Nocturnal dosing of a novel delivery system of verapamil for systemic hypertension. Verapamil Study Group.

To evaluate the efficacy and safety of a novel delivery system of physiologic pattern release (PPR)-verapamil administered nocturnally to patients with stages I and II hypertension using ambulatory blood pressure (BP) monitoring, we performed a multicenter (17 centers), double-blind, randomized, placebo-controlled, parallel-group trial with placebo and 120, 180, 360, and 540 mg of verapamil in 287 randomized patients. The delivery system has a delay in the release of verapamil for 4 to 6 hours, and then delivers the drug from an osmotic pumping system for approximately 12 hours. Patients were dosed at 10 P.M. The primary end point was change from baseline in trough diastolic BP assessed by ambulatory BP monitoring from 6 to 10 P.M. after 8 weeks of therapy, whereas secondary measures included changes from baseline in peak, early morning (6 to 10 A.M.) systolic and diastolic BP, trough clinic BP, and 24-hour average daytime (8 A.M. to 8 P.M.) and nighttime (8 P.M. to 8 A.M.) BP. The 180, 360, and 540 mg verapamil doses achieved statistically significant reductions in trough (6 to 10 P.M.) diastolic BP (-3.9 +/- 1.0, -7.8 +/- 1.2, and -10.6 +/- 1.1 mm Hg, respectively). Reductions in peak early morning (6 to 10 A.M.) diastolic BP were greater (-4.6 +/- 0.9, -13.3 +/- 1.2, and -19.0 +/- 1.2, for 180, 360, and 540 mg, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Chemotherapy of large bowel carcinoma--fluorouracil (FU) + hydroxyurea (HU) vs. methyl-CCNU, oncovin, fluorouracil, and streptozotocin (MOF-Strep). An Eastern Cooperative Oncology Group study.

In this prospective randomized study of initial chemotherapy for advanced measurable metastatic large bowel carcinoma, the response rate was 6/32 (19%) for FU + HU and 5/32 (16%) for MOF-Strep; the estimated median survival is 43 weeks for both treatments. Patients who received MOF-Strep experienced substantially greater vomiting and hematologic toxicity than patients who received FU + HU (p less than 0.001).

Pancreatic cancer. Assessment of prognosis by clinical presentation.

Three hundred ninety-three patients who were entered into pancreatic carcinoma treatment protocols of the Gastrointestinal Tumor Study Group (GITSG) were analyzed as to significant differences in clinical presentation and factors influencing survival. Patients were grouped according to the stage of the disease. Group I (21 cases) included those patients who had a potentially curative resection. Group II (182 cases) patients had a locally unresectable tumor less then 400 cm2 (surgically proven) and no distant metastases, and Group III (190 cases) had advanced disease. Group I patients had the smallest lesions (median area, 9 cm2), located in head of the gland in 90% and painless jaundice was the most frequent clinical presentation (52%). In Group II, 83% were located in the head of the gland but the median area was much larger (36 cm2). Pain was present in 80% of cases, and jaundice in 62% with 48% having jaundice and pain. In Group III patients, lesions of body and tail were over four-fold as frequent as in Group I and almost three-fold greater than in Group II. The median area of the lesion was large (30 cm2). Pain was present in 85% and jaundice in only 31%. Median survival in Group I patients was longer than Group III (73 versus 10 weeks; P less than 0.001). Ambulatory status, sex, race, abdominal pain, and histologic type influenced survival in one or more groups whereas age, jaundice, location of the tumor, degree of cellular differentiation, back pain, and nutritional status did not influence survival in any group. In all groups, those with a good performance status (Eastern Cooperative Oncology Group [ECOG] 0 and 1) survived longer than those with poor status (ECOG 2 and 3; P less than 0.05). The best potential prognosis is in those who are fully productive and present with painless jaundice, and who have resection of the tumor.

Eastern Cooperative Oncology Group phase II studies in advanced measurable colorectal cancer. I. Razoxane, Yoshi-864, piperazinedione, and lomustine.

During a 6-month interval, Eastern Cooperative Oncology Group randomized 127 patients who had received prior chemotherapy, and who had advanced measurable, surgically incurable colorectal cancer, to receive piperazinedione (PZD), Yoshi-864, or razoxane (ICRF-159). The observed response (and median survival) rates were: PZD, one of 35 patients (17 weeks); Yoshi-864, one of 34 (19 weeks), and ICRF-159, none of 38 (23 weeks). Among 107 evaluable patients, there were five episodes of life-threatening toxicity with PZD (one death) and four with ICRF-159 (two deaths). In the same protocol, 42 evaluable patients who had not received prior chemotherapy were randomized to be treated with lomustine (CCNU) or one of the three drugs in the "previously treated" trial. One CR (41 weeks) was seen with ICRF-159 and two PRs were seen with CCNU. Life-threatening toxicity occurred in three patients, two who received CCNU (one death) and one who received PZD. No survival advantage was seen. We do not encourage further phase II trials in colorectal cancer with the agents studied.

Treatment of locally unresectable cancer of the stomach and pancreas: a randomized comparison of 5-fluorouracil alone with radiation plus concurrent and maintenance 5-fluorouracil--an Eastern Cooperative Oncology Group study.

One hundred ninety-one patients with pathologically confirmed, locally unresectable adenocarcinoma of the stomach (57 patients) and pancreas (91 patients), were randomly allocated to therapy with 5-fluorouracil (5-FU) alone, 600 mg/m2 intravenously (IV) once weekly, or radiation therapy, 4,000 rad, plus adjuvant 5-FU, 600 mg/m2 IV, the first three days of radiotherapy, then follow-up maintenance 5-FU, 600 mg/m2, weekly. Forty-three patients (22%) could not be analyzed because of ineligibility or cancellation, thus 148 patients were evaluable. The median survival time was similar for both treatment programs and for both types of primary carcinoma, and was as follows: gastric primary carcinoma, 5-FU, 9.3 months; 5-FU plus radiotherapy, 8.2 months; pancreatic primary carcinoma, 5-FU, 8.2 months; 5-FU plus radiotherapy, 8.3 months. Substantially more toxicity was experienced by patients treated with the combined modality arm than by those patients receiving 5-FU alone. Severe or worse toxicity experienced by patients with gastric primary carcinoma treated by 5-FU was 19%, and the combined modality arm was 31%. The toxicity experienced by patients with pancreatic primary carcinoma treated with 5-FU was 27%, and the combined modality arm was 51%. Significant prognostic variables included: weight loss in stomach-cancer patients; and performance status, degree of anaplasia, and reduced appetite in pancreas-cancer patients.

Combination chemotherapy for advanced non-Hodgkin's lymphomas other than diffuse histiocytic or undifferentiated histologies.

A combination chemotherapy program using methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M-BACOD), which resulted in a high complete response rate and prolonged disease-free survival in lymphomas of the unfavorable diffuse histiocytic and diffuse undifferentiated histopathologic subgroups, was administered to 44 patients with advanced favorable and intermediate-prognosis non-Hodgkin's lymphomas, including nodular lymphoma of the poorly differentiated lymphocytic, mixed, and histiocytic subtypes, and diffuse lymphoma of the poorly differentiated lymphocytic or mixed histologic subtypes. High-dose methotrexate (3 g/m2) was given on Day 14 between cycles of bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone, administered every 3 weeks for ten cycles. Leucovorin factor (10 mg/m2) was given iv 24 hours after the methotrexate infusion was completed, and was continued at 10 mg/m2 by mouth every 6 hours for 72 hours. Therapy was well-tolerated, with predictable myelosuppression in the majority of patients. The complete response rate was 57% (25 of 44 patients), including ten of 18 (56%) patients with nodular and 15 of 26 (58%) patients with diffuse lymphomas. Median overall follow-up among living patients is 65 months, 58 months for patients with nodular and 69 months for patients with diffuse histologic subgroups. Overall survival at 5 years was 64% for patients who achieved complete response, 32% for partial responders, and 0% for those patients who did not respond. Disease-free survival of complete responders was 43% at 5 years, with only one disease-related death noted after 36 months. The nodular and diffuse patient subgroups had similar overall and disease-free survivals. Although initial bone marrow involvement was documented in nine of 18 (50%) nodular patients and in 13 of 26 (50%) diffuse patients, CNS relapse occurred in only one complete and two partial responders. The prolonged disease-free survival observed after M-BACOD therapy demonstrates that durable responses can be achieved with intensive chemotherapy.

Primary liver cancer. An Eastern Cooperative Oncology Group Trial.

One hundred ninety-two patients with unresectable primary liver cancer studied by members of the Eastern Cooperative Oncology Group (ECOG) were evaluable in a prospectively randomized clinical trial. Patient discriminants such as performance status were carefully evaluated to assess their influence on prognosis and to evaluate the importance of patient status on response and survival. Patients who were totally bedridden or with signs of overt liver failure were not entered on study. The median survival time for all evaluable previously untreated patients was 17 weeks (19 weeks for North American and European, and 10 weeks for South African black patients). Among the South African patients, however, there was a significantly larger proportion with an initially poor performance status. Prognostic variables (performance status, jaundice, and reduced appetite) dominate any differences among the treatments studied. Among North American and European patients on intravenous (IV) 5-fluorouracil (5-FU) + Methyl-CCNU (MeCCNU) + Adriamycin (ADM, doxorubicin), the 19% response rate is offset by 63% with severe toxicity and a median survival time of only 17 weeks, making this treatment unacceptable clinically. The median survival time of North American and European patients treated with IV 5-FU +/- MeCCNU was 28 weeks in contrast to a median survival time of 12 weeks with ADM (P less than or equal to 0.01). EST 2273 was the ECOG study of patients with primary liver cancer. The results of the first part of the trial were published in 1978. This report updates those findings and reports the results of patients entered subsequently on the second part of that study after it was amended in 1979. With more than 300 evaluable patients in EST 2273, this duet of studies is the largest ever conducted in patients with primary liver cancer, and draws a new baseline from which to measure the disease and its response to treatment.

Eastern Cooperative Oncology Group experience with chemotherapy for inoperable gallbladder and bile duct cancer.

In a prospective randomized Eastern Cooperative Oncology Group (ECOG) study, 53 eligible and evaluable patients with advanced gallbladder carcinoma and 34 with advanced bile duct carcinoma were treated with oral 5-fluorouracil (5-FU) or with oral 5-FU plus streptozotocin (Stz) or oral 5-FU + Methyl-CCNU (MeCCNU). Severe toxicity occurred in 2 of 30 patients receiving 5-FU (7%), in 14 of 26 receiving 5-FU + Stz (54%), and in 12 of 31 receiving 5-FU + MeCCNU (39%). Five of 53 patients with gallbladder carcinoma (2/18 [11%] on 5-FU, 2/16 [12%] on 5-FU + Stz, and 1/19 [5%] on 5-FU + MeCCNU) had objective response to treatment. There was no significant difference between treatments with respect to response or survival. Three of 34 patients with bile duct cancer (1/12 [8%] on 5-FU, 0/10 on 5-FU + Stz, and 2/12 on 5-FU + MeCCNU) had objective response to treatment. There was no significant difference between treatments with respect to response or survival. Patients with prior chemotherapy were randomized between MeCCNU alone and Stz alone. Among such patients, only 1 of 17 patients who had prior chemotherapy with other agents responded to MeCCNU alone, and none of 14 patients responded to Stz alone.

Chemotherapy of advanced colorectal carcinoma: fluorouracil alone vs. two drug combinations using fluorouracil, hydroxyurea, semustine, dacarbazine, razoxane, and mitomycin. A phase III trial by the Eastern Cooperative Oncology Group (EST: 1278).

Patients with advanced colorectal cancer and no prior chemotherapy were randomized to six treatment regimens: A) fluorouracil (FU) alone; B) FU + hydroxyurea (HU); C) semustine (SE) + dacarbazine (DA); D) FU + HU alternating with SE + DA; E) SE + razoxane (RA); F) mitomycin (MI) + DA. There were no significant treatment differences with respect to response, which ranged from 9-23% (overall 32/207 or 15%) or median survival duration, which ranged from 17 weeks to 32 weeks. Patients treated with FU or FU + HU experienced substantially less toxicity than those on the other treatment arms.

Neocarzinostatin versus m-AMSA or doxorubicin in hepatocellular carcinoma.

Sixty-one of 76 patients entered on a prospective randomized trial of neocarzinostatin ( NCZ ) versus m-AMSA or doxorubicin were eligible for analysis. Among these 61 patients at least one episode of severe toxicity was documented in 39% of patients on NCZ and 58% on m-AMSA. Fifty-one of the 61 patients were previously untreated with chemotherapy. Among these 51 patients objective response was documented in two of 25 patients treated with NCZ , none of 17 treated with m-AMSA, and one of nine treated with doxorubicin. Among previously untreated North American and European (NA/E) patients the median survival times were: NCZ 11 weeks and m-AMSA 12 weeks. The data on South African (SA) patients with similar entrance criteria entered on earlier Eastern Cooperative Oncology Group trials were analyzed with that from the randomized trial and show that for SA patients the median survival times were: NCZ , 11 weeks (31 patients); m-AMSA, 13 weeks (33 patients); and doxorubicin, 15 weeks (29 patients).

Advanced squamous carcinoma of the head and neck. A preliminary report of neoadjuvant chemotherapy with cisplatin, bleomycin, and methotrexate.

Between Oct 1, 1979 and Aug 1, 1982, 93 patients with advanced squamous carcinoma of the head and neck were given neoadjuvant treatment with cisplatin, bleomycin sulfate, and methotrexate before standard local treatment. Ninety-three patients were evaluable for response. The response rates were as follows: complete response, 24%; partial response, 64%; and no response, 12%. Differences in primary tumor site, performance status at presentation, histologic grade, and tumor size did not correlate with response to this chemotherapy. For patients achieving notable tumor reduction to 2 cm or less, standard local treatment with either surgery plus radiotherapy or high-dose radiotherapy alone was effective in controlling local disease. For patients with larger tumor masses following neoadjuvant chemotherapy, surgical resectability appeared to improve local control rates. In our series, patients not receiving maximal standard local treatment often had relapse of local disease despite favorable responses to chemotherapy.

Adriamycin and Cytoxan in the treatment of inoperable lung cancer.

The results of a clinical trial involving 599 patients with inoperable squamous cell, large cell anaplastic, and adenocarcinoma of the lung are summarized. Patients were randomized to initial therapy with Cytoxan (CTX) (cyclophosphamide), or to one of two schedules of Adriamycin (doxorubicin) 50, or 75 mg/m2 IV every three weeks, or to a combined regimen of ADR and CTX. Upon disease progression, CTX patients were randomized to one of the two ADR schedules, while ADR patients were randomly assigned to CTX alone, or in combination with Cisdiamminedichloroplatinum (Cis-Platinum) 15 mg/m2 IV every three weeks. No statistically significant response or survival differences were observed between the two dose schedules of Adriamycin for any of the cell types studied. The two dose levels did, however, differ with respect to toxicity. There were some response and survival differences among the various cell types in the comparison of low-dose Adriamycin and Cytoxan: (1) patients with adenocarcinoma treated with low-dose Adriamycin tended to survive longer (P = 0.04) than those treated with Cytoxan; and (2) patients with large cell carcinoma receiving Cytoxan experienced a greater tumor response rate than those receiving low dose Adriamycin (P = 0.03). Because of the difficulties involved in distinguishing these two cell types on pathologic examination, the evidence of apparent treatment differences should not be regarded as definitive. During the period when Adriamycin plus Cytoxan was open to patient entry 61 evaluable patients received that regimen, 21 received low-dose Adriamycin and 22 received Cytoxan. Because relatively few patients received the latter two regimens, comparisons of these treatments with Adriamycin plus Cytoxan lack statistical power. However, there is no suggestion in the available data that Adriamycin plus Cytoxan increased survival either in the overall population or in the subset of patients with squamous histology. Initial performance status, metastatic disease symptoms, primary disease symptoms, and weight loss were significantly correlated to survival time, and are recommended as stratification factors in future studies.

Combination chemotherapy containing semustine (MeCCNU) in patients with advanced colorectal cancer previously treated with 5-fluorouracil (5-Fu).

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.

Improved prognosis of diffuse histiocytic and undifferentiated lymphoma by use of high dose methotrexate alternating with standard agents (M-BACOD).

A new combination chemotherapy program (M-BACOD) was administered to 101 patients with advanced diffuse histiocytic and diffuse undifferentiated lymphoma (DHL and DUL). High dose methotrexate (M) 3 g/m2 with leucovorin factor rescue was given on day 14 between cycles of bleomycin (B), adriamycin (A), cyclophosphamide (C), oncovin (O), and dexamethasone (D) administered every 3 weeks for 10 cycles. The complete remission rate (CR) was 72% in all 101 patients or 77% in 95 evaluable patients. The median follow-up is 3 yr 2 mo with one-third of CR patients followed beyond 4 yr. Twenty-six percent of CR patients have relapsed with a projected 5-yr survival rate of 80% (5-yr disease-free rate 65%). The overall survival of all 101 study patients reaches a plateau at 59% projected out to 5 yr. Patients with prior therapy had a significantly lower CR rate than those without prior treatment (p = 0.001); however, no other unfavorable prognostic characteristics could be identified. Relapse in the central nervous system CNS occurred in only 5.4% of CR patients. M-BACOD results in prolonged survival and possible cure in a high proportion of all patients with DHL and DUL.

Clinical and chemotherapeutic study of hepatocellular carcinoma in Malaysia: a comparison with African and American patients.

Twenty Malaysian patients with unresectable primary liver cell cancer were prospectively studied at the General Hospital, Kuala Lampur, and were compared for clinical features with an equal number each of African and American patients being studied by the Eastern Cooperative Oncology Group. The patients received intravenous 5-FU and oral MeCCNU which was used for the first time in an Asian country. Most of the Malaysian patients were Chinese, belonged to younger age groups, and presented with massive hepatomegaly, jaundice, and fever. Toxicity to MeCCNU invariably occurred in the form of leukopenia or thrombocytopenia, but none life threatening. Partial response was seen in 20% of Malaysians as compared to 16% in Americans and none in Africans. Malaysians achieved a median survival of 16 weeks compared to 28 weeks in Americans and only eight weeks in Africans. Malaysian Chinese patients were all HBc Ab + ve. Other factors which may have played an etiologic role in the induction of primary liver cancer included alcohol, Chinese herbal medicines, aflatoxin and habitual use of medicated rubbing oils.

Combination chemotherapy of advanced colorectal cancer utilizing 5-fluorouracil, semustine, dacarbazine, vincristine, and hydroxyurea: a phase III trial by the Eastern Cooperative Oncology Group (EST: 4275).

Patients who had measurable evidence of recurrent or metastatic colorectal carcinoma following surgery and radiotherapy but no prior chemotherapy were randomized to one of five combination chemotherapy programs. Four of the treatments utilized five consecutive days of fluorouracil (FU) (days 1--5 and days 36--40) plus one oral dose of semustine (ME) (day 1) every ten weeks: (A) FU + ME; (B) FU + ME + vincristine (VC) (day 1 and day 36); (C) FU + ME + dacarbazine (DC) (days 1, 2, 36, 37); (D) FU + ME + VC + DC. The fifth treatment option(E) used a weekly treatment program of FU I.V. on day 1 plus hydroxyurea (HU) P.O. on day 4. The overall response rate was 13% (60/472) and the median survival time from start of therapy for all patients was 31 weeks. The response rate and the median survival time for each combination was (A) 9/103 = 9%, 26 weeks; (B) 10/92 = 11%, 28 weeks; (C) 15/101 = 15%, 37 weeks; (D) 11/91 = 12%, 27 weeks; (E) 15/85 = 18%, 38 weeks. There is no statistical difference in response rate or survival duration among any of the treatment options. The therapies containing DC produced the only complete responses (3 patients on treatment C and 2 on D). Treatment D was also associated with the longest median response duration (Treatment D = 55 weeks). Treatment A (FU + ME) was associated with the highest incidence of life-threatening toxicity.

Comparison of doxorubicin with cycloleucine in the treatment of sarcomas.

In this patient series, doxorubicin and cycloleucine at a dose of 300 mg/kg both show response rates in the treatment of advanced soft tissue sarcomas of about 15%. Lower doses of cycloleucine (200 mg/kg) yielded less toxicity but were less effective against the sarcomas (6% response rate, three of 51 patients). There were no complete responses with cycloleucine and there were three with doxorubicin. Survival times for patients receiving doxorubicin were significantly longer than those of patients receiving cycloleucine at doses of 300 mg/kg (P less than 0.001) or 200 mg/kg (P = 0.02). The estimated survival times were 29 weeks for doxorubicin and 21 (300 mg/kg) and 18 (200 mg/kg) weeks for cycloleucine. Toxic effects due to cycloleucine were excessive, with severe thrombocytopenia and central nervous system depression being the most prominent.