Laryngeal papillomatosis often involves a relentless growth of papillomas on the vocal cords, requiring repeated excisions to maintain an adequate airway. Because of its antiproliferative effects on epithelial tissues, 13-cis-retinoic acid (0.5-2.0 mg/kd/day p.o.) was used in five patients whose disease was poorly controlled by laser beam surgery. Control of disease for 24+, 5+, and 12 months has been achieved in three of the patients, with two complete and one partial responses. Side effects of treatment were mild and rapidly reversible, following a 25-50% reduction in drug dose.

The successful development of a soft agar clonogenic assay for human tumor stem cells provides an in vitro technique with a high degree of accuracy for predicting in vivo clinical response to standard anticancer drugs. We used this system to conduct an "in vitro phase II trial" in human ovarian cancer and melanoma. This approach can potentially identify active phase I--II drugs suitable for treatment of given tumor types for specific patients and eliminates the need to subject patients (who would be predicted not to respond) to toxic side effects. In vitro sensitivity for new agents was operationally defined as at least a 70% reduction of tumor colony-forming units (TCFU) at concentrations which are readily achievable pharmacologically. The new agents AMSA and vindesine (as well as vinblastine) appeared to have activity in melanoma, while PALA and thymidine were inactive. Pentamethylmelamine, mitomycin C, methyl-GAG, and AMSA were relatively ineffective in ovarian cancer. Vinblastine and vindesine had definite activity. The human tumor stem cell assay may thus provide the basis for a useful alternative to the current clinical phase II testing approach for identifying antitumor activity of new agents. Validation of this concept with correlative in vitro and in vivo phase II trials of new agents in patients with tumor types predicted to be sensitive is clearly warranted.

To the Editor: Since our group first reported on the potential clinical applications of the human tumor stem-cell, or clonogenic, assay in the Journal,1 we think some comment from us is warranted regarding the recent article by Selby et al.2 and the editorial by Von Hoff.3 We clearly agree that it is important to plate good single-cell suspensions, that drug-sensitivity criteria are still in the developmental stages,4 that some drugs may require the evaluation of various exposure times, that inappropriate drug concentrations may be misleading, that drugs requiring bioactivation present special problems, that radiation-survival curves with plateaus at. © 1983, Massachusetts Medical Society. All rights reserved.

A phase I trial was conducted of the vitamin A derivative beta-all-trans-retinoic acid (vitamin A acid; TRA), delivered via a collagen sponge and cervical cap for mild or moderate intraepithelial cervical neoplasia. On the basis of known skin and mucosal membrane toxicity, a concentration of 0.05% TRA in a cream-based vehicle was selected as the starting dose and was escalated later with the use of a modified Fibonacchi scale. The delivery device and the TRA were changed daily for 4 days, and side effects were assessed on days 1, 2, 3, 4, 8, and 30 by clinical and colposcopic examination. Vaginal, cervical, and systemic toxicity were evaluated in 35 patients. No dose-related systemic effects were found; mild cervical inflammation increased in many patients at higher doses. Unacceptably high vaginal toxicity was reached at a TRA concentration of 0.484%. A concentration of 0.372% TRA is recommended for use in phase II trials in mild and moderate cervical intraepithelial neoplasia.

Background

alpha-Difluoromethylornithine (DFMO) is a potent inhibitor of carcinogenesis in experimental animal models. In these animal models, DFMO has been especially active in preventing carcinogen-induced epithelial cancers, including those of the skin, colon, breast, and urinary bladder. Although DFMO is known to exert its diverse biological effects by suppressing intracellular pools of the polyamines putrescine and spermidine, the precise mechanism by which polyamine depletion, induced by DFMO, suppresses carcinogenesis is unknown.

Purpose

The specific aim of our study was to determine the lowest dose of DFMO that would deplete target tissue (colorectal mucosa) levels of these polyamines in humans who had undergone prior removal of colon polyps while producing minimal toxic effects.

Methods

A dose de-escalation chemoprevention trial of DFMO was conducted in 111 patients (36 female and 75 male) who were in generally good health, aged 39-79, and who had undergone colonoscopy for surgical removal of an adenomatous colon polyp greater than 3 mm within 5 years prior to entering the study. Groups of patients (12-20 patients per group) were orally treated with single, daily doses of DFMO ranging from 3.0 to 0.1 g/m2 for 4 weeks (28 days). Prior to initiation of DFMO treatment and at the end of treatment, six colorectal biopsy specimens were collected from each patient, along with serum samples. All biopsies were performed between 9 AM and noon to avoid possible effects of diurnal variations in laboratory end points. Samples for analysis of plasma DFMO levels were also collected during this time period on the day after the last day of drug administration.

Results

DFMO caused a decrease in both putrescine content and the ratio of spermidine to spermine for all dose groups down to 0.25 g/m2. Both putrescine content and the ratio of spermidine to spermine and changes in these parameters as a function of DFMO treatment decreased as a function of donor age. None of the 30 patients receiving either 0.25 or 0.5 g/m2 experienced any clinical ototoxicity in this trial.

Conclusions

DFMO is both safe and effective in reducing colorectal mucosal polyamine contents when it is administered orally to patients at doses as low as 0.25 g/m2 for 28 days. No ototoxicity was observed at doses up to twice this amount.

Implications

If DFMO is also found to be effective in suppressing polyamine contents in other target tissues, it may be useful in preventing a wide range of human epithelial cancers, including those of the prostate and breast.

Background

Retinoids enhance differentiation of most epithelial tissues. Epidemiologic studies have shown an inverse relationship between dietary intake or serum levels of vitamin A and the development of cervical dysplasia and/or cervical cancer. Pilot and phase I investigations demonstrated the feasibility of the local delivery of all-trans-retinoic acid (RA) to the cervix using a collagen sponge insert and cervical cap. A phase II trial produced a clinical complete response rate of 50%.

Purpose

This randomized phase III trial was designed to determine whether topically applied RA reversed moderate cervical intraepithelial neoplasia (CIN) II or severe CIN.

Methods

Analyses were based on 301 women with CIN (moderate dysplasia, 151 women; severe dysplasia, 150 women), evaluated by serial colposcopy, Papanicolaou cytology, and cervical biopsy. Cervical caps with sponges containing either 1.0 mL of 0.372% beta-trans-RA or a placebo were inserted daily for 4 days when women entered the trial, and for 2 days at months 3 and 6. Patients receiving treatment and those receiving placebo were similar with respect to age, ethnicity, birth-control methods, histologic features of the endocervical biopsy specimen and koilocytotic atypia, and percentage of involvement of the cervix at study. Treatment effects were compared using Fisher's exact test and logistic regression methods. Side effects were recorded, and differences were compared using Fisher's exact test.

Results

RA increased the complete histologic regression rate of CIN II from 27% in the placebo group to 43% in the retinoic acid treatment group (P = .041). No treatment difference between the two arms was evident in the severe dysplasia group. More vaginal and vulvar side effects were seen in the patients receiving RA, but these effects were mild and reversible.

Conclusions

A short course of locally applied RA can reverse CIN II, but not more advanced dysplasia, with acceptable local side effects.

Implications

A derivative of vitamin A can reverse or suppress an epithelial preneoplasia, lending further support to the notion that chemoprevention of human cancer is feasible.

We investigated the effect of the synthetic vitamin A derivative isotretinoin (13-cis-retinoic acid) on advanced cancers in 103 patients and on preneoplastic lesions in five patients. Six of 14 patients with squamous cell epithelial cancers had objective regressions of skin or subcutaneous metastases. Three of five patients with preneoplastic lesions had objective responses. The major dose-limiting toxic effects were reversible dermatitis, emotional lability, and headaches. We conclude that the growth of some squamous cell epithelial malignancies can be inhibited by isotretinoin and suggest that other retinoids should be evaluated as antitumor agents.

A preponderance of carcinogenesis studies in rodents and epidemiologic studies in humans suggests a potential role of dietary fiber in the prevention of colorectal cancer. Recently, wheat bran fiber used as a dietary supplement has been shown to decrease the growth of rectal adenomatous polyps in patients with familial polyposis; however, few studies of high-risk human populations have been attempted to determine the effects of dietary fiber supplementation on markers of carcinogenesis in the colon or rectum. We have designed a one-arm study to evaluate the effects of dietary supplementation with wheat bran fiber [i.e., 13.5 g/day for 8 wk; after 1 mo, 2 g/day (compliance evaluation period)] on [3H]thymidine rectal mucosa cell labeling (i.e., percent of epithelial cells incorporating [3H]thymidine into DNA in intact rectal crypt cells over a 90-min exposure as well as in minced rectal biopsy tissue over a 24-hr exposure) in rectal biopsy specimens. The biopsy specimens were obtained at sigmoidoscopy in 17 compliant patients with a history of resected colon or rectal cancer. We categorized patients as having initially low or initially high [3H]thymidine-labeling indices (i.e., percent of mucosa cells that incorporate [3H]thymidine into DNA during 1.5- or 24-hour in vitro incubations) by using the median baseline labeling index as a cutoff between high and low values. On the basis of a chi-square test used to identify patients with a statistically significant (P less than .001) change, six of the eight patients who initially had high 24-hour outgrowth labeling indices showed a significant decrease in the rectal mucosa biopsy specimens obtained after treatment. An overall 22% decrease was observed in rectal mucosa cell biopsy specimens obtained at study termination (P less than .001). Of the eight patients with initially high total [3H]thymidine-labeling indices in crypt organ culture, four had a significant (P less than .001) decrease from baseline values, one had a significant increase, and three showed no change following the fiber intervention. The wheat bran fiber dietary supplement of 13.5 g/day was well tolerated by this group of older (54-70 yr) patients. Although the [3H]-thymidine labeling index data suggest that the wheat bran fiber supplement can inhibit DNA synthesis and rectal mucosa cell proliferation in high-risk patients, the results of this small pilot study should not be overinterpreted vis à vis the potential role of wheat bran fiber as a chemopreventive agent for colorectal cancer.(ABSTRACT TRUNCATED AT 400 WORDS)

Precancer or intraepithelial neoplasia (IEN) is a noninvasive lesion that has genetic abnormalities, loss of cellular control functions, and some phenotypic characteristics of invasive cancer and that predicts for a substantial likelihood of developing invasive cancer. The AACR Task Force on the Treatment and prevention of IEN has delineated the relationship between IEN and cancer risk as well as the clinical benefit that can be derived from reducing IEN burden. Although several effective endoscopic and surgical treatments for IEN have become standard medical practice, these interventions can confer morbidity and do not treat the entire epithelial field at risk. The incidence of many epithelial cancers is continuing to rise, the number of individuals at risk is increasing with the aging population, and the rapid advancement of imaging and molecular diagnostics is bringing to light precancers that were heretofore clinically silent. There is therefore an urgent need to rapidly develop new treatment and prevention agents for IEN. The AACR IEN Task Force recommends focusing on established precancers as the target for new agent development because of the close association between dysplasia and invasive cancer and because a convincing reduction in IEN burden provides patient benefit by reducing cancer risk and/or by decreasing the need for invasive interventions. The IEN Task Force proposes several clinical trial designs that provide practical and feasible approaches to the rapid development of new agents to treat and prevent precancer.