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PubMed1981

Adriamycin and methyl-CCNU combination therapy in hepatocellular carcinoma: clinical and pharmacokinetic aspects.

Twenty-one patients with unresectable hepatocellular carcinoma (hepatoma) were treated with adriamycin (15-45 mg/m2 q21 D) and methyl-CCNU (75-150 mg/m2 q 63 D) with dosage adjusted for hepatic dysfunction. Objective response frequency was 14% with all responses occurring in patients with normal pretreatment bilirubin levels. Median survival of all patients was 87 days. Initial bilirubin levels greater than 2 mg/dl predicted for decreased survival (median 30 days vs. 115 days, P less than 0.05). Only moderate hematologic toxicity was observed. Plasma profiles of Adriamycin and adriamycinol were determined during 11 courses of Adriamycin administration in seven of these patients. Despite moderately elevated transaminase levels (all cases) and bilirubin levels (three cases), plasma Adriamycin profiles in hepatoma patients were not elevated (terminal half-life of 30 hours) and were indistinguishable from that of non-hepatoma patients with normal liver functions. However, delayed appearance of peak levels and prolongation of terminal half-lives were routinely observed for adriamycinol, a major metabolite of Adriamycin. This resulted ina significant increase in the CXT (concentration X time) ratio of adriamycinol/Adriamycin in hepatoma patients compared with nonhepatoma patients (2.36 +/- 2.12 vs 0.76 +/- 0.31, (P less than 0.05). We conclude that the combination of relatively mild toxicity and normal Adriamycin disposition indicates unusual tolerance to Adriamycin therapy for patients with hepatoma and cirrhosis. As a result, severe dosage adjustments of Adriamycin may not be indicated for all such patients having only moderate hepatic dysfunction.

Adult↗

PubMed1981

Nephrotoxicity of nitrosoureas.

Irreversible and progressive renal parenchymal damage and functional impairment occurred in the majority of patients receiving at least six courses (200 mg/m2 of BCNU and/or methyl CCNU at eight-week intervals) of nitrosoureas for therapy of malignant brain tumors. Seventeen of 18 patients who received at least six courses and all nine patients who received more than ten courses developed impaired renal function as judged by elevation of blood urea nitrogen and/or serum creatinine or decrease in filtration rate as determined by inulin clearance. Four patients have developed uremia. Renal tissue obtained from seven patients demonstrated tubular atrophy, interstitial fibrosis and glomerular sclerosis. This remarkably high incidence of renal damage occurred without a phase of acute renal failure and in the absence of significant urinary abnormalities, while producing an insidiously progressive interstitial renal lesion.

Adolescent↗

PubMed1982

Controlled trial of adjuvant chemotherapy following curative resection for gastric cancer. The Gastrointestinal Tumor Study Group.

Following curative resection for gastric adenocarcinoma, 142 patients were randomized to receive adjuvant chemotherapy of methyl-CCNU and 5-FU or to be closely followed without chemotherapy. The median patient has been followed for four years. At the present time, there have been 38 recurrences and 40 deaths among the 71 patients in the control arm and 28 recurrences with 29 deaths in the group of patients randomized to chemotherapy. Median survival for control patients is 33 months whereas it is estimated to be in excess of four years for the adjuvant therapy group. A survival advantage appears to be associated with adjuvant treatment, a test for treatment difference being significant (P less than 0.03) after adjustment for important covariates. Survival and disease-free intervals are longer in the chemotherapy arm for patients in all prospective stratification subgroups (proximal and total vs distal subtotal gastrectomy, presence or absence of lymph node metastases, invasion of adjacent organs vs confined to stomach wall and location of tumor within the stomach). A final assessment of this surgical adjuvant approach must await complete results of this trial, as well as of others currently in progress evaluating this same concept.

Adenocarcinoma↗

PubMed1982

A comparison of combination chemotherapy and combined modality therapy for locally advanced gastric carcinoma. Gastrointestinal Tumor Study Group.

This controlled trial compared to survival of 90 patients with locally advanced gastric carcinoma treated with either chemotherapy alone (5-FU and methyl-CCNU) or external radiotherapy of 5000 rad combined with the same chemotherapy. The minimum period of followup is 4 years. During the initial 12 months, combined modality therapy was associated with an increased number of early deaths attributable to progression of tumor within the radiation field, or nutritional and hematologic complications. During the second to fourth years of followup, patients treated with combined radiation therapy have shown a significantly lower death rate compared to those treated with chemotherapy alone, with eight of 45 patients alive and disease-free. Patients who received only chemotherapy, in contrast, have demonstrated a continued probability for tumor relapse and death, with three of 45 patients alive at 4 years. Palliative resection of the primary tumor was associated with an improved survival, independent of the form of postoperative therapy employed. It is possible that the superior late survival achieved with combined modality therapy in this program can be further improved with measures to decrease the toxicity of upper abdominal irradiation, and with the use of more effective forms of chemotherapy.

Adenocarcinoma↗

PubMed1982

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.

Adult↗

PubMed1982

Toxicity of very high dose nitrosourea administration.

We report a case of inadvertent administration of over twice the usual dose of methyl-CCNU. The patient exhibited an early onset of bone marrow suppression. Profound pancytopenia, including lymphopenia, persisted for over seven weeks, Although early recovery started at about five weeks. Permanent marrow damage was indicated by persistent thrombocytopenia and abnormal megakaryocyte morphology at autopsy, some six months after the single exposure to methyl-CCNU. There was no discernible toxicity to lung, liver, or kidneys. The case suggests that the cummulative bone marrow toxicity seen with nitrosoureas is not dose-schedule sensitive. There is also evidence suggesting that high dose nitrosourea therapy affects a bone marrow target population other than the early stem cell target affected by usual doses of these drugs.

Adenocarcinoma↗

PubMed1983

Efficacy of prolonged intermittent therapy with combined 5-FU and methyl-CCNU following resection for gastric carcinoma. A Veterans Administration Surgical Oncology, Group report.

This prospective evaluation of 5-fluorouracil (5-FU) and methyl-CCNU administered in combination to patients with surgery for histologically proved gastric adenocarcinoma is based upon 312 patients randomized between August 1974 and May 1980. Patients were stratified into three categories of resectability, (1) complete, (2) proven incomplete, and (3) nonresectable, prior to random treatment assignment to surgery alone or surgery followed by adjuvant chemotherapy. Drug therapy consisted of discrete 5-day courses administered at 7-week intervals. Toxic reactions were reported in association with 42% of the courses. Treatment was suspended or discontinued in 6% of the courses because of hematologic toxicity. Treated patients with curative resections experienced a more favorable survival than did controls, but the early advantage was lost by the end of the second follow-up year. However, no statistically significant improvements in survival or reductions in risks of recurrence were observed. Similar proportions of treated and control deaths were attributable to residual or recurrent disease.

Adenocarcinoma↗

PubMed1983

Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the multidisciplinary management of malignant gliomas. A joint Radiation Therapy Oncology Group and Eastern Cooperative Oncology Group study.

Recently, the RTOG and ECOG concluded a joint randomized study on malignant gliomas that was in progress for the past five years. A total of 626 patients entered this protocol. Sixty-seven percent of the 535 evaluable patients have died and thus this represents a preliminary report of a major joint clinical trial. The objective of this study was to evaluate the efficacy after neurosurgery of three new treatment options as compared with control treatment of radiotherapy alone. The four options were: (1) control radiation; 6000 rad/6-7 weeks to whole brain; (2) a higher radiation dose; Control dose plus a booster dose of 1000 rad/1-2 weeks to the tumor; (3) control radiation dose plus BCNU (80 mg/m2/day IV X 3 and repeat BCNU every 8 weeks); (4) Control radiation dose plus combination methyl-CCNU (125 mg/m2/day orally X 1 and repeat methyl-CCNU every 8 weeks), and DTIC (150 mg/m2/day IV X 5 and repeat DTIC every 4 weeks). All pertinent patient characteristics were studied and several important prognostic factors have been identified. Notably, age, histologic type (Astrocytoma with anaplastic foci, versus glioblastoma multiforme), initial performance status, time since first symptoms and presence or absence of seizure. At this time, it appeared that there was no treatment option which was significantly better than the control. The study identified that age was the most important prognostic factor. Patients who were younger than age 40 years had an 18-month survival of 64%, patients who were age 40-60 years had an 18-month survival of 20%, and patients who were older than age 60 had an 18-month survival of 8%. The study also demonstrated that a modified histologic classification of anaplastic astrocytoma versus glioblastoma provided better prognostic information than the astrocytoma grading system of Kernohan. Patients with anaplastic astrocytoma had a median survival of 27 months as compared to 8 months for patients with glioblastoma. In further evaluation of any beneficial effect of chemotherapy, it was identified that only among the 40-60-year-old groups, BCNU treated patients appeared to have significantly increased survival than patients in the control groups (P = 0.01, one-sided). Similarly, methyl-CCNU + DTIC was suggestively better than the control (P = 0.08, one-sided). The higher radiation dose, 7000 rad/8-9 weeks appeared to give no significantly better survival over the control dose option. Both BCNU and methyl-CCNU + DTIC produced some toxicity. The combination of methyl-CCNU + DTIC was more toxic than BCNU, producing severe or worse thrombocytopenia in 23% of the patients as compared to 6% on BCNU.

Adult↗

PubMed1983

Clinical trials and drug toxicity in the elderly. The experience of the Eastern Cooperative Oncology Group.

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.

Age Factors↗

PubMed1984

Randomized study of combination chemotherapy in unresectable gastric cancer. The Gastrointestinal Tumor Study Group.

Two hundred forty-one patients with unresectable gastric adenocarcinoma were entered, between December 1978 and March 1981, into a prospectively randomized comparison of three chemotherapy regimens to identify therapeutic activity and determine patient tolerability: (1) 5-fluorouracil plus Adriamycin (FA); (2) FA plus methyl-CCNU (FAMe); and (3) FA plus mitomycin C (FAMi). Patients were stratified by stage and performance status prior to randomization. Treatment groups were well balanced with respect to known prognostic discriminants. The primary endpoint to evaluate treatment effect was patient survival. Pair-wise comparisons using a proportional hazards model adjusted for stage and performance status documented a significant survival advantage for FAMe compared with FA (P less than 0.03). Toxicity was primarily hematologic and was seen more frequently in patients receiving FAMe. Further investigations of the FAMe regimen in the surgical adjuvant setting and combined with radiotherapy for patients with locally unresectable gastric cancer are under development.

Adenocarcinoma↗

PubMed1984

Efficacy of prolonged intermittent therapy with combined 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report.

This prospective evaluation of 5-FU and methyl-CCNU administered in combination to patients with curative surgery for histologically proved colorectal adenocarcinoma is based upon 645 patients randomized between August 1973 and July 1979. Beyond the requirement that the resection be clinically and microscopically complete, patients were not stratified prior to random treatment assignment to surgery alone or surgery followed by adjuvant chemotherapy. Drug therapy consisted of discrete 5-day courses administered at 7-week intervals, start to start. Toxic reactions were reported in association with 40% of courses. In 10% of patients with hematologic toxicity, the reactions were sufficiently severe to require the suspension or discontinuation of treatment. Treated patients experienced a slightly more favorable survival than did controls. However, the advantage was seen only in the 216 patients (34% of total) with one to four positive lymph nodes in the resected specimen. Similar proportions of treated and control deaths were attributed to residual or recurrent disease.

Adenocarcinoma↗

PubMed1984

Efficacy of MER immunotherapy when added to a regimen of 5-fluorouracil and methyl-CCNU following resection for carcinoma of the large bowel. A Veterans Administration Surgical Oncology Group report.

Two hundred four patients with a microscopically incomplete resection for carcinoma of the colon or rectum were accepted for study. All patients were treated with 5-fluorouracil and methyl-CCNU beginning about the second postoperative week. Concurrent immunotherapy with the methanol extraction residue of bacillus Calmette-Guérin (MER) was randomly assigned to 103 patients. Treatment was continued as long as acceptable to the patient, and until clinical recurrence. Toxic reactions to the drug were not increased by the addition of MER, and seldom were severe enough to require the discrimination of therapy. No evidence of improved survival was seen in treated patients. On the contrary, survival in patients who experienced severe reactions to treatment may have been impaired by MER, with the period of impairment continuing after all adjuvant therapy was stopped. Similar proportions of treated and control deaths were attributable to residual or recurrent disease.

Adult↗

PubMed1984

Methyl-CCNU, doxorubicin, and cis-diamminedichloroplatinum II in the management of recurrent and metastatic squamous carcinoma of the cervix.

Twenty-three patients with recurrent unresectable carcinoma of the cervix or distant metastasis at initial presentation were treated with methyl-CCNU (175 mg/m2) and doxorubicin (45 mg/m2) on day 1 and cis- diamminedichloroplatinum II (90 mg/m2) on day 22 of a 42-day treatment cycle. Twenty-two patients had squamous carcinoma and 1 had adenosquamous carcinoma. There were two complete responses (CR), five partial responses (PR) (greater than 50% tumor reduction, greater than 3-month duration), four patients with stable disease (less than 50% reduction, greater than 3-month duration), and 12 patients who had tumor progression. One CR has been maintained greater than 28 months, and the other greater than 8 months. Total CR and PR was 7 of 23 (30.4%). Three 23 responses occurred among 15 patients (20%) who had cancer primarily confined to the pelvis, while 4 of 8 patients (50%) with distant metastasis responded. During the initial 2 cycles of chemotherapy, 12 patients had myelosuppression, defined as a leukocytes less than 3000/mm3, granulocytes less than 1,000/mm3, or platelets less than 100,000/mm3. There were no treatment-related deaths.

Adult↗

PubMed1984

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.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1984

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.

Adenoma, Bile Duct↗

PubMed1990

The concept of locally advanced gastric cancer. Effect of treatment on outcome. The Gastrointestinal Tumor Study Group.

In previous Gastrointestinal Tumor Study Group (GITSG) reports, gastric cancer patients with locally unresectable disease, treated with combined radiation and chemotherapy had a shorter median survival (40 weeks) but more remained alive at 4 years (18%) when compared to those randomized to receive chemotherapy alone (76 weeks and 6%, respectively). To further test the concept that combined modality therapy might increase the number of long-term survivors, a second protocol was designed, but with three major modifications. A course of chemotherapy would precede the 5-fluorouracil-potentiated radiation therapy. Doxorubicin would be added to the 5-fluorouracil plus methyl-CCNU combination. Radiation therapy would be given as a single course of 4320 cGy, with 5-fluorouracil given daily for 3 days at the beginning and end of the course. Median survival of 46 patients treated with chemotherapy alone was 59 weeks, with 11% alive after 3 years. Following combined modality therapy, median survival was 62 weeks, but only 7% lived 3 years. Although the problem of early deaths in the combined modality group was resolved, long-term survival with combination therapy was not demonstrated in this study.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1992

Accomplishments in surgical adjuvant therapy for large bowel cancer.

In the past, effective surgical adjuvant therapy has been an elusive goal with little or no evidence of benefit from chemotherapy, immunotherapy, or radiation therapy. During the last 2 years, however, randomized trials have produced strong evidence of substantive progress. In colon cancer with regional nodal metastasis, therapy with combined 5-fluorouracil (5-FU) and levamisole has resulted in a 41% reduction in the recurrence rate (P less than 0.00005) and a 33% reduction in the death rate (P = 0.0052). In rectal cancer, combined technique adjuvant therapy using radiation (50.4 Gy) given in combination with 5-FU and preceded and followed by full-dose systemic chemotherapy with a 5-FU-based regimen was evaluated. In comparison with the same dose of radiation used alone, this combined regimen reduced the recurrence rate by 33% (P = 0.0016) and the death rate by 29% (P = 0.025). Of almost equal importance, there was a major reduction in local recurrence from 25% to 13%. Both these regimens would seem sufficiently well established to justify offering them as standard treatment. Of greater potential value to the patient, however, is entry into the currently available clinical trials that are pursuing hopeful avenues of research and offer the prospect of still greater accomplishments in the years to come.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Randomized phase III study of 5-fluorouracil plus high dose folinic acid versus 5-fluorouracil plus folinic acid plus methyl-lomustine for patients with advanced colorectal cancer.

BACKGROUND: Metastatic colorectal cancer is generally incurable. The most active regimen available, 5-fluorouracil (5-FU) and folinic acid (Leucovorin), produces response rates of approximately 25% to 30%. Methyl-lomustine is a nitrosourea with modest activity against colorectal cancer. A randomized trial was undertaken to evaluate the impact the addition of methyl-lomustine would have on response, duration of survival, and survival rates in patients with advanced colorectal cancer. METHODS: The methyl-lomustine/5-FU/Leucovorin (MFL) regimen consisted of methyl-lomustine (110 mg/m2), administered on Day 1 of each 8-week cycle with six weekly boluses of 5-FU (600 mg/m2), and Leucovorin (500 mg/m2). The FL treatment arm consisted of the administration of 5-FU and Leucovorin as described above. Patients were evaluated for response and toxicity after each 8-week cycle. RESULTS: Of 319 patients included in this trial, 297 (93.1%) had disease evaluable for response and toxicity: 145 received MFL, and 152 received FL. In this trial, 526 courses of MFL and 529 courses of FL were administered. Methyl-lomustine/5-FU/Leucovorin treatment resulted in 4 complete and 30 partial responses (response rate, 21.9%), and FL treatment resulted in 9 complete and 33 partial responses (response rate, 26.4%). There was no significant difference in median survival duration between patients in the two arms (MFL = 48 weeks, FL = 51 weeks). However, MFL was significantly more toxic with greater myelosuppression than was FL (Grade 3-4 neutropenia: MFL = 56 patients, FL = 27 patients, P < 0.001; Grade 3-4 thrombocytopenia: MFL = 49 patients, FL = 2 patients, P < 0.001; Grade 3-4 anemia: MFL = 15 patients, FL = 6 patients, P < 0.001; and more prolonged median duration of granulocytopenia: MFL = 9 days, FL = 7 days, P < 0.001; and thrombocytopenia: MFL = 14 days, FL = 7.5 days, P < 0.001). CONCLUSION: Because the addition of methyl-lomustine in the MFL schedule markedly increased the toxicity of the regimen and because the FL regimen was as effective as MFL, the authors recommend that Leucovorin and 5-FU remain the treatment choice for treating patients with metastatic colorectal cancer.

Adult↗