Oral diindolylmethane (DIM): pilot evaluation of a nonsurgical treatment for cervical dysplasia.

OBJECTIVE: Standard surgical treatment for CIN may impair fertility generating a need for alternative treatment options. We tested the efficacy and toxicity of oral DIM in the treatment of CIN 2 or 3 lesions. METHODS: Patients with biopsy-proven cervical intraepithelial neoplasia (CIN) 2 or 3 scheduled for loop electrosurgical excision procedure (LEEP) were randomized 2:1 to receive diindolylmethane (DIM) (BioResponse-DIM, BioResponse, Boulder, CO) orally at approximately 2 mg/kg/day for 12 weeks or placebo (defatted rice bran, BioResponse). Subjects were evaluated every 3-4 months for 1 year. Analysis of data up to 1 year was assessed including Pap smear, HPV, colposcopy, biopsy and physical examination were performed at follow-up. Central pathology review confirmed all histology diagnoses. RESULTS: To date, 64 subjects (mean age 28 years, range 18-61) have been enrolled (45 in the DIM arm, 19 in the placebo arm), with 60 available for analysis. Average follow-up was 6 months. At enrollment, 58% were diagnosed with CIN 2 and 42% with CIN 3, 57% of subjects were Caucasian, 15% African American, 12% Hispanic and 17% Asian. During treatment 2 subjects (3%) complained of nausea (grade 2) at the 3- to 4-month visit. No systemic toxicities were observed (normal CBC, LFTs, comprehensive metabolic). Forty-six subjects had biopsies at first follow-up (77%). Twenty-one subjects (47%) in the DIM group had improved CIN with a decrease by 1-2 grades or a normal result. Median time to improvement was 5 months. Improved Pap smear was seen in 49% (22/45) with either a less severe abnormality or normal result. Colposcopy improved in twenty-five subjects in the DIM group (56%). Of these 25 subjects, 21 (84%) had improved colposcopic impression, 13 (52%) had a decrease in involved quadrants and 18 (72%) had a decrease in lesion number. Complete colposcopic response was observed in 4 subjects (9%). Stratifying by level of dysplasia, age, race, HPV status, tobacco use, contraceptive used did not alter the results. At median follow-up of 6 months, 85% of subjects have not required LEEP based on routine clinical triage of improving global assessment. There was no statistically significant difference in any outcome between the DIM and placebo group. CONCLUSION: Oral DIM at 2 mg/kg/day is well tolerated with no significant toxicity. We observed a high rate of clinically significant improvement in confirmed CIN 2 or 3 lesions among both treatment groups in this randomized clinical trial.

For women receiving chemotherapy for clinically apparent early ovarian cancer, is there a benefit to surgical staging?

BACKGROUND: For women with early stage ovarian cancer (ESOC), comprehensive staging is the standard of care and studies suggest that these patients may not require further treatment. For women with incidentally diagnosed ovarian cancer there is a lack of consensus as to whether surgical staging be performed, particularly if chemotherapy is recommended. OBJECTIVE: We performed this retrospective study to determine the outcomes of women treated with chemotherapy for clinically apparent ESOC, stratified by whether staging was performed or not. METHODS: This study was approved by institutional review board. All patients presenting to the Multidisciplinary Gynecologic Oncology Tumor Board between 1998 and 2005 with a consensus opinion of having clinically apparent ESOC were identified. Staging (partial or complete) was determined by a study pathologist and patients were stratified as being staged or unstaged. Survival was estimated using the Kaplan-Meier method. STATA 8.0 was used for all calculations. RESULTS: Eighty-eight patients were identified: 52 (59%) were staged and 36 (31%) were not. Median follow-up was 50 and 59.5 months, respectively. The majority of patients received carboplatin and paclitaxel in both cohorts with a median of 6 cycles. Five-year Disease Free Survival was 85% versus 80%, respectively (P = 0.54). Five-year Overall Survival was 85% versus 88% (P = 0.688). CONCLUSION: For women presenting with a clinically apparent ESOC in whom chemotherapy is administered, there does not seem to be an additional benefit to surgical staging. A prospective trial of women with clinically apparent ESOC to test this hypothesis should be considered.

Retroperitoneal nodal metastasis in primary and recurrent granulosa cell tumors of the ovary.

OBJECTIVE: To describe the incidence of retroperitoneal pelvic or paraaortic lymph node metastasis in patients with primary and recurrent ovarian granulosa cell tumors. METHODS: At Memorial Sloan-Kettering Cancer Center, we conducted a retrospective chart review of all patients with ovarian granulosa cell tumors managed as inpatients from January 1991 to July 2005. The initial date of diagnosis ranged from 1971 to 2005. RESULTS: We identified 68 patients with a median age of 49 years (mean, 47.5 years; range, 19-78 years). Sixty-four (94%) patients had adult type and 4 (6%) had juvenile granulosa cell tumors. Fifty-three (78%) patients had their initial surgery at another institution and 55 (81%) were incompletely surgically staged at diagnosis due to the absence of pelvic and/or aortic lymph node dissection. Patients were assigned an International Federation of Gynecology and Obstetrics (FIGO) stage that included IA, 39; IC, 15; IIB, 3; IIC, 3; IIIC, 1. In 7 patients, the original stage was not assigned. Only 16 (24%) patients had a pelvic lymph node sampling and 13 (19%) also had a paraaortic lymph node sampling at primary surgery or at restaging surgery performed shortly following initial diagnosis; however, in these cases, lymph nodes were negative for metastasis. The median number of pelvic lymph nodes removed was 10 (mean, 11.6 nodes; range, 0-36 nodes). The median number of paraaortic lymph nodes removed was 4 (mean, 6 nodes; range, 0-19 nodes). Nine of 15 (60%) of patients managed initially at our institution were surgically staged compared to 4 of 53 (7.5%) who were managed initially elsewhere (P < 0.001). Thirty-four patients with recurrent granulosa cell tumors were managed during the study, 31 (91%) had adult type granulosa cell tumor, and 3 had juvenile histology. Thirty-three of 34 patients who recurred were incompletely surgically staged at the initial operation. Original "clinical" FIGO stage for patients who recurred included IA, 15; IC, 8; IIB, 1; IIC, 3; IIIC, 1; and in 6 patients, the original stage was not available. The median disease-free interval to first recurrence was 63 months (mean,69.4 months; range, 4-170 months). First recurrence sites included pelvis, 24/34 (70%); pelvis and abdomen, 3 (9%); retroperitoneum only, 2 (6%); pelvis and retroperitoneum, 2 (6%); pelvis/abdomen/retroperitoneum, 1(3%); abdomen only, 1 (3%); and bone, 1 (3%). CONCLUSIONS: Complete surgical staging was performed in approximately 1/5 women with ovarian granulosa cell tumors; however, in those initially surgically staged, no nodal metastasis was identified. Clinical stage IA disease was the most common original diagnosis in women who recurred, and approximately 15% of first recurrences appear to involve the retroperitoneum.