Combination cytotoxic chemotherapy (intravenous cyclophosphamide, methotrexate, and fluorouracil) was administered within 36 h of mastectomy to 368 women with operable breast cancer in a randomised, controlled clinical trial. The control group of 187 patients received either no chemotherapy or conventionally timed chemotherapy. Unpredictable and severe toxic effects were significantly more common in patients aged greater than or equal to 50 who had received at least 80% of the full chemotherapy dose and in patients who had received chemotherapy within 6 h of mastectomy than in other patients. Methotrexate was believed to be the principal cause of these toxic effects, because of potentiation by nitrous oxide anaesthesia. Leucovorin rescue was therefore added to the regimen.

One hundred and eight patients selected to receive combinations of highly emetic cytotoxic chemotherapy for malignant disease were included in a study of anti-emetic therapy. The patients were randomly allocated to receive levonantradol (0.5, 0.75 or 1 mg) or chlorpromazine (25 mg) prior to receiving their first course of cytotoxic therapy. The appropriate anti-emetic was administered 2 hr prior to the start of chemotherapy, 2 hr after chemotherapy and subsequently at 4-hourly intervals for a further 8 hr. The extent of anorexia, nausea and vomiting along with other side-effects were assessed at regular intervals by physicians and nursing staff during the 24 hr following chemotherapy. In addition, a self-assessment questionnaire was completed by the patients. Levonantradol (0.5 mg) was superior to chlorpromazine (25 mg) as an anti-emetic. Both were reasonably well tolerated, although at this dose of levonantradol 22% of patients experienced dysphoric reactions. At higher doses of levonantradol the proportion of patients experiencing these reactions rose to 50%, but without a concomitant increase in antiemetic activity. Neither drug achieved satisfactory control of vomiting in patients receiving combinations containing cis-platinum. We conclude that levonantradol (0.5 mg) is a more effective anti-emetic than chlorpromazine (25 mg) in patients receiving cytotoxic chemotherapy. However, its use cannot be recommended due to its high incidence of unacceptable central nervous system side-effects.

Sixty-five patients with high-grade soft tissue sarcomas of the extremities were treated in a prospective randomized trial evaluating the efficacy of adjuvant chemotherapy with doxorubicin, cyclophosphamide, and high-dose methotrexate. Local therapy was administered using either amputation or wide local resection plus radiation therapy and the chemotherapy was begun in the immediate postoperative period. Actuarial analysis with median follow-up of 653 days revealed an advantage in continuous disease-free and overall survival in the patient group receiving chemotherapy (P = 0.0008 and P = 0.04, respectively, one-sided Mantel-Haenszel test). The continuous disease-free survival at three years is 92% in the chemotherapy group compared to 60% in the no chemotherapy group. Overall survival is 95% and 74% in these two patient groups. Fifty-eight percent of patients had limb-sparing surgery plus radiation therapy and 42% underwent amputation. In both treatment subgroups analyzed separately, chemotherapy resulted in an improvement in disease-free survival compared to randomized controls not receiving chemotherapy (P = 0.006 and P = 0.04 for groups receiving amputation and limb sparing, respectively). There were no local failures in the patients receiving chemotherapy and two local failures in the no chemotherapy group. The results of this trial confirm the historically controlled pilot trial performed in 26 patients between 1975 and 1977. A current update of the patients in the pilot trial, with a minimum four-year follow-up, reveals an improvement in disease-free and overall survival due to chemotherapy (P less than 0.002). Analysis of the previous pilot trial indicates that only few recurrences are seen beyond three years. Thus, it appears that adjuvant chemotherapy should be a part of the treatment adult patients with soft tissue sarcomas of the extremities.

Eighty-six previously untreated patients with advanced squamous-cell carcinoma of the head and neck were entered into a prospective randomised controlled trial to evaluate whether the addition of a kinetically based chemotherapy regimen before and after radiotherapy would improve survival compared with radiotherapy alone. Survival at 30 months showed there was no evidence that the addition of chemotherapy to radiotherapy improved survival and that the chance of obtaining a significant result in favour of adjuvant chemotherapy was remote. We make a strong plea that all chemotherapy regimens for the treatment of squamous-cell carcinoma of the head and neck regions should be subjected to controlled prospective trials before they are widely adopted.

Twenty-seven patients with non-reticuloendothelial malignancies were treated with a single intramuscular injection of recombinant leukocyte alpha 2 interferon (rIFN) to assess clinical tolerance and define a maximum tolerated dose. A single patient in each of six increasing dosage groups (0.3 X 10(6) IU, 1 X 10(6) IU, 3 X 10(6) IU, 10 X 10(6) IU, 30 X 10(6) IU, 100 X 10(6) IU) received a low dose (0.01 X 10(6) IU) and served as a control for subjective and objective toxicity measurements. Severe fatigue proved dose-limiting at 100 X 10(6) IU, and all dosages above 3.0 X 10(6) IU produced one or more signs or symptoms, which typically resembled a 'flu-like' syndrome. Objective toxicity was mild to moderate (leukopenia, thrombopenia) and no toxicities were found not already known from work with interferon obtained directly from leukocytes. Evidence of an antitumor effect was apparent in 3/19 evaluable patients.

To assess the value of high-dose dexamethasone therapy in preventing the gastrointestinal (GI) side effects of chemotherapy, a randomized double-blind study was conducted in women receiving outpatient therapy for breast cancer. Single-dose dexamethasone sodium phosphate (10 mg) or placebo was administered intravenously in 57 trials in 22 women immediately before chemotherapy. Questionnaires (administered before therapy and 24 hours later) were compared for evidence of nausea, vomiting, and anorexia produced by chemotherapy. No GI intolerance to chemotherapy was noted in 24 (83%) of the 29 dexamethasone trials v 16 (57%) of the 28 placebo trials. Dexamethasone trials produced the following results: no side effects in 50% (14/29), insomnia the night after chemotherapy in 21% (6/29), an increase in energy levels in 24% (7/29), and an improvement in mood in 14% (4/29). High-dose dexamethasone therapy has useful application in alleviating the emetic effects of cancer chemotherapy.

In a prospective randomized study of treatment with radiation therapy (RT) or RT followed by chemotherapy (CT) for patients with Hodgkin's disease stages I-III, four patients developed acute nonlymphocytic leukemia (ANLL) during post-treatment follow-up. There was a significant relationship between the intensity of the treatment and the appearance of this complication: no cases of ANLL were observed among the 128 patients treated with involved field (IF) RT, IF RT followed by CT, total nodal RT alone (TNR), or total lymphoid irradiation alone (TLI) after a follow-up from 21 to 126+ months (median follow-up 76 months). In contrast, four of 36 patients treated with extensive RT followed by CT developed ANLL at 17, 63, 72, and 91 months. Three of these patients had received TLI + CT, the fourth one TNR + CT.

Forty-seven patients with advanced Hodgkin's disease were entered in a prospective, randomized trial comparing MOPP (mechlorethamine, vincristine, procarbazine, and prednisone) with a regimen containing lomustine (CCNU), vinblastine, and prednisone (CCNU-VP). Both groups were comparable for the variables of age, stage, substage (symptoms), histology, prior radiation, and sites of involvement. Seventy-two percent of CCNU-VP-treated patients achieved a pathologically documented complete remission (CR) compared to 41% of the MOPP-treated group. Two additional patients treated with MOPP had remission documented only clinically but have been long-term, disease-free survivors. There was a greater frequency of CR in the patients who had received previous irradiation when compared to patients with no prior irradiation. After a median follow-up of greater than 89 months, there is no statistical difference between the two treatment groups in survival (45% for MOPP and 60% for CCNU-VP). Further, no statistical difference in survival for the two treatment groups was noted when compared by histology, stage, or symptoms. The CCNU-VP combination was better tolerated with significantly less nausea and emesis. The alternative drug regimen of CCNU-VP appears to be as effective as MOPP in producing CR and long-term survival in patients with advanced Hodgkin's disease.

Two hundred thirty-two patients with advanced measurable colorectal cancer previously treated with 5-fluorouracil (5-Fu) were randomized to one of the following treatments: A) semustine (MeCCNU) plus vincristine (VCR); B) MeCCNU plus dacarbazine (DTIC); C) MeCCNU plus DTIC plus VCR; D) MeCCNU plus beta-2'-deoxythioguanosine (beta-TGdR). Platelet nadirs less than 50,000/mm3 were noted in 9% (Treatment A) to 19% (D) of the patients while WBC nadirs less than 2,000/mm3 were noted in 7% (B) to 12% (C,D) of the patients. Severe vomiting was noted in 2% (D) to 14% (B) of the patients. The partial response rates and median survival times from date of randomization were as follows: Treatment A: 3/54 (6%), 19 weeks; B: 9/59 (16%), 28 weeks; C: 3/60 (5%), 25 weeks; D: 2/59 (4%), 19 weeks. Differences in response rate and median survival are not statistically significant.

From May 1978 until November 1980, 169 previously untreated patients with advanced epithelial ovarian cancer were entered into a prospective randomized clinical trial comparing the combination of hexamethylmelamine, Adriamycin, and cyclophosphamide (HAC) to a combination of melphalan and cis-platinum. Eleven patients were excluded from analysis and another 5 patients were excluded from response analysis. Of 153 patients evaluable for response, there were 47, or 30.7%, complete responders (all determined surgically), 6 partial responders, and 100 nonresponders. The response rate for the HAC group was 31% and for the melphalan-platinum group was 37.8%. The overall response rate was 34.6%. Residual tumor diameter (less than or greater than 2 cm) exerted a statistically significant effect on response--47.8 vs 24.4%. Of the 47 complete responders, 7, or 14.9%, have relapsed, with the median duration of remission of 44+ months. Of the 158 patients evaluable for survival, 90 patients have died, with a median survival time of 27.9 months (HAC = 26.4 months, melphalan-platinum = 29.6 months). Age, FIGO stage, histologic grade, and residual disease all exerted a significant effect on survival time. Second-line therapy in the treatment failures was of no benefit. Hematologic toxicity was greater in the melphalan-platinum group. Gastrointestinal toxicity was severe in both groups. Other toxicities were minor and infrequent.

One hundred and two patients with advanced solid tumors receiving chemotherapy were treated with metoclopramide (MCP; 100 mg) to prevent emesis. Twenty-six of 102 patients who had more than five episodes of vomiting were considered MCP-resistant and were randomized to receive MCP (100 mg) plus placebo versus MCP plus dexamethasone (DM; 48 mg) iv in a double-blind, crossover trial. The median number of vomiting episodes was 18 after MCP plus placebo and five after MCP plus DM (P less than 0.001). The median duration of vomiting episodes was 40 hours after MCP plus placebo and 10 hours after MCP plus DM. Immediate toxicity of the antiemetics was not enhanced by the addition of DM to MCP.

From July, 1978 to September, 1981, 184 patients with localy advanced breast cancer (T3; T4a-b; any N; M0) regardless of their hormonal receptor status, entered a trial to evaluate the contribution of radiotherapy when added to an intensive preoperative chemoendocrine regimen. Seventy-eight patients were ultimately disqualified. All patients underwent sequentially: (1) two cycles of chemotherapy: Day 1--Oncovin 1.4 mg/m2, cyclophosphamide 350 mg/m2, Adriamycin 30 mg/m2; Day 2--methotrexate 20 mg/m2, 5-fluorouracil 350 mg/m2 (in addition, antiestrogens were given to postmenopausal patients); (2) mastectomy with complete axillary dissection combined with oophorectomy in patients before and one year after menopause; (3) radiotherapy randomly to one-half of the patients; and (4) ten additional chemotherapy cycles as above, with antiestrogens to all patients. No serious local sequellae were encountered from mastectomy or radiotherapy, but complications of chemotherapy were numerous, particularly in irradiated patients. One death due to toxicity occurred after preoperative chemotherapy. The results to date suggest that in irradiated patients metastases may become enhanced and that their local disease is not more effectively controlled than in patients not having radiotherapy. Two factors may have been largely responsible for the differences observed between the two groups: the delay of chemotherapy in irradiated patients and the sustained immunosuppression known to occur after mediastinal radiotherapy.

Between 1974 and 1977, 652 patients with non-Hodgkin's lymphoma without prior chemotherapy were randomized to 1 of 3 combination chemotherapy programs designed to induce complete remission (CR): COP-bleomycin (180 patients), CHOP-bleomycin (232 patients) or CHOP plus immunotherapy with Bacillus Calmette Guerin (BCG) (240 patients). With mature follow-up, the major effect of BCG immunotherapy was observed in patients with large cell lymphomas (diffuse or nodular "histiocytic") and not in other common lymphoma subtypes. CR rate for 65 patients with large cell lymphoma treated with CHOP-BCG was 68% compared to 48% in 61 patients treated with CHOP-bleomycin (P = 0.02) (two-tailed test) or 44% for 45 patients treated with COP-bleomycin (P = 0.02). CR duration for both CHOP-based regimens was similar and superior to that produced by COP-bleomycin (P = 0.03). Survival of patients with large cell lymphoma treated with CHOP-BCG was better than that observed with CHOP-bleomycin (P = 0.02) or COP-Bleomycin (P = 0.002). Although the explanation for the favorable effect of BCG remains unclear, further clinical trials to evaluate the combination of chemotherapy and other "biologic response modifiers" is warranted for patients with lymphoma.

We studied the effect of total parenteral nutrition on recovery from myelosuppression in patients receiving intensive chemotherapy. Twenty-seven patients (ages 11 to 33 years) with locally recurrent or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma were randomly selected to receive either conventional oral nutrition or total parenteral nutrition concurrently with intensive chemotherapy. The control group (15 patients) received significantly fewer calories (range 380 to 880/m2 per day, median 685 versus range 1,020 to 2,100 median 1,650) and less nitrogen (0-3.7 g/m2 per day, median 1.5 versus range 5.3 to 12.4, median 8.9) than the group receiving total parenteral nutrition (12 patients). Assessment of recovery from myelosuppression was based on the length of time the absolute granulocyte count was below 500/mm3, the length of time the platelet count was below 40,000/mm3, the number of days the platelet count was below 20,000/mm3, and the number of blood transfusions required. There was no statistical difference in any of the parameters evaluated between the group that received total parenteral nutrition and the control group (p less than 0.05); granulocyte and platelet recovery and the difference in transfusion requirements favored the control group with marginal statistical significance (p = 0.05). The frequency of clinical infections was similar in the patients receiving total parenteral nutrition (five of 12) and in those receiving conventional oral nutrition (five of 15). Thus, although total parenteral nutrition could be safely administered in this severely myelosuppressed population, no benefit could be defined in recovery from bone marrow suppression or frequency of clinical infections.

The treatment-associated toxicity in 189 patients entered in the COSS-80 Study was analyzed. The sequential use of high-dose methotrexate (HDMTX) with citrovorum factor rescue (CFR) and cis-platinum may be additive or synergistic in causing renal toxicity. However, evaluation of the 48-h serum methotrexate level and the incidence of elevated serum creatinine levels throughout treatment failed to indicate prolonged methotrexate elimination or severe kidney damage from this regimen where an interval of 3 weeks between cis-platinum administration and the next course of HDMTX was mandatory. The treatment-related mortality was 3.2% (6 out of 189 patients). Three patients died of septicemia during chemotherapy-induced bone-marrow depression following treatment with adriamycin or the combination of bleomycin, cyclophosphamide, and dactinomycin (BCD). Three deaths occurred following the use of high-dose methotrexate with citrovorum factor rescue. Two of these deaths were associated with delayed excretion of methotrexate. The toxicity is within the range reported in the literature.