Multiple in vitro mechanisms of tumor cytotoxicity demonstrated in the line-1 guinea pig hepatoma model.

The line-1 guinea pig hepatoma was used to study in vitro tumor cytotoxicity. Cytotoxicity was determined by measurement of the loss of tritiated thymidine-labeled target cells from culture vessels. With this technique, we demonstrated that significant tumor cytotoxicity was caused by lymphoid cells from tumor-immune guinea pigs, by cells from guinea pigs immunized against an antigen urelated to the tumor target, and by cell-free supernatants rich in lymphocyte mediators. Addition of normal peritoneal exudate cells enhanced the cytotoxic potential of a small number of highly purified immune lymphocytes, which suggested that recruitment of normal cells is an additional mechanism of tumor cell death in this system.

Comparison of adjuvant chemotherapy with methotrexate and fluorouracil with and without cyclophosphamide in breast cancer patients with one to three positive axillary lymph nodes.

BACKGROUND: Alkylating agents administered as single agents or in combination with antimetabolites or anthracyclines delay the appearance of metastases and prolong the survival of breast cancer patients after surgery. PURPOSE: This phase III clinical trial was designed to evaluate the therapeutic efficacy and toxicity of the alkylating agent cyclophosphamide in combination with the antimetabolites methotrexate and fluorouracil adjuvant to breast cancer surgery. METHODS: This study consisted of 255 breast cancer patients (a) with one to three histologically positive axillary lymph nodes and either no detectable primary tumor or operable primary tumors 5 cm or less (T0-T2) (95% of the patients) or (b) with tumors larger than 5 cm (T3) and with negative axillary nodes. Patients were randomly allocated to receive either methotrexate (60 mg/m2) and fluorouracil (600 mg/m2) (MF) intravenously on days 1 and 8 every 28 days for eight cycles or cyclophosphamide (100 mg/m2) orally on days 1-14 plus MF (CMF) every 28 days for the same duration. Median follow-up was 7.8 years, and maximum follow-up was 13 years. RESULTS: There were no statistically significant differences in time to treatment failure or overall survival for patients treated with MF or CMF. At 8 years after completion of treatment, time to treatment failure was 55% (95% confidence interval [CI] = 50%-60%) and 59% (95% CI = 54%-64%) and overall survival was 69% (95% CI = 65%-73%) and 67% (95% CI = 62%-72%) for MF- and CMF-treated patients, respectively. The hazard ratios (MF to CMF) for time to treatment failure and for survival, estimated with a proportional hazards model, were 1.02 (95% CI = 0.69-1.50) and 0.87 (95% CI = 0.56-1.34), respectively. Myelosuppression was significantly greater (P < .0001) in CMF-treated patients during cycles 1-6. Median white blood cell count nadirs were between 4.4 x 10(3)/microL and 3.5 x 10(3)/microL in patients receiving MF and between 3.0 x 10(3)/microL and 2.4 x 10(3)/microL in those receiving CMF. Dose reductions were more frequent in CMF-treated patients, which led to statistically significant differences (P < .0001) in amounts of methotrexate and fluorouracil administered. Primary cancers at other sites occurred in 14 patients (5.5%)--six treated with MF and eight treated with CMF. CONCLUSIONS: Our findings suggest that the addition of cyclophosphamide to adjuvant chemotherapy with MF offers no therapeutic advantage but results in increased myelosuppression. IMPLICATIONS: Future trials will define the possible advantages of antimetabolites in adjuvant therapy. Further information will also become available when results of the ongoing National Surgical Adjuvant Breast and Bowel Project trial comparing adjuvant MF to CMF in node-negative breast cancer patients are presented.

Malignant mesothelioma: prognostic variables in a registry of 180 patients, the Dana-Farber Cancer Institute and Brigham and Women's Hospital experience over two decades, 1965-1985.

All mesothelioma patients identified by a computer search of pathologic diagnoses at the Dana-Farber Cancer Institute (DFCI) between 1965 and 1985 were the subjects of this analysis. A total of 180 patients were identified, 136 with pleural and 37 with peritoneal mesothelioma. There were five pericardial and two testicular primaries. Of the two decades included in the study, later patients were significantly older, with a more advanced disease stage, and a lower performance status than those accrued early in the study. Factors at diagnosis associated with a significantly prolonged survival for all patients with mesothelioma included a 0 to 1 performance status, absence of chest pain, age less than 50 years, and epithelial histology. Factors at diagnosis associated with prolonged survival for the subset of patients with pleural mesothelioma included epithelial histology, 0 to 1 performance status, the absence of chest pain, an interval of greater than 6 months from onset of symptoms, and treatment with chemotherapy and pleuropneumonectomy. This last result must be interpreted with caution, since this was not a randomized study.

Peritoneal mesothelioma: natural history and response to chemotherapy.

Twenty-three patients with malignant peritoneal mesothelioma seen at the Dana Farber Cancer Institute and the University of Maryland Cancer Center from 1968 to 1982 were studied to assess the natural history of the disease and the efficacy of current treatment. Asbestos exposure was reported by 57%. Of 18 patients receiving a doxorubicin-containing regimen, 14 had measurable or evaluable disease. One complete response, four partial responses and one regression (in a patient with evaluable but not measurable disease) were observed, ranging in duration from 6 to 36 months. A single patient remains disease free for more than 36 months after subsequent radiotherapy. Significant clotting abnormalities (including disseminated intravascular coagulation, massive thrombosis, fatal pulmonary emboli, Coombs-positive hemolytic anemia, and phlebitis) occurred in 22% of the patients. Trends toward decreased survival were observed for smokers, patients presenting with ascites, and those with stage II-IV disease.

Regional nodal failure after conservative surgery and radiotherapy for early-stage breast carcinoma.

We retrospectively analyzed the likelihood of regional nodal failure (RNF) for 1,624 patients with stage I or II invasive breast carcinoma treated with conservative surgery and radiotherapy (RT) at the Joint Center for Radiation Therapy (JCRT) between 1968 and 1985. The median follow-up time was 77 months. RNF was the first site of failure for 38 of the 1,624 patients (2.3%). The incidence of axillary failure for patients undergoing axillary dissection (AXD) who were irradiated to the breast only was 2.1% (nine of 420) for patients with negative nodes and 2.1% (one of 47) for patients with one to three positive nodes. The incidence of supraclavicular failure in these two groups was 1.9% (eight of 420) and 0% (zero of 47), respectively. The incidences of axillary and supraclavicular failure in patients without clinically suspicious axillary involvement who did not have AXD but were treated with RT were 0.8% (three of 355) and 0.3% (one of 364), respectively. Despite various combinations of salvage surgery, RT, and systemic therapy, only 47% of patients (18 of 38) achieved complete regional control after nodal relapse. We conclude that RNF is uncommon in patients treated to the breast alone following an adequate AXD when the axillary nodes are negative or when one to three nodes are positive. RNF is also uncommon in patients with a clinically uninvolved axilla treated with nodal RT without AXD. Symptoms of RNF can be controlled in most but not all patients. Further study is needed to determine if the benefits of RT in preventing a small number of symptomatic RNF outweigh the potential toxicity for any subgroup of patients.

Stage IA and IIA supradiaphragmatic Hodgkin's disease: prognostic factors in surgically staged patients treated with mantle and paraaortic irradiation.

A total of 315 pathologically staged (PS) patients with IA and IIA Hodgkin's disease (HD) were treated with mantle and paraaortic irradiation, and evaluated for freedom-from-first relapse (FFR), survival, prognostic factors, and long-term complications. The 14-year actuarial FFR and survival were 82% and 93%, respectively, with a median follow-up time of 9 years. Mediastinal size was the only factor that predicted for a lower FFR, P less than .001. Forty-nine patients have developed recurrent HD. Thirty-six patients are disease-free following retreatment and only 13 patients have died of HD. Patients with mixed cellularity (MC) histology were more likely to relapse below the diaphragm (11%) as compared with patients with nodular sclerosis (NS) (5.1%) or lymphocyte predominant (LP) (3.6%) histology. These relapses were often associated with bulky pelvic nodal adenopathy and salvage treatment with chemotherapy alone often failed to control recurrent disease. Alternative diagnostic and therapeutic recommendations are presented for these patients. Thyroid abnormalities represented the most common long-term complication with an actuarial risk at 16 years of 37%. Major complications were rare. Mantle and paraaortic irradiation is associated with a high FFR and a low risk of complications and should remain standard treatment for early-stage HD.

Prognostic factors for positive surgical staging in patients with Hodgkin's disease.

Staging laparotomy was performed as part of the routine recommended diagnostic evaluation following clinical staging (CS) in 692 patients presenting with supradiaphragmatic Hodgkin's disease (HD). Various clinical factors were analyzed by multivariate analysis for prediction of abdominal involvement. Factors that were statistically significant for predicting disease below the diaphragm included CS III-IV disease (P less than .001), B symptoms (P less than .001), mixed cellularity (MC) or lymphocytic depletion (LD) histology (P = .017), number of supradiaphragmatic sites greater than or equal to 2 (P = .001), male sex (P = 0.034) and age greater than or equal to 40 years (P = .004). Separate analyses were performed for various subgroups of CS IA-IIA, CS IB-IIB, CS IIIA-IVA, and CS IIIB-IVB patients. Upstaging was seen in 0% to 55% of CS I-II patients based on subgroup. Male sex, B symptoms, and number of sites above the diaphragm greater than or equal to 2 all independently predicted for positive surgical staging in CS I-II patients. Sixty-four percent of CS I-II patients who were upstaged had extensive abdominal disease by positive lower abdominal nodes or multiple splenic nodules (greater than or equal to 5). Downstaging (to pathological stage [PS] I-II) was seen in 9% to 68% of patients with CS III-IV disease based on subgrouping. Age greater than or equal to 40, MC or LD histology, and B symptoms all independently predicted for positive surgical staging in CS III-IV patients. Downstaging was more frequently seen in CS IIIA-IVA patients (55%) than in patients who were CS III-IVB (22%). Four subgroups of patients who had a low probability (less than 10%) of stage or treatment change following laparotomy were identified. These included CS IA female patients, CS IA male patients with lymphocyte predominance histology or high neck presentations, and patients with CS IIIB-IVB disease and account for 21% of the study population. Staging laparotomy altered the stage and treatment of a significant number of the remaining 79% patients and should continue to be recommended for this group of patients.

Long-term hepatic arterial infusion of 5-fluorodeoxyuridine for liver metastases using an implantable infusion pump.

Twenty-one patients with liver metastases of various histologies (predominantly colorectal carcinoma) underwent Infusaid pump implantation for long-term hepatic arterial 5-fluorodeoxyuridine (5-FUdR) infusion. Patients received 5-FUdR infusion on a 2-wk cycle alternating with a 2-wk saline--heparin infusion. A dosage of 0.2-0.3 mg/kg/day (average 0.23 mg/kg/day) was infused for a cumulative 5-FUdR administration of 1940 days. Six patients (29%) responded to therapy (five colorectal, one carcinoid); median response duration was 6 mo. Median survival for the treated group was 17 mo from diagnosis of liver metastases and 13 mo from pump implantation. Median survival among the six responding patients was 15 mo from diagnosis of liver metastases and 11 mo from pump implantation. Comparison of survival from the diagnosis of liver metastases of the treated group to ten patients found ineligible for the study by virtue of extrahepatic metastases revealed no significant difference in median (18 mo for ineligible group) or overall survival. However, median survival for the treated group after pump implantation (13 mo) was significantly better than the median survival of the ineligible group after evaluation for this study (4 mo). Toxicities of therapy included fatigue, anorexia, nausea, vomiting, toxic hepatitis, epigastric pain, and diarrhea. No patients died of toxicity, but six patients required hospitalization for management of pain or vomiting. No serious technical complications developed in any patient except separation of the infusion catheter at its junction with the pump in one patient, necessitating pump replacement for continuation of therapy. These survival data suggest identification of new anticancer agents for hepatic arterial infusion.

Recurrence in the breast following conservative surgery and radiation therapy for early-stage breast cancer.

This report summarizes the experience of the Joint Center for Radiation Therapy (JCRT) in treating patients with clinical stage I and II breast cancer with conservative surgery and radiation therapy. The study population consisted of 1396 patients treated between 1968 and 1985. All patients underwent a gross excision of the tumor and received breast irradiation (with or without nodal irradiation) including a "boost" to bring the primary tumor site to a total dose of at least 60 Gy. The method of treatment evolved over the study-time period. During the interval from 1968 to 1982, patients typically underwent a limited gross excision of the tumor without regard to the microscopic margins of resection. During the period 1983 to 1985, film-screen mammography, inking of specimen margins, and reexcisions for inevaluable or involved margins were more commonly performed. With a median follow-up of 80 months, the 5-year crude rate of failure in the breast (as the first site of failure) was 8% (106/1396) and the crude rate of regional nodal/distant failure (as the first site of failure) was 16% (228/1396). The time-course of failures in the breast was protracted, occurring at a fairly constant rate over the first 7 years after treatment, but still seen beyond that point. Most recurrences in the breast (75%) developed at or near the original tumor site. The most important risk factor for developing a breast recurrence was the presence of an extensive intraductal component in the tumor. The cosmetic results following treatment were excellent or good in the majority of patients (87%) and were most adversely affected by extensive surgery.(ABSTRACT TRUNCATED AT 250 WORDS)

Can the clinical and mammographic findings at presentation predict the presence of an extensive intraductal component in early stage breast cancer?

The presence or absence of an extensive intraductal component (EIC) in early stage infiltrating ductal breast carcinoma has been considered to be an important factor in determining the extent of breast resection required prior to radiation therapy. It would therefore be useful if the presence or absence of an extensive intraductal component in a breast tumor could be predicted pre-operatively. To determine whether selected radiographic features might be correlated with whether or not a cancer is EIC+, we reviewed the pre-operative mammographic findings in 105 cases of Stage I and II infiltrating ductal carcinoma. Forty-one cases were EIC+ and 64 were EIC-. Both EIC+ and EIC- tumors were commonly detectable by mammography (93% and 83%, respectively, p = NS). EIC+ cancers, however, were significantly more likely to show microcalcifications with or without a mass compared to EIC- cases (83% vs 27%, p less than 0.0001). In particular, the presence of microcalcifications without a mammographic mass was more common for EIC+ cancers than EIC- cancers (34% vs 5% p = 0.0002). Conversely, a soft tissue mass without microcalcifications was seen mammographically in 56% of EIC- cases, compared to only 10% of EIC+ cases (p less than 0.0001). Predictive value calculations showed that the presence of microcalcifications in the absence of a mammographic mass conveys a 73% likelihood a cancer will be EIC+ (95% confidence interval = 39-94%). The positive predictive value of a mammographic mass or architectural distortion without microcalcifications for an EIC- cancer was 92% (95% confidence interval = 79-98%). We conclude that the mammographic findings may be useful pre-operatively in differentiating between patients with and without an EIC. Microcalcifications are much more commonly associated with EIC+ cancers than EIC- cancers, and the presence of an EIC- cancer without a mammographic mass is infrequent. Further characterization of the extent and pattern of microcalcifications might improve the predictive value of mammography in the pre-operative identification of patients with an EIC.

Late cosmetic outcome after conservative surgery and radiotherapy: analysis of causes of cosmetic failure.

Although the majority of patients with early breast cancer treated with conservative surgery and radiotherapy have acceptable cosmetic outcomes, the specific causes of a less-than-acceptable result are not well known. To assess the technical factors associated with late cosmetic failure, we reviewed the records of 593 patients treated with conservative surgery and radiotherapy at the Joint Center for Radiation Therapy, Boston, between 1968 and 1981. Median follow-up was 76 months with a range of 37-186 months. Using a 4-point scoring system (excellent, good, fair, poor) patients were noted to have cosmetic "failure" if scored as either fair or poor. Cosmetic results were similar at 3, 5, and 7 years with excellent or good scores seen in 88%, 90%, and 78% of patients, respectively. Three technical factors were associated with a significant worsening of the cosmetic results. The resection of 70 cm3 or more of breast tissue was more common among the failed patients than among matched patients with good or excellent results (p = 0.03). Eighty-nine percent of patients treated with a tangent pair technique had excellent results at 5 years compared to 69% of patients treated with a three-field technique (p = 0.004). The use of a larger volume implant was associated with a greater risk of a fair or poor cosmetic result compared to the use of a smaller volume implant. We conclude that overall cosmesis has been acceptable in this series, but there are technical (surgery and radiotherapy) factors which can be modified to optimize the cosmetic result without compromising local tumor control.

Early breast cancer: predictors of breast recurrence for patients treated with conservative surgery and radiation therapy.

The identification of factors associated with breast recurrence following conservative surgery (CS) and radiation therapy (RT) is of potential use in refining patient selection criteria and treatment technique. In an attempt to define such factors we examined the relationship between various clinical, pathologic and treatment characteristics and the likelihood of breast recurrence in 783 patients with clinical stage I or II breast cancer treated between July 1968 and December 1982. Treatment consisted of complete gross excision of the primary tumor and RT to a total dose of at least 60 Gy to the primary site. During this period, pre-treatment mammograms and detailed histologic assessment of the margins of resection were not routinely performed. Median follow-up for surviving patients was 80 months. Thirteen patients (1.6%) were lost to follow-up. Ninety-one patients (12%) have developed a breast recurrence, corresponding to 5- and 10-year actuarial rates of 10 and 18%, respectively. The major feature associated with breast recurrence was the presence of an "extensive intraductal component" (EIC+). An EIC+ tumor was seen in 28% of evaluable cases with infiltrating ductal carcinoma and accounted for 60% of breast recurrences. Forty-three of 166 patients (26%) with EIC+ tumors developed a breast recurrence compared with 29 of 418 patients (7%) without an EIC (EIC-) (p = 0.0001). The 5-year actuarial rates of breast relapse were 24 and 6%, respectively (p = 0.0001). Very young age (defined as 34 years of age or younger) was also a significant factor associated with the risk of breast recurrence. Very young patients comprised 8% of the patient population and accounted for 16% of breast recurrences. Fifteen of 61 very young patients (25%) developed a breast recurrence compared with 76 of 722 older patients (11%) (p = 0.001). The corresponding 5-year actuarial rates of breast recurrence were 21 and 9% (p = 0.005). None of the other clinical or pathological factors examined by univariate analysis were significantly correlated with recurrence in the breast. A multivariate model of site of first failure (polychotomous logistic regression) also showed that EIC+ tumors and very young age were the main factors associated with a high relative risk of breast recurrence. We conclude that EIC+ tumors and very young age are associated with a high risk of breast recurrence for patients treated with limited excision prior to RT.

Malignant intestinal obstruction.

The records of 66 consecutive patients who developed intestinal obstructions after treatment for cancer were reviewed. Approximately one third of the patients were found to have a benign cause of obstruction. The chances that an obstruction was due to cancer were increased if the patient had known metastatic cancer, previous colorectal cancer, if the primary was an advanced stage, and if the interval since treatment of the primary was short. Incomplete obstructions were treated with nasogastric suction. Although resolution of the obstruction on nasogastric suction without operation occurred in 24% of the admissions, 41% of those patients had to be readmitted for surgical relief of recurrent intestinal obstruction. Resolution of an obstruction on nasogastric suction occurred early, and there was little point in continuing a trial of suction for longer than 3 days.

Surgical therapy of localized abdominal non-Hodgkin's lymphomas.

Non-Hodgkin's lymphomas may involve a variety of abdominal organs, including the liver, spleen, gastrointestinal tract, and retroperitoneum. The number of organs potentially involved and the noncontiguous mode of spread make non-Hodgkin's lymphoma a difficult tumor to evaluate at the time of laparotomy. To clarify the surgical management of patients with this tumor, we retrospectively reviewed the medical records of 202 patients with histologically proven abdominal lymphomas. Within this group, 36 patients underwent laparotomy before they had chemotherapy or radiation therapy. Ten patients were explored to establish a histologic diagnosis of lymphoma. The remaining 26 patients underwent laparotomy because of presumed benign disease. Twenty patients were found to have localized disease at laparotomy. Patients with localized disease demonstrated significantly better survival than patients with extranodal and nodal involvement (p less than 0.05). Four patients with local resection received no adjuvant therapy and were free of disease a median of 50 months after surgery.

Identification of patients at high risk for local recurrence after conservative surgery and radiation therapy for stage I or II breast cancer.

The extent of excision prior to radiation for breast cancer is controversial. Three hundred evaluable patients with invasive ductal carcinoma received radiation therapy after gross tumor excision. The median follow-up was 70 months. Local recurrence was related to the presence of an extensive intraductal component (EIC) in addition to the invasive ductal carcinoma. From operative notes and pathology reports, patients with an EIC were categorized as having discrete masses with the extent of disease confirmed histologically or as having one of five criteria in which the final pathologic findings revealed more intraductal disease than was evident grossly or by frozen section. After ten years of follow-up, the local failure rate of patients without an EIC (193) was 3% compared with 35% for those with an EIC (107). Eight-year recurrence rates were 18% for clearly defined tumors and 71% for tumors in which the intraductal component was detectable only histologically.

Anticoagulants, venous thromboembolism, and the cancer patient.

The records of 32 cancer patients who were treated with heparin sodium and warfarin sodium for thromboembolic disease were reviewed. Standard techniques for anticoagulation were neither safe nor effective. Sixteen patients experienced 21 different hemorrhagic complications. Eight patients had major hemorrhages that led to cessation of therapy or death. Six of 32 patients had pulmonary embolisms while receiving anticoagulants. It is suggested that venous interruption may be a safer and more effective method of prophylaxis against pulmonary embolism in cancer patients.

Neoadjuvant therapy for unresectable pancreatic adenocarcinoma.

The purposes of this study were to determine whether continuous infusion of fluorouracil combined with external-beam radiation therapy improved the resectability and survival of patients with pancreatic carcinoma. Sixteen patients with unresectable disease confined to the pancreas and celiac nodes were treated, and their outcome was compared with that of 24 patients with potentially resectable disease who were treated concurrently. The neoadjuvant therapy was completed with acceptably few toxic effects but with only a minor decrease in tumor size. Two patients underwent resection and remained free of disease 20 and 22.5 months later. However, the median survival of the entire neoadjuvant group was 8 months. All 24 patients with potentially resectable carcinoma underwent surgical exploration. Fifteen of the 24 patients underwent resection and survived a median of 12.5 months. Neoadjuvant chemoradiation may have improved outcome and resectability for two (12.5%) of 16 patients with unresectable pancreatic carcinoma, but more effective therapy options must be developed to improve outcome.

Predictors of local recurrence following conservative breast surgery and radiation therapy. The influence of tumor size.

Size of tumor has not been established as a predictor of tumor recurrence in the breast following conservative surgery and radiation therapy. We analyzed 783 patients with infiltrating carcinoma treated with simple excision and radiation therapy. Median follow-up was 91 months. Median age at diagnosis was 50 years. There was a 13% recurrence among patients with T1 lesions compared with a 12% recurrence among patients with T2 tumors. Size did not predict for local recurrence when the tumor was analyzed by 1-cm increments and whether the tumor was estrogen receptor protein positive or estrogen receptor protein negative. Patients with an extensive intraductal component had a significantly higher local recurrence rate for every tumor size compared with patients with extensive intraductal component-negative tumors. We concluded that size did not predict local recurrence.

Conservative surgery and radiation therapy for early breast cancer. Long-term cosmetic results.

To evaluate the cosmetic outcome of conservative surgery (CS) and radiation therapy (RT) for early-stage breast cancer and its stability over time, we reviewed the records of 593 patients treated from 1968 to 1981. The breast appearance was scored as "excellent," "good," "fair," or "poor". Median follow-up was 76 months (range, 37 to 186 months). Cosmetic results were generally excellent or good. The percents of excellent, good, fair, and poor results at three years were 65%, 25%, 7%, and 3%, respectively. Patients not receiving adjuvant chemotherapy were more likely than those receiving chemotherapy to have excellent scores at five years (71% vs 40%). Tumor size also influenced cosmetic outcome: 73% of patients with T1 tumors vs 55% with T2 tumors had excellent scores at five years. Our results were stable over time: of 36 patients assessable at seven years whose cosmetic scores were good or excellent at three years, 34 (94%) continued to have good or excellent scores, and only two (5%) deteriorated to fair. We conclude that the cosmetic results achieved with CS and RT are good to excellent in approximately 90% of patients and that these results remain stable for at least seven years.

Clinical staging and the tendency of malignant pleural mesotheliomas to remain localized.

Thirty-two patients who had been treated for diffuse, malignant pleural mesotheliomas were retrospectively staged according to the system of Butchart. Nineteen of the 26 patients who were seen with disease confined to one hemithorax have died. Twelve patients died without progression to a higher clinical stage, and only 1 patient died of systemic metastases. Nineteen of the 32 patients died of local tumor invasion. Regimens containing Adriamycin (doxorubicin hydrochloride) appeared to prolong the survival of patients with epithelial-type tumors. Combination chemotherapy, designed to treat soft-tissue sarcomas, produced partial responses in a small number of patients.