Retinoic Acidinterferona Combination Cancer Therapy

Retinoids and interferons (IFNs) show clinical promise in several carcinogenic settings. Retinoids have demonstrated significant clinical activity in randomized chemopre-vention trials in the head and neck, skin, liver, and cervix (82-90). Interest in retinoids for cancer therapy was greatly stimulated by the high complete response rate of acute promyelocytic leukemia (APL) to all-trans-retinoic acid (ATRA) (91-93). Retinoids have shown activity in certain other hematologic malignancies as well (10,94,95). In general, however, ATRA and other retinoids have disappointing single-agent results in established cancers. There are data indicating that 13cRA and ATRA may improve the antitumor efficacy of radiation, cisplatin, and IFN (96-105).

Evidence that 13cRA and IFN-a interact favorably at the molecular level is provided by in vitro and in vivo preclinical data (63-68,71,75,76,78,79,106-111). This combination has achieved encouraging results in locally advanced untreated cervical cancer (112-114), squamous cell carcinoma (SCC) of the skin (115,116), and renal cell carcinoma (117).

Combined 13cRA and IFN-a has achieved an overall major response rate of 45% in 55 patients with untreated locally advanced primary SCC of the cervix (114-116). Based on promising pilot data on 13cRA/IFN-a integrated with radiotherapy (RT) (117), a phase III study of 13cRA plus IFN-a plus RT vs RT alone was launched. This trial has produced promising preliminary data, including significantly improved survival for patients with locally advanced cervical cancer receiving the combined regimen (118). Negative results with RA-IFN combinations have been reported by Hallum et al. (no response to 13cRA/ IFN-a among 13 patients with heavily RT-plus-chemotherapy-pretreated recurrent SCC of the cervix) (119) and by Wadler et al. (no response among 26 patients with chemotherapy-naive recurrent cervical cancer to ATRA plus IFN-a-2A); 120).

Results have been recently reported from a Southwest Oncology Group (SWOG)/NCI trial activated in 1992 (121). This randomized phase II trial evaluated ATRA plus IFN-a and 13cRA plus IFN-a in 60 evaluable patients with recurrent chemotherapy-naive cervical SCC. Major response rates in the ATRA/IFN-a and 13cRA/IFN-a arms were 5 and 8%, respectively. All confirmed responses were partial, and one additional unconfirmed partial responses occurred in the 13cRA arm. Both regimens were generally well-tolerated, producing expected toxicities consistent with each agent's single-agent toxic effects. This trial represents the first clinical test of 13cRA plus IFN-a in chemotherapy-naive recurrent cervical SCC and the first randomized study of any IFN-a/retinoid combination in the setting of recurrent cervical SCC. There were nonsignificant differences between the two arms, including greater numbers, degrees, and durations of responses achieved by 13cRA/IFN-a. The basically promising clinical and laboratory data profile of 13cRA plus IFN-a supports further study of these combined agents plus concomitant radiation to establish the best role for these modalities in locally advanced, untreated cervical cancer.

The first phase II trial of a RA and IFN combination involved 28 evaluable patients receiving 13cRA (1 mg/kg/d) plus IFN-a2a (3 million units/d) for advanced SCC of the skin (115). The overall major response rate was 68%. Other results of this trial included a significant inverse correlation between response and disease extent, significantly higher response rate in chemotherapy-naive patients, median response duration of approx 5 mo, and substantial toxicity (grade 3 or greater fatigue occurring in 12 patients, possibly because of study population age—median 67 yr).

A subsequent phase II trial of similar doses of 13cRA plus IFN in unresectable, recurrent, and/or metastatic SCC from many sites involved 32 evaluable patients (116). There was a 50% major response rate in both head and neck as well as skin cancers, the two largest study subsets. Cancers of other sites with major responses included vulvar, esoph-ageal, and penile cancers.

Combining cisplatin with the combination RA and IFN is a major thrust of current efforts with this combination. This direction is suggested by cisplatin's activity in advanced SCC of several sites and the ability of both RA and IFN-a to potentiate cisplatin antitumor activity in several in vitro and human tumor xenograft systems (96,97).

The poor overall response rate of renal cell carcinoma (RCC) to cytotoxic and hormonal agents is <2%. The overall response rate for IFN-a in RCC is 12% (over 600 cases reported in the literature). Memorial Sloan Kettering Cancer Center conducted a phase II trial involving 44 evaluable RCC patients receiving 13cRA (1 mg/kg/d) and IFN-a

(3-9 MU/d) that achieved a major response rate of 30% (13 patients), including three complete responses (117). Responses were durable (>10 mo in 7 responding patients) and were observed in sites typically resistant to IFN. These investigators also found that results of in vitro studies of this combination in RCC suggested that activity is mediated by RAR-p. Prior Memorial Sloan Kettering clinical trials of IFN alone or combined with vinblastine or interleukin-2 achieved an overall response rate of 10% in 149 patients, which is threefold lower than the combined 13cRA-IFN-a rate.

Two German studies have involved RA plus IFN plus subcutaneous interleukin-2 plus 5-FU in 44 patients with progressive metastatic RCC, and RA plus IFN in 19 patients with metastatic disease refractory to IFN, interleukin-2, and chemotherapy (122). The first study achieved a major response rate of 44% (20/44; 95% CI, 30-60%), including six complete responses. Responding cancers included lung, liver, and adrenal cancers; responses were durable in 19 of the 20 responding cases, and prolonged stabilization of disease occurred in 21 patients (47%). The second study achieved a major response rate of 21% (4/19).

Very recent, promising translational data on this combination come from a NCI-supported chemoprevention study in the head and neck (122a). These data indicate that 13cRA plus IFN-a achieved striking clinical and molecular activity (e.g., effects on LOH and p53) in very high-grade premalignant lesions of the larynx.

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