John H. Malfetano

Randomized Comparison of Fluorouracil Plus Cisplatin Versus Hydroxyurea as an Adjunct to Radiation Therapy in Stage IIB-IVA Carcinoma of the Cervix With Negative Para-Aortic Lymph Nodes: A Gynecologic Oncology Group and Southwest Oncology Group Study

PURPOSE In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities. METHODS All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU. RESULTS Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018). CONCLUSION This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.

Phase III Trial of Doxorubicin With or Without Cisplatin in Advanced Endometrial Carcinoma: A Gynecologic Oncology Group Study

PURPOSE Doxorubicin and cisplatin have activity in endometrial carcinoma and at initiation of this study ranked as the most active agents. This trial of stage III, IV, or recurrent disease evaluated whether combining these agents increases response rate (RR) and prolongs progression-free survival (PFS) and overall survival (OS) over doxorubicin alone. PATIENTS AND METHODS Of 299 patients registered, 281 (94%) were eligible. Regimens were doxorubicin 60 mg/m(2) intravenously or doxorubicin 60 mg/m(2) plus cisplatin 50 mg/m(2) every 3 weeks until disease progression, unacceptable toxicity, or a total of 500 mg/m(2) doxorubicin. RESULTS There were 12 (8%) complete (CR) and 26 (17%) partial responses (PR) among 150 patients receiving doxorubicin versus 25 (19%) CRs and 30 (23%) PRs among patients receiving the combination. The overall response rate was higher among patients receiving the combination (42%) compared with patients receiving doxorubicin (25%; P =.004). Median PFS was 5.7 and 3.8 months, respectively, for the combination and single agent. The PFS hazard ratio was 0.736 (95% CI, 0.577 to 0.939; P =.014). Median OS was 9.0 and 9.2 months, respectively, for the combination and single agent. Overall death rates were similar in the two groups (hazard ratio, 0.928; 95% CI, 0.727 to 1.185). Nausea, vomiting, and hematologic toxicities were common. The combination produced more grade 3 to 4 leukopenia (62% v 40%), thrombocytopenia (14% v 2%), anemia (22% v 4%), and nausea/vomiting (13% v 3%). CONCLUSION Adding cisplatin to doxorubicin in advanced endometrial carcinoma improves RR and PFS with a negligible impact on OS and produces increased toxicity. These results have served as a building block for subsequent phase III trials in patients with disseminated and high-risk limited endometrial carcinoma.

Clinical-pathologic study of stage IIB, III, and IVA carcinoma of the cervix : extended diagnostic evaluation for paraaortic node metastasis : a gynecologic oncology group study*

Three hundred twenty patients were entered into GOG Protocol 63, a clinical-pathologic study of stage IIB, III, and IVA cervical carcinoma. Following the completion of FIGO staging prerequisites, patients had computerized tomography (CT), a lymph-angiogram (LAG), and an ultrasound (US) of the aortic area. If any study was positive, a cytologic or histologic evaluation by fine-needle aspiration or selective paraaortic lymphadenectomy was performed. Paraaortic node dissection was mandated for patients with negative extended staging studies. Results of extended staging evaluations were compared with histologic or cytologic results. Two hundred sixty-four patients were eligible and evaluable. One hundred sixty-seven patients (63%) were stage IIB, 89 (34%) were stage III, and 8 (3%) were stage IVA. Positive paraaortic nodes occurred in 21% of stage IIB, 31% of stage III, and 13% of stage IVA. LAG sensitivity was 79% with a specificity of 73%. Sensitivity of CT and US was 34 and 19%, respectively, with specificities of 96 and 99%, respectively. The frequency of false-negative results with LAG for patients with stage IIB disease was 6%. This decrease is consistent with a stable sensitivity and specificity. These findings suggest that a negative LAG may be adequate to eliminate surgical staging in subgroups with low risk of metastasis to the aortic nodes. Until new noninvasive testing methods are developed, LAG appears to be the most reliable noninvasive examination to evaluate spread of cervical cancer to aortic nodes.

Positive peritoneal cytology is an adverse factor in endometrial carcinoma only if there is other evidence of extrauterine disease

The prognostic significance of peritoneal cytology among 269 women with clinical stage I and II carcinoma of the endometrium was studied. All patients were surgically staged and had undergone selective pelvic and para-aortic lymphadenectomies. Patients with clear cell and papillary serous carcinomas were excluded from the analysis. Thirty-four (12.6%) patients had malignant cells in the peritoneal washings (positive peritoneal cytology). The effect of positive peritoneal cytology on survival depended upon the extent of disease present. If the disease was confined to the uterus, positive peritoneal cytology did not influence survival; if the disease had spread to the adnexa, lymph nodes, or peritoneum, positive peritoneal cytology had a significant adverse effect on survival, decreasing it at 5 years from 73 to 13%, all recurrences being at distant sites. These findings suggest that treatment specifically directed at positive peritoneal cytology is not warranted unless extrauterine disease is present, and when it is, systemic rather than intra-abdominal treatment will be required to affect survival.

Phase II trial of ifosfamide and mesna in advanced ovarian carcinoma: a Gynecologic Oncology Group Study.

Ifosfamide (isophosphamide) and mesna (2-mercaptoethane sodium sulfonate) were administered intravenously at monthly intervals to 46 patients with advanced epithelial ovarian carcinoma refractory to or recurrent after cisplatin-containing combination chemotherapy. Initially, ifosfamide was given as 1.5 g/m2/d x 5 days and mesna as 300 mg/m2 every 4 hours for three doses following ifosfamide, but the initial dose of ifosfamide was reduced to 1.2 g/m2 because of toxicity. Four of the patients initially entered were found to be ineligible: two who had had more than one prior chemotherapy regimen and two who did not have ovarian primaries. One patient received an inadequate trial and four patients had discontinuation of therapy because of toxicity, leaving 41 evaluable for response. Three patients (7.0%) had complete responses and five (13.0%) had partial responses for an overall response rate of 20.0%. Response duration ranged from 2.1 to 20.3 + months with a median of 6.9 + months. Two patients died of renal failure, one of whom had no known renal disease and received 1.5 g/m2/d x 5 days ifosfamide. The second patient received the 1.2 g/m2 dose and was found to have chronic pyelonephritis and pyonephrosis at autopsy. Gynecologic Oncology Group (GOG) grade 3 or 4 granulocytopenia was seen in eight (19.5%), grade 3 or 4 thrombocytopenia in four (9.8%), and grade 3 or 4 neurotoxicity in six (14.6%) of the 41 patients evaluable for toxicity. Ifosfamide/mesna is active in epithelial ovarian cancer. GOG trials in untreated patients are being initiated and toxicity is being evaluated.

Tamoxifen-associated endometrial carcinoma in postmenopausal breast cancer patients

Tamoxifen citrate, a nonsteroidal antiestrogen with agonistic properties, is prescribed as an adjuvant to surgery in the treatment of breast cancer. Recent reports have suggested that tamoxifen has an estrogenic property and may be implicated in the development of endometrial carcinomas. Seven new cases are reported to the existing literature in which endometrial carcinomas developed in postmenopausal women on tamoxifen therapy for breast carcinomas.

Paclitaxel, an Active Agent in Nonsquamous Carcinomas of the Uterine Cervix: A Gynecologic Oncology Group Study

PURPOSE A phase II trial of paclitaxel was initiated in advanced nonsquamous carcinoma of the cervix to determine its activity in patients who had failed standard chemotherapy. PATIENTS AND METHODS Eligible patients had at least one measurable lesion. The starting dose of paclitaxel was 170 mg/m(2) (135 mg/m(2) for patients with prior pelvic radiation) given as a 24-hour continuous intravenous infusion with courses repeated every 3 weeks. Dose escalation to 200 mg/m(2) and de-escalation to 110 mg/m(2) were allowed based on adverse effects. RESULTS In this trial, 42 assessable patients were initially entered onto the study, and 13 responses were seen; four patients had a complete response, and nine patients had a partial response. The overall response rate was 31%. The primary and dose-limiting toxicity was neutropenia. CONCLUSION The response rate to paclitaxel exceeds the rates reported using other single agents in nonsquamous carcinoma of the cervix.

Observations on tumor and metastatic suppressor gene status in endometrial carcinoma with particular emphasis on p53

Background. Genetic changes in the development of endometrial carcinoma have not been characterized, and little is known of tumor or metastatic suppressor gene status in these malignancies. The current study on endometrioid carcinoma was undertaken to examine the status of two tumor suppressor genes that frequently have been found to be altered in human malignancies (the p53 gene and the retinoblastoma [Rb] gene) and to examine the status of the candidate metastatic suppressor gene, nm23‐H1.

Vulvar Malignant Melanoma Associated With Human Papillomavirus Dna: Report of Two Cases and Review of Literature

Oncogenic human papillomavirus (HPV) types such as HPV 16 are known to play a crucial role in the development of anogenital carcinomas. The etiology of anogenital malignant melanoma is unknown. We report two case of vulvar malignant melanoma in which multiple HPV types including HPV 16 and putative novel HPV types (alb-1, alb-2, alb-7, and alb-10) were identified by degenerated nested polymerase chain techniques (polymerase chain reaction) in both the malignant melanoma and surrounding skin. One melanoma was associated with lichen sclerosus, and the other, with melanoma in situ and pigmented vulvar squamous papillomatosis. These melanomas harbored HPV types alb-7, and HPV 16 as well as alb-1, respectively. HPV types 16, 20, 21, 36, alb-2, and AJ001060 were detected in vulvar skin affected by lichen sclerosus. Vulvar squamous papillomatosis harbored HPV types 28 and alb-10. HPV 16 was physically integrated into the host genome in lichen sclerosus skin and possibly in the melanoma associated with pigmented vulvar squamous papillomatosis. Twenty-two percent (4 of 18) of normal control specimens from skin tumor excisions were found to harbor HPV DNA (HPV types 3, 54, and alb-7); none of these control samples harbored multiple HPV DNA. These findings of multiple HPV DNA and integrated HPV 16 in skin associated with vulvar malignant melanoma indicate that HPV may play a role in the development of vulvar malignant melanoma. The role of HPV could be either direct through infection of melanocytes or indirect as a cofactor with free radicals in chronic fibroinflammatory vulvar disorders such as lichen sclerosus.

Comparative immunophenotypic study of lichen sclerosus: epidermotropic CD57+ lymphocytes are numerous--implications for pathogenesis.

To characterize the immunophenotype of inflammatory cells in lichen sclerosus (LS), we performed a comparative case control study using one- and two-color immunohistochemistry and the nitro blue tetrazolium (NBT) reaction. Study material consisted of 100 biopsies from patients with LS or from 12 control groups consisting of inflammatory, scarring, and depigmenting cutaneous disorders. In addition, fresh tissue was sampled from four vulvectomy specimens for NBT testing. The typical inflammatory infiltrate of LS contained numerous epidermotropic CD3+, CD8+, CD57+ cells, increased intraepidermal HLA-DR+ cells, and a dermal infiltrate rich in CD8+, CD57+, HLA-DR+, and CD68+ inflammatory cells. Comparing LS to the 12 control groups, epidermotropic CD57+ lymphocytes independently predicted LS (P = 0.006, logistic regression, multivariate analysis). Among the 12 control groups, only specimens of the inflammatory stage of morphea exhibited numerous dermal CD57+ lymphocytes. Two-color immunohistochemistry confirmed the CD3+/CD8+CD57+ and CD3+/ CD8+/CD57+HLA-DR+ epidermotropic and dermal lymphocytic phenotypes and the dermal macrophage CD68+HLA-DR+ phenotype. In LS, the NBT reaction revealed evidence of superoxide production associated with CD68+HLA-DR+ cells. Expansion of CD8+CD57+lymphocytes is associated with viral infections, autoimmune disease, malignancies, and transplantation and is suspected to be the result of chronic excessive antigen challenge. In these pathologic states, CD8+CD57+ lymphocytes (as terminally differentiated, antigen-specific T cells) participate in the suppression of cytolytic activity to limit tissue damage. In LS, activated macrophages and lymphocytes indicate persistent antigen-driven inflammation. LSs numerous CD8+CD57+ lymphocytes may be either the mediators or the consequence of its hallmark sclerosis.