Fifty-five patients harboring a variety of neoplasms and previously found to have severe nausea or emesis from antitumor drugs were given antiemetic prophylaxis in a double-blind, randomized crossover fashion. delta 9-Tetrahydrocannabinol (THC), prochlorperazine, and placebo were compared. Nausea was absent in 40 of 55 patients receiving THC, in 8 of 55 patients receiving prochlorperazine, and in 5 of 55 in the placebo group. THC appeared to be more efficacious in controlling the emesis associated with cyclophosphamide, 5-fluorouracil, and doxorubicin and less so for nitrogen mustard and the nitrosourea. THC appears to offer significant control of nausea in most patients and exceeds by far that provided by prochlorperazine (P less than 0.005).

Eighty evaluable patients receiving chemotherapy were entered on a random prospective double-blind study to evaluate the effectiveness of nabilone, a synthetic cannabinoid, compared to prochlorperazine. Most of these patients received cisplatin, a drug that universally produces severe nausea and vomiting, as part of a combination chemotherapy regimen. The patients served as their own controls, receiving either nabilone or prochlorperazine during two consecutive treatment courses with the identical chemotherapy. Side effects consisting of hypotension and lethargy were more pronounced with nabilone. Toxicity, in general, did not preclude antiemetic treatment and in no way interfered with chemotherapy. Sixty patients (75 per cent) reported nabilone to be more effective than prochlorperazine for relief of nausea and vomiting. Of these 60 patients, 46 required further chemotherapy and continued taking nabilone as the antiemetic of choice.

A prospective, randomized and double-blinded trial of the comparative effects of delta-9-tetrahydrocannabinol (THC) and haloperidol (H) was begun in February 1980. Patients were randomized to initially receive either THC or haloperidol with cross-over to the other agent after two courses. All patients evaluated efficacy and toxicity of each agent and those patients completing the study expressed a preference for either THC or haloperidol. All patients are receiving chemotherapeutic agents known to induce severe vomiting (cis-platinum, nitrogen mustard, or doxorubicin) or have a history or retching with chemotherapy. Fifty-two patients are evaluable as of October, 1980. THC and haloperidol were equally effective in controlling nausea and vomiting as judged by number of vomiting episodes, patient evaluation of efficacy, and patient preference. About 10% of patients had complete control of vomiting and a third had less than five episodes. Patients failing one of the antiemetics had good control with the other about half the time. Toxicities from THC were less well tolerated than those from haloperidol, but most patients had no serious side effects. Nonoverlapping toxicities and efficacy raise the possibility that a combination of the agents might be worthwhile.

One hundred twenty patients about to receive their first treatment with potentially nauseant cancer chemotherapy were randomized to one of six antiemetic treatments: (1) no treatment; (2) placebo; (3) prochlorperazine (PCPZ), 10 mg; (4) delta 9-tetrahydrocannabinol (THC), 5 mg; (5) THC, 10 mg; (6) THC, 15 mg. Four doses of each medication were given orally at 4-hour intervals starting 2 hours before chemotherapy. A study nurse was responsible for both objective (nurse) and subjective (patient) symptom questionnaires. Serum levels were obtained at intervals for cross-reacting cannabinoids. Physiologic measurements including intraocular pressure (IOP), blood pressure, and pulmonary function were also recorded. In summary, the patients were remarkably free of adverse physiologic effects. All intraocular pressures before and after treatment were within the normal range, although a surprising statistically significant increase in IOP occurred in the group receiving 5 mg THC.

A total of 202 patients with advanced breast cancer were entered into two prospectively randomized Phase II trials conducted by the Eastern Cooperative Oncology Group, in an effort to identify promising agents and combinations for previously treated cases. Patients in Study 1 received bleomycin, CCNU, or streptozotocin and those in Study 2 received tilorone, Baker's antifol, or a combination of 5-fluorodeoxyuridine plus arabinosyl cytosine. Partial responses were seen only with bleomycin, Baker's antifol, and 5-fluorodeoxyuridine plus arabinosyl cytosine. The median times to treatment failure ranged from 3.6 weeks to 5.7 weeks, and the median survival times, from 8 weeks to 25 weeks for tilorone and bleomycin, respectively. Toxic reactions was primarily hematologic and gastrointestinal, but skin, neurologic, respiratory, and renal abnormalities were noted in some treatment arms. The treatment schedules outlined and the toxic effects noted provide background information that might prove useful in designing complex new chemotherapeutic programs, since there is pharmacological rationale for incorporating some of the agents tested into present standard combination chemotherapy regimens.

Fever, clinical infection, bacteriologically documented infection, and death from infection were evaluated in 95 consecutive uninfected patients with severe granulocytopenia (less than 0.5 x 10(6)/liter). Patients were randomly allocated to reverse isolation and prophylactic oral nonabsorbable antibiotics or to open ward care. The microbiologic surveillance of air samples and stool cultures showed reduction of pathogenic organisms in patients treated in protective environment units. There was a statistically significant reduction in the incidence of fever (80% vs. 39.6%; P less than 0.001), clinical infections (55.3% vs. 25%; P less than 0.01), bacteriologically documented infections (53.2% vs. 20.8%; P less than 0.01), and deaths from infections (25.5% vs. 8.3%; P = 0.02) in patients treated in a protective environment as compared with patients treated on the open ward.

In a cooperative group study of 433 breast cancer patients treated with 2 years of postmastectomy chemotherapy, 22 (5%) developed venous thromboses of various types. Two patients died. None of the patients had demonstrable tumor metastases at the time of the venous thrombosis, although seven had metastases a median of 11 months after the thromboses. Thirteen living patients have not had tumor recurrences. No patient developed thrombosis after the chemotherapy was completed. It is possible that one or more of the chemotherapeutic agents initiated the clotting problems. Thrombophlebitis is a possible problem occurring during adjuvant chemotherapy for breast cancer and requires prompt treatment.

A total of 133 patients with advanced or metastatic adenocarcinoma of the kidney were stratified according to performance status and time from initial diagnosis to recurrence and were then randomized to one of three different drug treatment arms or the crossover secondary treatment. The study drugs (combination vinblastine-CCNU and single-agent triazinate or dactinomycin) failed to provide any meaningful antitumor activity for these patients with advanced renal cell cancer.

Fifty-four patients with localized and extensive small cell carcinoma of the lung and no prior therapy were treated with intensive induction chemotherapy. The induction regimen consisted of two courses of high-dose cyclophosphamide, doxorubicin, and VP-16-213. The objective response rate was 78% (42 responses among 54 patients), with 14 complete (26%) and 28 partial (52%) responses. The median survival time for the entire group of patients is 378 days, with a projected 2-year survival rate of 22%. The most significant determinant of survival was the attainment of a complete response. Tumor progression in most relapsing patients occurred at the sites of initial involvement. Toxicity was significant, as expected, but treatment-related mortality did not exceed that of less intense regimens. Despite the use of such intensive induction regimens, the major challenge in the therapy for small cell carcinoma remains the achievement of more durable complete remissions.

A complete remission rate of 82% was obtained in a group of 68 patients with acute myelogenous leukemia treated with a high-dose induction chemotherapy (TAD) consisting of 7-day courses of 6-thioguanine, cytarabine, and daunorubicin. The patients who achieved remission received intensive consolidation chemotherapy and were randomized to receive maintenance chemotherapy with or without immunotherapy. Median remission duration was 13 months and median survival, 21 months. Neither central nervous system prophylaxis nor the addition of immunotherapy to the maintenance regimen prolonged remissions or improved survival. Age, sex, and subclassification of acute myelogenous leukemia had no effect on the remission rate or survival. These data indicate that a large proportion of patients with acute myelogenous leukemia can achieve remission with intensive induction chemotherapy. Attempts to prolong remission have been less successful.

A prospective randomized study was carried out to compare the effectiveness of concomitant or delayed multiagent chemotherapy combined with irradiation to the primary tumor and regional lymph nodes and to the brain in a group of 70 patients with histologically proven small cell undifferentiated carcinoma of the lung. Complete and partial response in both groups was comparable, and the overall survival was comparable. However, relapse-free survival was significantly higher in patients receiving concomitant chemotherapy and irradiation in comparison with the radiotherapy alone group. Disease-free survival was higher in the concomitant chemotherapy-radiotherapy patients, although survival was not significantly modified, probably because of suboptimal chemotherapy. The initial intrathoracic failure rate was 40.7% inthe concomitant chemotherapy-irradiation group, compared with 53.8% in the radiotherapy-alone patients. None of the patients receiving delayed chemotherapy following the radiotherapy recurrence showed significant tumor response to the drugs. The incidence of distant metastasis was slightly lower in the chemotherapy groups. Brain metastases were noted in 7% of the patients in both groups. Increased intrathoracic recurrences were noted in patients with lower doses of irradiation. Nine of 13 patients treated with inadequate portals developed intrathoracic recurrences in comparison to 13 of 40 treated with adequate irradiation fields. The study emphasizes the need for intensive chemotherapy and adequate radiation therapy to improve survival of patients with small cell undifferentiated carcinoma of the lung. Additional trials are necessary to assess the role of each modality in the management of these patients.

Effects of the addition of MER, a nonspecific, nonviable immunostimulant, to two combination chemotherapy programs were explored in patients with metastatic breast cancer. Patients were randomized to either CDVFP [cyclophosphamide (C), doxorubicin (D), vincristine (V), fluorouracil (F) and prednisone (P)] or CD alternating with methotrexate (M) and F (CD/MF). Each group was also randomized to receive MER, 0.4 mg S.C. every four weeks or no immunotherapy. The response rates were CDVFP 56%, CDVFP + MER 54%, CD/MF 43%, and CD/MF + MER 43%. No significant differences were noted in response rate. Median durations of response and survival were similar for each group: CDVFP 16.2 and 25.2 months, respectively; CDVFP + MER 14.0 and 23.3 months, CD/MF 12.1 and 26.1 months, and CD/MF + MER 15.5 and 25.6 months. Patients who achieved CR frequently had soft-tissue disease (7/17) and patients with disease in 1 or 2 metastatic sites had a significantly higher response rate than those in greater than or equal to 3 sites. MER did not enhance response rate, duration of response, or survival. Also MER did not diminish myelosuppression.

Since 1972, the National Surgical Adjuvant Breast and Bowel Project (NSABP) has carried out a series of clinical trials evaluating the worth of adjuvant chemotherapy in the management of patients with primary breast cancer. This report provides information concerning (a) protocol compliance relative to drug administration and (b) acute toxicity encountered by patients in three separate trials who were given one-, two- or three-drug chemotherapy within 1 month of operation. The findings are derived from 1548 women who received 20,765 courses of chemotherapy, the most extensively documented experience yet reported. They indicate that despite the large number of physicians and the heterogeneity of the institutions participating, large cooperative efforts can be accomplished with credibility. Only 13 (0.8%) of the women failed to complete all courses of therapy for reasons directly related to nonprotocol compliance by physicians. Only 4.3% failed to complete therapy for miscellaneous reasons other than toxicity, treatment failure, occurrence of a second primary, or death unrelated to tumor. While almost all patients experienced toxic reactions during the therapy, only 3%--4% of recipients of melphalan (L-PAM; P) and 4%--5% of recipients of L-PAM + 5-FU(F)(PF) failed to complete 2 years of therapy because of toxicity. Of those patients receiving PF + methotrexate (MTX; M) (PMF), 15% did not finish their treatment for that reason. While there was little difference in hematologic and nonhematologic toxicity between those patients receiving P or PF, and such toxicity was generally acceptable to both patients and physicians, the addition of MTX (PMF) resulted in greater toxicity (vomiting, stomatitis, and alopecia) which was less readily accepted. Tolerance of any of these regimens was unrelated to patient age, despite the belief that older women are less tolerant of chemotherapy. The earlier toxicity occurred, the greater was the number of subsequent courses associated with toxicity, and the lower was the total amount of drug received. The extent of the toxicity produced by the NSABP regimens and the end results obtained with them, must be compared with the end results and toxicity obtained by other regimens before making a choice of the adjuvant therapy to be used.

Two hundred and eighty-four patients with inoperable non-small cell lung carcinoma were randomized by the Eastern Cooperative Oncology Group to receive one of seven primary chemotherapy regimens: cyclophosphamide and methotrexate; Baker's antifol; vincristine, bleomycin, and methotrexate; melphalan; cyclophosphamide and CCNU (control arm); 5-FU procarbazine; and hexamethylmelamine, doxorubicin, and methotrexate (HAM). Patients with disease progression were eligible for treatment with VM-26 or ascorbic acid. HAM resulted in higher response rates than cyclophosphamide and CCNU in patients with adenocarcinoma (32%) and large cell carcinoma (23%). It was not tested in patients with squamous cell carcinoma. In terms of survival, HAM was significantly better than cyclophosphamide and CCNU in patients with limited disease. Its toxicity was predominantly hematologic and gastrointestinal. This regimen is being further evaluated by the Eastern Cooperative Oncology Group in patients with inoperable non-small cell lung carcinoma. Crossover therapy with VM-26 or ascorbic acid had no therapeutic benefit.

Sixty-four patients receiving cancer chemotherapy known to induce severe emesis entered a randomized double-blind study of the antiemetic efficacy of haloperidol (Haldol) and benzquinamide (Emetecon). Patients preferred haloperidol for control of emesis induced by cis-platinum (78 vs. 22%) or nitrogen mustard (67 vs. 16%). Patients receiving Doxorubicin preferred benzquinamide by a small margin (46 to 38%). Individual patients who experienced no relief with their first antiemetic (13 of 15) usually got some relief with the other after crossover. Haloperidol was more effective than benzquinamide (54 vs. 29%) in patients previously unrelieved by prochlorperazine (Compazine). Complete relief of vomiting was obtained in 14 of 45 patients receiving haloperidol but only five of 41 patients receiving benzquinamide experienced no vomiting, again dependent on the anticancer agent used. Although haloperidol is a more effective antiemetic agent overall, efficacy is related to the anticancer treatment and probably to individual patient characteristics.

Cancer patients who had developed negative conditioned responses to their chemotherapy either did (relaxation training) or did not (no relaxation training) receive progressive muscle relaxation training and guided relaxation imagery instructions immediately before and during their chemotherapy treatments. Physiological (blood pressure and pulse rate) measures of arousal, frequency of vomiting, and patient-reported and nurse-reported indices of negative affect and nausea were collected during pretraining, training and posttraining chemotherapy sessions. Results indicated that during both the training and the posttraining sessions, patients in the relaxation training condition reported feeling less emotionally distressed and nauseated, and showed less physiological arousal following the chemotherapy infusion, than patients in the no relaxation training condition. The attending nurses' observations confirmed the patients' self-reports. No differences were found in frequency of vomiting between conditions. These data clearly suggest that the use of relaxation procedures may be an effective means of reducing several of the adverse side effects of cancer chemotherapy.

With the objectives of improving response rate, duration of response, and survival in small-cell carcinoma of the lung, 39 patients were randomized to remission-induction with either one of two potentially non-cross-resistant drug combinations: APE (consisting of adriamycin, 35 mg/m2 IV, D1 Q 3 weeks; procarbazine, 60 mg/m2 PO, D1-10 Q 3 weeks; and the epipodophyllotoxin (VP16-213), 130 mg/m2 IV, D8, 15 Q 3 weeks) or MOCC (composed of methotrexate, 15 mg/m2 IV (with [vincristine] Oncovin) or PO twice weekly D8-21 Q 3 weeks; Oncovin, 1.5 mg/m2 IV, D8, 15 Q 3 weeks; cyclophosphamide, 600 mg/m2 IV, D1 Q 3 weeks, and CCNU, 60 mg/m2 PO Q 6 weeks). A fixed crossover to the alternate regimen occurred at three months. Radiotherapy was delivered to the primary tumor (locoregional disease only) by a split course technique (1,750 rads for five days with a three-week split, followed by 3,400 rads over 17 days). The median survival including both arms was 11 months for regional and nine months for extensive disease. The chemotherapeutic activity of both regimens was comparable, with 15/17 (88 percent) of the patients responding to APE (including six complete) and 14/17 (82 percent) responding to MOCC (including five complete). The median survival for the complete responders was 11.7 months, while the partial responders survived for a median of 9.7 months. There were 2/9 (22 percent) responders to the alternate regimen at progressive disease. The overall incidence of CNS progression was 17 percent. The toxicity of the regimens was moderate, except for one instance of granulocytopenic death. This study establishes two equipotent drug combinations for the treatment of small-cell carcinoma of the lung.

Two-hundred-thirty-two evaluable patients with metastatic sarcomas received a palliative experimental treatment program consisting of Adriamycin, 60 mg/m2, cyclophosphamide, 600 mg/m2, and methotrexate, 25 mg/m2 intravenously every three weeks for two courses. This program was followed by a randomization to maintenance therapy consisting of either the same regimen (ACM), an alternative regimen ADV (actinomycin-D, 1 mg/m2, DTIC, 250 mg/m2, and vincristine, 1.4 mg/m2 intravenously weekly), or alternating ACM and ADV. Twenty percent of patients had complete (6%) or partial (14%) responses, and an additional 41% of patients were stable throughout the remission and maintenance regimens. Response rates were similar regardless of the degree of toxicity observed during induction therapy. Although improved quality of responses after maintenance therapy was more frequent on ACM-ADV (19%) than on ADV (3%) or ACM (10%) maintenance therapy, the durations of response were similar for the three regimens (25 weeks, 19.7 weeks, and 19.6 weeks, respectively). Complete responses lasted a median of 44.5 weeks versus 19 weeks for partial responses. Although the length of survival depended upon the quality of response ultimately achieved (16 months for complete responders, 13.6 for partial responders, 11.6 months for patients with stable disease versus 4.0 months with progressive disease), median survival was similar for patients on each of the three randomized maintenance regimens (12 months for ACM, 13 months for aDV, and ten months for ACM-ADV). Toxicity was significantly worse on either of the regimens containing ADV, particularly peripheral neuropathy and gastrointestinal toxicity. Therefore, the ACM regimen for remission induction and remission maintenance is the most desirable of the treatment programs tested.

In order to prevent vomiting induced by anti-cancer chemotherapy, the efficiency of domperidone has been compared to metoclopramide in a randomised trial. No difference has been observed between both emetic treatments.

From October 1973 to October 1977 the ECOG prospectively evaluated cyclophosphamide, methotrexate, and fluorouracil (CMF) versus CMF plus fluoxymesterone (CMFH) maintenance therapies in responders to 6 months of induction therapy which consisted of either CMF, CMF plus prednisone (CMFP), or adriamycin plus vincristine (AV). Following the maintenance randomization 12% of the patients converted from a PR to a CR status. The median time from randomization to treatment failure was 9.5 months for CMFH and 6.7 months for CMF (p = 0.03). This difference was observed only for partial responders (p = 0.01) and not for complete responders. Patients receiving CMFH tended to maintain higher hemoglobin, leukocyte, and platelet levels, and receive a higher dosage of each of the cytotoxic drugs. The results are taken as evidence that the addition of fluoxymesterone to a maintenance CMF regimen provides a therapeutic advantage. It is hypothesized that this effect is due at least in part to fluoxymesterone associated maintenance of improved marrow function resulting in greater myelosuppressive drug delivery.