Edgar Cheng

Trabecular (merkel cell) carcinoma of the skin. Treatment of primary, recurrent, and metastatic disease

Four new patients with trabecular (Merkel cell) carcinoma of the skin are described, and an additional 76 patients from the literature are reviewed. The mean age of the combined group of patients was 68; 84% were 60 years or older. Primary tumors appeared most frequently on the head and neck (44%), leg (28%), arm (16%), or buttock (9%). No primary tumor appeared on the trunk. The rate of local recurrence was 36%, regional metastatic disease, 53%; distant metastases, 28%; and death due to metastatic tumor (minimally), 25%. It appears that trabecular carcinoma of the skin is more aggressive and lethal than previously thought. The authors recommend that patients with this tumor undergo wide resection of the primary site and, in healthy patients, prophylactic regional node dissection. Both radiation therapy and chemotherapy are effective in palliating unresectable disease.

Germ cell tumors (II): VAB II in metastatic testicular cancer.

Between June 1974 and January 1976, 50 patients with metastatic nonseminometous testicular carcinoma were treated with the V AB II protocol. The induction phase consisted of vinblastine (0.4 mg/kg) and actinomycin D (0.02 mg/kg) on day 1. Bleomycin (0.5 mg/kg) was given by continuous infusion for 7 days, and cis‐diammine‐dichloroplatinum (II) (DDP) (1 mg/kg) was given on day 8. A weekly maintenance of vinblastine and bleomycin, with actinomycin D and DDP on a rotating schedule was given followed by vinblastine, actinomycin D and chlorambucil every 3–4 weeks. Therapy was discontinued after 30–36 months of treatment in the face of continued remission. The response rate was 50% CR, 34% PR with 60% CR and 36% PR in previously untreated patients. Second‐look surgery and excision of residual lesions was performed in selected cases. Alopecia, mucositis, nausea, and vomiting were universal. One patient died in the postsurgical period of toxicity from the combination of bleomycin and high concentrations of oxygen. There were seven instances of allergic reactions to DDP. Eleven of 25 complete responders and 4 partial or minor responders who underwent excision of stable disease remain alive from 19 to 35 months following start of therapy, 12 of them without evidence of disease. Cancer 42:2162–2168, 1978.

VAB–4 combination chemotherapy in the treatment of metastatic testis tumors

Forty‐two patients with advanced testis carcinoma without previous chemotherapy were treated with VAB‐4, and 41 were evaluable. The program consisted of three in‐hospital inductions 16 weeks apart, and outpatient treatments every three weeks. Of the patients, 80% achieved complete remissions (CR). Chemotherapy alone induced CR in 61%, partial remissions (PR), in 24% and minor response (MR), in 15%. An additional 20% of patients (six PRs and 2 MRs) achieved CR following resection of residual tumor deposits. With a median follow‐up of 27 months, the median duration of CR has not been reached. Of those achieving CR to chemotherapy alone, 12% had relapses. Bulk and extent of metastatic disease, histology of primary tumor, and tumor markers at the beginning of therapy influenced the frequency of CR. Of those with minimal disease, 90% achieved CR. The CR rate was 67% for those with advanced thoracic disease and 29% for those with advanced abdominal disease. Patients who had embryonal carcinoma and those who had no elevation of alpha‐fetoprotein had a higher frequency of CRs. Myelosuppression with a leukocyte count drop < 1000/mm3 occurred in three patients, and no patient had chronic renal failure or pulmonary fibrosis. One patient died from sepsis while in complete remission. Cancer 47:833–839, 1981.

Flow cytometry as a predictive indicator in patients with operable gastric cancer

Adenocarcinoma of the proximal portion of the stomach (gastroesophageal [GE] junction and cardia) is increasing in incidence. The inferior survival of patients with GE-cardia lesions as compared with patients with tumors located in the body and antrum has been attributed to anatomic features. To determine if a biological difference could explain the varying prognosis, flow cytometric studies were performed prospectively in 50 patients with operable gastric cancer and analyzed for association with site, histology, gender, age, stage, and disease-free survival. DNA aneuploidy significantly correlated with tumor location: 96% of GE-cardia carcinomas were aneuploid as compared with 48% of body-antrum tumors (P = .0008). Nodal involvement was more common in aneuploid tumors (P = .0548), and women were more likely to have diploid tumors than were men (P = .0233). The median disease-free survival for patients with diploid tumors was 18.5 months as compared with 5.4 months for patients with aneuploid carcinomas (P = .076). Furthermore, within the body-antrum of the stomach, patients with diploid tumors had a significantly better disease-free survival than did those with aneuploid tumors from the same site (18.4 v 4.7 months, P = .0185). These results indicate there is a difference in the DNA content of gastric tumors located in different sites within the stomach and that DNA content correlates with prognosis.

VAB-3 combination chemotherapy of metastatic testicular cancer

The initial response and long‐term follow‐up of 74 evaluable patients who received combination chemotherapy for metastatic nonseminomatous testicular cancer are reported. Patients were treated with a protocol (VAB‐3) including vinblastine, actinomycin‐D, bleomycin, and cis‐dichlorodiammine platinum (DDP). VAB‐3 alone caused complete remission (CR) in 54% (40/74) and partial remission (PR) in 26% (19/74). Five patients with less than CR to chemotherapy achieved CR following surgical excision of residual mature teratoma after starting VAB‐3 protocol, resulting in an overall CR rate of 61% (45/74). With a minimum follow‐up of 24+ months, and a median follow‐up of 35+ months for those still living, 45% (33/74) of the patients are living free of evidence of disease, 4% (3/74) are living with disease, and 51% (38/74) are dead. Response to VAB‐3 protocol was examined with respect to performance status, histology, prior therapy, extent of disease, tumor markers, and duration of disease from diagnosis. No one died because of toxicity of VAB‐3, and life‐threatening toxicity was uncommon. Long survival is significantly associated (P < 0.001) with achievement of CR. The treatment goal for metastatic testicular cancer is cure. The achievement of CR, using aggressive combination chemotherapy and surgery, is essential in reaching this goal.

A phase II trial of streptozotocin and adriamycin in advanced APUD tumors

Thirty-three patients with advanced carcinoid tumors, islet cell carcinomas, or medullary carcinomas of the thyroid were entered into a phase II trial combining streptozotocin (STZ) and Adriamycin. Thirty-one patients are evaluable for response, and 29 are evaluable for survival. Six (19%) patients achieved objective partial responses (95% confidence limits: 5.4–33). The median duration of response for partial responders was 282 days. The median survival for responders and nonresponders was 16.2 months and 7.8 months, respectively, with an overall median survival of 10.9 months. At 10.9 months median follow-up, 4(14%) of 29 patients are surviving. Toxicity was mild, except that nausea or vomiting occurred in 25 of 31 patients evaluable for toxicity. With this dose and schedule of administration, STZ and Adriamycin produce modest response rates with objective palliation of disease in patients with advanced amine precursor uptake and decarboxylation (APUD) tumors.

Phase II trial of cisplatin (CPDD) in previously treated patients with advanced soft tissue sarcoma

Thirty‐six previously treated adult patients with advanced soft tissue sarcomas received CPDD 120 mg/m2 with mannitol diuresis. There were only two (6%) partial responses and five (15%) minor responses in 34 evaluable patients. Toxicity included nausea and vomiting, myelosuppression, mild ototoxicity and mild to moderate, transient nephrotoxicity. CPDD has minimal antitumor activity in previously treated patients with soft tissue sarcomas.

Pharmacokinetics of cisplatin regional hepatic infusions

Cisplatin (DDP), a potent antineoplastic agent, is usually administered via a peripheral vein. Recently, there has been considerable interest in intraarterial regional infusions of DDP. The pharmacokinetics of DDP when administered by this technique have not been explored in detail. We studied DDP pharmacokinetics in dogs given DDP by infusion and bolus injection in the hepatic artery (H.A.), portal vein (portal V), and peripheral vein (P.V.). Blood and biliary platinum concentrations ([Pt]) were assayed by flameless atomic absorption spectrophotometry. During an infusion into the H.S., peak [Pt] in the vessel were markedly higher (mean value 19 micrograms/ml) than those found, simultaneously, in the portal V or superior vena cava. Following a bolus injection of DDP into the H.A., higher H.A. [Pt] were also seen, but [Pt] rapidly (within 5-10 minutes) equilibrated in all sites sampled. During the H.A. infusion, most [Pt] was in its free (active) form. Bile and hepatic tissue were also sampled. Hepatic artery infusions of DDP give high drug concentrations in the perfusing blood, while systemic [Pt] are much lower. During the infusion, the majority of DDP is in its active (unbound) state.

Cisplatin: a phase II evaluation in previously untreated patients with soft tissue sarcomas

A Phase II trial of moderately high‐dose cisplatin (120 mg/m2 with mannitol diuresis) was conducted in 26 previously untreated patients with soft tissue sarcomas. One partial response (major response rate, 4%) and two minor responses were seen. Severe nausea and vomiting and transient increases in the serum creatinine level were the most common side effects of treatment. Cisplatin has minimal activity as a single agent in patients with soft tissue sarcoma. Cancer 59:884‐886, 1987.

Oral piritrexim : a phase II study in patients with advanced soft tissue sarcoma

Piritrexim is a lipid soluble dihydrofolate reductase (DHFR) inhibitor that rapidly and passively diffuses into cells [1,2]. It has been synthesized as an antifolate compound potentially capable of circumventing methotrexate resistance from arising via various mechanisms [3]. A phase II evaluation of this drug was organized at the Memorial Sloan Kettering Cancer Center (MSKCC) to evaluate the anti-tumor activity and toxicity in patients with advanced soft tissue sarcoma. Preliminary results have been previously presented [4]. Adult patients with soft tissue sarcoma with a clearly measurable indicator lesion(s) and a Karnofsky Performance Status of 70% or greater were eligible for entry regardless of prior treatment. Classic oncologic response criteria were used. Patients were scheduled to receive a dose of 160 mg/m 2, administered orally twice daily for five consecutive days every three weeks. Following unexpected severe toxicity in two patients (both with prior pelvic irradiation who initiated treatment at a dose of 120 mg/m2), the protocol was amended to initiate treatment at a dose of 120 mg/m 2 in all patients and 80 mg/m 2 in those patients with prior radiation to the pelvis. The dose was subsequently escalated or deescalated based on toxicity. Twenty-six patients with soft tissue sarcoma were entered on study. Table 1 summarizes the demographic data and the results. One-hundred and thirty-one courses of therapy were administered to the 26 patients for a mean of 5 courses and a median of 3.5 courses per patient. Fourteen of the patients initiated treatment at a dose of 120 mg/m 2 bid, eleven initiated treatment at a dose of 80 mg/m 2 bid and one initiated treatment at a dose of 160 mg/m z. Two patients obtained a partial response. Of twelve evaluable patients with leiomyosarcoma, one patient obtained a partial response (for response rate of leiomyosarcoma upper limit 95% confidence interval = 34%). The other patient who obtained a partial response was the only patient entered with endometrial stromal sarcoma. Grade 2 or greater toxicity was observed in 80% of patients. Severe (grade 3 -4 ) myelopoietic toxicity was associated with 17 courses of treatment in nine patients, severe oral mucositis with nine courses of treatment in seven patients, severe maculo-papular pruritic rash with four courses in four patients and severe emesis with three courses in three patients. Generally, these toxicities occurred concurrently. This complex of toxicities represents the dose limiting toxicity of piritrexim. Piritrexim was evaluated in this phase II study because of its activity in the sarcoma 180 preclinical model, because of the activity of methotrexate in patients with soft tissue sarcoma and because of the anti-tumor efficacy of metoprine in previous studies in patients with sarcoma. Two clinically beneficial objective responses were observed, an overall response rate of 11%. Piritrexim is a potentially active agent in the treatment of soft tissue sarcoma but with an upper limit of a 95~ confidence