Eli Glatstein

Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity.

PURPOSE This randomized, prospective study assesses the impact of postoperative external-beam radiation therapy on local recurrence (LR), overall survival (OS), and quality of life after limb-sparing resection of extremity sarcomas. PATIENTS AND METHODS Patients with extremity tumors and a limb-sparing surgical option were randomized to receive or not receive postoperative adjuvant external-beam radiotherapy. Patients with high-grade sarcomas received postoperative adjuvant chemotherapy whereas patients with low-grade sarcomas or locally aggressive nonmalignant tumors were randomized after surgery alone. RESULTS Ninety-one patients with high-grade lesions were randomized; 47 to receive radiotherapy (XRT) and 44 to not receive XRT. With a median follow-up of 9.6 years, a highly significant decrease (P2 = .0028) in the probability of LR was seen with radiation, but no difference in OS was shown. Of 50 patients with low-grade lesions (24 randomized to resection alone and 26 to resection and postoperative XRT), there was also a lower probability of LR (P2 = .016) in patients receiving XRT, again, without a difference in OS. A concurrent quality-of-life study showed that extremity radiotherapy resulted in significantly worse limb strength, edema, and range of motion, but these deficits were often transient and had few measurable effects on activities of daily life or global quality of life. CONCLUSION This study indicates that although postoperative external-beam radiotherapy is highly effective in preventing LRs, selected patients with extremity soft tissue sarcoma who have a low risk of LR may not require adjuvant XRT after limb-sparing surgery (LSS).

The treatment of soft-tissue sarcomas of the extremities: prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy.

Between May 1975 and April 1981, 43 adult patients with high-grade soft tissue sarcomas of the extremities were prospectively randomized to receive either amputation at or above the joint proximal to the tumor, including all involved muscle groups, or to receive a limb-sparing resection plus adjuvant radiation therapy. The limb-sparing resection group received wide local excision followed by 5000 rads to the entire anatomic area at risk for local spread and 6000 to 7000 rads to the tumor bed. Both randomization groups received postoperative chemotherapy with doxorubicin (maximum cumulative dose 550 mg/m2), cyclophosphamide, and high-dose methotrexate. Twenty-seven patients randomized to receive limb-sparing resection and radiotherapy, and 16 received amputation (randomization was 2:1). There were four local recurrences in the limb-sparing group and none in the amputation group (p1 = 0.06 generalized Wilcoxon test). However, there were no differences in disease-free survival rates (71% and 78% at five years; p2 = 0.75) or overall survival rates (83% and 88% at five years; p2 = 0.99) between the limb-sparing group and the amputation treatment groups. Multivariate analysis indicated that the only correlate of local recurrence was the final margin of resection. Patients with positive margins of resection had a higher likelihood of local recurrence compared with those with negative margins (p1 less than 0.0001) even when postoperative radiotherapy was used. A simultaneous prospective randomized study of postoperative chemotherapy in 65 patients with high-grade soft-tissue sarcomas of the extremities revealed a marked advantage in patients receiving chemotherapy compared with those without chemotherapy in three-year continuous disease-free (92% vs. 60%; p1 = 0.0008) and overall survival (95% vs. 74%; p1 = 0.04). Thus limb-sparing surgery, radiation therapy, and adjuvant chemotherapy appear capable of successfully treating the great majority of adult patients with soft tissue sarcomas of the extremity.

Ten-Year Results of a Comparison of Conservation with Mastectomy in the Treatment of Stage I and II Breast Cancer

BACKGROUND Breast-conservation therapy for early-stage breast cancer is now an accepted treatment, but there is still controversy about its comparability with mastectomy. Between 1979 and 1987, the National Cancer Institute conducted a randomized, single-institution trial comparing lumpectomy, axillary dissection, and radiation with mastectomy and axillary dissection for stage I and II breast cancer. We update the results of that trial after a median potential follow-up of 10.1 years. METHODS Two hundred forty-seven patients with clinical stage I and II breast cancer were randomly assigned to undergo either modified radical mastectomy or lumpectomy, axillary dissection, and radiation therapy. The 237 patients who actually underwent randomization have been followed for a median of 10.1 years. The primary end points were overall survival and disease-free survival. RESULTS At 10 years overall survival was 75 percent for the patients assigned to mastectomy and 77 percent for those assigned to lumpectomy plus radiation (P = 0.89). Disease-free survival at 10 years was 69 percent for the patients assigned to mastectomy and 72 percent for those assigned to lumpectomy plus radiation (P = 0.93). The rate of local regional recurrence at 10 years was 10 percent after mastectomy and 5 percent after lumpectomy plus radiation (P = 0.17) after recurrences successfully treated by mastectomy were censored from the analysis. CONCLUSIONS In the management of stage I and II breast cancer, breast conservation with lumpectomy and radiation offers results at 10 years that are equivalent to those with mastectomy.

The grading of soft tissue sarcomas results of a clinicohistopathologic correlation in a series of 163 cases

A multidisciplinary study of 163 patients treated at the NCI for soft tissue sarcomas allowed the correlation of a number of histologic features (histologic type, mitosis, necrosis, pleomorphism, cellularity, and matrix) of the primary lesion to time to recurrence and overall survival of the patients. The results of the stratified analyses show that necrosis is the single best histopathologic parameter to predict the time to recurrence (P = 0.025) and the overall survival of the patients (P = 0.002). Necrosis in the primary lesion is also of value in predicting survival after the first recurrence has taken place (P = 0.001). The value of necrosis in the primary lesions predicting the clinical course after recurrence appears to be independent of age, sex, location, and size of the tumor. The authors propose a grading system based on histologic typing and histologic parameters to identify a group of lesions with minimal metastatic potential (Grade 1), and on the use of necrosis to distinguish between aggressive lesions with good patient survival (Grade 2) and aggressive lesions with poor patient survival (Grade 3).

Conventional-dose salvage combination chemotherapy in patients relapsing with Hodgkin's disease after combination chemotherapy: the low probability for cure.

PURPOSE The study was undertaken to evaluate clinical prognostic factors, probability of response to therapy, duration of response, and overall survival of patients with Hodgkins disease relapsing from a chemotherapy-induced complete remission. PATIENTS AND METHODS Study population comprised 107 patients with Hodgkins disease treated with combination chemotherapy at the National Cancer Institute who relapsed after achieving a complete remission. RESULTS Half of the relapses occurred within the first year of achieving complete remission; among patients in remission 5 years or longer, only 4% relapsed. The overall survival of the relapsed patients is projected to be 17% at 20 years, calculated from the date of relapse. Primary treatment regimen, presence of B symptoms, stage, sex, liver involvement, pleural involvement, marrow involvement, and histologic subtype did not affect the survival of relapsed patients. Only age at diagnosis (older or younger than 30 years) and length of initial remission (shorter or longer than 1 year) made a significant impact on survival. Patients whose initial remission was longer than 1 year had significantly higher complete response rates to salvage therapy, significantly more durable second remissions, and significantly longer survival than patients whose initial remission was shorter than 1 year. Survival beyond 11 years from relapse of patients with long initial remissions was 24%; for those with short initial remissions, 11% (P2 = .027). Despite the fact that with salvage therapy, patients with long initial remission had an 85% complete response rate to mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) with a disease-free survival of 45% at 20 years, acute leukemia and other treatment-related complications combined to lower the survival rate of this more favorable subset. CONCLUSIONS These data with conventional-dose salvage therapy provide results for comparison with novel salvage approaches including myeloablative therapy with autologous marrow or peripheral-blood stem-cell support.

High-grade soft tissue sarcomas of the extremities

From July 1975 to December 1982, 358 patients were referred to the Surgery Branch of the National Cancer Institute (NCI) with the diagnosis of soft tissue sarcoma of the extremities. Two hundred eleven of these patients presented with resectable, localized high‐grade soft‐tissue sarcomas and have been included in the present analysis of the management and outcome of patients with high‐grade soft tissue sarcomas of the extremity treated at the NCI. One hundred forty‐seven of these 211 patients have been included in randomized prospective trials. The remaining 64 patients in this analysis have been followed at the NCI, but were not included in randomized trials because of patient refusal or ineligibility. Tumor size was identified as a highly significant prognostic variable for disease‐free and overall survival (P2 = 0.00001 and 0.0081, respectively). Tumor site, histologic type, and microscopic margins of resection were not significant prognostic variables. There was no difference between patients undergoing amputation compared to those undergoing limb‐sparing procedures plus postoperative radiotherapy in disease‐free or overall survival for all 211 patients in this study (P2 = 0.068 and 0.131, respectively). A significantly greater frequency of local failure among patients treated by local excision was noted compared to patients undergoing amputation (12/128 versus 0/83, P2 = 0.004), but this did not result in decreased overall survival in patients undergoing combined modality limb‐sparing procedures. Adjuvant chemotherapy significantly prolonged disease‐free survival (P2 = 0.005) for the 124/211 patients treated with adjuvant chemotherapy, although analysis of overall survival did not reveal a significant increase (P2 = 0.10). In a subset of 65 patients included in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy, a significant improvement in both disease‐free (P2 = 0.033) and overall (P2 = 0.055) survival was seen in patients receiving chemotherapy. Sixty‐five patients developed recurrent disease (65/211, 31%) and 42 of these patients were rendered disease‐free surgically. Survival from the time of first recurrence was significantly prolonged among the 42 patients who were rendered disease‐free (median survival, 31 months) compared to those who were not (median survival, 9 months, P2 < 0.001) Cancer 58:190–205, 1986.

Chemosensitivity testing of human lung cancer cell lines using the MTT assay.

Thirty human lung cancer cell lines were tested for chemosensitivity using the semi-automated, non-clonogenic MTT assay. The tumour cell lines came from three major categories of patients: untreated small cell lung cancer (SCLC); SCLC relapsing on chemotherapy; and non-SCLC predominantly from untreated patients. From these data IC50 values were derived for each drug in each cell line. While some inter-experimental variability was observed, the rank order of chemosensitivity of each cell line within this panel was significantly correlated between experiments. These results show that tumour cell lines derived from untreated small cell lung cancer patients were the most chemosensitive for adriamycin, melphalan, vincristine and VP16 compared to the other cell types. In addition, untreated SCLC was more sensitive than non-SCLC to BCNU and cis-platin, while vincristine was the only drug to which treated SCLC was more sensitive compared to the non-SCLC lines. In contrast, no significant differences between the lung cancer types were observed for vinblastine. Thus, this panel of lung cancer cells exhibited a drug sensitivity profile paralleling that observed in clinical practice. These results suggest that this lung cancer cell line panel in combination with a relatively simple but reproducible chemosensitivity assay, such as the MTT assay, has potential for the testing of drug combinations and evaluating new anti-cancer agents in vitro.

Second malignant neoplasms complicating Hodgkin's disease: the National Cancer Institute experience.

The medical records of all patients treated for Hodgkins disease during the years 1964-1981 were reviewed. Four hundred seventy-three previously untreated patients were analyzed. Thirty-four subsequent second malignant neoplasms were observed in 33 patients among those treated for Hodgkins disease. Eight cases of acute nonlymphocyctic leukemia, one case of chronic myeloid leukemia, three cases of non-Hodgkins lymphoma, three cases of sarcoma, and 19 other tumors were identified. The ten-year estimated risk of leukemia by treatment was the following: radiotherapy only (0), chemotherapy only (0.02), initial combined radiotherapy-chemotherapy (0.06), and salvage combined radiotherapy-chemotherapy (0.09). The ten-year estimated risk of solid tumors was 0.07 overall, with all treatment groups associated with similar risks. Unlike some other reports, a greater risk of leukemia in patients who began treatment for Hodgkins disease at age 40 or older was not found. However, a positive association was noted between increasing risk of solid tumors and increasing patient age.

Prospective randomized evaluation of adjuvant chemotherapy in adults with soft tissue sarcomas of the extremities

Sixty‐five patients with high‐grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high‐dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow‐up of 653 days revealed an advantage in continuous disease‐free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one‐sided Mantel‐Haenszel test). The continuous disease‐free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty‐eight percent of patients had limb‐sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease‐free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four‐year follow‐up, reveals an improvement in disease‐free and overall survival due to chemotherapy (P < 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment of adult patients with soft tissue sarcomas of the extremities.

Radiation therapy versus combination chemotherapy in the treatment of early-stage Hodgkin's disease: seven-year results of a prospective randomized trial.

The study population included 136 patients with stage IA, IB, IIA, IIB, or IIIA1 Hodgkins disease. The median follow-up is 7.5 years. Among the 30 patients with peripheral IA disease, all patients achieved a complete response (CR) with radiation therapy, and no patient has relapsed. Patients of other stages were randomized to receive radiation therapy or mechlorethamine, vincristine, procarbazine, and prednisone (MOPP). Among the 51 patients randomized to receive radiation therapy, 49 (96%) achieved complete remission, 17 (35%) have relapsed, and 10 (20%) have died. Fifty-two of the 54 (96%) assessable patients randomized to receive MOPP obtained CRs, seven (13%) have relapsed, and four (7%) have died. The projected 10-year disease-free survival of patients randomized to receive radiation therapy is 60%; for those randomized to receive MOPP, it is 86% (P2 = .009 in favor of MOPP). The projected 10-year overall survival for patients randomized to radiation therapy is 76%, and for MOPP-treated patients it is 92% (P2 = .051 in favor of MOPP). When the randomized patients with massive mediastinal disease or stage IIIA1 disease were excluded from the analysis, the disease-free (67% for radiation v 82% for MOPP) and overall survival (85% for radiation v 90% for MOPP) were not significantly different between the two arms. Subset analysis showed significant superiority of MOPP in the treatment of the following patient groups: stage IIIA1 or massive mediastinal disease, no B symptoms, initial erythrocyte sedimentation rate greater than 20 mm, four or more sites of disease, and younger than age 40 years. Preliminary analysis of this ongoing study shows that MOPP chemotherapy is at least as effective as radiation therapy in the treatment of the specific groups of early-stage Hodgkins disease patients randomized. The final assessment of these two diverse treatment options will depend largely on the long-term survival and the incidence of early- and late-treatment complications for which patients are continuing to be observed.