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Nineteen studies of advanced cancer in 8 disease sites have been examined using data from the Eastern Cooperative Oncology Group. The purpose of the investigation was to determine susceptibility of elderly patients (greater than or equal to 70 years of age) to cancer chemotherapy and to compare the results with corresponding figures in control patients (less than 70 years of age). The results indicate that in general, the elderly patients have identical rates of severe toxicity as their younger counterparts. The only exception is for hematologic reactions in a few of the sites studied. On closer examination, the agents that appear to be responsible for these especially adverse effects are methotrexate and methyl-CCNU. It is demonstrated that the elderly patients have similar response rates and survival expectancy to the nonelderly patients. Consequently, it is concluded that the apparent discrimination in not treating elderly patients as aggressively as younger patients, and in excluding elderly patients from protocols, does not appear to be justified. Exclusions should be based on physiologic functional parameters, such as measures of renal, liver and marrow function, or performance status, rather than on an arbitrary age limit. Exceptions should only be made for agents which have a clearly demonstrated adverse effect on the elderly.

One hundred and forty-four evaluable patients with recurrent or metastatic renal cell carcinoma (RCC) were treated with vinblastine infusion (n = 35), L-alanosine (n = 36), acivicin (n = 27), or aminothiadiazole (n = 46). Observed objective response rates of 9%, 3%, 4%, and 2%, respectively indicate that noe of these agents has significant antineoplastic activity in recurrent or metastatic RCC. Multivariate analysis of survival data suggests that initial performance status, time from initial diagnosis to study entry, and the presence or absence of lung metastases are important prognostic factors for survival. After adjustment for these factors, treatment assignment was also seen to be of prognostic value. All four treatments were generally well tolerated. There were no reports of life-threatening or lethal toxicities; however, 37% of the patients experienced severe reactions to treatment, primarily myelosuppression, anemia, neuropathies, and mucositis.

Two hundred and fifty-eight patients with small cell carcinoma and 185 patients with adenocarcinoma were centrally randomized to receive either cyclophosphamide (1000 mg/m2 every 3 weeks) iv or cyclophosphamide (700 mg/m2 every 3 weeks) iv plus CCNU (70 mg/m2 every 6 weeks) orally. Those patients who were initially treated with the single agent were then treated with CCNU (130 mg/m2 every 6 weeks) at the time of cyclophosphamide failure. Objective tumor regression occurred more frequently with the combination regimen in patients with small cell carcinoma (43% vs 22%, P = 0.002), but no difference in response rates was apparent in patients with adenocarcinoma. In both cell types patients survived somewhat longer following treatment with the combination. The overall incidence of severe toxicity was equal for the two regimens in both cell types; however, the therapeutic index of the combination was superior to that of the single agent in small cell carcinoma. Severe drug toxicity was more frequent in small cell carcinoma patients with extensive disease, and survival was reduced in both cell types with extensive disease. Survival was better for ambulatory patients in both cell types and women survived longer than men. In women with small cell carcinoma, ambulatory status also was associated with a higher incidence of tumor regression. In patients with small cell carcinoma those who had prior lung surgery survived longer than those without prior surgery. Previous radiation therapy was associated with a reduced incidence of objective regression in men with small cell carcinoma. In both cell types patients with tumor regression lived longer than nonresponders; however, objective disease stability was associated with improved survival only in patients with adenocarcinoma. Stratification in future studies should consider extent of disease, performance status, sex, and prior therapy.

Thirty-six patients with stage III and IV Hodgkin's disease and non-Hodgkin's lymphoma, who had become refractory to conventional chemotherapy, were treated with VM-26. Complete remissions were documented in two patients with diffuse histiocytic lymphoma. Six patients (four with non-Hodgkin's lymphomas and two with Hodgkin's disease) had partial remissions. The overall response rate was 22% (eight of 36 patients). Hematologic toxicity was the most frequent dose-limiting toxicity. Nonhematologic toxic effects were mild and acceptable. This study demonstrates that VM-26 can produce tumor responses in refractory lymphomas. The Eastern Cooperative Oncology Group is currently planning two new phase II studies to incorporate VM-26 with other active new agents, one involving hexamethylmelamine and the other involving cis-dichlorodiammineplatinum(II).

Chemotherapy once relegated to end stage patients has markedly improved with the use of combinations. Response rates with single agents have improved from 15 to 35%, to 50 to 70%, using combinations with an increase in complete response rates to about 25%. A series of four studies completed by the Eastern Cooperative Oncology Group over the past eight years typifies the improvement in response rates achieved by combinations as compared to single agents. Survival gain can be demonstrated for responders vs non-responders; however with current combinations, there is an apparent plateau in response rates (55 to 60%), durations of response (eight months) and survival for responders (18-22 months) as compared to survival of non-responders (six to eight months). Further improvement in response rates may occur by searching for new agents, combining hormonal and immunostimulation with chemotherapy or by sequencing non-crossresistant combinations. However, since most patients with breast cancer present with local or regional disease but go on to die of disseminated cancer, major improvements in survival are most likely to occur by treating this neoplasm as a systemic disease through cobmining effective local therapy with systemic treatments.

The propensity for metastatic testicular teratocarcinoma to undergo differentiation, particularly when associated with successful cancer chemotherapy, means that the histology of residual disease following chemotherapy cannot be assumed without biopsy. We present 4 cases in which biopsy of a metastasis was important in determining the management of the patient. We conclude that because of the variable nature of the transformation of metastases in testicular germ cell tumors, particularly after chemotherapy, residual disease will often need further biopsy to establish whether it represents residual malignant disease or benign transformation.

A syndrome, including microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and renal insufficiency, has been recognized to occur as a complication of antineoplastic therapy with mitomycin. The clinical presentation can vary from a chronic course with mild anemia and slowly progressive renal dysfunction to a fulminant course with severe anemia, rapid deterioration of renal function, and death. The optimal treatment of the mitomycin-associated MAHA syndrome is unknown. Therapy with steroids, antiplatelet agents, and heparin sodium has failed to reverse the MAHA. Plasmapheresis has improved the MAHA in a few patients without reversing the renal failure. We treated two patients who had MAHA and renal dysfunction during chemotherapy that included mitomycin; the MAHA and hypertension both objectively improved after treatment that included vincristine sulfate.

Adjuvant therapy in the past 10 years has gone from experimental to clinical practice for women who are premenopausal. For the postmenopausal and the elderly patient the treatment for some is still experimental and for others proven. Obviously, we need to collect data for all patients because we do not have information on 10 or 20 year survivals, the long-term effects of chemotherapy, or the role of adjuvant hormonal therapy. Likewise further trials are needed to define the optimal duration of treatment, the role of adriamycin combinations, and the utility of chemotherapy in node negative patients. Future trials will undoubtedly include lesser surgery options. The hope of the future lies in the definition of more specific options for treatment, avoiding the unnecessary toxicity of radical surgery, extensive X-ray therapy or needless chemotherapy. These answers will come from well-designed clinical trials, well-integrated with good laboratory studies designed to explore biological as well as mechanistic questions.

A system is proposed by the UICC for assessing response to treatment of advanced breast cancers.

Thirty evaluable patients with histologically confirmed primary liver cancer (PLC) were treated with neocarzinostatin (NCS). All patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 2, or 3. NCS 2250 units/m2 was given daily for 5 days, repeated at 28-day intervals. Hemopoietic suppression was the major side effect. In 23 of 30 patients (13 with leukopenia and 19 with thrombocytopenia), this toxic effect was documented. Other toxic effects included nausea, vomiting, allergic-type reaction, and elevation of NPN. Partial response, with a median duration of 12.7 weeks (range 4--37 weeks) was observed in seven patients. In nine patients the response was classified as no change, and in 14 patients there was progressive disease. NCS has some therapeutic activity in patients with PLC.

A total of 43 patients with non-small cell carcinoma from a small preliminary trial and a larger in-house study were evaluated after treatment with cisplatin (50 mg/m2), doxorubicin (50 mg/m2), cyclophosphamide (300 mg/m2), and vincristine (1.4 mg/m2), all given iv on Day 1, and lomustine (50 mg/m2) given orally on Day 1. The response rate in the larger trial was 9%, with a 95% confidence interval of 2%-24%. For the combined group of all patients, median survival was 200 days, with a 95% confidence interval of 115-229 days. Hematologic toxicity and nausea and vomiting were moderate to severe and there were two treatment-related deaths. This combination drug regimen appears to have no advantages over other, less toxic regimens in the treatment of non-small cell bronchogenic carcinoma.

Thirty-two women with advanced local regional breast carcinoma, including nine patients with histologically diagnosed inflammatory cancer, were entered on a prospective pilot study. They were treated aggressively with initial surgery, two courses of induction chemotherapy with cyclophosphamide, methotrexate, 5-fluorouracil, +/- prednisone, +/- tamoxifen (CMF [P] [T]), local-regional radiotherapy, and then maintenance chemotherapy with CMF(P) (T) alternating with doxorubicin, vincristine, +/- tamoxifen (AV[T]). The patients have been followed for 19-70 months from the time of mastectomy and their actuarial three-year survival is 65% with a median survival that has not yet been reached. Median disease-free survival (time to progression) is currently 29.5 months. Women whose gross disease could not be totally resected surgically had shorter disease-free survivals than those rendered surgically free of disease (p = 0.01). Clinically evident cardiotoxicity was seen in 25% of the patients and was felt to be primarily due to the combination of doxorubicin and radiation therapy. It was significantly more common (Plt less than 0.05) in patients with left chest irradiation (seven of 18 women) as opposed to those with right-sided irradiation (one of 14).

A 20-yr-old male had compression of the thoracic aorta by a large malignant mediastinal germinoma. The symptoms and signs that simulated coarctation of the aorta included hypertension, markedly decreased femoral pulses, and a systolic murmur that radiated to the back. Following X-ray therapy, the femoral pulses were palpable and the blood pressure became normal. To our knowledge, compression of the aorta by a malignant teratocarcinoma with manifestations mimicking coarctation of the aorta has not been reported.

The results of treatment of 198 patients with Hodgkin's disease with MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) were analyzed. Eighty percent attained complete remission, and 68% of patients achieving a complete remission have remained disease free beyond 10 years from the end of treatment. Results of autopsy on patients who died of other causes while in clinical complete remission did not show evidence of residual tumors except in one patient. Asymptomatic patients and patients with mixed-cellularity or lymphocytic-depleted Hodgkin's disease do significantly better than symptomatic patients and those with nodular sclerosing histologic type. Advanced Hodgkin's disease appears to be curable by chemotherapy.

The Eastern Cooperative Oncology Group has studied 113 patients with generalized progressive malignant lymphomas in a randomized clinical trial. Pathologic diagnosis was subclassified by cell type and nodal pattern by The Pathology Panel for Lymphome Clinical Trials. Patients were randomly assigned treatment with either cyclophosphamide (C), vincristine (O), and prednisone (P) (COP) or CO without prednisone. Initial treatment was given for 8 weeks and further randomization of responders to observation or additional chemotherapy was carried out. A significant difference in complete remission rate between treatments was shown: with COP, 43%, and with CO, 17%, indicating an important role for prednisone in inducing CR. COP was also associated with longer remission durations and improved survival. Complete remission following initial chemotherapy is also associated with longer duration of disease-free time and survival. The initial pathologic cell types and nodal pattern also strongly influence survival. Extended "maintainence" CO treatment improved disease-free remission duration, but not survival.

The medical records of 52 patients from the University of Wisconsin Hospital and Clinics with carcinoma of the gallbladder were examined retrospectively. The cases were reviewed for factors in their medical history, presenting physical examination, laboratory data, therapy, pathological grade, and histology that might effect median survival. Only a prior complaint of anorexia, an elevated lactic dehydrogenase (LDH), or advanced pathologic stage at time of diagnosis provided significant prognostic information. Combining pathologic stage and histologic grade additively provided the most significant prognostic information [1]. Division of gallbladder carcinoma patients in future clinical trials by this combined (stage and grade) stratification scheme may prove helpful in assessing the efficacy of new therapies. The knowledge that anorexia and elevated LDH are poor prognostic findings may assist physicians in counseling patients with this malignancy.

While new, community-based family practice residency programs desperately need support from sister departments in academic centers, a variety of problems frequently prevents such cooperation. At the University of Wisconsin, Madison, the Department of Human Oncology, which is University Hospital-based, has worked to develop an appropriate educational program in oncology, together with and for the Department of Family Medicine and Practice, which is community-based. This paper, relating how and why these two departments have cooperated in this project, is presented to assist other departments in similar situations.

A prospective randomized trial was conducted comparing the clinical response of 78 previously untreated patients with advanced metastatic breast cancer to a combination of cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) or to a combination of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF). Sixty-two percent of the patients receiving CMF responded to treatment compared to an 82% response rate for the patients receiving CAF. Although within acceptable limits, hematologic and GI toxicity was greater with CAF. There was no significant difference in the duration of response to the two regimens. Therefore, the therapeutic difference between the two therapies is a higher initial response rate to the adriamycin containing regimen.

The acceptance of ACT has been very rapid since 1974 although earlier studies by Nissen-Meyer and the NSABP in the 1960's originally suggested the effectiveness of modest short-term chemotherapy [16, 17]. The current practice is to administer combination chemotherapy for at least 6 months in all node-positive women. The survival benefits are clearly established only for women who are premenopausal and who have fewer than three positive nodes. Trials in other groups of patients are highly suggestive but have lacked some or all of the rigorous standards of the randomized clinical trial. The reasons for this widespread acceptance of ACT are not clear, but both patients and physicians are able to appreciate the concepts and bear the costs in terms of money as well as toxicity. The risks of ACT are mainly short term and reversible. Long-term consequences are not so readily apparent as yet. The benefits of improved survival will only be appreciated as more time passes, either through the long-term analyses of the current trials or the overwhelming success of a new strategy. Then all the past arguments about one therapy or another will become irrelevant. At that point this new miracle treatment will be so good that none will ask whether CMF is better than surgery alone. In essence, the old standard has become the control.

After mastectomy, 265 postmenopausal patients with node-positive breast cancer were stratified according to pathologic nodal status and estrogen-receptor (ER) status and randomized to receive either 12 cycles of cyclophosphamide, methotrexate, 5-fluorouracil, and prednisone (CMFP), or CMFP plus tamoxifen (CMFPT), or observation alone. Patients entered the study between March 1978 and July 1981. Cox regression analysis indicated that, compared to observation alone, chemotherapy (CMFP and CMFPT groups combined) led to a significant reduction in relapses by the end of the first year of study in every examined prognostic subgroup. However, after the first year the relapse-free survival curves of all treatment groups tended to merge, so that by three years 52% of the observation group and 51% of the chemotherapy groups remained disease free. Chemotherapy continued to show a significantly superior relapse-free survival rate for three years only in the subgroup of patients with ER-negative tumors (the subgroup with the largest relapse-free survival advantage at one year). The addition of tamoxifen produced no benefit or harm in any prognostic subcategory examined. ER status was prognostically important for predicting early relapse only in those patients not receiving chemotherapy, due to the greater effectiveness of this chemotherapy to prevent early relapse in the ER-negative subgroup. Treatment has had no early effect on survival. As breast cancer continues to recur even after ten or more years, later relapse patterns may alter these results.

An enhancing interaction of a human serum factor with other sources of colony stimulating activity (CSA) is described. Using a mouse colony forming cell assay, the enhancing effect of human serum was observed with suboptimal doses of colony stimulating material from monocytic cell feeder layers, supernatant from peripheral monocytic cells, and L cell supernatant. The enhancing factor is heat stable, is not dialyzable and is not extractable by ether. The enhancing phenomenon does not require the presence of viable cells in the feeder layers. The observation of enhancing interaction makes interpretation of all data from CSA stimulation experiments more complex than previously appreciated.

34 patients with the diagnosis of diffuse well-differentiated lymphocytic lymphoma (DLWD), confirmed by a Pathology Panel, who were entered on a previously reported Eastern Cooperative Oncology Group study (EST 1472), were analyzed for response and survival. The response rates were as follows: CR 32%, PR 39%, NC or PD 29%. Survival analysis according to chemotherapy response revealed an estimated two-year survivorship of CR 89%, PR 65%, NC 69%, and PD 44%. Comparison with NLPD entered on the same study showed a two-year survival of 83% for NLPD and 67% for DLWD, indicating significantly poorer survival for DLWD as compared to NLPD (p less than .05). Median survival for DLWD from diagnosis was 39.0 + months. The presence of lymphocytosis over 4000/mm3 had little effect on response rates or survival. We conclude that DLWD is a less favorable lymphoma type than NLPD and should be treated with aggressive chemotherapy since achievement of CR seems to effect survival favorably.

Pharmacological data are currently available for a number of antineoplastic agents which have shown clinical activity in advanced breast carcincoma. Preclinical data reveal a relationship between therapeutic response and certain pharmacokinetic parameters such as time of effective cytotoxic exposure (Teff) and the product of concentration with time (Cxt). We have attempted to apply human pharmacologic data to get estimates of these parameters for 6 active agents in breast cancer, to relate them to response rates, and to suggest a method for estimating the role of individual drugs in a multidrug combination. The response rates for 6 single agents were obtained from literature review and related to estimates of Teff and Cxt. The Cxt-response relations for single drugs were linear for cyclophosphamide, 5-fluorouracil, and thiotepa; exponential for vincristine; and relatively flat for methotrexate and cytoxine arabinoside. Most Teff values for the active single agents clustered about 15 hr/dose. From the graphs of response rate vs Cxt, the individual contribution of each agent in a combination study was estimated to arrive at a predicted response rate. The predicted response rates for the combination studies correlated with the actual response rates determined in the clinical study, for 6 of 6 nonrandomized studies and for 12 of 14 randomized studies analyzed. In 2 studies, deviations from the predicted response rate were attributed to differences in study design or analysis. There was no correlation between Teff and predicted response rate. Analyses of pharmacokinetic data may be useful to simulate combination chemotherapy studies to predict the effectiveness of clinical trials in breast cancer. Since the pharmacologic data were not obtained for any of the agents in the actual clinical trials done, we can only speculate on the usefulness of this method. We would encourage the prospective collection of this data in future clinical trails.

The Eastern Cooperative Oncology Group assessed the activity of diglycoaldehyde (DGA), VP-16-213, and the combination of methyl-CCNU and beta-2'-deoxythioguanosine in previously treated patients with advanced colorectal cancer. Objective responses were seen in two of 40 evaluable patients receiving methyl-CCNU and beta-2'-deoxythioguanosine and in one of 35 patients receiving DGA. None of 33 patients responded to VP-16-213, but one death related to sepsis and bone marrow failure occurred. Survival of patients whose previous chemotherapy included a nitrosourea was markedly shortened compared to those who had not been exposed to nitrosoureas. With the possible exception of DGA, further treatment of patients with colorectal cancer with these therapies is not warranted.

This is a comparative study to evaluate response rate to mitoguazone (MGBG) and vinblastine (VLB) in 52 evaluable patients with advanced transitional cell carcinoma of the urinary tract. Of 38 patients with measurable disease, two of 18 (11%) on MGBG had partial remission (95% confidence interval: 0.01, 0.35), whereas four of 20 (20%) responded on the VLB arm (95% confidence level: 0.06-0.44). Both responses on the MGBG arm were seen in patients given prior chemotherapy. Side effects of both drugs were significant, with 46% of patients given VLB developing severe or life-threatening hematologic toxicity. Data indicate that both drugs, as single agents, are probably inferior to cisplatin for control of advanced transitional cell carcinoma of the urinary tract.

One hundred and sixteen patients with advanced and metastatic adenocarcinoma of the pancreas were randomized to treatment with combined Streptozotocin and 5-fluorouracil or combined Streptozotocin and cyclophosphamide. Toxic reactions to each regimen were qualitatively similar and consisted of nausea and vomiting during the time of treatment and subsequent leukopenia and thrombocytopenia. Renal toxicity was less frequent and only rarely severe. Among 51 eligible and evaluable patients treated with the Streptozotocin-cyclophosphamide combination, 12% showed objective response and among 42 patients treated with Streptozotocin + 5-fluorouracil, 12% showed objective response. The Streptozotocin + 5-fluorouracil-treated patients showed a slight advantage in survival. Neither regimen can be considered of substantive value to the patient with advanced pancreatic carcinoma.

The 99mTc diphosphonate scan is important in the study of primary breast cancer. The short-term prognosis for scan-positive patients is poor. Serial bone scans provide a safe and reliable prognostic index in patients following mastectomy. By correlating the scan with biochemical tumor markers, a matrix of diagnostic tests may be developed that is capable of identifying high-risk patients who may benefit from systemic therapy.

We observed major responses in two patients with adenocarcinoma of the lung who had received a combination of interferon (IFN)-beta and IFN-gamma, immediately followed by chemotherapy. To verify these observations, we initiated a prospective randomized phase II-III trial of etoposide and cisplatin, with or without IFN-beta and IFN-gamma, in patients with inoperable non-small cell lung cancer. Thirty-seven patients were randomized to receive either two cycles of chemotherapy or 6 weeks of IFN-beta plus IFN-gamma followed by two cycles of chemotherapy. Chemotherapy consisted of 60 mg of cisplatin/m2 on day 1 and 120 mg of etoposide/m2 on days 4, 6, and 8, repeated every 21 days. Patients who were randomized to the IFN plus chemotherapy arm received 200 micrograms of IFN-gamma and 30 x 10(6) U of IFN-beta three times per week for 6 weeks, followed by two cycles of chemotherapy. Three of 18 (17%) eligible patients in the chemotherapy arm and two of 18 (11%) patients in the combination arm had partial responses. All responses occurred while patients were receiving chemotherapy. Median survival was 190 days for the chemotherapy arm and 246 days in the combined modality arm, as estimated from Kaplan-Meier curves (P = .35). We observed no significant difference in subjective toxic effects between the two arms. We observed more hematologic toxicity during chemotherapy on the combined modality arm (P = .02). We conclude that pretreatment with IFN-beta and IFN-gamma does not enhance the efficacy of etoposide and cisplatin in this disease. Although the combined modality arm is relatively well tolerated, it does result in more chemotherapy-associated toxic effects. This study also exemplifies a hybrid phase II-III trial design, which is useful in allowing phase II results to be quickly incorporated into a phase III trial.

Thirteen patients with lymphoma of the breast are presented. In addition, 163 previously reported cases of lymphoma of the breast are reviewed. Complete staging was performed on all patients. No patient had a diagnosis of lymphoma prior to breast biopsy. The histologic findings were diffuse histiocytic lymphoma (DHL) in eight patients, nodular lymphocytic poorly differentiated lymphoma (NLPD) in two patients, nodular mixed lymphoma (NM) in two patients and nodular sclerosing Hodgkin's disease (NSHD) in one patient. Five patients had Stage IV disease, two had Stage III disease, four had stage II disease and two Stage I disease. Nine patients each underwent an excisional biopsy and four patients each had a modified radical mastectomy as initial therapy. Two patients each underwent a staging laparotomy. In advanced disease, chemotherapy achieved complete remissions in approximately 50% of patients. Unfavorable histologic findings are most common in lymphoma of the breast and thorough staging is necessary to select the best form of therapy. The absolute survival rate (61%) and the disease free survival rate (46%) are similar to nodal lymphoma of corresponding histologic factors and stage.

By random assignment a total of 176 eligible patients with advanced nonmeasurable pancreatic carcinoma were treated with 5-fluorouracil (5-FU) either alone or in combination with a nitrosourea (streptozotocin), in combination with a "lactone" (spironolactone), or in combination with both. By random assignment a total of 179 patients with advanced nonmeasurable gastric carcinoma were treated with 5-FU either alone or in combination with a nitrosourea (methyl CCNU), in combination with a lactone (testolactone), or in combination with both. The median survival period for all pancreatic carcinoma patients was 17 weeks, and for all gastric carcinoma patients 30 weeks. The addition of the nitrosoureas or the lactones or a combination of both produced no improvement in length of patient survival for either primary carcinoma when compared to treatment with 5-FU alone.