A phase I-II trial of carboplatin and 5-fluorouracil combination chemotherapy in advanced carcinoma of the head and neck.

Twenty-nine patients with recurrent or advanced, incurable head and neck cancer were entered into a phase I-II trial of carboplatin in combination with 5-fluorouracil (5-FU), 1,000 mg/m2/d continuous intravenous (IV) infusion for five days every 28 days. The initial dose of carboplatin was 300 mg/m2 for patients with Karnofsky performance scores greater than or equal to 70%, and 240 mg/m2 for patients with scores of 50% to 60%. Subsequent doses were modified to achieve grade 2 myelo-suppression: WBC, 2,000 to 2,999 cells/microL; granulocytes, 1,000 to 1,499 cells/microL; and platelets, 50,000 to 75,000 cells/microL. Dose levels were 180, 240, 300, 360, and 420 mg/m2. Twenty-eight patients had squamous-cell cancers and one had an adenoid cystic carcinoma of the parotid. There were 26 patients with recurrent disease; 22 had received prior RT; only two had received other chemotherapy immediately before study entry. Three patients had newly diagnosed incurable stage IV disease. The median performance status was 80% (range, 60% to 90%). All patients had objectively measurable disease, and 28 were evaluable for response. There were three complete responses (CRs) and ten partial responses (PRs) (48% CR and PR); the median duration of response was 4.7 months (range, 1.5 to 15+ months). Dose-limiting toxicities were granulocytopenia, thrombocytopenia, and stomatitis. Prolonged myelosuppression delayed retreatment in eight patients and delayed 19 of 107 (18%) courses. Stomatitis occurred in 61% and diarrhea in 29%. 5-FU dosage was decreased in ten patients (36%) for grade 2 or greater stomatitis or diarrhea. Mild to moderate nausea and vomiting occurred in 66% of patient trials in which no pretreatment antiemetics were administered. Other toxicities included phlebitis from 5-FU in 71%, skin toxicity in 11%, mild alopecia in 25%, and fatigue in 54% of patients. Nephrotoxicity (creatinine greater than 2.0 mg/dL) occurred in one patient. The dose of carboplatin resulting in grade 2 toxicity was 180 mg/m2 in one patient, 240 mg/m2 in one, 300 mg/m2 in seven, 360 mg/m2 in ten, and 420 mg/m2 in one. Based on these results, we recommend a starting dose of carboplatin, 300 mg/m2, in combination with five days of continuous infusion 5-FU. In this dose and schedule, this combination was well tolerated and demonstrated antitumor activity in head and neck cancer. To confirm these promising results, a Southwest Oncology Group prospective randomized trial is in progress comparing carboplatin and 5-FU, cisplatin and 5-FU, and standard-dose weekly methotrexate in recurrent-disease patients.

Concurrent chemotherapy and radiation therapy followed by transhiatal esophagectomy for local-regional cancer of the esophagus.

Forty-three patients with local-regional squamous-cell carcinoma of the esophagus or adenocarcinoma of the esophagus, cardia, or gastroesophageal junction were treated with concurrent cisplatin, vinblastine, fluorouracil (5-FU), and radiation therapy (RT) over 21 days. A transhiatal esophagectomy (THE) was planned on day 42. Seventy-nine percent had T2 primaries by clinical staging and 56% had enlarged regional nodes (N) on computed tomographic (CT) scan. Forty-one patients completed the preoperative treatment and went to surgery (95% operability rate), and 36 (84%) were completely resected. Ten of the 41 operative candidates had no evidence of tumor in the resected esophagus and nodal tissue (tumor0 node0; T0N0), 24% complete response (CR). Myelosuppression was the major toxicity with grade 3 or 4 leukopenia in 93% of patients and two preoperative treatment-related deaths. At a median follow-up of 26 months, the median survival time (MST) of all 43 patients registered on study has not been reached. The MST of the 36 completely resected patients and the 10 complete responders has not been reached; 70% and 100%, respectively, are alive at 24 months. The MST by histology is 21 months for the 22 squamous patients and has not been reached for the 21 adenocarcinoma patients registered on study. In a prognostic factor analysis, clinical N status, histology, and the percent of cisplatin and vinblastine tolerated were significant predictors for survival. These survival results suggest a significant improvement over the 14-month MST observed in our previous trial using preoperative chemotherapy only in a similar patient population, and a 12-month MST in a historic control group undergoing THE. A randomized trial is now in progress to convincingly determine if survival is prolonged by this therapy.

Chemotherapy and radiation therapy before transhiatal esophagectomy for esophageal carcinoma.

Recent efforts to improve survival in patients with esophageal carcinoma have combined both systemic and local therapy. From October 1985 to October 1987, 43 patients with local-regional esophageal cancer (adenocarcinoma in 21, squamous cell in 22) were treated with cisplatin, vinblastine, and 5-fluorouracil chemotherapy concurrent with 4,500 cGy radiation therapy for 21 days before transhiatal esophagectomy 3 weeks later. Two patients died of chemotherapy/radiation therapy toxicity. Forty-one completed preoperative chemotherapy/radiation therapy. At operation, 2 patients had incurable metastatic disease; 39 underwent transhiatal esophagectomy. Eleven patients had no residual tumor in the resected specimen for a 27% (11 of 41) pathological complete response rate. Preoperative chemotherapy/radiation therapy resulted in no increased perioperative morbidity as compared with our historical controls. One patient died postoperatively of an unrecognized brain metastasis (2% operative morbidity). At a median follow-up of 27 months, 20 patients (47%) are alive and clinically disease-free and 21 have died, 19 from progression of their carcinoma. The median survival time for all 43 patients is 29 months (Kaplan-Meier estimate), and cumulative survival is 72% at 12 months, 60% at 24 months, and 46% at 36 months. All 11 patients with a complete response are alive at a median follow-up of 36 months, and all are disease-free. The 2-year survival of 60% of this group as compared with 32% in our earlier patients treated with transhiatal esophagectomy alone suggests that intensive combined modality therapy improves survival in these patients. A randomized prospective trial is now in progress.

High-dose cisplatin in advanced head and neck cancer.

In 22 patients with advanced squamous cell carcinoma of the head and neck we evaluated the efficacy and toxicity of 200 mg/m2 cisplatin administered in 3% NaCl with vigorous hydration. Six patients had previously untreated stage IV disease and 16 patients had recurrent disease, including eight with prior chemotherapy including low-dose cisplatin and carboplatin. Cisplatin was administered as a brief infusion, either 40 mg/m2/day X 5 or 50 mg/m2/day X4, every 28 days. Objective responses were observed in 16 of 22 (73%) patients, including 5 of 6 (83%) previously untreated patients and 11 of 16 (69%) patients with recurrent disease. This included two complete responses, one confirmed pathologically. Fifty-seven courses of drug were administered and toxicity was monitored with serial creatinine clearance determinations, audiograms, and sensorimotor exams. Neuropathy and ototoxicity were dose-limiting and led to the stopping of treatment in 12 of the 16 responders after one to four courses (median three courses). Only two responding patients continued treatment until disease progression occurred at 3 and 4 months after achieving maximum response. Acute, transient nephrotoxicity occurred in four patients; two were retreated. Moderate myelosuppression occurred in all patients but was not treatment-limiting. For most patients the maximally tolerated number of courses was three. The median survival time was 33.5 weeks for recurrent disease patients, 108 weeks for newly diagnosed patients. This regimen is not recommended for the palliation of recurrent disease. However, the very high response rate suggests that high-dose cisplatin may have a useful role in induction or adjuvant chemotherapy regimens.

A phase II trial of cisplatin and methylglyoxal bis-guanylhydrazone (MGBG) in recurrent squamous cell carcinoma of the head and neck.

Thirty-one patients with unresectable squamous cell carcinoma of the head and neck, 28 with local or distant recurrences following primary surgery and/or radiation and three with distant metastases at diagnosis, were treated with cisplatin and methylglyoxal bis-guanylhydrazone (MGBG). Cisplatin was given at 60 mg/m2 i.v. every 21 days X 3, followed by 80 mg/m2 every 28 days in responding patients. MGBG 500 mg/m2 i.v. was given weekly X 5, then every 14 days. Each dose of MGBG was to be escalated in the absence of toxicity, but in the majority of patients doses greater than 500 mg/m2 resulted in unacceptable toxicity. Gastrointestinal symptoms were the major side effects of this combined treatment. In 28 evaluable patients there were two complete remissions and nine partial remissions. This 39% response rate is not different from that reported with either drug alone. Combined cisplatin and MGBG as administered in this study had no apparent advantage compared to either agent alone in this group of patients.

Phase II trial of vinzolidine, an oral vinca alkaloid, in Hodgkin's disease and non-Hodgkin's lymphoma.

Vinzolidine, a semisynthetic vinblastine derivative, was tested in an oral formulation in 21 heavily pretreated patients with lymphoma. Partial remissions were seen in four patients with Hodgkin's disease (50%) and in one patient with non-Hodgkin's lymphoma (8%). Significant side effects included neurotoxicity and dose-related myelosuppression. Vinzolidine is an active vinca alkaloid which merits further evaluation in patients with lymphoma, particularly Hodgkin's disease.

Antitumor activity of vinzolidine in the human tumor clonogenic assay and comparison with vinblastine.

Vinzolidine (VZL), a semisynthetic vinblastine (VLB) derivative, was tested against a variety of solid tumors in the human tumor clonogenic assay (HTCA). The emphasis was on continuous drug exposure because of the schedule-dependency of the vincas and long half-life of VZL. Of tumor types with more than ten samples tested, the percentage of cases exhibiting inhibition (50% or less of control) of tumor colony forming units (TCFU) was as follows: melanoma (48%), lung cancer (48%), breast cancer (40%), renal cancer (33%), and ovarian cancer (24%). In tumor types tested less frequently, inhibition of TCFU after continuous or one hour drug exposure was observed in 2/7 colon cancers, 1/3 pancreatic cancers and 3/4 gastric cancers. Paired analysis of tumors tested to both VZL and VLB demonstrated no significant difference in overall activity of these two vinca alkaloids. VZL appears to be a promising drug for clinical trials, with in vitro activity in melanoma, lung and breast cancers. More interesting is the suggestion of activity in gastrointestinal tumors, especially colon cancer which is generally resistant to drugs in the HTCA and in vivo.

Phase II trial of N-methylformamide in advanced head and neck cancer.

Eighteen patients with advanced epidermoid carcinoma of the head and neck were entered into a phase II trial of N-Methylformamide (NMF), 800 mg/M2 IV daily for 5 days every 4 weeks. Seventeen patients had received prior radiation therapy and 11 were previously treated with chemotherapy. No complete or partial responses were observed. The major toxicity was gastrointestinal. Fifty percent of patients experienced nausea and vomiting or reversible hepatotoxicity with greater than a 3-fold elevation of liver enzymes. Mild reversible myelosuppression occurred in 2 patients. NMF in this dose and schedule was not a useful agent to treat recurrent epidermoid carcinoma of the head and neck.

A unique malignant T-cell lymphoproliferative disorder with neutropenia simulating hairy cell leukemia.

The association of neutropenia with an indolent chronic T-suppressor cell lymphoproliferative disorder (LPD) has been well documented. The morphologic features and course suggest that this is a benign disorder. The authors studied a 58-year-old man with a chronic T-cell LPD, splenomegaly, and neutropenia. Chromosomal analysis revealed multiple abnormalities which progressively increased in number as the marrow lymphocytosis became more prominent. Subsequently he developed small bowel infiltration. A splenectomy resulted in only brief improvement in the neutropenia. Immunopathologic examination of the spleen was consistent with a well-differentiated lymphocytic lymphoma of a mature peripheral T-cell type without subset specific markers. Granulocyte-monocyte colony (CFU-GM) formation from the patient's marrow was normal and not augmented by T-cell depletion. Neither the patient's splenic T-cells nor serum suppressed granulopoiesis. In contrast to previous T-LPD with neutropenia whose malignant nature has been questioned, the clinical, cytogenetic, and pathologic features and course in this case indicate a malignant lymphoid process which was effectively treated with chemotherapy. Although the histologic pattern of red pulp involvement simulated hairy cell leukemia, that diagnosis was excluded by this patient's clinical, morphologic, and cytochemical features.

Five-day schedule of vinzolidine, an oral vinca alkaloid, in a variety of tumors.

This Phase I-II trial evaluated vinzolidine (VZL), a semisynthetic vinblastine derivative administered on a five-day oral schedule every 21 days, with 60% of the total dose on day 1 followed by 10% of the total on each of the following four days. Forty-four patients with advanced malignancies were entered in this study and 34 were evaluable for response. Three patients responded, with complete remissions in patients with adenocarcinoma of the lung (39+ weeks) and adenocarcinoma of the pancreas (20+ weeks) and a minor response in a patient with metastatic carcinoid (6 weeks). Myelosuppression was the dose-limiting toxicity, and was remarkable for its unpredictability among patients and even in the same patient receiving a constant dose of vinzolidine. There was one drug related death associated with myelosuppression. This study was closed because of the erratic myelotoxicity of oral vinzolidine. However, the activity observed with vinzolidine merits future trials, using a parenteral formulation which may have more predictable toxicity.