Harold O. Douglass

Streptozocin plus fluorouracil versus doxorubicin therapy for metastatic carcinoid tumor.

EST 5275 is a phase II and III study of fluorouracil plus streptozocin (5-FU plus STZ) or doxorubicin in patients with measurable progressive carcinoid tumor. Among one hundred seventy-two cases with no prior chemotherapy and no heart disease, the response rate was 22% for 5-FU plus STZ and 21% for doxorubicin, while the median response duration and median survival were 31 weeks and 64 weeks for the combination and 26 weeks and 48 weeks for doxorubicin. Thirty-three patients who failed 5-FU plus STZ crossed over to doxorubicin and achieved an 18% response. Of the thirty-five patients who failed on doxorubicin, 29% responded to 5-FU plus STZ. Hematologic toxicity was similar for both treatments; however, the 5-FU plus STZ patients experienced more vomiting but acceptable renal toxicity. Both chemotherapy regimens have antitumor activity in carcinoid tumors.

Neutropenic enterocolitis. Clinical diagnosis and treatment.

Review of the consultation records of the Gastrointestinal Surgical Oncology service at Roswell Park Memorial Institute from 1982 to 1987 revealed 22 patients with a finical diagnosis of neutropenic enterocolitis. Ninety one percent of the patients had hematologic malignancies and 95% were receiving cytotoxic chemotherapy, Sixteen patients were treated nonsurgically; 11 died. Of those 11 cases, autopsies were performed in 9. At autopsy, the clinical diagnosis was confirmed in four cases; four cases were found to have normal intestinal tracts, and one case had a small bowel volvulus. In none of the four cases for which autopsy proved neutropenic enterocolitis was transmural bowel necrosis or perforation found. Laparotomy was performed in six patients; three survived. The clinical diagnosis was verified in four of the six patients. Neutropenic enterocolitis must be considered a diagnosis of exclusion. Care of these patients should be individualized. Nonoperative management with bowel rest, decompression, nutritional support, and broad spectrum antibiotics is recommended initially. Operative intervention is recommended for those with perforation or those whose condition deteriorates clinically during close, frequent observation.

Etoposide pharmacokinetics in patients with normal and abnormal organ function.

Precise guidelines for dose modification of etoposide in patients with hepatic dysfunction have not been determined. Etoposide pharmacokinetics were determined in 17 patients. Nine patients had bilirubin less than or equal to 1 mg/dL and eight had bilirubin ranging from 1.9 to 23 mg/dL. Twelve patients received etoposide 100 mg/m2 days 1, 3, and 5, in combination with cisplatin 70 mg/m2 or iproplatin 225 mg/m2 on day 1. Five patients received only one dose of etoposide. Etoposide was measured using a published high pressure liquid chromatography (HPLC) method which also quantitates picro etoposide and its hydroxy acid. Systemic clearance, Vdss and t1/2 beta averaged (+/- SD) 21.4 (+/- 7.4) mL/min/m2, 10.7 (+/- 4.1) L/m2, and 8.1 (+/- 2.8) hours in the nine patients with bilirubin less than or equal to 1 mg/dL, and 22.4 (+/- 9.6) mL/min/m2, 13.6 (+/- 11.3) L/m2, and 8.4 (+/- 3.9) hours in the eight patients with bilirubin 1.9 to 23.0 mg/dL. Stepwise multiple linear regression analysis of liver and renal function tests and other patient-specific variables identified creatinine clearance as the strongest predictor of etoposide systemic clearance (r2 = 40.8). Serum albumin was identified as the next strongest predictor, improving the r2 to 57.3%. Cumulative biliary excretion of unchanged etoposide and glucuronide or sulfate conjugates over 48 hours accounted for less than 3% of the dose in six patients studied. Toxicity occurred in patients with normal and abnormal bilirubin and was unrelated to etoposide clearance. Patients with total bilirubin 1.9 to 23 mg/dL, but creatinine clearance greater than 30 mL/min/m2 had etoposide clearance within the range for patients with normal liver function (16.8 to 35 mL/min/m2). Although these patients did not have reduced etoposide clearance, the major routes of etoposide non-renal elimination remain to be clearly defined. Additional patients should be evaluated to establish more precise guidelines for dosing etoposide in patients with abnormal liver function.

Carcinoma of the gallbladder. The Roswell Park experience.

The median survival, from diagnosis, of patients with cancer of the gallbladder is 6 months. Our purpose in reviewing our experience was to identify factors, either in patient characteristics or treatment, that influence this statistic. In 22 years 71 cases of gallbladder carcinoma were referred to Roswell Park Memorial Institute in Buffalo, New York. Most had a cholecystectomy that revealed an unsuspected neoplasm, before referral. Mean age was 62 years and 75% were female. Symptoms, signs, and laboratory and imaging studies were uniformly unhelpful in determining the diagnosis. Early diagnosis at a stage amenable to surgical excision remains the sole salvation. Patients who receive chemotherapy did better than those who did not, but this is probably a reflection of patient selection. Newer treatment modalities are urgently needed.

Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity.

Twenty-two patients with newly diagnosed nonmetastatic osteosarcoma of the extremity were treated with an adjuvant chemotherapeutic regimen consisting of Adriamycin (Adria Laboratories, Columbus, Ohio) and cisplatin. Fourteen of the 22 patients remain continuously disease free for 65+ to 113+ months, with a median time on study of 70+ months. The 72-month disease-free survival estimate is 64%. Pulmonary metastases occurred in six patients, an isolated stump recurrence was seen in one patient, and one patient had a local recurrence following a limb-salvage procedure. For those patients in whom pulmonary metastases developed, the onset was late in three of six, and the number of metastases was three or fewer in all patients. Two patients with pulmonary metastases and one with a stump recurrence have apparently been salvaged, thus resulting in a 77% 72-month survival. Toxicity observed in patients treated with this regimen was in keeping with previous reports. This chemotherapeutic regimen is effective in the adjuvant therapy of nonmetastatic osteosarcoma of the extremity. It should be incorporated into other adjuvant protocols in an effort to continue to improve the outcome in patients with osteosarcoma.

A phase II trial of 5-fluorouracil, doxorubicin, mitomycin C, and leucovorin in advanced gastric carcinoma

To determine the feasibility and toxicity of combining leucovorin (CF) with a 5‐fluorouracil (5‐FU) combination chemotherapy regimen currently accepted by many as standard treatment for gastric cancer, CF (500 mg/m2) was administered in combination with the Georgetown 5‐FU, doxorubicin, and mitomycin C (FAM) regimen. Thirty‐two patients with advanced adenocarcinoma of the stomach were evaluable for toxicity and 26 patients with measurable disease were evaluable for response. Fifty‐four percent of patients were previously treated with chemotherapy or radiation therapy. The response rate was 38% (95% confidence interval, 21% to 59%). The median duration of response was 6 months (range, 2 to 23+ months). The estimated median survival time was 6.8 months for patients with measurable disease and 11.5 months for all 32 patients. Although diarrhea is dose limiting when 5‐FU and CF are administered weekly for 6 of 8 weeks, diarrhea occured rarely on this combination regimen with 5‐FU and CF administered only 4 of every 8 weeks. The dose‐limiting toxicity of FAM‐CF was cumulative myelosuppression, which also occurs with the standard FAM regimen. As a result, the administered dose intensity of 5‐FU decreased as patients continued on study. Thus, a randomized comparison of FAM with FAM‐CF would not determine whether CF modulation increases the efficacy of 5‐FU when it is administered in optimal doses to patients with gastric cancer.

UNUSUAL GASTROINTESTINAL COMPLICATIONS OF INTERLEUKIN-2 THERAPY

Minor and reversible gastrointestinal side effects are common when patients receive interleukin-2 (IL-2) with or without lymphokine-activated killer (LAK) cells. We treated 42 cancer patients with IL-2 therapy and 3 patients developed serious gastrointestinal problems during treatment. Complications included sigmoid colon perforation, ischemic necrosis of the small and large intestine, and diffuse bowel ulceration. These were not associated with tumor implants or hypotension. Two patients died as a direct result of these problems despite aggressive surgical and medical management. The incidence of major gastrointestinal complications with IL-2 therapy may be greater than previously reported and a heightened awareness of potential gastrointestinal problems may circumvent considerable morbidity and mortality.

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 (β-TGdR). Platelet nadirs <50,000/mm3 were noted in 9% (Treatment A) to 19% (D) of the patients while WBC nadirs <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.

Phase II trial of etoposide, doxorubicin, and cisplatin combination in advanced measurable gastric cancer. An Eastern Cooperative Oncology Group study.

A phase II study was performed to determine the efficacy and toxicity of the etoposide, doxorubicin, cisplatin (EAP) regimen in the treatment of patients with advanced measurable gastric cancer in a multi-institutional cooperative group setting. Thirty-one evaluable patients with advanced measurable gastric adenocarcinoma were treated with etoposide 120 mg/m2 on days 3, 4, and 5, doxorubicin 20 mg/m2 on days 1 and 8, and cisplatin 40 mg/m2 on days 2 and 9. The treatment was repeated every 28 days. Objective responses were seen in 7 (23%) patients, all achieving partial remissions. Median survival was 9 months for the entire group. Toxicity was mostly hematologic, with grade 3 leukopenia in 26% and grade 4 leukopenia in 55% of the patients. There were 4 treatment-related deaths that were attributable to severe leukopenia and sepsis. Because of the high toxicity and moderate response rate, this regimen is not superior to other less toxic regimens and cannot be recommended for the treatment of advanced gastric cancer outside of an investigational protocol.

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.