Eighty-eight children younger than 15 years with acute lymphoblastic leukemia were treated with two similar protocols. Both regimens consist of multidrug combinations, with CNS prophylaxis. Sixty-four patients were enrolled on first protocol 0171 with vincristine and prednisone induction therapy. After remission induction patients were randomized on two arms: regimen A which consists of intensive courses of methotrexate with vincristine and prednisone reinductions and administration of cyclophosphamide. Regimen B is similar to regimen A, only courses of methotrexate are alternated with courses of 6-mercaptopurine during consolidation and intensification therapy. In maintenance phase both regimens have daily administration of 6-mercaptopurine and twice weekly administration of methotrexate, with vincristine and prednisone reinductions. The second protocol 0276/A is similar to regimen B of protocol 0171, but L-asparaginase is administered in the end of induction phase and total duration of therapy since induction of complete remission is prolonged from 2.5 to 4 years. Complete remission rate ranged from 92 to 96% in the patients achieving complete remission. In protocol 0171 actuarial proportion of children alive in complete remission for more than 10 years is 60% at present. The actual median survival of all children treated with protocol 0171 is 46+ months and actual median duration of complete remission is 43+ months. There was no significant difference between patients treated with methotrexate alone and those treated with combination of methotrexate and 6-mercaptopurine during consolidation and intensification phase. In protocol 0171 the relapse rate was 28% and the death rate in complete remission was 15%. More than 70% of complete responders in protocol 0276 is in continuous complete remission from 2+ to 57+ months, relapse rate is only 4% at present and the death rate in complete remission is 9% in this protocol.

Seventy-seven patients with small cell lung carcinoma were assigned randomly to two chemotherapy regimens to assess their psychological response to each regimen. One produced less depression and fatigue than the other, despite the absence of differences in tumor response.

The nausea and vomiting experienced by one in four cancer patients in anticipation of chemotherapy is probably a learned response to treatment. To determine whether behavioral approaches for altering learned responses might be useful treatments for these symptoms, we compared the effects of "systematic desensitization" (a behavioral treatment in which relaxation is learned as a response to situations in which patients have had anticipatory nausea and vomiting) with those of counseling and of no treatment. Sixty ambulatory cancer patients with anticipatory nausea and vomiting before their third and fourth chemotherapy treatments were randomized equally to the three groups. Significantly more patients receiving desensitization reported no anticipatory nausea before their fifth and sixth chemotherapy treatments than patients given counseling (P less than 0.05) or no treatment (P less than 0.01). Desensitized patients also reported significantly less severe anticipatory nausea (P less than 0.01) and vomiting (P less than 0.05) and a shorter duration of anticipatory nausea (P less than 0.01). We conclude that systematic desensitization appears to have an antiemetic effect in cancer patients who receive chemotherapy, and may be useful in the management of these problems.

In a prospective randomized study of treatment with radiation therapy (RT) or RT + chemotherapy (CT) for patients with non-Hodgkin's lymphoma Stages I-III, one patient developed an acute malignant myeloproliferative syndrome (AMMS) and four others acute nonlymphocytic leukemia (ANLL). There was correlation between the intensity of treatment and development of this complication: Among patients treated with local radiation with or without chemotherapy no cases of AMMS or ANLL were observed. However, patients treated with total lymphoid irradiation alone (TLI) had an observed to expected ratio of 162. Among patients treated with TLI plus CT this ratio increased to over 1000. The cytogenetic, clinical, and hematologic abnormalities of these patients are discussed.

Eighty-one evaluable patients with recurrent or metastatic breast cancer were randomized to receive either vincristine 1 mg/m2, doxorubicin 40 mg/m2 on day one and cyclophosphamide 200 mg/m2 orally days 3-6 (VAC); or cyclophosphamide 350 mg/m2, methotrexate 20 mg/m2, and 5-fluorouracil 350 mg/m2 (CMF) intravenously, all on day 1. Courses of each of the above regimens were repeated every three weeks. Twenty-one of 45 patients (47%) on VAC and seven of 44 patients (16%) on CMF had complete or partial response (P less than 0.05). The duration of response was six months for CMF and nine months for VAC. Hematologic toxicity was minimal for both groups but three patients receiving VAC developed cardiac toxicity. Overall survival projections at this time indicate no differences between the VAC or CMF treated patients.

Thirty-nine patients with Stage III nonseminomatous testicular cancer were treated in a prospective randomized trial comparing cytoreductive surgery followed by a cis-platinum containing combination chemotherapy regimen versus chemotherapy alone. All patients had one or more of the following poor prognostic signs: palpable retroperitoneal disease, liver involvement, invasion or obstruction of the inferior vena cava, or lung metastases larger than 2 cm in diameter. Cytoreductive surgery was technically feasible in this group of patients as assessed radiographically (70-90% reduction in tumor mass) and by the decline in serum levels of alpha-fetoprotein and human chorionic gonadotropin in 75% of the patients following surgery. However, there was no statistically significant improvement in overall response rate (75% versus 84%), complete response rate (50 versus 37%) or in survival between the patients treated with surgery prior to chemotherapy or with chemotherapy as the initial treatment. It is unlikely (P less than 0.028) that any true beneficial effect of surgery was missed due to the relatively small number of patients in each treatment arm. The authors of this study conclude that cytoreductive surgery prior to chemotherapy in patients with poor prognosis Stage III testicular carcinoma is not routinely indicated. Since the overall complete response rate to chemotherapy in these 39 patients with bulky Stage III disease was only 43%, alternate approaches, other than cytoreductive surgery, are necessary to improve the prognosis for this group of patients.

A total of 361 evaluable patients with previously untreated multiple myeloma were randomized to receive oral melphalan (0.15 mg/kg/day for seven days, followed by 0.05 mg/kg/day after recovery from the nadir of the leukocytes), BCNU (150 mg/m2 intravenously every six weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-weeks) or CCNU (100 mg/m2 orally every six weeks). All patients received a tapering six-week course of prednisone starting at 0.8 mg/kg for the first two weeks. At week 22, one-half of the patients were randomized to receive vincristine (1 mg/m2) and prednisone (0.6 mg/kg for seven days) every two months in addition to previous therapy. The melphalan treated patients showed a significantly higher overall objective response frequency (59%), according to Myeloma Task Force criteria, when compared to those treated with BCNU (40%) or CCNU (42%). The survivals for all patients were not statistically different for the three treatment programs. However, the good-risk patients treated with melphalan had significantly longer survival (P = 0.02) than the equivalent patients who received BCNU or CCNU. The addition of vincristine and prednisone at week 2 did not significantly increase the percentage of subsequent objective responses or prolong the subsequent survival of any treatment group. It is concluded that oral melphalan is superior to BCNU and CCNU in producing objective responses and in prolonging survival in good risk patients.

Patients with advanced breast carcinoma and no prior chemotherapy were prospectively evaluated to assess the induction capabilities of cyclophosphamide, methotrexate and 5-fluorouracil (CMF), Adriamycin and vincristine (AV), and CMF plus prednisone (CMFP). The crossover responsiveness from CMF or CMFP to AV and of AV to CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF were also assessed. A disproportionate randomization led to 166 analyzable cases on AV, 79 on CMF and 86 on CMFP induction. One hundred and twelve patients were evaluated on crossover. Induction response rates were similar with 56% on AV, 57% on CMF and 63% on CMFP. Crossover response rates ranged from 32% to 41%. CMFP and AV were superior to CMF in terms of response duration (P = 0.05), and CMFP was superior to either in terms of time to treatment failure (P = 0.04), and survival (P = 0.03). Treatment failures occurred in only the on-study organ sites of disease in 73% of the patients and did not appear to be related to the response achieved. CMF was associated with more thrombocytopenia than either AV or CMFP (P = 0.03). AV was associated with fewer infections than CMFP (P = 0.02), less diarrhea than CMFP (P = 0.04), more emesis than CMF (P = 0.02), and more neurologic toxicity than either CMF or CMFP (P less than 0.0001). There was also more emesis with CMF than with CMFP (P = 0.006). CMFP was associated with greater delivery of CMF than was the CMF regimen despite a similar day 1 leukocyte distribution. These results strongly suggest that CMF(P) and AV are clinically noncross-resistant regimens, that AV and CMF are essentially equivalently active induction regimens, and that CMFP is superior to CMF and AV.

We evaluated the effectiveness of total parenteral nutrition and placing the "bowel at rest," as compared to that of ad libitum food intake, on nutritional status and tolerance to combined chemotherapy and radiotherapy in a randomized, prospective trial in children with previously untreated malignancy requiring abdominal and pelvic irradiation and chemotherapy. Administration of TPN was found to be safe and efficacious in maintaining the children in good nutritional status during combined therapy; one-third of the control patients became malnourished and required TPN. There was no beneficial effect of "bowel at rest" and TPN on the ability of patients to tolerate combined therapies in terms of decreased toxicity; however, use of TPN was associated with improved adherence to chemotherapy schedules. Following termination of TPN or ad libitum food intake, and while receiving chemotherapy, the majority of the children who had previously received TPN lost significant weight. To date there has been no difference in mortality rate between the control and TPN groups. Although we conclude that TPN per se had little beneficial effect beyond that of maintaining good nutritional status, every child undergoing intensive combined therapy should have early and periodic assessments of nutritional status, so that the early signs of malnutrition can be detected, and the adverse effects of malnutrition can be prevented by nutritional replenishment, by TPN, or by other methods.

Two hundred ninety-three patients were randomly assigned to three treatment regimens following mastectomy for operable but prognostically unfavorable breast cancer: L-PAM, CFP, or CFP with radiation therapy. For premenopausal patients an increased risk of recurrence was associated with the presence of unfavorable local signs, large number of lymph nodes involved, greater body weight, younger age, and L-PAM treatment. For the postmenopausal patients only three factors were associated with an increased risk of recurrent disease: large tumor size, large number of lymph nodes involved, and inner/central location of the primary lesion. Specifically, the treatment employed has shown no effect. Of particular importance is the fact that for neither group of patients does our experience presently demonstrate clear association of recurrent disease with the level of drug dose administered. Furthermore, evidence suggests that although patients who experience little or no myelosuppression have significantly worse disease-free intervals than patients who experience moderate or severe myelosuppression, here is no benefit for severe myelosuppression over moderate, myelosuppression.

The Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer in Japan with the participation of 334 institutes nation-wide had conducted the secondary study in order to investigate the usefulness of futraful in long term treatment, based on the results obtained by the primary study. The following method was taken for the study and patients were randomly divided into three groups: A group-given a high dose of MMC immediately after operation; B group-given futraful for one year after MMC administration; C group-given futraful alone for long-term. The number of eligible cases for data analysis was 3,o30. Side effects observed during the long term treatment with futraful were considered to be minor. Although the occurrence of hematocytopenia was slightly frequent because of possible increase of influence by the concomitant use of MMC, no tendency of hepatic disorders and any subjective side effects to be strengthened by MMC combination was observed at all. As for 2-year survival, an elevated survival was found in the group of concomitant use of MMC and futraful; Especially, a significantly high survival was found in the cases of stage III and n (+) . ps (+). Furthermore, the survival was elevated in proportion to the increase of total dosage of futraful. This suggested the usefulness of futraful for long term treatment.

We report the results of two clinical trials in which patients receiving either doxorubicin (Adriamycin)/cyclophosphamide or cis-platinum cytotoxic chemotherapy were assigned at random either a single or a combination antiemetic treatment. The aim of each trial was to assess whether combination antiemetic therapy would result in improved efficacy. Sixty patients commencing doxorubicin/cyclophosphamide therapy were divided in two random groups to receive either haloperidol or haloperidol plus amitriptyline, and 80 patients commencing cis-platinum therapy were divided at random to receive either metoclopramide or metoclopramide plus promethazine. No statistically significant differences were apparent between single and combination antiemetic regimens in either of the two treatment groups. Antiemetic agents were generally well-tolerated, but minor side effects were common. The failure of our combination antiemetic regimens to intensify the proven antiemetic efficacy of single agents emphasises the need for re-evaluation of currently used antiemetic agents and their dosage schedules.

A prospective randomized trial in patients with previously untreated multiple myeloma was performed comparing carmustine (BCNU), cyclophosphamide, and prednisone (BCP) to melphalan (Alkeran) and prednisone (AP). Induction response rates, remission duration, and survival were similar with both regimens. Hematologic toxicity was greater with AP. Crossover studies in patients who relapsed did not illustrate any significant activity with either drug treatment program. Therefore, BCP can be utilized as initial therapy in myeloma because of comparable remission rates and less hematologic toxicity.

Seventy-three patients with small cell lung carcinoma refractory to standard chemotherapy were entered in this phase II randomized study of cisplatin, maytansine, and chlorozotocin. Of the 58 evaluable patients, only one partial response was observed among 21 patients given cisplatin, and no responses were seen among 19 given maytansine or 18 given chlorozotocin. One patient treated with chlorozotocin and two treated with cisplatin experienced life-threatening thrombocytopenia. One third of the maytansine-treated patients experienced moderate or severe neurologic toxicity. The overall median survival was 9.7 weeks. Chlorozotocin treatment was associated with inferior survival (7.7 weeks).

A total of 109 patients with advanced lung cancer, all cell types, were randomized between MACC chemotherapy only, consisting of methotrexate, doxorubicin (Adriamycin), cyclophosphamide, and lomustine (CCNU); MACC plus levamisole (LMS) orally; and MACC plus Corynebacterium parvum (CP) sc. Of these patients, 101 were evaluable, with no differences among the three treatment groups for overall response rate and survival time. Objective response rates and median survival times were 41% and 230 days for patients given MACC only, 39% and 257 days for those given MACC plus LMS, and 44% and 223 days for those given MACC plus CP, respectively. There was a significant increase in survival for patients with large cell anaplastic carcinoma receiving CP or LMS, particularly in the good-performance-status category. Pretreatment delayed cutaneous hypersensitivity to recall antigens in 50 patients had prognostic significance, but repeat tests after 2 months of treatment in 30 patients did not show different patterns of conversion among the three groups. There was no difference in hematologic toxicity among the three groups. With the possible exception of large cell anaplastic carcinoma, immunotherapy with LMS or CP as given in this trial does not appear to be therapeutically advantageous in advanced lung cancer.

Two combination chemotherapy programs, ACOMLA (doxorubicin, cyclophosphamide, vincristine, methotrexate and leucovorin rescue, and cytarabine) and CHOP-B (cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin), were evaluated in 29 prospective randomized patients with advanced diffuse histiocytic lymphoma. A complete response was achieved in 13 of the 15 patients (87%) treated with CHOP-B and in nine of the 14 patients (64%) treated with ACOMLA. The overall complete response rate was 75%. Two patients treated with ACOMLA and none of the CHOP-B-treated patients have relapsed. Median followup is 32 months for ACOMLA patients and 26 months for CHOP-B patients. Actuarial freedom from relapse at 2 years is 49.9% for ACOMLA and 93.3% for CHOP-B (P = 0.04). Toxicity was substantial, with eight nonfatal episodes of sepsis and three drug-related deaths. There have been no central nervous system relapses. Although patients treated with CHOP-B have a better response rate, the small numbers of patients treated to date preclude definitive conclusions.