The role of ifosfamide in gynecologic cancer.

Ifosfamide exhibits promising activity in a variety of gynecologic neoplasms. In carcinoma of the ovary, the drug shows clear-cut activity, effecting responses in patients who have proven clinically resistant to cisplatin-based combination chemotherapy. In carcinoma of the cervix, the drug also appears to be highly active, both as a single agent and in combination with other agents, such as the platinum compounds. The drug is active in uterine sarcomas and appears to be the most active agent studied to date in mixed mesodermal sarcomas of the uterus. The drug's role in combination with other agents in the treatment of all of these neoplasms is under study, but cannot be determined from currently available data on combination therapy. Its activity in other gynecologic tumors, such as endometrial carcinoma and ovarian germ cell tumors, is also indeterminate at present. Although further studies are needed, current evidence supports the contention that ifosfamide is a major new active drug in the management of gynecologic cancers.

Combined versus sequential chemo-endocrine therapy in advanced prostate cancer: final results of a randomized Southwest Oncology Group study.

Cytotoxic chemotherapy has not provided survival benefit in metastatic prostate cancer, although it has been used most frequently in patients with far-advanced, refractory disease. To evaluate the effects of chemotherapy given earlier in the course of the disease, the Southwest Oncology Group (SWOG) performed a randomized trial between September 1982 and October 1986 comparing endocrine therapy (diethylstilbestrol [DES] or orchiectomy) alone followed by cyclophosphamide-Adriamycin (doxorubicin; Adria Laboratories, Columbus, OH) chemotherapy at progression versus initial combined chemo-endocrine therapy. One hundred forty-three patients were registered, and only six were declared ineligible. Patients on the combined chemo-endocrine therapy arm had a slightly higher response rate (63%) compared with endocrine therapy alone (48%). A log-linear model of tumor response and treatment arm adjusted for the stratification factors favored the combination arm (P = .059). Only three of 27 patients on the endocrine therapy alone arm had an objective partial response when crossed over to chemotherapy, while two others had stable disease. Despite the difference in initial response rate, time to treatment failure and survival were identical in the two treatment arms. Seventy-seven percent of patients on the initial endocrine therapy alone arm have died (median survival, 25.6 months) compared with 78% on the chemo-endocrine therapy arm (median survival, 22.0 months). No significant effect of treatment on survival was observed even after adjustment for the stratification variables in a Cox regression model. Exploratory survival analyses with patients on both arms combined did show a marginally significant time to treatment failure and survival advantage for patients treated with DES rather than orchiectomy as initial endocrine therapy. Eighty-six percent of patients treated by orchiectomy have died compared with only 65% of those treated with DES. These data do not support the addition of cytotoxic chemotherapy to initial endocrine therapy in patients with metastatic prostate cancer.

Ifosfamide in the management of gynecologic cancers.

Ifosfamide, an alkylating agent chemically similar to cyclophosphamide, has been tested both as a single agent and in combination therapy for a variety of gynecologic cancers. In celomic epithelial carcinoma of the ovary, single agent ifosfamide yields response rates ranging from 19% to 79% and, most significantly, responses in patients who are refractory to cisplatin. Use in combination with both cisplatin and carboplatin has been reported, but the relative merits of these two combinations are indeterminate at present. In carcinoma of the cervix, response rates for ifosfamide alone range from 20% to 40% in patients who have not received prior chemotherapy. Very high response rates from 67% to 86% have been reported with ifosfamide in combination with platinum compounds with or without other agents such as doxorubicin and bleomycin. No studies have yet demonstrated superiority of combination therapy. Data from the Gynecologic Oncology Group demonstrate activity for ifosfamide alone in mixed mesodermal sarcomas of the uterus. Finally, anecdotal data note responses in endometrial carcinoma and germ cell carcinomas of the ovary. Thus, it appears that ifosfamide has significant activity in a variety of gynecologic cancers and deserves further testing as a part of combination chemotherapy in at least celomic epithelial carcinomas of the ovary, cervix carcinomas, and mixed mesodermal sarcomas of the uterus.

Chemotherapy in ovarian carcinoma: present role and future prospects.

Epithelial carcinoma of the ovary is characterized by presentation at an advanced stage, spread primarily by an intraperitoneal (IP) route, and relative sensitivity to chemotherapy. An initial surgical approach is essential to proper staging of the disease process and to aggressive cytoreduction, which in turn improves response to chemotherapy and survival. The use of chemotherapy is the mainstay of definitive therapy after completion of the initial surgery. A large number of drugs have activity against the disease, with the most important single category of agents being the platinum compounds. Studies by the Gynecologic Oncology Group (GOG) document the superiority of cisplatin-based combination chemotherapy over single alkylating agents and combinations that do not include cisplatin. The current regimen of choice is a two-drug combination of cisplatin plus cyclophosphamide. Efforts to improve results further focus on enhancing dose intensity of the drug combination through either escalating intravenous (IV) doses or administering cisplatin via an IP route. Also offering an opportunity for further improvement of therapeutic results are three drugs identified as having activity in patients no longer candidates for cisplatin: carboplatin, ifosfamide, and taxol. Biologic agents, such as alpha-interferon, also have potential roles in future combination therapy. The management of patients with limited (stage I or II) disease is based on studies of the GOG and the Ovarian Cancer Study Group, which indicate that this population can be divided by prognostic factors into a group at low risk for recurrence and a group at high risk. Those at low risk require only surgery, whereas those at high risk should receive either IP radioactive chromic phosphate or systemic chemotherapy following surgery. The future prospects for additional improvement of results in all patients appear bright on the basis not only of studies of dose intensity and IP therapy but also of efforts directed at overcoming multidrug resistance and at devising noninvasive means of assessing disease status.

Ovarian carcinoma: the role of chemotherapy.

Maximum surgical effort will yield improved survival and response to subsequent therapy in patients with minimal residual disease (less than 2 cm diameter of any remaining nodule). Systemic therapy is the mainstay of later management. Studies have focused on single-agent v combination chemotherapy, optimal combination, dose intensity, and route of administration. In advanced disease, studies of the Gynecologic Oncology Group (GOG) demonstrate the superiority of cisplatin based combination chemotherapy over a single alkylating agent in regard to overall response, clinical complete response, response duration, and survival. Subsequent GOG and other studies suggest that a two-drug combination of cisplatin and cyclophosphamide is therapeutically equivalent to more toxic three- and four-drug combinations. Whether continued escalation of drug dose intensity beyond usual clinical schedules yields incremental gain in benefit remains under study. Administration of drug, particularly cisplatin, via the intraperitoneal (IP) route produces objective responses in patients who have progressed after prior cisplatin based therapy. Whether IP therapy is superior to IV therapy as first-line treatment is under investigation. In limited disease, patients can be assigned to low- and high-risk groups based on careful surgical staging. Patients with low-risk limited disease have a 5-year disease-free survival exceeding 95% with no adjuvant therapy. Those with high-risk disease, even with IP chromic phosphate or systemic melphalan, have a relapse rate of 20% or more after a similar period. The potential role of cisplatin based combination therapy in such patients is under study. Future improvement in results depends on current investigations of noninvasive methods for diagnosis and evaluation, better definition of the value of greater dose intensity and alternate route of administration, the value of methods for choosing appropriate drugs, the development of new agents, and methods to overcome drug resistance.

Surgery in small cell lung cancer.

Surgery in small cell lung cancer (SCLC) was abandoned in the late 1960s but is currently being cautiously reassessed, after the Armed Forces Asymptomatic Pulmonary Nodule Study demonstrated an unexpectedly prolonged 5-year survival (36%) with surgery. Subsequent prospective studies have reported five-year survival following resection in 22 to 83% of patients with Stage I disease and in 0 to 50% of patients with Stages II and III disease. Ten percent of patients with SCLC may be amenable to this approach. Additional patients may become candidates for resection following intensive combination chemotherapy. The optimal postoperative management remains unsettled. Combination chemotherapy and prophylactic cranial irradiation is recommended following complete resection. Postoperative thoracic irradiation may benefit patients with pathologically involved mediastinal nodes. Correlation of clinical response with our new understanding of the molecular biology of SCLC may further improve our approach to this disease.

Extramammary Paget's disease: an annotated review.

The incidence, clinical features, histogenesis, and treatment of extramammary Paget's disease (EMPD) are reviewed. This unusual skin lesion is associated with an underlying adnexal neoplasm in about 50% of cases. Also, the incidence of distant organ malignancies of EMPD is higher than expected by chance. Even in the absence of a recognizable underlying cancer, EMPD may occasionally produce distant metastases, indicating the malignant potential of this condition. Histochemical, immunohistological, and lectin binding studies demonstrate that the cell of origin of EMPD is the exocrine cell of sweat glands. Although EMPD may arise from eccrine cells, derivation from apocrine cells appears more common. The treatment of the primary lesion, by wide margin excision, is fraught by a high recurrence rate. Chemosurgery may reduce local relapse of EMPD. The value of adjuvant radiation therapy is unestablished. Chemotherapy has induced remission in 2 cases of advanced EMPD and needs testing in clinical trials.

Chemotherapy for advanced or recurrent gynecologic cancer.

Studies of chemotherapy in advanced or recurrent gynecologic cancer have focussed on ovarian, cervical, and endometrial carcinoma. For celomic epithelial carcinomas of the ovary, a large number of cytotoxic agents have been shown to be active. Dramatic improvement in frequency of response with lesser improvement in survival has been noted with the use of cisplatin-based combination chemotherapy as compared to single alkylating agents. More recent studies have evaluated alternative ways to employ cisplatin: higher dose schedules, intraperitoneal administration, and platinum compounds with a potentially better therapeutic index. None has yet been shown superior to a combination of relatively low-dose cisplatin plus an alkylating agent with or without doxorubicin. Cisplatin remains the best studied and most active single agent in patients with squamous cell carcinoma of the cervix. While a number of other agents have demonstrated moderate activity, no combination of drugs has as yet proved superior to single-agent cisplatin. In endometrial carcinoma, progestins and doxorubicin are the most active agents. Tamoxifen, cisplatin, and hexamethylmelamine appear to have moderate activity. No combination has yet been shown to be superior to single agents. Information on chemotherapy for less common gynecologic malignancies is largely anecdotal. Two observations are of note. Cisplatin-based combination chemotherapy is highly active against germ-cell neoplasms of the ovary. Cisplatin also has definite activity against mixed mesodermal sarcoma of the uterus.