Vinay K. Malviya

Intraperitoneal cisplatin plus intravenous cyclophosphamide versus intravenous cisplatin plus intravenous cyclophosphamide for stage III ovarian cancer

BACKGROUND Intravenous platinum-based chemotherapy is the standard primary therapy for advanced ovarian cancer. We conducted a phase 3 trial to compare the effects of intraperitoneal and intravenous cisplatin on the survival of women with previously untreated, stage III, epithelial ovarian cancer. METHODS The patients underwent an initial exploratory laparotomy and resection of all tumor masses larger than 2 cm. Within four weeks after surgery, six courses of intravenous cyclophosphamide (600 mg per square meter of body-surface area per course) plus either intraperitoneal cisplatin (100 mg per square meter) or intravenous cisplatin (100 mg per square meter) were administered at three-week intervals. RESULTS Of 654 randomized patients, 546 were eligible for the study. The estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months; 95 percent confidence interval, 42 to 56) than in the group receiving intravenous cisplatin (41 months; 95 percent confidence interval, 34 to 47). The risk of death was lower in the intraperitoneal group than in the intravenous group (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P = 0.02). Moderate-to-severe tinnitus, clinical hearing loss, and neuromuscular toxic effects were significantly more frequent in the intravenous group. CONCLUSIONS As compared with intravenous cisplatin, intraperitoneal cisplatin significantly improves survival and has significantly fewer toxic effects in patients with stage III ovarian cancer and residual tumor masses of 2 cm or less.

Inhibition of c-myc in breast and ovarian carcinoma cells by 1,25-dihydroxyvitamin D3, retinoic acid and dexamethasone.

The role and regulation of the c-myc protooncogene in breast and ovarian neoplasms is receiving increased attention. The downregulation of the c-myc protooncogene by 1,25-dihydroxyvitamin D3 (calcitriol), retinoic acid (RA) and dexamethasone (Dex) is closely associated with growth inhibition in leukemic cells. Calcitriol, RA and Dex have anti-proliferative activity in breast and gynecologic carcinoma cells; however, the regulation of c-myc by these agents in breast and ovarian cancers is mostly unknown. We have addressed the regulation of c-myc in these cancers using an adaptation of a novel method which employs an immunohistochemical procedure to detect c-myc protein followed by quantification of c-myc staining with computerized image analysis. This system represents an alternative to protein product assay by Western blotting and is straightforward, rapid (1 day), can be carried out on a small scale and provides a sample size that readily facilitates statistical analysis of assay data. In MCF-7 human breast cancer cells, c-myc was suppressed 29% by 0.5 nM Dex, 45% by 0.01 nM RA and 54% by 100 nM calcitriol after 24 h of drug treatment. At the same hormone concentrations, growth was inhibited 18% by Dex, 18% by RA and 39% by calcitriol after 3 days of treatment (p < 0.05 for all hormones). Similar patterns of growth and c-myc inhibition were seen in T47D human breast cancer cells and NIH:OVCAR3 human ovarian cancer cells, with the exception of Dex in T47D cells, which caused no inhibition of c-myc or growth.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of frozen section examination in identifying poor prognostic indicators in Stage I endometrial adenocarcinoma

Management of Stage I adenocarcinoma of the uterus includes hysterectomy, bilateral salpingo-oophorectomy, and selective paraaortic and pelvic lymphadenectomy. Postoperative radiation therapy (RT) is selectively employed in patients with histologically defined poor prognostic indicators. We attempted to identify these poor prognostic indicators by frozen section (FS) at primary surgery in 55 patients with Stage I endometrial adenocarcinoma; we found an excellent correlation between the results obtained on gross examination of the uterus with selected FS and the results after extensive sampling and microscopic examination of permanent section (PS). The depth of myometrial invasion was accurately predicted in 96.5%, and histologic grade in 94.5% of these patients. Sixty-six percent of patients with occult invasion of the cervix on PS were identified on FS. Using the above criteria, we identified by FS all patients (15/55) who required adjuvant RT obviating the need for pelvic lymph node dissection. On the basis of our preliminary data, we recommend the use of careful gross examination and selective FS to identify patients requiring selective pelvic and paraaortic lymphadenectomy and adjuvant therapy, thereby eliminating the need for staging lymph node dissection with its associated morbidity and complications.

Receptors for 1,25-dihydroxyvitamin D3 in gynecologic neoplasms

To determine if gynecologic malignancies are candidates for 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) therapy we measured vitamin D receptor (VDR) levels in 11 tumor specimens using a radiolabeled ligand-binding assay. VDR was demonstrated in 3 of 6 ovarian tumors and 1 of 1 uterine sarcomas, but not in endometrial tumors (2), cervical tumors (1), or Krukenberg tumors (1). Scatchard plots revealed that [3H]1,25(OH)2D3 was bound to a single class of high-affinity (Kd = 0.3 to 0.6 nM), saturable sites characteristic of authentic 1,25(OH)2D3 receptors. Specificity of binding activity for 1,25(OH)2D3, the active vitamin D3 metabolite, was demonstrated by failure of 25-hydroxy- and 24,25-dihydroxyvitamin D3 to compete effectively against 1,25(OH)2D3 binding in total cellular tumor extracts. The ovarian carcinoma cell line NIH:OVCAR3 was shown to possess VDR (binding capacity = 137 fmol/mg protein, Kd = 0.48 nM). A 3-day incubation of NIH:OVCAR3 cells with 100 nM 1,25(OH)2D3 resulted in 49% inhibition of cell growth. The growth inhibition of an ovarian carcinoma line and the observation that 36% of gynecologic tumors assayed were shown to be VDR-positive suggest that further study is warranted to delineate the mechanism and possible therapeutic aspects of 1,25(OH)2D3 action in gynecologic tumors.

Evaluation of amonafide in cervical cancer, phase II. A SWOG study.

The Southwest Oncology Group conducted a Phase II study of amonafide in patients with metastatic or recurrent squamous cell cervical cancer. Twelve of the 15 patients were fully evaluable for response and toxicity. There were no clinical responses seen; 2 patients had stable disease while 13 had progressive disease. The major complication of this therapy was myelosuppression. Four patients had life-threatening granulocytopenia (<500/μ1), 3 patients had life-threatening leukopenia (<1000/μl), while 2 patients had life-threatening thrombocytopenia (<25,000/μ1). Amonafide has significant toxicity but appears to be an inactive drug in metastatic or recurrent squamous cell cancer of the cervix.

Inhibition of breast and ovarian carcinoma cell growth by 1,25-dihydroxyvitamin D3 combined with retinoic acid or dexamethasone

This study examined the growth inhibitory effects of combining 1,25-dihydroxyvitamin D3 (calcitriol) with retinoic acid or dexamethasone against cultured breast and ovarian carcinoma cells. Retinoic acid (12.5-50 nM) increased the effectiveness of calcitriol (12.5-50 nM) against MCF-7 and NIH:OVCAR3 cells, with synergistic interactions at two of the three ratios tested. Dexamethasone augmented calcitriol effects, with synergism at 0.05 and 0.1 nM dexamethasone in MCF-7 cells and 5 nM in Caov-4 ovarian cells. This study showed favorable interactions for calcitriol-retinoic acid and calcitriol-dexamethasone combinations in breast and ovarian cancer cell lines.

Debulking surgery for ovarian cancer with the Cavitron Ultrasonic Surgical Aspirator (CUSA)—A preliminary report

The Cavitron Ultrasonic Surgical Aspirator (CUSA) can be used to fragment and aspirate tissue precisely. The CUSA was utilized as an adjunctive procedure to standard operative techniques to optimally debulk 11 women with advanced epithelial carcinoma of the ovary. No significant intraoperative or postoperative complications were encountered. It is suggested that this technique may be safely attempted in combination with the standard surgical techniques for debulking nonfibrous ovarian tumors or may allow removal of nonfibrous tumor masses which cannot be resected safely utilizing the standard surgical techniques. The authors found the CUSAs efficiency was limited in dense and fibrotic tissue. On the basis of our experience with this small number of patients, we believe this technique deserves further study.

Vascular access in gynecologic cancer using the Groshong right atrial catheter

From December 1986 through July 1987, forty-one Groshong catheters were inserted in 38 patients with invasive gynecologic cancer for a cumulative total of 4170 days of patient use. (mean catheter indwelling time: 93 days; range: 3-300 days). A supraclavicular approach was used to cannulate the brachiocephalic vein in 31 patients. In 6 patients, the subclavian vein was cannulated via an infraclavicular approach, while 4 patients had the catheters placed via external jugular venous cutdown. Thirty-seven catheters were inserted at the bedside without fluoroscopy using the Seldinger technique and a peel-away catheter introducer sheath. A chest x-ray was used to confirm the right atrial position of the catheter. Major complications included two pneumothoraces, and three catheter-related cases of sepsis. A unique feature of the Groshong catheter is a pressure-sensitive two-way valve at the intravascular end, minimizing the potential for air embolism and back-bleeding. This eliminates the need for a heparin flush or external clamping, but permits blood sampling. Catheter insertion and maintenance procedures at bedside are simple, time saving, and cost effective. With the increasing use of continuous chemotherapy infusion protocols, use of vesicant drugs, hyperalimentation, and the need for outpatient therapy, we recommend early placement of the Groshong catheter in the oncology patient.

Postoperative radiation for cervical cancer with pathologic risk factors

PURPOSE To examine the efficacy of postoperative radiation therapy for early-stage cervical cancer with pathologic risk factors. METHODS AND MATERIALS We reviewed the charts of 83 patients who received postoperative radiation therapy at our facility from March 1980 to November 1993 for early stage cervix cancer with positive surgical margins, positive pelvic or periaortic lymph nodes, lymphovascular space invasion, deep invasion, or for disease discovered incidently at simple hysterectomy. Twenty-eight patients received low dose rate (LDR) intracavitary radiation with or without external beam pelvic irradiation and 55 patients received external beam pelvic irradiation with high dose rate (HDR) intracavitary implants. Of these 83 patients, 66 were evaluable--20 LDR and 46 HDR patients. All patients received 45-50 Gy external beam irradiation and 20 Gy LDR equivalent intracavitary irradiation prescribed to 0.5 cm below the mucosa. Ninety percent of the LDR group and 92% of the HDR group completed treatment within < 56 days. Treatment-related toxicities were scored according to the GOG toxicity scale. Mean and median follow-up times were 101 months and 111 months (3-172 months) for the LDR group and 42 and 40 months (3-98 months) for the HDR group. RESULTS The 5-year disease-free survival was 89% for the LDR group and 72% for the HDR group. Local control was observed in 90% (18 out of 20) of the LDR patients and 89% (41 out of 46) of the HDR patients for an overall local control rate of 89.5%. Two of 20 LDR patients (10%) experienced recurrence (two pelvic with distant metastasis). Nine of 46 HDR patients (22%) had recurrence of disease (three pelvic, four distant metastasis, and two pelvic with distant metastasis). In the HDR group, 6 out of 16 (38%) with positive lymph nodes died of disease whereas, 27 out of 30 (90%) of the patients with negative lymph nodes remain free of disease. Three of 20 (15%) LDR patients and 4 out of 46 (9%) HDR patients experienced Grade 2 or 3 late treatment- related complications. No patient in either group had Grade 4 or 5 complications. Pathologic risk factors were analyzed. Lymph node positivity and lymphovascular space invasion were found to be significant (p = 0.01 and p = 0.02). Positive margins, deep invasion, and age were not significant. CONCLUSION Our results demonstrate the efficacy of postoperative irradiation for cervical cancer with pathologic risk factors. Overall, the local control rate was 89.5% The HDR results demonstrate that this method can be delivered safely and effectively.

Surgical approach to diaphragmatic metastases from ovarian cancer

Fourteen patients underwent surgical debulking of diaphragmatic metastases as part of cytoreductive surgery for advanced ovarian epithelial cancer from 1983 to 1984. The surgical technique is described. Morbidity from this approach was not excessive in this small series of patients. It is suggested that this technique can be safely used and may benefit a few patients with advanced ovarian cancer.