John H. Edmonson

Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin, and cisplatin against advanced soft tissue sarcomas.

PURPOSE This three-armed phase III study in adults with advanced soft tissue sarcomas was planned as a comparison of objective regression rates, toxicity, and survival of patients receiving doxorubicin alone, ifosfamide plus doxorubicin, and mitomycin plus doxorubicin plus cisplatin. PATIENTS AND METHODS Between December 1987 and July 1990, 279 patients with histologically confirmed sarcomas were enrolled to receive treatment A (doxorubicin 80 mg/m2), treatment B (ifosfamide 7.5 g/m2 plus doxorubicin 60 mg/m2), or treatment C (mitomycin 8 mg/m2 plus doxorubicin 40 mg/m2 plus cisplatin 60 mg/m2). RESULTS Of 262 assessable patients, 74 (29%) achieved objective tumor regression. Objective regression occurred in 20% of the 90 patients who received doxorubicin alone (complete remission [CR] rate, 2%), in 34% of the 88 who received ifosfamide plus doxorubicin (CR rate, 3%), and in 32% of the 84 who received mitomycin plus doxorubicin plus cisplatin (CR rate, 7%). With grade 3 or greater myelosuppression in 53% of group A, 80% of group B, and 55% of group C, regimen B was significantly more myelosuppressive than either regimen A or C (P = .01) with two, three, and one treatment-related deaths, respectively. Synovial sarcomas were responsive to ifosfamide plus doxorubicin, especially among patients younger than 40 years of age. CONCLUSION Ifosfamide plus doxorubicin produced a significantly higher regression rate (P = .03) than did doxorubicin alone; however, this was achieved at a level of myelosuppression significantly more intense than that produced by the single agent or by the three-drug combination. Mitomycin, doxorubicin, and cisplatin also appeared to be more active than the single agent; however, at a myelosuppression level similar to that of doxorubicin alone, this trend (P = .07) did not attain the usual level for significance. No significant survival differences were observed.

Randomized Clinical Trial of Diethylstilbestrol versus Tamoxifen in Postmenopausal Women with Advanced Breast Cancer

Before the introduction of tamoxifen, diethylstilbestrol (DES) was widely considered to be the hormonal treatment of choice in postmenopausal women with advanced breast cancer. We performed a randomized clinical trial of these two agents to determine their relative efficacy and toxicity. The trial involved 143 evaluable patients, of whom 99 had received no prior systemic therapy and 44 had received previous chemotherapy. The regression rates (complete plus partial) were higher in patients receiving DES (41 per cent) than in those receiving tamoxifen (33 per cent), but not significantly so (P = 0.37). In patients who had had no prior systemic therapy, the rates were 44 per cent and 38 per cent, respectively (P = 0.55), and in those who had had previous chemotherapy, 32 per cent vs. 23 per cent (P = 0.50). Analysis of the time until treatment failure for the two treatment groups showed no significant difference (medians: DES, 142 days; tamoxifen, 171 days). Toxicity was greater in patients receiving DES; nine of 74 patients (12 per cent) discontinued therapy solely because of adverse reactions. Since there was no statistically significant difference in efficacy and since tamoxifen was less toxic, tamoxifen appears to be the preferred agent.

Prognostic significance of p53 immunostaining in epithelial ovarian cancer.

PURPOSE To evaluate the prognostic significance of p53 expression in epithelial ovarian cancer, including a subset of stage I patients, and to look for correlations between p53 expression and other disease parameters, including stage, grade, age, histologic subtype, second-look results, ploidy, and percent S phase. PATIENTS AND METHODS We analyzed p53 expression in 284 patients with epithelial ovarian cancer using immunohistochemical techniques in paraffin-embedded specimens. There were 36 patients with stage I disease, 20 with stage II disease, 186 with stage III disease, and 42 with stage IV disease. RESULTS p53 immunoreactivity was present in 177 cases (62%). p53 expression was associated with grade 3 to 4 disease (P = .003). The following factors were associated with a decrease in overall survival in a univarate analysis: stage III or IV disease (P = .0001), grade 3 or 4 disease (P = .0001), age above the median (P = .0002), and p53 reactivity (P = .04). In a multivariate analysis, stage, grade, and age retained independent prognostic significance. In the subset of 36 stage I patients, p53 positively approached statistical significance (P = .10) as a negative prognostic factor in a univariate analysis. CONCLUSION Abnormalities of p53 expression occur commonly in epithelial ovarian cancer. Although associated with decreased survival in a univariate analysis, this biologic marker did not retain independent prognostic significance in a multivariate analysis. p53 expression should be studied in a larger cohort of early-stage patients, where accurate prognostic information is needed to direct therapy.

Papillary serous carcinoma of the peritoneum. A review of 33 cases treated with platin-based chemotherapy

Thirty‐three patients were identified who had papillary serous carcinoma of the peritoneum (PSCP). The gross operative specimens, histopathologic condition, and treatment records were reviewed. The median age at presentation was 60 years (age range, 22 to 78 years). Abdominal pain and distention were the most common presenting symptoms. All patients had a total abdominal hysterectomy and bilateral salpingo‐oophorectomy, and all but two had debulking surgery. All patients had disease involving the omentum, the abdominal and pelvic peritoneum, and the surface of the ovaries, but none had intrinsic disease of the ovaries. Eight patients had disease outside of the abdominal cavity. Seven of these patients had malignant pleural effusions. All patients received platin‐based chemotherapy. Sixteen patients underwent second‐look laparotomy, two had no evidence of disease, and one had microscopic disease only. The median survival time for all patients was 17 months. Three patients are alive 6 to 7 years after the initial diagnosis. In conclusion, longterm survival can be achieved in some PSCP patients by debulking surgery and platin‐based chemotherapy.

Contrast of response to dacarbazine, mitomycin, doxorubicin, and cisplatin (DMAP) plus GM-CSF between patients with advanced malignant gastrointestinal stromal tumors and patients with other advanced leiomyosarcomas.

Background. Previous observations have suggested that leiomyosarcomas, and especially gastrointestinal leiomyosarcomas, may be less responsive to cancer chemotherapy than other histologic types of non-osseous sarcomas; however, this difference has not been characterized well until quite recently, with the recognition of the special identity of gastrointestinal stromal tumors (GIST). Prior to the general acceptance of this new histologic classification, we decided to study patients with gastrointestinal leiomyosarcomas in concert with other leiomyosarcomas for relative responsivity to a combination cytotoxic regimen developed specifically for leiomyosarcomas. Patients and Methods. Adult patients with advanced leiomyosarcomas received intravenous chemotherapy as outpatients with dacarbazine 750 μg/m2, mitomycin 6 mg/m2, doxorubicin 40 mg/m2, and cisplatin 60 mg/m2 on day 0, with granulocyte macrophage colony stimulating factor (GM-CSF, sargramostim) 250 mcg/m2 given SC every 12 hr on days −6 to −3 and on days 1–14 of each 4-week treatment cycle. Our original plan to escalate dacarbazine doses to 1000 mg/m2 following cycle one was abandoned after the first six patients because of toxicity. Results. We studied 21 patients with GIST and 18 patients with other types of leiomyosarcomas, for a total of 131 treatment cycles, with a median of four cycles per patient in each of the two groups of patients. Toxicity was significant, with 33% having grade 3 vomiting at some time during treatment. Grade 3 leukopenia occurred in 42%, and grade 3 thrombocytopenia was observed in 68% of our patients. In one patient, grade 4 pulmonary toxicity developed during the fourth cycle, and this was considered a major factor in her death. Objective tumor regression was observed in one of 21 (1.8%) (95%CI = 0–14.5%) GIST and in 11 of 18 (61%) (95%CI = 38–84%) other leiomyosarcomas, including eight of 10 uterine cases. In five cases, we interrupted chemotherapy to attempt complete surgical excision of residual tumor, and four of the patients were rendered apparently free of disease. Median survivals for the two groups have been similar with 16.7 months (95%CI = 8.8–27.5 months) for the GIST and 17.5 mos (95%CI = 10.9–35.3%) for the other leiomyosarcomas. Three patients with uterine leiomyosarcomas are still alive more than 2 years after completing this chemotherapy and subsequent secondary surgical excision (±irradiation) and two of them are free of disease. Conclusions. While this regimen is ineffective against GIST, its value against uterine leiomyosarcomas deserves further study in a larger population.

Recurrence-free survival time for surgically treated soft tissue sarcoma patients. Multivariate analysis of five prognostic factors.

A staging system, based upon the experience of 1215 patients, was published by the American Joint Committee Task Force on Soft Tissue Sarcoma in 1977. A subset of these patients, 594, was selected to study recurrence‐free survival time. The authors found 331 patients with a recurrence within 5 years (100 local only, 123 metastatic only, and 108 local + metastatic); median months to recurrence was 9.7. Within 5 years, recurrence was clearly associated with mortality: among the 331 patients who experienced a recurrence, 245 died, whereas only 31 died among the 263 who had no recurrence. To further evaluate the utility of the published staging system, a multivariate analysis of five factors was carried out for 297 of the 594 patients (patients with unknown information for any one of these factors were excluded). Factors in addition to grade that exerted a significant influence on recurrence were: direct extension, symptoms, and location of tumor when survival was measured to the first of any recurrence, and tumor size, measuring survival to the first metastatic recurrence. It is therefore recommended that these factors be taken into account in staging this disease. Estimates of probable recurrence‐free survival time based upon the multivariate model (Weibull) are also presented.

Complete responses and long-term survivals after systemic chemotherapy for patients with advanced malignant melanoma.

Five hundred three patients with advanced malignant melanoma were exposed to a number of clinical investigative chemotherapeutic regimens between 1971 and 1984 in an effort to assess the clinical activity of these regimens in this disease. Of the 503 patients participating in the studies, ten patients experienced a complete response. However, only three of these patients survived more than 5 years. Of this group of 503 patients, seven additional patients who did not experience a complete response survived more than five years. Of the ten patients surviving more than 5 years, two had immediate progression after institution of investigative regimens, whereas five remained stable for brief periods of time before progressive metastatic disease. Three patients experienced a complete response. It appeared that systemic therapeutic interventions in these trials were conspicuously ineffective for this large group of patients. A few long‐term survivors attest to the capricious nature of this neoplasm and its association with likely spontaneous regressions. Although these long‐term survivors did survive after institution of systemic chemotherapy, it is likely that this survival was related temporally, but perhaps not causally, to the institution of treatment.

Phase II trial of gemcitabine in advanced sarcomas

Care for patients with advanced sarcomas is mainly palliative. Gemcitabine, a nucleoside antimetabolite, is an analog of deoxycytidine that has shown antitumor activity in several tumors. The aim of the current study was to determine the clinical activity of gemcitabine in patients with sarcomas.

Randomized study of systemic chemotherapy following complete excision of nonosseous sarcomas.

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, Kaposis 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.

Trends and Variability in Survival Among Patients With Osteosarcoma: A 7-Year Update

This report is an update of a 1978 article on osteosarcoma in Mayo Clinic patients. It includes additional follow-up on previously reported cases and incorporates new cases treated since the time of that original study. From 1963 through 1981, 336 patients with classic, previously untreated osteosarcoma received their first definitive treatment at our institution. Survival of these patients was studied in detail. The most significant result was that survival in the 1960s was much worse than that in the 1970s. The first evidence of improvement in survival was noted in 1969; subsequently, further improvement occurred but was not consistent. This finding prevailed with respect to duration of survival to death, survival to detection of metastasis, and survival from occurrence of metastasis to death. On the basis of detailed regression analysis, several variables had independent prognostic value. From these findings, a prognostic score was developed, which was based on the number of the following unfavorable characteristics: age younger than 10 years, male sex, tumor diameter more than 15 cm, cell type osteoblastic or chondroblastic, duration of symptoms 2 months or less, and involvement of the femur or humerus. Patients with five or six of these unfavorable characteristics had a very poor survival; in contrast, patients with only one or two characteristics had a good outcome. Even when these scores were fairly constant, however, the calendar period had a strong influence on survival. Likewise, when treatment was considered and adjustments by score were made, no significant differences could be found between those patients treated by amputation only and those treated by amputation supplemented with chemotherapy or radiotherapy.