Adjuvant chemotherapy with doxorubicin in high-grade soft tissue sarcoma: a randomized trial of the Scandinavian Sarcoma Group. Adjuvant chemotherapy for patients with high-grade soft-tissue sarcomas of the extremity. Eastern Cooperative Oncology Group: a comparison of adjuvant doxorubicin and observation for patients with localized soft tissue sarcoma. Adjuvant CYVADIC chemotherapy for adult soft tissue sarcoma--reduced local recurrence but no improvement in survival: a study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. Preliminary results of a randomized trial of adjuvant doxorubicin for sarcomas: lack of apparent difference between treatment groups. Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas. A randomized, prospective trial of adjuvant chemotherapy in adults with soft tissue sarcomas of the head and neck, breast, and trunk. A randomized clinical trial of adjuvant adriamycin in uterine sarcomas: a Gynecologic Oncology Group Study. A randomized trial for the treatment of high-grade soft-tissue sarcomas of the extremities: preliminary observations.
From January 1981 to February 1986, a total of 240 patients with primary, malignancy-grade III or IV soft tissue sarcoma were entered into an adjuvant chemotherapy multicenter trial conducted by the Scandinavian Sarcoma Group (SSG). Of these patients, 181 were evaluable. The tumor was located in the extremities in 155 patients. After radical surgery (wide and compartmental) the patients were randomized to treatment with single-agent doxorubicin 60 mg/m2 administered as an intravenous (IV) bolus once a month for 9 months (group 1, n = 77) or to control (group 2, n = 77). If the surgical procedure was marginal, the patients initially received postoperative radiotherapy, followed by doxorubicin (group 3, n = 16) or control (group 4, n = 11). The control groups did not receive any adjuvant chemotherapy. Adjuvant therapy was initiated within 6 weeks of surgery (group 1) or within 10 weeks of surgery for patients receiving postoperative radiotherapy (group 3). With a median follow-up of 40 months, there was no significant difference between the four treatment groups in overall survival (group 1, 75%; group 2, 70%; group 3, 69%; group 4, 73%), disease-free survival (group 1, 62%; group 2, 56%; group 3, 62%; group 4, 64%), or local tumor control (group 1, 92%; group 2, 92%; group 3, 87%; group 4, 90%). The conclusions were the same whether the total group or evaluable patients only were included in the analysis. The local recurrence rate for patients undergoing radical surgery was 8% and for patients undergoing marginal surgery followed by radiotherapy was 12%. This study indicates that the use of single-agent doxorubicin as postoperative adjuvant chemotherapy has no significant clinical benefit in patients with high-grade soft tissue sarcoma. We have previously reported the results of a randomized trial that demonstrated the survival benefit of adjuvant chemotherapy in the treatment of patients with high-grade extremity sarcomas compared with no chemotherapy. This regimen included doxorubicin, cyclophosphamide, and methotrexate. This report updates and extends our experience. The median follow-up of this trial is now 7.1 years and reveals a 5-year disease-free survival of 75% and 54% for chemotherapy and no chemotherapy groups, respectively (two-sided P [P2] = .037). The 5-year overall survival for patients in this trial was 83% and 60% for the chemotherapy and no chemotherapy groups, respectively, with a trend towards improved survival in the chemotherapy arm (P2 = .124). Because of doxorubicin-induced cardiomyopathy we performed a subsequent randomized trial comparing this high-dose regimen to reduced cumulative doses of doxorubicin and cyclophosphamide without methotrexate. Eighty-eight patients were entered into this trial which has a median follow-up of 4.4 years. The 5-year disease-free and overall survival for patients treated with the reduced doses of chemotherapy was 72% and 75%, respectively, and was not significantly different from the high-dose regimen. No patients developed congestive heart failure on this study. We conclude that adjuvant chemotherapy improves disease-free survival in patients with extremity soft-tissue sarcomas. The overall survival advantage in patients receiving adjuvant chemotherapy in our initial randomized high-dose chemotherapy trial has diminished though it continues to favor the chemotherapy group. A reduced-dose chemotherapy regimen was found to be comparable to the high-dose regimen. Forty-seven patients with stage I, II, or III soft tissue sarcoma were entered into a prospective randomized Eastern Cooperative Oncology Group (ECOG) adjuvant protocol. Eligibility included conservative or radical primary treatment for local cure. Patients were then randomized to control or Adriamycin (Adria Laboratories, Columbus, OH). Adriamycin was administered at 70 mg/m2 (slow push, every 3 weeks for seven courses for a maximum of 550 mg/m2). To date, 32 patients, 17 males and 15 females, with an age range of 17 to 75 years (median, 44 years) have been followed sufficiently long to be included in this analysis. Nine patients have died. The median follow-up of the remaining 23 patients is 30 months (range, 2 to 50 months). Survival was not significantly different between Adriamycin or control. However, the disease-free interval was slightly different in favor of observation. This preliminary report does not support the hypothesis that Adriamycin is an effective adjuvant therapy for soft tissue sarcoma. Due to the small numbers, these results must be interpreted in relation to our ability to detect a difference, if in fact one existed. These preliminary data suggest that adjuvant Adriamycin not be used outside the confines of a clinical trial such as the current intergroup adjuvant sarcoma study. To evaluate the benefit of adjuvant chemotherapy in adult patients with soft tissue sarcomas. The principal end points were freedom from local recurrence and/or metastases and overall survival.
                Between January 1977 and June 1988, 468 patients entered this randomized study and 317 were considered eligible. Following complete surgical resection with or without radiotherapy, outcome in 145 eligible patients receiving cyclophosphamide 500 mg/m2 intravenously (IV) bolus on day 1, vincristine 1.4 mg/m2 IV bolus on day 1, doxorubicin (Adriamycin; Adria Laboratories, Columbus, OH) 50 mg/m2 IV bolus on day 1, and dacarbazine (DTIC) 400 mg/m2 by 1-hour infusion on days 1 to 3 (CYVADIC) cycles repeated every 28 days for eight courses was compared with that in 172 control patients.
                With a median follow-up duration of 80 months (range, 39 to 165), actuarial percentage survival figures at 7 years were compared. Relapse-free survival rates were higher for CYVADIC, 56% versus 43% (P = .007), and local recurrence was significantly reduced in the CYVADIC arm at 17% versus 31% (P = .004). In contrast, distant metastases occurred with similar frequency in both arms, 32% for CYVADIC versus 36% for control patients (P = .42), and overall survival rates were not significantly different at 63% versus 56% (P = .64). A reduction in local recurrence was only apparent in the group of head, neck, and trunk sarcomas (P = .002), but not in limb tumors (P = .31).
                Adjuvant chemotherapy with CYVADIC cannot be recommended outside the context of a clinical trial. Experience from this study has been used to plan a trial of neoadjuvant chemotherapy with doxorubicin/ifosfamide, which is currently in progress. Forty-two patients with localized intermediate and high-grade sarcoma were randomized after optimal primary treatment to receive five cycles of adjuvant doxorubicin 90 mg/m2 every three weeks (20 patients) or observation (22 patients). Patients were stratified for grade, size, extent of surgical margin, and soft tissue versus other sarcomas. Groups appeared balanced for histology and superficial versus deep lesions. Eight patients (19%) have died. Follow-up times range from two to 69 months (median, 16 months). Two patients receiving doxorubicin (10%) developed cardiotoxicity presenting as pulmonary edema. One patient returned to normal activity on digoxin and diuretics; the other (age, 28 years) died of intractable failure and arrhythmias after four weeks. While a nonsignificant difference in local control, metastasis-free survival, disease-free survival, and survival was observed for extremity lesions, the advantage may be outweighed by the risk of cardiotoxicity. Seventy-six percent of the control patients with extremity lesions remain disease free. Because control patients do well, a very large study is required to define the role of adjuvant doxorubicin. Between June 1975 and April 1981, 61 of the 177 eligible patients whose nonosseous sarcomas of extremity or trunk origin had been completely excised primarily or after local recurrences agreed to participate in a randomized study of adjuvant chemotherapy. Dermatofibrosarcoma, lymphomas, myeloma, Kaposi's sarcoma, and embryonal rhabdomyosarcoma were excluded as were patients with significant second primary cancers and those who received either preoperative or postoperative radiation therapy. After stratification by anatomic status of disease, site of origin, and histologic grade, a random one half of the 61 participants began alternating courses of vincristine/cyclophosphamide/dactinomycin, and vincristine/doxorubicin/dacarbazine at six-week intervals for one year. The control group was evaluated at six-week intervals without adjuvant chemotherapy, but these patients were offered this chemotherapy later if they had progressive disease excised. Although 30% of the 61 patients experienced local recurrence of disease within the first five years after randomization, and only 54% were continuously disease free for five or more years, 82% were surviving at five years (Kaplan-Meier calculations) with a median follow-up of 64.3 months. Partial suppression of distant metastasis by adjuvant chemotherapy was apparent in the overall study, in the extremity tumor category, and in the subgroup of patients who had received limb-sparing surgery; however, no survival advantage for chemotherapy-treated patients was demonstrated. The 30 adjuvant chemotherapy-treated patients received a total of three thoracotomies as compared with 17 salvage thoracotomies for the 31 control patients; however, salvage surgery for local recurrences has been similar in the two groups. Recent improvement in the survival of patients with soft-tissue sarcomas is not necessarily a result of adjuvant chemotherapy or radiation therapy. Since 1977, 31 patients were entered in a randomized, prospective study testing the efficacy of adjuvant chemotherapy after aggressive local treatment of high-grade sarcomas of the head, neck, breast, and trunk (excluding retroperitoneal sarcomas). All patients had complete resection of gross tumor and underwent postoperative radiotherapy (6000-6300 rads over 7-8 weeks). Seventeen patients received adjuvant chemotherapy consisting of doxorubicin (less than or equal to 550 mg/m2), cyclophosphamide (less than or equal to 5500 mg/m2), and methotrexate (less than or equal to 1000 mg/kg). Three-year actuarial disease-free survival in the chemotherapy arm was 77%, compared to 49% in the no-chemotherapy arm (P = 0.075). Three-year overall actuarial survivals in the two treatment arms, however, were 68% and 58%, respectively (P = 0.38). Considering only patients with tumors of the trunk (22 patients), 3-year actuarial disease-free survival in the chemotherapy arm was 92%, compared to 47% in the no-chemotherapy arm (P = 0.006). Actuarial 3-year overall survival in the chemotherapy arm was 82%, compared to 61% in the no-chemotherapy arm (P = 0.18). An additional 26 patients were treated in an identical fashion, but were not part of the randomized trial because of contraindications to chemotherapy, refusal to enter the randomized trial, or because they were treated before 1977 in a trial in which all patients received chemotherapy. Considering the entire group of 57 patients, follow-up ranged from 10 to 86 months (median, 35 months). Local control was achieved in 46 patients (81%); 3-year actuarial disease-free and overall survivals were 67% and 77%, respectively. A tendency toward improved disease-free survival was apparent among patients treated with chemotherapy (P = 0.018), but there was no statistically significant improvement in overall actuarial survival (P = 0.46). The subgroup of patients with sarcomas of the trunk (39 patients) demonstrated the greatest benefit from chemotherapy, with regard to disease-free survival (P less than or equal to 0.001). The most significant toxicity associated with chemotherapy was doxorubicin-induced cardiomyopathy, which resulted in clinically apparent congestive heart failure in five patients. Thus, the use of chemotherapy when combined with aggressive local measures appears to improve disease-free survival, but additional patients and longer follow-up are necessary to determine if improved overall survival will result. After hysterectomy, 156 evaluable patients with stage I (limited to the corpus) or stage II (limited to the corpus and cervix) uterine sarcomas were randomly assigned to adjuvant chemotherapy with Adriamycin (Adria Laboratories, Columbus, Ohio) for six months or to no further treatment. Pelvic irradiation (external or intracavitary) was optional before randomization. Of 75 patients receiving Adriamycin, 31 have suffered recurrences compared with 43 of 81 receiving no adjuvant chemotherapy. This difference is not statistically significant. Moreover, there is no difference in progression-free interval or survival. The optional radiotherapy did not influence the outcome although there was a suggestion that vaginal recurrence was decreased by pelvic radiotherapy. The recurrence rates in specific cell types (leiomyosarcoma, homologous mixed mesodermal sarcoma, or heterologous mixed mesodermal sarcoma) were not significantly different although the pattern of recurrence differed, with pulmonary metastases being more common in leiomyosarcoma and extrapulmonary recurrence being more common in mixed mesodermal sarcoma. The outcome with respect to chemotherapy was not altered even after adjusting for maldistribution of cases. Thus, we could not show a benefit for this dose schedule of Adriamycin as adjuvant treatment for uterine sarcomas. A new trial for evaluating the effectiveness of adjuvant chemotherapy in high-grade soft-tissue sarcomas of the extremities in adult patients is presented. All patients after local treatment were randomized into two arms, one without further therapy and the other to receive adjuvant chemotherapy (Adriamycin [Farmitalia-Carlo Erba, Milan, Italy], 450 mg/m2). The preliminary results of the study are reported at a median observation period of 27.6 months. Of the 59 patients who entered the study, 79.1% in the chemotherapy group are without sign of disease, whereas the corresponding figure in the nonadjuvant chemotherapy group is 54.3%. The difference between the two groups is statistically significant (P less than .005, log rank test). These preliminary observations encourage continuation of the study.