Ronald L. Stephens

Dose-response and dose-survival advantage for high versus low-dose cisplatin combined with vinblastine and bleomycin in disseminated testicular cancer a southwest oncology group study

One‐hundred fourteen patients with advanced testicular cancer were randomized to treatment consisting of either high‐dose (120 mg/m2, monthly) or low‐dose (15 mg/m2, daily X 5 monthly) cisplatin, both combined with vinblastine and bleomycin. There were 60 (53%) complete remissions and 42 partial remissions for an overall response rate of 90%. An additional 11 patients, 4 with carcinoma and 7 with mature teratoma, following surgical cytoreduction, were rendered free of disease. There was a significantly higher complete response rate for high dose induction chemotherapy, 63%, when compared with low dose, 43% (P = 0.03). A survival advantage was also observed for patients receiving high‐dose therapy (P = 0.009). For the subgroup of patients with maximal disease and embryonal ± teratoma ± seminoma histology there was a clear advantage in favor of high‐dose over low‐dose therapy both in complete response rate and survival (P = 0.03). There have been only four relapses, all occurring within 1 year of study entry. While there has been a higher frequency of leukopenia, renal, neuromuscular, and mucosal toxicity with high‐dose therapy, thus far no irreversable toxicity leading to functional impairment has been seen. The authors have demonstrated a clear‐cut relationship for dose of therapy, not only with response and survival, but with the increased potential for cure as well. Cancer 53:1029‐1035, 1984.

Overexpression of Her-2/Neu may be an Indicator of Poor Prognosis in Prostate Cancer

Previous reports have shown that Her-2/neu oncogene expression in human breast cancer and ovarian cancer may be associated with poorer prognosis. We report the expression of Her-2/neu on fresh samples of known prostatic adenocarcinoma but not on those of benign prostatic hypertrophy. Using a monoclonal antibody (TA1) directed against human Her-2/neu oncogene product and an immunohistochemical staining method, no Her-2/neu expression was noted with benign prostatic hypertrophy (15 samples). With prostatic adenocarcinoma samples, a subset (9 of 25) showed overexpression of Her-2/neu. Such overexpression is correlated with higher histological grade, higher stage of disease, and high S phase and aneuploidy on flow cytometric analysis. These findings suggest that Her-2/neu may be a prognostic marker in prostate cancer as well.

Superiority of adriamycin‐containing combination chemotherapy in the treatment of diffuse lymphoma. A southwest oncology group study

As a part of an ongoing prospective controlled trial, the Southwest Oncology Group compared the results of treatment of advanced non‐Hodgkins lymphoma with two CHOP regimens (cyclophosphamide, adriamycin, vincristine and prednisone with either low‐dose bleomycin or BCG by scarification) to a COP regimen (cyclophosphamide, vincristine and prednisone) with low‐dose bleomycin (COP‐Bleo). The study design emphasized histopathology review and systematic restaging to define complete remission (CR). Confirmed rates of CR for 443 evaluable patients were 59% for 286 patients receiving the CHOP regimens and 59% for 157 patients receiving COP‐Bleo. Rates of CR were higher for patients with nodular lymphoma (69%) compared to those with diffuse lymphoma (54%) (p = 0.005). For patients with nodular lymphoma there was no difference in CR rates according to treatment. For patients with diffuse lymphomas the CR rate was higher with the CHOP programs (58%) than with COP‐Bleo (44%) (p = 0.10). Overall duration of CR and survival was significantly longer for patients with nodular lymphoma compared to diffuse lymphoma (p < 0.01). At this time, remission duration and survival were similar regardless of induction regimen used in patients with nodular lymphoma. However, in patients with diffuse lymphoma, the duration of CR and overall survival were improved by treatment with the CHOP regimens compared to COP‐Bleo (p = 0.02). Thus, in this controlled study we have demonstrated that initial combination chemotherapy employing the CHOP regimen was a superior remission induction therapy for patients with diffuse lymphoma. Cancer 43:417–425, 1979.

Pyridoxine therapy for palmar-plantar erythrodysesthesia associated with continuous 5-fluorouracil infusion

SummaryThe limiting toxicity of low dose continuous infusion 5-fluorouracil (200–300 mg/m2/day) is often palmarplantar erythrodysesthesia (PPE). PPE developed in 16/25 patients (exact 95% confidence interval of 42% –82%) with metastatic colon cancer enrolled in a phase II trial. In this trial, 5-FU was given continuously at a dose of 200 mg/m2/day until toxicity or progressive disease forced discontinuation.The first signs of the syndrome developed at a median of 2 months following infusion initiation and, unless treatment was interrupted, became progressively worse. The incidence of moderate to severe PPE was 71% in the 14 previously untreated patients (exact 95% confidence intervals of 42–92%). Seventy-eight percent of the responders in the no prior treatment group developed PPE. The incidence of moderate to severe PPE was only 27% in the 11 previously treated patients (exact 95% confidence intervals of 6–61%). The higher incidence of PPE in the previously untreated patients probably resulted from a longer total infusion time (median = 7.3 months) than the previously treated (median = 4.5 months). The longer infusion time in turn was a result of the higher response rates (64 vs 18%) in the previously untreated versus treated groups.Five previously untreated patients who developed PPE received 50 or 150 mg of pyridoxine/day when moderate PPE changes were noted. Reversal of PPE without interruption of the 5-FU was seen in 4/5 patients. Four of these patients who received pyridoxine had responded to 5-FU treatment. No adverse affect of pyridoxine on clinical response was noted.The five previously untreated patients who received pyridoxine for PPE continued 5-FU for a median of 6 months after development of the syndrome. The six previously untreated patients who did not receive pyridoxine when they developed PPE were able to continue 5-FU for a median of only 2.5 months after development of the syndrome. A similar number of clinical responders to 5-FU were present in both groups.Considering the high incidence of PPE and response in previously untreated colon cancer patients who receive protracted continuous 5-FU, prophylactic pyridoxine in conjunction with this treatment modality might be useful.

A phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors. A southwest oncology group study

A prospective Phase II trial of combination chemotherapy in patients with metastatic carcinoid tumors was conducted by the Southwest Oncology Group. The therapy included 5‐fluorouracil, Adriamycin, cyclophosphamide, and streptozotocin (FAC‐S) or the same combination without Adriamycin (FC‐S) in patients with heart disease. Seventy‐four patients were entered and two were ineligible. Sixty‐nine of the 72 were histologically reviewed. Six patients were declared ineligible after this review. Fifty‐six patients received FAC‐S, and nine received FC‐S (one patient was inevaluable). The response rates were 31% and 22%, respectively. The median survival of all patients was 10.8 months. The analyses of various clinical and histologic parameters indicated that responses were more common in patients with gastrintestinal carcinoids; there was also a tendency toward shorter survival in patients with tumors that had a higher mitotic rate or the atypical and/or undifferentiated histologic pattern. The FAC‐S combination can produce objective responses in patients with metastatic carcinoid tumors, but these are generally partial and brief. It was also concluded that currently available chemotherapy is inadequate.

Vinblastine (VLB), bleomycin (BLEO), cis-diamminedichloroplatinum (DDP) in disseminated extragonadal germ cell tumors. A southwest oncology group study

Nineteen patients considered to have metastatic primary extragonadal germ cell cancer were entered on a Phase II chemotherapy study using as induction therapy a combination of vinblastine (VLB) 12 mg/m2 day 1, bleomycin (BLEO) 15 U/m2 I.V. or I.M. twice weekly, and cis‐diamminedichloroplatinum (DDP) 15 mg/m2 days 1–5, with vinblastine and DDP repeated at 28‐day intervals for four months. All complete or partial responders were then placed on a maintenance regimen of vinblastine 12 mg/m2 alternating monthly with actinomycin‐D 1.5 mg/m2 day 29, and chlorambucil, 10 mg/m2 P.O. days 32–37. There were three complete remissions (CRs), six partial remissions (PRs), and two stable disease. The response rate (CRs + PRs) was 56%; however, the mean duration of response was only two months (range, 1–8 months). Drug toxicity was significant and there was one toxic death. Unlike patients with disseminated testicular cancer, patients with primary metastatic extragonadal germ cell carcinoma appear to do less well on this particular drug regimen. Further investigation using different drug regimens seems necessary.

Phase III comparison of the treatment of advanced gastrointestinal cancer with bolus weekly 5‐FU vs. methyl‐CCNU plus bolus weekly 5‐FU. A southwest oncology group study

In a randomized and stratified study, 294 patients with advanced gastrointestinal cancer were treated either with 5‐fluorouracil (5‐FU) 400 mg/m2 weekly intravenously (i.v.) or 5‐FU 400 mg/m2 i.v. weekly plus methyl‐CCNU 175 mg/m2 orally (p.o.) every 6 weeks. The response rate in colorectal cancer with 5‐FU was 9.5% while the two‐drug treatment produced a response of 31.8% (p = .009). The response in all gastrointestinal cancers to 5‐FU was 10.6% as compared with 29.3% for the combination (p = .012). All responses were partial. The two‐drug regimen is more effective and more toxic than weekly 5‐FU therapy.

Improved survival duration with combination chemotherapy induction for multiple myeloma: a Southwest Oncology Group Study.

Four hundred forty previously untreated patients with active multiple myeloma were entered into a randomized trial (Southwest Oncology Group [SWOG] study 7927/28) comparing vincristine, melphalan, Cytoxan (Mead Johnson & Company, Evansville, Ind), and prednisone (VMCP) alternating with vincristine, BCNU, Adriamycin (Adria Laboratories, Columbus, Ohio) and prednisone (VBAP) with or without levamisole with vincristine, Cytoxan, and prednisone (VCP) with or without levamisole for induction therapy. The treatment groups were well balanced for all of the known major prognostic factors. Patients receiving VMCP-VBAP responded (greater than or equal to 75% regression) more frequently to induction therapy, both without (54%) and with (44%) levamisole v VCP without (28%) or with (28%) levamisole (P less than .001). In addition, patients receiving VMCP-VBAP (+/- levamisole) had a survival duration determined to be significantly increased by all forms of analysis: 48 and 33 months for VMCP-VBAP without and with levamisole v 29 and 26 months for VCP without and with levamisole (P = .011 overall). Levamisole did not improve response rates or survival duration (P greater than or equal to .1), nor did it prolong remission in the maintenance phase (P = .85). Analysis of SWOG study 7704/05 (updated April 1985) confirmed improved survival for combination therapy v MP, but no benefit for levamisole. The overall findings support the use of VMCP-VBAP as an excellent treatment option for remission induction in patients with active myeloma of all stages and prognostic categories.

Long-term survival and toxicity in small cell lung cancer. Southwest oncology group study

In the first study of combined chemotherapy and radiation therapy for small cell lung cancer by the Southwest Oncology Group, 17 patients survived more than five years after treatment was initiated (4.6 percent). Late relapse, or a second primary malignancy three to six years after diagnosis, accounted for death in five of these patients. Late recurrences involved the chest, bone, and liver; none occurred in the central nervous system. Disease-free survival continues in 10 patients (6 percent of those with limited disease and 1 percent of those with extensive-stage diseases) at a minimal follow-up in excess of six years. One definite case of chronic treatment-related toxicity occurred: congestive cardiomyopathy after 450 mg/m2 of doxorubicin, successfully managed with digitalis and diuretics. One severe neurologic problem (orthostatic hypotension with preterminal dementia) and two less severe neurologic complications (occasional falling episodes without documented cause and cerebrovascular accident) may be treatment-related. Progressive pulmonary disability, post-herpetic pain syndromes, organic brain syndrome, and hematologic abnormalities have not been observed to date. Nitrosourea administration and/or co-administration of a nitrosourea or methotrexate during the induction phase of treatment with radiotherapy to the brain may account for the higher incidence of complications observed by others in long-term survivors.

Adjuvant therapy in large bowel adenocarcinoma: long-term results of a Southwest Oncology Group Study.

The Southwest Oncology Group (SWOG) colorectal adjuvant study 7510 went through two phases. From 1975 to 1977, 309 patients were randomized to chemotherapy alone or the same chemotherapy plus immunotherapy. From 1977 until 1980, 317 patients were randomized among the same two therapy programs and a control group. With a minimum follow-up in either phase of greater than 7 years, data are now mature. They show no difference in relapse-free survival (RFS) nor overall survival (OS) in either the two-way phase or in the three-way phase. There is no indication, except possibly in one very small subset, that the addition of immunotherapy to chemotherapy provides an improvement in OS or in RFS. Using data from patients accrued after randomization to the control group, we fail to find evidence that either chemotherapy alone or chemoimmunotherapy improves OS or RFS when contrasted to outcomes obtained by patients on the control arm. In fact, we have significant evidence, at the P = .016 level, that chemotherapy does not improve OS by at least 50%; we also have significant evidence, at the P = .011 level, that chemoimmunotherapy will not improve OS by at least 25%. No evidence of efficacy was demonstrated for either treatment regimen, even though enough therapy was given to result in significant toxicities. Acute toxicity was at least moderate, but not fatal, in 75% of patients. Recognizable delayed toxicity included rare cases of fatal renal failure and acute leukemia.