Results of a Phase II Double-Blinded Randomized Clinical Trial of Difluoromethylornithine for Cervical Intraepithelial Neoplasia Grades 2 to 3

ABSTRACT Purpose: Our purpose was to conduct a double-blinded randomized trial of difluoromethylornithine (DFMO) at 0.125, 0.5 gm/m 2 , versus placebo in the treatment of cervical intraepithelial neoplasia (CIN) grades 2 to 3. A promising phase I study has shown histopathologic responses at these dose levels. Experimental Design: Patients with histopathologically confirmed CIN 2-3 lesions were recruited from a colposcopy clinic and underwent Papanicolaou testing, human papillomavirus testing, and colpophotography. They took oral contraception and DFMO or placebo elixir for 28 days and filled out the National Cancer Institute common toxicity calendars. They returned for follow-up and a repeat Papanicolaou smear, colpophotograph, and loop excision of the cervix. Results: There were no statistically significant differences among the arms in histopathologic response. This could not be explained by any biases in risk factors. The prominent toxicities were diarrhea, dizziness, nausea, and headaches. There were no differences in the toxicities among arms. The Papanicolaou smear was a poor biomarker of response and correlated poorly with the histopathology. Conclusions: DFMO is not active at 0.125 and 0.5 gm/m 2 for 28 days when given orally in CIN 2-3. Higher oral doses or longer administration is necessary, supporting data from breast trials. Alternatively, a trial of topical DFMO might merit attention as activity has been noted in trials of actinic keratoses

Thymoma. A retrospective study of 87 cases

Background. The authors retrospectively analyzed 87 patients with malignant thymoma treated at M. D. Anderson Cancer Center between 1951 and 1990. The analysis examined the clinical stages, histologic types, and treatment modalities and attempted to determine if chemotherapy had an impact on survival. Methods. The patients were divided into three groups by their year of treatment and treatment modality. Patients treated between 1951 and 1975 were in Group I; patients treated between 1976 and 1980 were in Group II; and patients treated between 1981 and 1990 were in Group III. Most of the patients (18 [72%] in Group I; 16 [62%] in Group II; and 18 [50%] in Group III) had surgical resection alone or with radiotherapy. Patients with advanced‐stage disease in Group I received single‐agent chemotherapy, whereas patients with advanced‐stage disease in Group II received a different, combination chemotherapy regimen, and those in Group III were treated primarily with cisplatin‐ and doxorubicin‐based combination chemotherapy, e.g., the cyclophosphamide doxorubicin, and cisplatin with or without prednisone. The 17 patients treated with cisplatin with or without prednisone were separately evaluated for survival according to their response. Results. Twenty‐eight patients (5 [20%] in Group I; 6 [23%] in Group II; and 17 [47%] in Group III) received chemotherapy alone or after surgery or radiotherapy. The cisplatin with or without prednisone regimen was used in 17 Group III patients for initial treatment or for relapse. The overall response rate among the patients receiving the cisplatin with or without prednisone regimen was 64%; 6 (35%) had a complete response, and 5 (29%) had a partial response. Thirty‐one (36%) of the 87 total patients had 45 recurrent tumors; the lung (29%), pleura (22%), and mediastinum (18%) were the most common sites of recurrence, whereas bone was the most common distant metastatic site. The 5‐year survival rate was 70% in patients with Stage I disease, 71% in patients with Stage II or III disease, and 46% in patients with Stage IV disease. The 10‐year survival rate was 70% in patients with Stage I disease, 47% in patients with Stage II or III disease, and 21% in patients with Stage IV disease. Statistical analysis indicated a significant difference among the survival rates of patients with noninvasive Stage I, invasive Stage II plus III (P = 0.033), and Stage II plus III and IV tumors (P = 0.056), but not between patients with Stage II or III tumors. Patients with a major response to the cisplatin with or without prednisone regimen had a significant survival improvement compared to those with no response (P = 0.002, log‐rank test). Conclusions. Because thymoma is a chemosensitive tumor and frequently recurs in patients with Stage II or greater disease, chemotherapy carries a potential survival benefit and should be incorporated into the multimodality approach to prolong disease‐free survival

Identification of three distinct tumor suppressor loci on the short arm of chromosome 9 in small cell lung cancer

Deletion at 9p21 is frequent in many tumor types. A candidate tumor suppressor gene, p16(INK4a), was mapped to this region and is frequently inactivated by several different mechanism in many tumor types, including non-small cell lung cancer, but not in small cell lung cancer (SCLC). p16 functions as a cyclin/CDK inhibitor to prevent phosphorylation of pRB. It has been demonstrated that most SCLCs have lost pRB but retained p16, and the inactivation of pRB excludes the inactivation of p16 and vice versa. To determine the potential existence of other tumor suppressor genes on the short arm of chromosome 9 in SCLC, we tested 46 primary SCLCs by microsatellite analysis. We found that more than 89% of the tumors exhibited loss of heterozygosity (LOH) at 9p with three distinct minimal deleted areas. Among those areas, LOH at 9p21 was most frequent (86%), with a peak at a marker 150 kb telomeric to p16(INK4a). LOH was also observed in more than 50% of the tumors at two other regions, 9p22 and 9p13. Our data strongly suggest the presence of at least three novel tumor suppressor loci on 9p in SCLC, and further investigations to clone candidate tumor suppressor genes are warranted