Jeffrey A. Gottlieb

Adriamycin cardiomyopathy—risk factors

The records of 53 patients treated with Adriamycin, 17 of whom developed congestive heart failure and 36 of whom received a similar total dose of Adriamycin without developing congestive heart failure, were analyzed for factors associated with Adriamycin cardiomyopathy. The risk of cardiomyopathy was significantly greater in patients who developed a ≥30% decrease in limb‐lead QRS voltage. Concurrent cyclophosphamide and mediastinal radiotherapy lowered the cumulative Adriamycin dose necessary for the development of cardiac toxicity. Uncontrolled hypertension also appears to be a risk factor in potentiating the development of Adriamycin cardiomyopathy at lower doses. Congestive heart failure was more likely to be fatal if it developed shortly after the last dose of Adriamycin. These findings can be utilized to increase the safety of Adriamycin therapy in the future.

Chemotherapy of thyroid cancer with adriamycin. Experience with 30 patients.

Abstract Thirty patients with advanced refractory metastatic thyroid carcinoma received chemotherapy with adriamycin at a starting dose of 45 to 75 mg per square meter intravenously every three weeks. Eleven patients demonstrated a greater than 50 per cent decrease in the size of their metastases. Subjective improvement, particularly relief of pain from bony metastases, was also observed. Histologic cell types responding included medullary (solid) (three of five), papillary-follicular (three of 10), Hurthle cell (two of five), spindle and giant cell (two of nine) and unclassified thyroid carcinoma (one of one). Although the rate of disease progression in the responding and nonresponding patients was similar before the start of adriamycin, the median survival from this point on was significantly superior (p<0.005) in the responders (median 11 + and range of over five to 40 + months, six of 11 living) to that of the nonresponders (median four and range of 0.1 to 23 + months, five of 19 living). Before the n...

Chemoimmunotherapy of disseminated malignant melanoma with dimethyl triazeno imidazole carboxamide and bacillus calmette--guérin.

Abstract Eighty-nine patients with disseminated malignant melanoma were treated with a combination of dimethyl triazeno imidazole carboxamide (DTIC) administered intravenously and bacillus Calmette–Guerin (BCG) administered by scarification. The results were compared to those in a comparable retrospective group of 111 patients treated with DTIC alone. Metastatic areas regional to BCG immunization showed an augmented response to chemotherapy. Thus, chemoimmunotherapy-treated patients with lymph-node metastasis had a remission rate of 55 per cent compared to one of 18 per cent for patients treated with chemotherapy alone (p = 0.025). The duration of remissions and survival was significantly longer for patients (both nonvisceral and visceral metastases) treated with chemoimmunotherapy than for those treated with chemotherapy alone (p = 0.05, 0.001, respectively). A good prognosis was associated with immunocompetence before treatment or an increase in immunocompetence during treatment. Chemoimmunotherapy was ...

Phase II evaluation of bleomycin. A Southwest Oncology Group study

Bleomycin given intravenously (i.v.) or intramuscularly (i.m.) in twice‐weekly doses of 10 mg/m2 was evaluated for efficacy and toxicity in 382 patients. Responses were observed in 11/27 Hodgkins diseases, 10/30 lymphomas, 9/22 squamous cell cancers of ectodermal origin, 12/26 germinal cancers, and 3/8 renal adenocarcinomas. The i.m. route is less, likely to cause pulmonary toxicity or hypotension than the i.v. route. Advanced age and total doses exceeding 200 mg were Associated with a higher risk of lung toxicity. All responders had shown at least improvement upon receiving 200 mg; higher total doses should be used only in responding patients.

Chemotherapy of thyroid cancer. An evaluation of experience with 37 patients

Thirty‐seven patients who were treated with antineoplastic drugs for metastatic thyroid carcinoma were evaluated to determine the effectiveness of chemotherapy in this disease. All cell types were included in the series, but there was a predominance of the spindle and giant cell and medullary types. Three patients had no treatment prior to the chemotherapy, with the remainder having been treated previously by surgery,131I, and radiotherapy, either separately or in combination. A wide variety of drugs were used. Five of 37 patients had partial remission of their disease. The median duration of response is now 3+ months, with two patients still responding. Three of the five responders were treated with the new antitumor antibiotic, adriamycin. The preliminary results with this drug have encouraged us to use it as a drug of choice in a prospective protocol for the treatment of metastatic thyroid cancer, and to explore its use earlier in the course of treatment.

Chemoimmunotherapy of advanced breast cancer: prolongation of remission and survival with BCG.

Forty-five patients with disseminated breast cancer were given a trial of combination chemotherapy consisting of fluorouracil, adriamycin, and cyclophosphamide (FAC) and immunotherapy with BCG given by scarification. The results were compared with those in a comparable group of 44 patients treated with FAC alone immediately before the chemoimmunotherapy study. The remission rates (73% and 76% for FAC and FAC-BCG respectively) were similar in both studies. The durations of remission for patients on FAC-BCG (medium 12 months) were longer than remissions achieved for patients given FAC alone (median 8 months) (P = 0.068). The most notable effect of BCG was on survival. Thus 21 out of 34 patients achieving remission on FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 11 out of 32 patients achieving remission on FAC (median 15 months) (P = 0.01). Twenty-six of the 45 patients given FAC-BCG were alive at the time of the last follow-up examination (median over 22 months) compared with 12 of the 44 patients given FAC (median 15 months) (P = 0.005). Although the apparent benefit of BCG could be explained by a maldistribution of some prognostic factors, the data suggest that further trial of chemoimmunotherapy of breast cancer should be carried out.

COMB (cyclophosphamide, oncovin, methyl-CCNU, and bleomycin): a four-drug combination in solid tumors.

One hundred eighty‐nine patients received a four‐drug combination consisting of cyclophosphamide, Oncovin (vincristine), methyl CCNU, and bleomycin (COMB), according to three different drug regimens, performed sequentially. Of the 189, 62 had a partial response (33%) including 11/33 with squamous lung cancer, 11/32 with squamous carcinoma of the head and neck, 13/15 with oat cell carcinoma of the lung, and 7/41 with malignant melanoma. The response rate for patients with squamous lung or head and neck cancer appeared to be higher at weekly bleomycin doses of 30 and 60 mg (15/33 = 45%), compared to a weekly bleomycin dose of 15 mg (7/32 = 25%). A median survival from treatment of 30 weeks was observed in oat cell carcinoma, which represents considerable prolongation over that expected from supportive care alone or single‐agent chemotherapy. Toxicity included: 1) myelosuppression, resulting in hospitalization for antibiotics in 20% of patients; 2) probable bleomycin lung damage in 4% of patients; and 3) dose‐limiting vincristine neuropathy in 11%. The combination of twice‐weekly vincristine and bleomycin for more than 6 weeks produced a disturbing “debilitation syndrome,” characterized by weakness, anorexia, weight loss, and apathy. The encouraging response rate suggests a future role for these drugs in combination, especially for vincristine and bleomycin, with other agents showing activity in squamous and oat cell carcinoma. Toxicity precludes recommendation of this combination, in the regimens tested, for broader Phase III studies.

CCNU (1‐[2‐chloroethyl]‐3‐cyclohexyl‐1‐nitrosourea, NSC‐79037) in the treatment of cancer. Phase II study

CCNU (1‐[2‐chloroethyl]‐3‐cyclohexyl‐1‐nitrosourea, NSC‐79037), was used to treat 141 evaluable patients with a variety of advanced malignancies, 56% of whom had not received prior chemotherapy. Patients with an adequate bone marrow reserve received 130 mg/m2 as the initial dose and those with an impaired reserve received 100 mg/m2. Therapy was repeated every 6 weeks and the dosage modified according to the hematologic toxicity. Responses greater than 50% reduction in tumor size were noted in 26 patients; stable disease or reduction in tumor size of less than 50% was observed in 21 patients. The well‐differentiated adenocarcinomas and squamous cell tumors appeared to be least sensitive to CCNU. Bone marrow depression was the major dose‐limiting factor. Without adequate antiemetic therapy, all patients would have had nausea and vomiting. Hepatocellular toxicity was noted in two patients.

A phase II study of methyl CCNU in the treatment of solid tumors and lymphomas: A Southwest oncology group study

In March of 1972, the Southwest Oncology Group initiated a Phase II study, No. 7200, utilizing methyl‐CCNU in the treatment of patients with solid tumors and lymphomas. Initially, they received 200 mg/m2 orally as a single dose every 6 weeks. The dose was subsequently reduced in poor‐risk patients to 150 mg/m2. There were 69 responses noted in 675 evaluable patients (10%). The highest response rates were noted in patients with Hodgkins disease (13/31, 35%), malignant gliomas of the brain (8/29, 28%), anaplastic carcinomas of the lung (5/20, 25%), and squamous cell carcinomas of the head and neck (5/29, 17%). Squamous cell tumors appeared to be more responsive than adenocarcinomas (15% vs. 5%, respectively). Hematologic toxicity was cumulative, and was influenced by dose and prior treatment. There appeared to be no cross‐resistance in patients previously treated with alkylating agents. Methyl‐CCNU is an active antineoplastic agent. Further studies are indicated in order to determine relative effectiveness.

Pharmacokinetics and metabolism of β-2′-deoxythioguanosine and 6-thioguanine in man

SummaryResistance to the antileukemic agent 6-thioguanine (TG) inevitably develops in animal tumors. However, a new agent, β-2′-deoxythioguanosine (β-TGdR) can overcome TG resistance in animal tumor models and is therefore of potential clinical use. The pharmacokinetics of radiolabeled TG were compared with those of β-TGdR in patients with cancer after intravenous administration. [35S]-β-TGdR (5.4 mg/kg, 200 mg/m2, 200 μCi total) was administered to five patients; the radiolabel in the plasma declined with an initial half-life (t1/2) of 14 min and a terminal t1/2 of 19.3 h. Within 24 h, 65% of the radiolabel was excreted in the urine. In contrast, after administration of [35S]-6-TG (3.4 mg/kg, 125 mg/m2, 200 μCi total) the average initial t1/2 was 40 min while the terminal phase t1/2 was 28.9 h. Urinary excretion of the radiolabel was 75% of the dose 24 h after administration. Both thiopurines were rapidly and extensively degraded and excreted as 6-thioxanthine, inorganic sulfate, S-methyl-6 thioxanthine, and 6-thiouric acid in addition to other products. Small amounts of unchanged drug were also excreted. These studies suggest that β-TGdR is merely a latent form of TG.