Phase II trial of aminocamptothecin (9-AC/DMA) in patients with advanced squamous cell head and neck cancer.

Fourteen patients with squamous cell carcinoma of the head and neck received 9-AC/DMA infusions of 850 mg/M2/day over 72 hours. Eligibility criteria included good performance status, advanced disease incurable by conventional means, no prior treatment of metastatic disease, and measurable lesions for objective response assessment. The infusions were repeated at 21 day intervals until progression or prohibitive toxicity occurred. A median of 3 cycles (range 1-7) was given. No objective responses were observed. Median survival of the group was 6 months. Toxicity was hematologic which was modest and promptly reversible. 9-AC/DMA is inactive against this tumor type at the dose and schedule employed in this study.

Pharmacokinetics and pharmacodynamics of 9-aminocamptothecin infused over 72 hours in phase II studies.

A novel derivative of camptothecin, 9-aminocamptothecin (9-AC), is currently under Phase II evaluation in various cancers. Exceptionally mild toxicities were observed in patients with brain tumors who were treated with anticonvulsants. To investigate a pharmacokinetic interaction between 9-AC and anticonvulsants, and to evaluate the pharmacodynamics of 9-AC, we investigated the clinical pharmacology of 9-AC, administered by a 72-h infusion, in three Phase II studies. Plasma concentrations of total 9-AC (lactone plus carboxylate) at a steady state were measured in 56, 10, and 14 patients with non-small cell lung cancer, malignant glioma, and head and neck cancer, respectively. For lung cancer or glioma patients, 9-AC was infused at 45 (51 patients) or 59 (15 patients) microg/m2/h, and 9-AC was infused at 35.4 microg/m2/h in head and neck cancer patients. All glioma patients had been treated with phenytoin or carbamazepine. 9-AC clearance did not differ among the dosage rates, but differed according to the diseases (P = 0.002). Glioma patients had a higher clearance (1.0-18.0; median, 2.0 liters/h/m2) than lung cancer patients (0.3-5.1; median, 0.9 liters/h/m2). A logistic regression model described the relationship between the 9-AC concentration and the probability of grade 4 neutropenia, which was the main toxicity. Observed incidences of grade 4 neutropenia for patients with model-predicted probability of 0-20%, 20-40%, and 40-100% were 10%, 32%, and 67%, respectively, and corresponded to 9-AC concentration of <54, 54-86, and >86 ng/ml, respectively. Anticonvulsants seem to induce the clearance of 9-AC, and the concentration of 9-AC predicts the probability of grade 4 neutropenia.

A phase II study of 9-aminocamptothecin in advanced non-small-cell lung cancer.

BACKGROUND: 9-Aminocamptothecin (9-AC) is a synthetic analogue of camptothecin. Phase I studies, identified the maximum tolerated dose as 1416 micrograms/m2/day x 3 as continuous intravenous infusion (CVI) with dose-limiting neutropenia. PATIENTS AND METHODS: Eligible patients had stage IIIB or IV non-small-cell lung cancer (NSCLC) with measurable disease. Patients were initially treated at 1416 micrograms/m2/d x 3 by CVI followed by granulocyte-colony stimulating factor (G-CSF) support. This dose was decreased to 1100 micrograms/m2/d after the first 13 patients. Cycles were repeated every 14 days until tumor progression. RESULTS: Fifty-eight patients were treated, thirteen at 1416 micrograms/m2/d and 45 at 1100 micrograms/m2/d. Fifty percent had adenocarcinoma and 17% squamous cell carcinoma. Seventy-one percent had stage IV disease. Five patients had a partial response (response duration 9-28 weeks) for an overall response rate of 8.6%, (95% confidence intervals (CI): 2.9%-19%). Median time to progression was 2.3 months and the median survival for the entire study population 5.4 months with a one-year survival rate of 30%. The one-year survival rate for 27 patients who received second line chemotherapy was 56.7%. Toxicities at 1416 micrograms/m2/d included grade 4 neutropenia and thrombocytopenia in six and five of 13 patients, respectively; at 1100 micrograms/m2/d these toxicities were observed in 12 and three of 45 patients, respectively. CONCLUSION: 9-AC has modest single-agent activity in previously untreated NSCLC. Its further evaluation at the dose and schedule employed in this study does not seem indicated. Exploration of more prolonged administration schedules may be warranted.

Cisplatin nephrotoxicity in a patient with a single kidney.

OBJECTIVE: To describe a patient with a single kidney who experienced cisplatin-associated nephrotoxicity. CASE SUMMARY: A 78-year-old African-American woman with squamous cell carcinoma of the base of her tongue (T4N2M1) was admitted electively to our institution for the first cycle of chemotherapy. Her past medical history was significant for a left nephrectomy secondary to well-differentiated papillary transitional cell carcinoma of the left renal pelvis, hypothyroidism, asthma, and coronary artery disease. Her blood urea nitrogen (BUN) was 27 mg/dL of urea, and serum creatinine was 1.2 mg/dL. On admission she was hydrated adequately, and was treated with an evening dose of cisplatin 100 mg/m2 (180 mg) in 250 mL of NaCl 0.9% solution in a 3-hour infusion, and a 5-day course of fluorouracil 1000 mg/m2 (1800 mg) in a 24-hour infusion. Serum creatinine and BUN concentrations following cisplatin administration were 1.1 mg/dL and 8 mg/dL, respectively. Four days after cisplatin therapy, a decline in renal function was observed, with an increase in serum creatinine and BUN concentrations to 4.0 mg/dL and 31 mg/dL, respectively. These tests remained elevated throughout her hospitalization. With hemodialysis treatments a resolution in altered mental status was observed; however, her chronic renal failure persisted. She was subsequently discharged and followed in the outpatient renal, geriatric, and oncology clinics. DISCUSSION: Cisplatin is a principal chemotherapeutic agent used in the treatment of a variety of solid tumors. Nephrotoxicity is a major complication associated with this compound. Although many clinicians believe that cisplatin nephrotoxicity is unlikely to occur in patients with a single kidney, recent reports have suggested otherwise. The physiologic changes of the aging kidney are such that they should foster cisplatin clearance rather than expose the kidney to the drug's nephrotoxic potential. In addition, evening administration of cisplatin is thought to minimize nephrotoxicity. We describe a 78-year-old woman with a single kidney who developed nephrotoxicity following a single evening dose of cisplatin. Details of the patient's history and cisplatin-associated complication and therapy are discussed. CONCLUSIONS: Cisplatin circadian rhythmic pharmacotherapy to minimize cisplatin toxicity in patients with a single kidney appears to be controversial and needs further evaluation.

Radiotherapy alone compared with radiotherapy and chemotherapy in patients with squamous cell carcinoma of the esophagus.

PURPOSE: The purpose of this study is to determine whether primary treatment with both radiotherapy and chemotherapy is superior to radiotherapy alone in patients with squamous cell carcinoma of the esophagus. PATIENTS AND METHODS: From January 1980 to December 1988, 77 patients from two Veterans Affairs hospitals with clinically staged nonmetastatic squamous cell carcinoma of the esophagus received either radiotherapy alone (RT group) or concomitant radiotherapy and chemotherapy (RT + CT group) with curative intent. Each group originated at a different hospital, but all patients were irradiated in the same radiotherapy department. Chemotherapy consisted of cisplatin and 5-fluorouracil. Forty-two patients received RT alone, and 35 received RT + CT. Locoregional control, disease-free survival, and overall survival rates were compared. RESULTS: Locoregional control, disease-free survival, and overall survival rates were significantly higher in the RT + CT group when compared to RT group, 26% vs 5%, 20%, vs 2%, and 29% vs 7%, respectively, at 2 years (P = .01, 0.02 and 0.02, respectively). The median survival was 14 months for the RT + CT group and 7.5 months for the RT group. There was no difference in the incidence of distant metastases except for bone metastases. No one in the RT + CT group developed bone metastases compared to nine patients in the RT group (P = .01). CONCLUSION: This retrospective analysis shows improved locoregional control, disease-free survival, and survival when chemotherapy consisting of cisplatin and 5-FU is given in addition to radiation for patients with squamous cell carcinoma of the esophagus. Bony metastases were absent in those who received chemotherapy.

Phase II study of amonafide in the treatment of patients with advanced squamous cell carcinoma of the head and the neck. An Illinois Cancer Center study.

Amonafide (nafidimide), a synthetic organic compound with an inhibitory effect on cellular replication, was used in a phase II study conducted by the Illinois Cancer Center in order to assess its efficacy and toxicity in advanced or recurrent squamous cell cancer of the head and neck. Eligible patients had received no more than one prior adjuvant or neoadjuvant chemotherapy, had normal bone marrow, renal and hepatic function, ECOG performance status of 0-2, and bidimensionally measurable disease. Eligible patients were administered amonafide at a starting dose of 300 mg/m2 for five consecutive days every 3 weeks with dose escalation or de-escalation according to established hematologic criteria in the absence of disease progression. Nineteen of 22 entered patients were evaluable for response and all patients were evaluable for toxicity. Eleven of 19 patients achieved stable disease. Median time to progression after start of treatment was 57 days, for the 18 patients for whom the date of progression is known. There were no partial or complete responses. Hematologic toxicity was dose limiting with grade 3-4 neutropenia in 50 percent of patients and 4 deaths associated with neutropenic sepsis. Non-hematologic toxicity was mild to moderate with nausea and vomiting predominating. In this study, amonafide was a myelotoxic, inactive treatment in advanced/recurrent head and neck cancer. Further use in head and neck cancer appears unwarranted.

The comparison of CAP chemotherapy and radiotherapy to radiotherapy alone for resected lung cancer with positive margin or involved highest sampled paratracheal node (stage IIIA). LCSG 791.

This study was conducted to determine the effect of adjuvant chemotherapy on locally advanced resected non-small cell lung cancer. Anatomic eligibility requirements were either positive resection margins or tumor involvement of the highest sampled mediastinal lymph node. One hundred seventy-two patients were randomized to receive either postoperative thoracic irradiation alone or together with six cycles of CAP chemotherapy (cyclophosphamide, doxorubicin, and cisplatin). The chemotherapy arm showed significantly longer recurrence-free survival (p = 0.004). This benefit accrued to patients with both nonsquamous (p = 0.01) and squamous (p = 0.08) cell carcinoma. At 1 year following randomization, there was a 14% difference in survival favoring the chemotherapy arm. Chemotherapy significantly reduced distant metastases. Median survival was 20 months for the chemotherapy arm and 13 months for the radiotherapy alone arm. The 2-year survival rate for the entire study population was 35%. Toxic reactions were primarily predictable hematologic, GI, and alopecia toxicity expected from CAP. Esophagitis was not a significant problem.

A prospective randomized trial to determine the benefit of surgical resection of residual disease following response of small cell lung cancer to combination chemotherapy.

Three hundred twenty-eight patients with limited stage small cell lung cancer were enrolled in a trial to evaluate surgical treatment for such patients responding to chemotherapy. Cyclophosphamide, doxorubicin, and vincristine were administered every 21 days for five cycles. Patients achieving at least partial response who had confirmation of pure small cell histologic features by pathology review and who were fit enough for thoracotomy were randomized to undergo or not to undergo pulmonary resection. All randomized patients received radiotherapy to the chest and brain. Two hundred seventeen (66%) of the patients achieved objective response (90 complete response; 127 partial response). One hundred forty-six patients were randomized (66% of responders, 44% of all patients): 70 to surgery and 76 to no surgery. Results of surgery were 83% resection rate, 19% pathologic complete remission rate, and 9% with residual non-small cell histologic features only, for a total of 28% eradication of small cell lung cancer. The survival curves for the two arms are not different (log rank p = 0.78). Median survivals were 12 months for all enrolled patients and 16 months for those who were randomized. Actuarial 2-year survival is 20%. The results of this trial do not support the addition of pulmonary resection to the multimodality treatment of small cell lung cancer.

Randomized phase 2 evaluation of preoperative radiation therapy and preoperative chemotherapy with mitomycin, vinblastine, and cisplatin in patients with technically unresectable stage IIIA and IIIB non-small cell cancer of the lung. LCSG 881.

Between June 1988 and January 1980, 67 patients with pathologic stage III non-small cell lung cancer were randomized to receive either preoperative mitomycin, vinblastine, and cisplatin (MVP) chemotherapy (cisplatin 120 mg/m2, and mitomycin, 8 mg/m2 day 1 + 29, and vinblastine, 4.5 mg/m2 on day 1, 15, 22, and 29 and 2.0 mg/m2 day 8), or preoperative radiotherapy (44 Gy in 22 fractions to the primary tumor and mediastinum). The purpose of this study was to identify a treatment approach that showed sufficient effectiveness and acceptable toxicity to warrant testing by prospective randomized trial against "standard" nonsurgical treatment. All patients had surgical staging of the mediastinum and had either unresectable N2 disease or T4 disease with proximal extension of disease along the pulmonary artery. Response to preoperative therapy was evaluated 8 weeks after beginning treatment and patients with complete or partial radiographic response were to undergo surgical exploration and resection if possible. Fifty-seven patients were eligible and evaluable for response. Of the 67 total patients, 3 were unavailable for follow-up, 4 were ineligible, 1 was canceled, and 2 refused all treatment after having been randomized. Of the eligible and evaluable patients, 49 had stage IIIA and 8 had stage IIIB disease. Randomization was to MVP in 26 cases and to radiotherapy (XRT) in 31. Radiographic response to treatment was virtually identical for the two approaches, with 29 of the 57 evaluable patients achieving objective responses. In patients achieving radiographic response, 24 underwent surgical exploration and 20 underwent resection, of which 18 were complete. The mediastinum was free of tumor in seven patients but only two pathologic complete responses were seen (one each to XRT and MVP). In addition, ten nonresponders underwent surgery; seven underwent resection. Median survival for the entire group is 12 months, with a 27% actuarial survival at 4 years. Two patients died of treatment toxicity during preoperative therapy. Overall toxicity included 2 preoperative toxic deaths and 6 postoperative deaths in 34 patients who underwent surgical exploration (3 each with XRT and MVP) due to adult respiratory distress syndrome (3), myocardial infarction (1), pulmonary edema (1), and esophageal fistula (1), for an overall death rate 8 of 57 (14%) and a perioperative death rate in surgically explored patients of 6/34 (18%). These preoperative regimens, in the population studied herein, were of modest efficacy and substantial toxicity.(ABSTRACT TRUNCATED AT 400 WORDS)

High-dose aminothiadiazole in advanced colorectal cancer. An Illinois Cancer Center phase II trial.

Thirty-three patients with advanced colorectal carcinoma were entered on a phase II trial of weekly IV aminothiadiazole (175 mg/m2 escalated to 200 mg/m2) with concomitant allopurinol and non-steroidal anti-inflammatory agents (NSAID's). Toxicity was predominantly GI, cutaneous, and chest pain/dyspnea. Twenty-five percent of patients had grade 3 or 4 toxicity. There were no responses in 27 evaluable patients. Median survival was 12 months. Aminothiadiazole, at higher doses than used in previous reports, when given with NSAID's, had no significant activity against large bowel cancer.

Treatment of hypercalcemia of malignancy with intravenous etidronate. A controlled, multicenter study. The Hypercalcemia Study Group.

In a prospective, randomized, double-blind, multicenter study, 202 patients with cancer from 19 medical centers were treated for hypercalcemia of malignancy with daily intravenous infusions of etidronate disodium (136 patients) or saline alone (66 patients) for 3 consecutive days. Patients also received up to 3.25 L of saline daily during the treatment period. Of 157 patients for whom data could be evaluated for efficacy, 63% (72/114) of etidronate-treated and 33% (14/43) of saline-treated patients had a normalization of total serum calcium levels. When serum calcium levels were adjusted for albumin (147 assessable patients), 24% of the etidronate- and 7% of the saline-treated patients responded to treatment. No serious side effects or treatment-related deaths occurred. When accompanied by adequate hydration and diuresis, intravenous etidronate was safe and more effective than hydration and diuresis alone in controlling hypercalcemia of malignancy.

Postsurgical adjuvant therapy in stages I, II, and IIIA non-small cell lung cancer.

The prognostic importance of accurate staging of non-small cell lung cancer was established in 1974 and reaffirmed and refined in 1986. The concept of adjuvant therapy after pulmonary resection for lung cancer is justified by the behavior of the disease. The best available data pertinent to adjuvant therapy of lung cancer have been collected by The Lung Cancer Study Group over the past 13 years. These data are based on a commitment to prospective and standardized surgical staging as a basis for large-scale prospective randomized control trials. A treatment effect of combination chemotherapy has been detected for stage II and IIIA nonsquamous cancer and is suggested for squamous cancer as well. This treatment effect is of marginal clinical significance. Adjuvant therapy for stage I disease has not shown a detectable benefit. Adjuvant radiation therapy for stage II and IIIA squamous cell carcinoma likewise has not resulted in survival benefit. Systemic metastasis continues to be the major clinical problem in lung cancer treatment, and better systemic therapy is necessary to improve the outcome in this disease. However, some patients do benefit from adjuvant chemotherapy, and efforts to identify such patients prospectively are also the subject of current clinical research.

Phase II trial of 4' deoxydoxorubicin (DXDX) for unresectable non-small cell bronchogenic carcinoma. An Illinois Cancer Council study.

A phase II trial of 4' Deoxydoxorubicin (DXDX) was conducted in unresectable previously untreated non-small cell lung cancer patients. DXDX was administered every 3 weeks by short intravenous infusion at a starting dose of 30 mg/m2, with dose escalation to 40 mg/m2 toxicity permitting. Four responses, all partial, were observed in 35 evaluable patients, for a response rate of 11% (95% confidence limits 3.2% and 26.7%). Myelosuppression was the dose-limiting toxicity. Cardiotoxicity was not seen. DXDX has minimal activity against non-small cell lung cancer as a single agent at the dosage used in this study.

Phase II trial of spirogermanium in advanced non-small cell lung cancer. An Illinois Cancer Council Study.

A phase II trial of spirogermanium was conducted in advanced previously untreated non-small cell lung cancer patients. The drug was given by intravenous infusion 3 times per week for 2 weeks, twice per week for the next 2 weeks, and then weekly. Starting dose was 125 mg/m2, and dose escalation of 25 mg/m2 per week was required in the absence of toxicity to a maximum dose of 200 mg/m2 per infusion. Fifteen eligible patients were treated, and no objective responses were seen. Primary toxicity was neurologic and reversible after withdrawal of the drug. We conclude that spirogermanium is not active against non-small cell lung cancer in the dosage used in this study.

Phase II trial of fludarabine phosphate in advanced renal cell carcinoma: an Illinois Cancer Council Study.

Fludarabine Phosphate (FP), the 2-fluoro, 5'phosphate derivative of adenosine arabinoside (ara-A), was studied in 18 patients with advanced renal cell carcinoma. These patients had measurable disease and had not received chemotherapy. FP was administered at a loading dose of 20 mg/m2 followed by a 48-hour infusion at 30 mg/m2/day given every 21 days. There were no complete or partial responses seen. Toxicity was mainly hematologic, with leukopenia most commonly observed. FP given in this manner had no activity in advanced renal cell carcinoma.