John M. Macintyre

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 < 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 <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 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.

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 ≤ 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.

Pain characteristics and treatment in an outpatient cancer population

Thirty of 100 consecutive outpatients at a comprehensive cancer center were assessed by their physicians as having pain due to cancer severe enough to require regular or narcotic medication. These 30 patients and their physicians then were approached with a semistructured questionnaire about pain characteristics and management. Pain severity correlated only with age older than 55 years. Patients tended to rate their pain as more severe than did their physicians, but believed that pain medications generally were effective. Side effects of pain medication and patient fears of dependence on medication appeared to be more important limiting factors in achieving complete pain relief from medication than undermedication by physicians. Both patients and physicians acknowledged a relationship between emotional state and pain, but there was a greater appreciation among patients than physicians of the usefulness of techniques such as relaxation and distraction in pain control.

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.

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.

A computerized patient registration and treatment randomization system for multi-institutional clinical trials

Computerized registration and randomization for a cooperative clinical trials group is a useful addition to its data gathering and managing process. An automated system eliminates unnecessary paperwork, allows more sophisticated randomization algorithms to be implemented, and makes available a variety of computer-generated reports such as confirmation of registration forms, accrual results, and other statistical tables. This paper describes the design and implementation of such a system for a relatively large cooperative group, the Eastern Cooperative Oncology Group (ECOG), as well as gives general recommendations for conversion of a manual registration and randomization process to an automated one. Our general interactive system, known as PRS for Patient Randomization System, was designed to be easily expandable as its functions increase over time, and transportable to other clinical trials settings.

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.

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 < 0.001).

ECOG phase II trials of MGBG, chlorozotocin COM multidrug therapy in advanced measurable, colorectal cancer

The Eastern Cooperative Oncology Group (ECOG) entered 326 patients with advanced measurable colorectal cancer into four phase II drug or drug combination trials. Previously treated and chemotherapy-naive patients were eligible. Chlorozotocin was administered to 83 patients (51 previously treated), methyl-glyoxal-bis-guanylhydrozone (MGBG) to 90 patients (58 previously treated), and two regimens of the three-drug combination of cyclophosphamide, vincristine, and methotrexate (COM) to 153 patients (120 previously treated). The multidrug regimen had been developed specifically for previously treated patients. In this trial, chemotherapy-naive patients were no more likely to respond than were members of the previously-treated group. Even among previously untreated patients, response rates did not exceed 10% in any of these phase II programs. They are not recommended for further trials in patients with colorectal cancers.