Grade
B)
Radiotherapy details
1) Tailored portals for every patient
2) Entire Medullary cavity need not be included in the RT portal
3) Target volumes (GTV) mentioned are MRI based. Includes bone
+ soft tissue component.
4) Try and spare a strip of normal tissue for lymph drainage.
5) If disease involves non-infiltrating extension into pre-formed
body cavities e.g. lung & pelvis, radiotherapy volume includes
post induction volume with 2cm margin in order to reduce treatment
related toxicity
6) 3D-CRT / IMRT wherever necessary
A) Post Operative
Depending on margins and histopathology
| Surgical
Margins |
Radiotherapy
Dose If Necrosis 100% |
Radiotherapy
Dose If Necrosis <100% |
| Negative |
No
Radiotherapy |
45
GY |
| Marginal
resection/Close |
45
Gy |
50
GY |
| Microscopic
Positive (R1) |
45
Gy |
50
GY |
| Gross
+ Positive (R2) |
50
Gy |
50
GY |
|
|
PTV
:
Phase I : Pre-chemotherapy volume
+ 2cm. margin
Phase II : Post - surgery site of
residual disease + 2cm. margin
TOTAL DOSE
Phase I : 45Gy / 25# / 5wks (@1.8Gy
/ fr.)
Phase II : 1) If R0 :
<100%
necrosis – no further boosts
2) If Marginal resection/ close
margins :
100%
necrosis – no further boost
<100%
necrosis – 5.4Gy / 3# / 0.5wk (@1.8Gy / fr.)
3) If R1 :
100%
necrosis – no further boost
<100%
necrosis – 5.4Gy / 3# / 0.5wk (@1.8Gy / fr.)
4) If R2 :
100%
necrosis – 5.4Gy / 3# / 0.5wk (@1.8Gy / fr.)
<100%
necrosis – 10.8Gy / 6# / 1 wk (@1.8Gy / fr.)
B) Borderline Resectable (As evaluated by multidisciplinary
Joint Clinic)
All patients to receive radical RT
doses
Patients to be evaluated for surgery
at 6th week after completion of RT
PTV:
Phase I : Pre-chemotherapy volume
+ 3cm. margin
Phase II : Post-chemotherapy volume
+ 2cm. margin
(There
is no field reduction for bony component).
TOTAL DOSE :
Phase I : 45Gy / 25# / 5wks (@1.8Gy
/ fr.)
Phase II : 1) If complete response
after induction
No
further boost
2)
If >50% regression after induction
10.8Gy
/ 6# / 1wk (@1.8Gy / fr.)
3)
If <50% regression after induction
14.4Gy
/ 8# /1.5wks (@1.8Gy / fr.)
C) Unresectable
Same as borderline resectable lesions
D) Hyperfractionation
Unresectable lesions of the extremity. Although there is no
evidence of significant improvement in disease free &
overall survival, there is evidence to show that it is possible
to do concurrent Chemo + RT using hyperfractionated RT with
equivalent or marginally superior local control.
PTV :
Phase I : Pre-chemotherapy
volume + 3cm. margin
Phase II : Post-chemotherapy
volume + 2cm. margin
(There
is no field reduction for bony component).
TOTAL DOSE :
Phase I : 45.6 Gy / 38# / 4wks (@1.2
Gy/ fr. X 2 # / day)
Phase II : 20.4 Gy / 17# / 1.5wks
(@1.2 Gy/ fr. X 2 # / day)
24.0
Gy / 20 # / 2wks (@1.2 Gy/ fr. X 2 # / day)
Total Dose : 66 Gy / 55# / 5.5wks
(@1.2 Gy/ fr. X 2 # / day)
69.6Gy
/ 37# / 7wks (@1.2 Gy/ fr. X 2 # / day)
E) Lung Bath (Whole Lung Irradiation)
All
patients with metastatic disease to the lungs at presentation
receive whole lung irradiation (“Lung Bath”),
even if complete remission of pulmonary metastatic disease
has been achieved after chemotherapy.
Rt Target Volume : Bilateral Lung
No
Cardiac Shield
Shield
Bilateral Shoulder
Dose : 12.6Gy/ 7#/ 1week
F – Histopathology report and its importance
The specimen is evaluated for margins of surgical resection.
Response to chemotherapy is noted based on percentage necrosis
of tumor cells. This is an important prognostic factor. (Level
III, Grade A)
The radiation dose is adjusted depending upon the percentage
necrosis of tumor and margins of resection. (Level III, Grade
B)
Grading of response in Ewing’s sarcoma is based on percentage
of viable tumor.
Grade I : Tumor specimen contains at least one macroscopic
nodule of viable tumor mass which is larger than one 10 X
magnification field.
|
Grade
II – Isolated small nodules of tumor are found, the total
area of these nodules not exceeding 10 X field.
Grade III – No viable tumor nodules are identified within
the surgical specimen.
An ideal pathology report should include
- Type of specimen received with entire gross description
- A numerical list of the various sections submitted for histological
examination
- Histological diagnosis with grade of tumor where applicable
- The exact anatomical location of the soft tissue or bone tumor
- The extent of the tumor with respect to the various cut margins
and also with respect to skin and bone including involvement
of cortex, periosteum, muscle, subcutaneous fat , joint capsule
and articular cartilage
- Evidence of angiolymphatic invasion, perineural invasion,
lymph node invasion
- Status of cut margins of bone, skin, soft tissue, neurovascular
cut margins
- Comments on response to chemotherapy with percentage of necrosis
G – Follow up schedule
Patient is followed up at 3 monthly interval for the first 2
years, 6 monthly intervals for next 3 years and annually thereafter.
At every follow up , an X ray of the local part & chest
radiograph is done. A CT scan of the chest and a bone scan is
done at 6 monthly intervals for the first 2 years and annually
for the next 3 years.
(Currently there is inadequate evidence to suggest that intensive
follow up with early detection of recurrent disease would significantly
impact on survival). |
Ewing’s
Sarcoma -
Investigations
|
Neuroectodermal
differentiation in Ewing's sarcoma family of tumors does not
predict tumor behavior.
Parham DM, Hijazi Y, Steinberg SM et al.
Hum Pathol; 30(8):911-8, 1999.
Abstract : The observation that neuroectodermal differentiation
imparts a worse prognosis to the Ewing family of tumors has
been suggested by some studies and refuted by others. To assess
whether the diagnosis of Ewing’s sarcoma versus peripheral
primitive neuroectodermal tumor (PNET) affects prognosis, we
analyzed tumors from 63 analogously treated pediatric and young
adult patients from the National Cancer Institute and St Jude
Children’s Research Hospital and retrospectively compared
the results with clinical outcomes. The tumors were assessed
using standard light microscopy and immunohistochemical stains
for neuron-specific enolase, CD57, S100 protein, neurofilament
protein, and synaptophysin with or without antigen retrieval.
Ultrastructural evaluation was also performed in 39 tumors.
Classification was performed using Kiel criteria as well as
a modified classification. Kaplan-Meier analyses, with Mantel-Haenzel
evaluation of the significance of the differences, were performed
separately for localized or metastatic tumors. Using the Kiel
classification on a subset of 60 cases, 39 tumors qualified
as PNET and 21 as Ewing’s sarcoma. Using the modified
classification on a subset of 61 cases, 14 were classified as
PNET, 21 as atypical Ewing’s sarcoma, and 26 as Ewing’s
sarcoma. The addition of electron microscopy to the diagnostic
armamentarium significantly increased the likelihood of identifying
PNET. No significant differences in event-free or overall survival
were seen using either the modified or Kiel classification,
regardless of the ancillary diagnostic techniques employed.
In this exploratory analysis, neuroectodermal differentiation
did not play a role in clinical outcome. Confirmation of
this finding will require a larger, separate study of similarly
treated patients, and it may not apply to older patients. |
SERUM
LDH IN EWING’S SARCOMA OF BONE - A PROGNOSTIC INDICATOR
Prognostic significance of serum LDH in Ewing’s sarcoma
of bone.
Bacci G, Ferrari S, Longhi A et al.
Oncol Rep; 6(4):807-11, 1999.
Abstract : The pretreatment serum lactic dehydrogenase (SLDH)
levels of 618 patients with Ewing’s sarcoma of the extremities
(136 metastatic at presentation and 482 localized) were analyzed
to evaluate whether the enzyme level had a clinical value in
predicting the course of the disease. The percentage of patients
with increased SLDH was significantly higher in the metastatic
group than in the group of patients with localized disease (68%
vs 32%; P<0.0001). In the latter group treated with neoadjuvant
chemotherapy the 5-year disease-free survival rate was significantly
higher in patients with normal pretreatment SLDH than in those
with high levels (65% vs 41%; P<0.0001). The time to relapse
was significantly shorter for patients with elevated SLDH than
in patients with normal values of the enzyme. The site of the
tumor was significantly related with the stage of the disease,
and for patients with localized disease, with the disease survival
rate, at the multivariate analyses site of the tumor and SLDH
levels were independently related with the stage of disease
and with prognosis. These data demonstrate that in Ewing’s
sarcoma of bone pretreatment SLDH have a prognostic value and
should be considered in the comparison of the results achieved
with different therapies and in planning new randomized clinical
therapeutic trials. |
EFFICACY
OF MRI AS A DIAGNOSTIC AND STAGING MODALITY
Radiographic imaging of musculoskeletal neoplasia.
Sanders TG, Parsons TW 3rd.,
Cancer Control. 2001 May-Jun; 8(3): 221-31.
BACKGROUND : Imaging is an integral part of the diagnosis, staging
and evaluation of outcomes for bone and soft-tissue neoplasms.
Each of the available imaging tools has a different role. METHODS
: The authors reviewed the efficacy of the current imaging modalities
in the diagnosis, staging, and follow-up of patients with musculoskeletal
neoplasia. RESULTS : Plain-film radiography remains the gold
standard in the differential diagnosis of bone lesions. Bone
scintigraphy is an excellent screening modality, and computed
tomography is especially useful in evaluating lesions of the
axial skeleton. The superior soft-tissue resolution and multiplanar
capabilities achieved with magnetic resonance imaging, however,
has replaced the need for CT scans in many cases. CONCLUSIONS
: The technological advances seen in recent years in all areas
of imaging have improved the capabilities of these modalities
to assist in the diagnosis, definition of tumor extent, and
accurate staging of musculoskeletal tumors. |
|
Ewing’s
Sarcoma -
Chemotherapy
|
Addition
of ifosfamide and etoposide to standard chemotherapy for Ewing’s
sarcoma and primitive neuroectodermal tumor of bone.
Grier HE, Krailo MD, Tarbell NJ et al.
N Engl J Med. 2003 Feb 20;348(8):694-701.
BACKGROUND : Ewing’s sarcoma and primitive neuroectodermal
tumor of bone are closely related, highly malignant tumors of
children, adolescents, and young adults. A new drug combination,
ifosfamide and etoposide, was highly effective in patients with
Ewing’s sarcoma or primitive neuroectodermal tumor of
bone who had a relapse after standard therapy. We designed a
study to test whether the addition of these drugs to a standard
regimen would improve the survival of patients with newly diagnosed
disease. METHODS : Patients 30 years old or younger with Ewing’s
sarcoma, primitive neuroectodermal tumor of bone, or primitive
sarcoma of bone were eligible. The patients were randomly assigned
to receive 49 weeks of standard chemotherapy with doxorubicin,
vincristine, cyclophosphamide, and dactinomycin or experimental
therapy with these four drugs alternating with courses of ifosfamide
and etoposide. RESULTS: A total of 518 patients met the eligibility
requirements. Of 120 patients with metastatic disease, 62 were
randomly assigned to the standard-therapy group and 58 to the
experimental-therapy group. There was no significant difference
in five-year event-free survival between the treatment groups
(P=0.81). Among the 398 patients with nonmetastatic disease,
the mean (+/-SE) five-year event-free survival among the 198
patients in the experimental-therapy group was 69+/-3 percent,
as compared with 54+/-4 percent among the 200 patients in the
standard-therapy group (P=0.005). Overall survival was also
significantly better among patients in the experimental-therapy
group (72+/-3.4 percent vs. 61+/-3.6 percent in the standard-therapy
group, P=0.01). CONCLUSIONS : The addition of ifosfamide
and etoposide to a standard regimen does not affect the outcome
for patients with metastatic disease, but it significantly improves
the outcome for patients with nonmetastatic Ewing’s sarcoma,
primitive neuroectodermal tumor of bone, or primitive sarcoma
of bone. |
Italian
Cooperative Study for the treatment of children and young adults
with localized Ewing sarcoma of bone: a preliminary report of
6 years of experience.
Rosito P, Mancini AF, Rondelli R et al.
Cancer. 1999 Aug 1;86(3):421-8.
BACKGROUND : In 1991, the Italian Association for Pediatric
Hematology-Oncology and the National Council of Research (CNR)
initiated an Italian Cooperative Study (SE 91-CNR Protocol)
with the main objective of improving the overall survival (SUR)
and the event free survival (EFS) of children and young adults
with localized Ewing sarcoma and primitive neuroectodermal tumors
of bone compared with a previous study (IOR/Ew2 Protocol). METHODS
: Between November 1991 and November 1997, 165 patients were
enrolled in this study, 160 of whom were evaluable. The patients
were treated with a multimodal approach characterized by intensified
chemotherapy, hyperfractionated and accelerated radiation therapy,
and the addition of ifosfamide and etoposide to standard chemotherapy
with vincristine, actinomycin-D,doxorubicin, and cyclophosphamide.
RESULTS : After a median follow-up of 37 months, 126 of the
160 evaluable patients remained free of disease recurrence.
Thirty-one patients developed a disease recurrence (20 with
disseminated disease). CONCLUSIONS : The 3-year SUR and EFS
rates found in the current study (83.6% and 77.8%, respectively)
may be considered satisfactory. Only age at diagnosis < or
=14 years and a good histologic response appeared to affect
the outcome of patients with localized Ewing sarcoma positively.
These results appear to demonstrate the efficacy of the addition
of ifosfamide in induction chemotherapy to four-drug standard
combination chemotherapy, as confirmed by the improved outcome
in terms of 3-year EFS reported in the SE 91-CNR Protocol compared
with the IOR/Ew2 Protocol (77.8% vs. 60.7%). In addition, the
better outcome also could be explained by the change in treatment
strategy with a trend toward the use of more surgery than radiation
therapy compared with the authors’ previous protocol. |
|
Ewing’s
Sarcoma -
Surgery
|
IMPROVED
RESULTS WITH SURGERY AND IMPORTANCE OF MARGINS
Role of surgery in local treatment of Ewing’s sarcoma
of the extremities in patients undergoing adjuvant and neoadjuvant
chemotherapy
Bacci G, Ferrari S, Longhi A et al.
Oncol Rep. 2004 Jan;11(1):111-20.
Abstract : Although more and more patients with Ewing’s
sarcoma of bone (ESB) are being treated by surgery, the relative
role of surgery and radiotherapy in the local treatment of this
tumor has yet to be determined. Because the outcome of ESB may
differ according to the anatomical site of the tumor, results
reported in the literature, which generally refer to series
with tumors located in all sites, may be selection biased. Therefore,
we have retrospectively evaluated patients with ESB exclusively
in the extremity and locally treated by surgery or radiotherapy.
Two hundred and sixty-eight patients treated at Rizzoli 1979-1996
for non-metastatic ES of the extremities were assessed. Chemotherapy
was administered according to four sequentially activated protocols.
One hundred and thirty-six patients were treated by surgery,
70 by surgery and radiotherapy, and 60 patients by radiotherapy.
Two patients underwent only chemotherapy. The follow-up range
was 5-23 years (mean 13 years). One hundred and fifty-two patients
remained continuously free of disease, 108 relapsed, 2 died
of chemotherapy toxicity and 6 developed a second malignancy.
The 5-year event-free survival (EFS) and overall survival (OS)
were respectively 62 and 69%. Although patients of all groups
were matched for possible risk factors, the rates of 5-year
EFS and local control were significantly lower in patients treated
with radiotherapy compared to patients treated by surgery or
surgery and radiotherapy (48% vs 66%, p=0.002; 80% vs 94%, p=0.0001).
Furthermore, in group 3 there were 6 secondary malignancies.
Our results indicate that surgery should always be considered
in the local treatment of ES of the extremities. Postoperative
radiation therapy must be added in case of inadequate surgical
margins. |
Local
therapy in localized Ewing tumors: results of 1058 patients
treated in the CESS 81, CESS 86, and EICESS 92 trials.
Schuck A, Ahrens S, Paulussen M et al.
Int J Radiat Oncol Biol Phys. 2003 Jan 1;55(1):168-77.
PURPOSE : The impact of different local therapy approaches on
local control, event-free survival, and secondary malignancies
in the CESS 81, CESS 86, and EICESS 92 trials was investigated.
METHODS AND MATERIALS : The data of 1058 patients with localized
Ewing tumors were analyzed. Wherever feasible, a surgical local
therapy approach was used. In patients with a poor histologic
response or with intralesional and marginal resections, this
was to be followed by radiotherapy (RT). In EICESS 92, preoperative
RT was introduced for patients with expected close resection
margins. Definitive RT was used in cases in which surgical resection
seemed impossible. In CESS 81, vincristine, adriamycin, cyclophosphamide,
and actinomycin D was used. In CESS 86, vincristine, adriamycin,
ifosfamide, and actinomycin D was introduced for patients with
central tumors or primaries >100 cm(3). In CESS 92, etoposide,
vincristine, adriamycin, ifosfamide, and actinomycin D was randomized
against vincristine, adriamycin, ifosfamide, and actinomycin
D in patients with primaries >100 cm(3). RESULTS : The rate
of local failure was 7.5% after surgery with or without postoperative
RT, and was 5.3% after preoperative and 26.3% after definitive
RT (p=0.001). Event-free survival was reduced after definitive
RT (p=0.0001). Irradiated patients represented a negatively
selected population with unfavorable tumor sites. Definitive
RT showed comparable local control to that of postoperative
RT after intralesional resections. Patients with postoperative
RT had improved local control after intralesional resections
and in tumors with wide resection and poor histologic response
compared with patients receiving surgery alone. Patients with
marginal resections with or without postoperative radiotherapy
showed comparable local control, yet the number of patients
with good histologic response was higher in the latter treatment
group (72.2% vs. 38.5%). CONCLUSION : Patients with resectable
tumors after initial chemotherapy had a low local failure rate.
With preoperative RT, local control was comparable. RT is indicated
to avoid intralesional resections. After intralesional or
marginal resections and after a poor histologic response and
wide resection, postoperative RT may improve local control. |
|
Local
and systemic control in Ewing’s sarcoma of the femur
treated with chemotherapy, and locally by radiotherapy and/or
surgery.
Bacci G, Ferrari S, Longhi A et al.
J Bone Joint Surg Br. 2003 Jan;85(1):107-14.
Abstract : The role of radiotherapy and/or surgery in the
local treatment of Ewing’s sarcoma has still to be determined.
The outcome of Ewing’s sarcoma may differ according
to its location and a selection bias towards surgery limits
the ability to compare methods of local treatment. We have
carried out a retrospective review of 91 consecutive patients
treated for non-metastatic Ewing’s sarcoma of the femur.
They received chemotherapy according to four different protocols.
The primary lesion was treated by surgery alone (54 patients),
surgery and radiotherapy (13) and radiotherapy alone (23).
One was treated bychemotherapy alone. At a median follow-up
of ten years, 48 patients (53%) remain free from disease,
39 (43%) have relapsed, two (2%) have died from chemotherapeutic
toxicity and two (2%) have developed a radio-induced second
tumour. The probability of survival without local recurrence
was significantly (p=0.01) higher in patients who were treated
by surgery with or without radiotherapy (88%) than for patients
who received radiotherapy alone (59%). The five- and ten-year
overall survival rates were 64% and 57%, respectively. Patients
who were treated by surgery, with or without radiotherapy,
had a five- and ten-year overall survival of 64%. Patients
who received only radiotherapy had a five and ten-year survival
of 57% and 44%, respectively. Our results indicate that
in patients with Ewing’s sarcoma of the femur, better
local control is achieved by surgical treatment (with or without
radiotherapy) compared with the use of radiotherapy alone.
Further studies are needed to verify the impact of this strategy
on overall survival.
Role of Surgery and Resection Margins in the Treatment
of Ewing´s Sarcoma.
Maria Sluga, Reinhard Windhager, Susanna Lang et al.
Clinical Orthopaedics And Related Research 2001;2001:394-399.
Because of the enormous progress in surgery in the treatment
of patients with tumors, the current study analyzed the influence
of wide surgical resection margins on the outcome of patients
with Ewing´s sarcoma. Between 1980 and 1994, 86 patients
were treated with systemic therapy and surgery (biopsy in
six patients, tumor resection in 80 patients). Forty-four
patients also had radiation therapy. The 5-year overall survival
was 56.8% (5-year disease-free survival, 59.4%). The 5-year
overall survival after radical or wide resection was 60.2%
(5-year disease-free survival, 58.2%), in comparison with
40.1% (46.7%) after marginal or intralesional resection. Two
patients with inadequate resection margins had local recurrences.
In addition to the influence of neoadjuvant chemotherapy
for higher survival rates (5-year overall survival with a
good response was 80.2% versus 41.7% with a poor response),
adequate surgical margins significantly affect the outcome
for patients with Ewing´s sarcoma.
Significance of surgical margin on the prognosis of patients
with Ewing’s sarcoma. A report from the Cooperative
Ewing’s Sarcoma Study.
Ozaki T, Hillmann A, Hoffmann C et al.
Cancer. 1996 Aug 15;78 (4): 892-900.
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Preface
