Loretta M. Itri

Prevention of Second Primary Tumors with Isotretinoin in Squamous-Cell Carcinoma of the Head and Neck

BACKGROUNDnPatients with head-and-neck cancers who are free of disease after local therapy remain at high risk for both recurrent and second primary tumors. Retinoids have proved efficacious in the treatment of premalignant oral lesions and are promising agents for the prevention of epithelial carcinogenesis.nnnMETHODSnWe prospectively studied 103 patients who were disease-free after primary treatment for squamous-cell cancers of the larynx, pharynx, or oral cavity. After completion of surgery or radiotherapy (or both), these patients were randomly assigned to receive either isotretinoin (13-cis-retinoic acid) (50 to 100 mg per square meter of body-surface area per day) or placebo, to be taken daily for 12 months.nnnRESULTSnThere were no significant differences between the two groups in the number of local, regional, or distant recurrences of the primary cancers. However, the isotretinoin group had significantly fewer second primary tumors. After a median follow-up of 32 months, only 2 patients (4 percent) in the isotretinoin group had second primary tumors, as compared with 12 (24 percent) in the placebo group (P = 0.005). Multiple second primary tumors occurred in four patients, all of whom were in the placebo group. Of the 14 second cancers, 13 (93 percent) occurred in the head and neck, esophagus, or lung.nnnCONCLUSIONSnDaily treatment with high doses of isotretinoin is effective in preventing second primary tumors in patients who have been treated for squamous-cell carcinoma of the head and neck, although it does not prevent recurrences of the original tumor.

Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-Trans-retinoic acid)

BACKGROUND AND METHODSnPatients with acute promyelocytic leukemia have a characteristic (15;17) translocation, with a breakpoint on chromosome 17 in the region of the retinoic acid receptor-alpha (RAR-alpha). Since this receptor has been shown to be involved with growth and differentiation of myeloid cells in vitro, and since recent clinical studies have reported that tretinoin (all-trans-retinoic acid) induces complete remission in patients with acute promyelocytic leukemia we studied the effects of tretinoin on cellular maturation and molecular abnormalities in patients undergoing the induction of remission with this agent.nnnRESULTSnEleven patients with acute promyelocytic leukemia were treated with tretinoin administered orally at a dose of 45 mg per square meter of body-surface area per day. Nine of the 11 patients entered complete remission. In two patients, complete remission was preceded by striking leukocytosis that then resolved despite continued drug treatment. Serial studies of cellular morphologic features, cell-surface immunophenotypic analysis, and fluorescence in situ hybridization with a chromosome 17 probe revealed that clinical response was associated with maturation of the leukemic clone. All patients who responded to treatment who were tested by Northern blot analysis had expression of aberrant RAR-alpha. As patients entered complete remission, the expression of the abnormal RAR-alpha message decreased markedly; however, it was still detectable in several patients after complete morphologic and cytogenetic remission had been achieved.nnnCONCLUSIONSnTretinoin is a safe and highly effective agent for inducing complete remission in patients with acute promyelocytic leukemia. Clinical response to this agent is associated with leukemic-cell differentiation and is linked to the expression of an aberrant RAR-alpha nuclear receptor. Molecular detection of the aberrant receptor may serve as a useful marker for residual leukemia in patients with this disease.

Resistance to Recombinant Interferon Alfa-2a in Hairy-Cell Leukemia Associated with Neutralizing Anti-Interferon Antibodies

To explain the hematologic deterioration occasionally observed during interferon therapy, we assayed serum specimens from 51 patients with hairy-cell leukemia receiving treatment with recombinant interferon alfa-2a for the presence of anti-interferon antibodies. After a median of seven months of therapy, anti-interferon antibodies were found in 31 patients. Fifteen of these patients had only non-neutralizing antibodies, but antibody from the other 16 neutralized the antiviral effects of recombinant interferon alfa-2a in vitro. In no case, however, did neutralizing antibody inhibit the antiviral effects of purified natural interferon alfa. Clinical resistance to interferon of various degrees was present in 6 of 16 patients with neutralizing antibodies; the remaining 10 patients and all 20 patients without antibody continue to respond after a minimum of two years of therapy. In all the patients with interferon resistance, antibody was present when it developed. These data suggest that the development of clinical resistance to interferon alfa-2a in hairy-cell leukemia is not necessarily related to an altered cellular response to interferon. Treatment with other interferons, such as purified natural interferon alfa, may be useful in patients with clinically important neutralizing antibodies against interferon alfa-2a.

Interferon-??2a in the Treatment of Acquired Immunodeficiency Syndrome-Related Kaposi??s Sarcoma

Summary In a series of studies, recombinant interferon-α2a (rIFNα2a, Roferon- A) was administered alone (273 men) or combined with vinblastine (91 men) to patients with acquired immunodeficiency syndrome (AIDS)-related Kaposis sarcoma (KS). Patients were treated with daily doses of rIFNα2aranging from 3 to 54 million international units (I.U.) administered intramuscularly. A dose of 36 million I.U. daily for approximately 10 weeks followed by a three times weekly maintenance schedule with the same dose resulted in the best overall therapeutic benefit. An escalating-dose regimen of 3, 9, and 18 million I.U. daily, each for 3 days, followed by 36 million I.U. daily, produced equivalent therapeutic benefit with amelioration of acute toxicity in some patients. Response was more likely in patients without a history of opportunistic infection or B symptoms (fever, night sweats, or weight loss). Response rate increased with increasing baseline CD4 lymphocyte count and was 45.5% in patients with a CD4 count of greater than 400/mm3. Responding patients with a CD4 count of greater than 200/mm3 had a distinct survival advantage over patients who had similar CD4 counts but whose tumors did not regress with therapy. The addition of vinblastine increased toxicity and did not improve the response rate or prolong survival. Side effects included fatigue, fever, chills, myalgias, headaches, anorexia, nausea, diarrhea, and dizziness. Mild abnormalities in hematologic and liver function tests occurred in some patients. Most adverse effects diminished or resolved with continued therapy. We conclude that rIFNα2a offers important therapeutic benefit in a select group of patients with AIDS-related KS.

Cisplatin, vindesine and bleomycin (CVB) combination chemotherapy of advanced non-small cell lung cancer

Fifty‐four patients with advanced squamous, large‐cell or adeno‐carcinoma of the lung were treated with a three drug regimen of high‐dose cisplatin, vindesine and a four‐day bleomycin infusion (CVB). All patients had measurable disease; none had previously received chemotherapy. Of 52 patients evaluable for response, 20 (38%) had complete or partial remissions. The median duration of remission was 8 months (range, 6 1/2‐19+ months), with eight patients continuing in remission. The median duration of survival for responding patients was 16 months versus five months for nonresponding patients (P > 0.001). Toxicity included mild to moderate myelosuppression, peripheral neuropathy, and nephrotoxicity, and was generally manageable. The addition of a four‐day bleomycin infusion did not appear to offer a significant advantage over the combination of high‐dose cisplatin and vindesine in the treatment of NSCLC. The response rate and survival duration produced by the CVB protocol were similar to those reported for the two‐drug combination of vindesine and high‐dose cisplatin.

Phase II trial of VP16-213 in non-small cell lung cancer (NSCLC)

SummaryFifty-one patients with non-small cell lung cancer (NSCLC) were treated, during a phase II trial, with 4′ demethylepipodophyllotoxin-β-d-ethylidene glucoside (VP16-213). Forty-nine were evaluable for response, and of these two (4%) had partial responses lasting 5 and 6 months. Prior treatment with chemotherapy may have adversely affected response rate; none of the 24 previously treated patients had a major response. Myelosuppression was the dose limiting toxicity. Anorexia, nausea and vomiting, partial alopecia, and chills plus hypotension during drug infusion were the other toxic effects. We conclude that VP16-213 has only minimal activity as a single agent in NSCLC.

Phase II trial of VP-16-213 in non-small-cell lung cancer

Fifty-one patients with metastatic non-small-cell lung cancer (NSCLC) were treated with VP-16-213 (4-demethylepipodophyllotoxin) during a phase II trial. Of the 49 patients who had adequate trials, 2 patients achieved a partial response (PR), for an overall 4% major response rate. The median Karnofsky performance status (PS) was 80%; 85.7% of patients had adenocarcinoma and 14.2% had epidermoid carcinoma. Prior treatment with chemotherapy may have adversely affected response rate; the two responses occurred among the 25 previously untreated patients, while no responses were seen in patients who had previously received chemotherapy. Myelosuppression was the most frequent side effect and two drug-related deaths due to septicemia occurred. Other toxic effects noted included anorexia, nausea and hypotension during drug infusion. We conclude that VP-16-213 has minimal activity as a single agent in NSCLC.