Ovarian Cancer: Neo-Adjuvant Chemotherapy & Other Treatment Modalities
WHEC Practice Bulletin and Clinical Management Guidelines for healthcare providers. Educational grant provided by Women's Health and Education Center (WHEC).
Epithelial ovarian cancer is the most lethal gynecologic malignancy in adult women. Exploratory laparotomy is required for histologic confirmation, staging and tumor debulking and should be performed by a surgeon trained in these aspects of ovarian cancer management. Because of the propensity of epithelial ovarian cancer to spread beyond the confines of the ovary, the majority of patients will require postoperative chemotherapy in an attempt to eradicate residual tissue. With advanced-stage disease (stages III and IV), postoperative combination chemotherapy with a taxane and platinum combination is the standard of care. Such treatment is capable of inducing responses in >70% of patients with residual epithelial ovarian cancer and is also capable of prolonging both disease-free and overall survival.
The purpose of this document is to enhance the understanding, to identify effective multiagent first-line regimens, and to develop more effective strategies for management of epithelial ovarian cancer. Ongoing efforts to identify anti-angiogenesis compound to incorporate agents with novel mechanisms of action are also discussed. Role of radiotherapy and other modalities are explored. Ultimately, it is hoped, a combination of these approaches will result in an improvement in the survival of patients with this devastating disease.
Therapeutic Options for Primary Treatment:
The staging of ovarian cancer is surgical and based on the operative findings at the commencement of the procedure. Proper staging is the key to an accurate prognosis. Borderline malignant epithelial neoplasms, which account for approximately 15% of all epithelial ovarian cancers, have almost benign behavior. Serous lesions appear to be more common than mucinous lesions, but both have similar natural histories. The majority of patients with borderline serous tumors have stage I tumors (70%-80% in most cases). About 30% of patients have extra ovarian tumor at the time of diagnosis, with equal numbers in stage II and stage III. Stage IV borderline tumors of low malignant potential have been described, but they are rare. Appropriate treatment of patients with serous or mucinous tumors of low malignant potential, remains to be determined. The standard surgical therapy is total abdominal hysterectomy and bilateral salpingo-oopherectomy (1). Genadry and colleagues believe that adjuvant therapy is unwarranted regardless of clinical stage because any extra ovarian neoplasm should be viewed as multifocal and in-situ, rather than metastatic.
Due to the propensity of epithelial ovarian cancer to spread beyond the ovary, most patients with this disease will require postoperative adjuvant chemotherapy. However, it is possible to identify a subset of patients with early-stage disease that has an excellent prognosis after surgery alone and that is not improved with the use of postoperative adjuvant chemotherapy. Such low-risk, early-stage patients include those with stage IA, grade 1 disease and many authors also include stage IA, grade 2 disease or stage IB, grade 1 or 2 disease in this group as well (2). Five-year survival in this low-risk is >90-95% with surgery alone, and postoperative adjuvant chemotherapy is generally not required.
Since relatively high response rates have been traditional with alkylating agent chemotherapy, there have been few trials with other single agents in patients who have not previously received chemotherapy. Because previous drug therapy lessens the likelihood of response, response-rate from non-alkylating agent chemotherapy, as often reported in the literature, may be falsely low. Hexamethylmelamine has been shown to be an active alkylating agent in epithelial ovarian cancer. Caution should be used in the administration of this agent to patients who have already had extensive chemotherapy because severe bone marrow suppression may occur. Doxorubicin also has a broad spectrum antineoplastic activity, with demonstrated effectiveness in the treatment of epithelial cancer of the ovary. Liposomal doxorubicin, a formulation of doxorubicin in liposomes, was developed in an attempt to reduce toxicity, including cardiomyopathy, as well as increases its anti-cancer effectiveness. Of the antimetabolites, 5-fluorouracil has shown low but consistent efficacy in several trials. In the opinion of most, 5-fluorouracil should not be considered a second-line agent or a possible member of combination therapy (3).
Methotrexate, the most widely used of the anti-folate drugs, has been used only sporadically as a single agent in ovarian cancer. Paclitaxel, a new chemotherapeutic agent that acts by promoting microtubular assembly and stabilizes tubulin polymer formation, has a great deal of activity in ovarian cancer. Although used primarily for salvage therapy, it has moved into trials of first-line therapy in combination with platinum and had become the "gold standard" in advanced disease. Topotecan, a drug with topoisomerase I-inhibitory activity, induces reversible single-stranded breaks. Several phase II studies have indicated a response rate of 13%-14% in patients with platinum-refractory ovarian cancer. Toxicity of topotecan can be significant, particularly bone marrow suppression. Vinorelbine tartrate (Navelbine) is another emerging chemotherapeutic agent that has demonstrated some activity in ovarian cancer in a salvage role. A 30% response rate was obtained in a small group of patients with both platinum-resistant and platinum-sensitive recurrences of epithelial ovarian cancer. A larger trial is needed before more definitive estimates of the activity of this drug can be made.
In the "modern era", platinum-based combinations have proven to be the most successful. A study by the GOG comparing doxorubicin (Adriamycin) and cyclophosphamide (AC) with cisplatin (CAP) indicated improvement with the three-drug combination. Statistical significance for survival is seen for the CAP arm. Cyclophosphamide-cisplatin, are considered the "standard" for the management of ovarian cancer who require combination therapy. A combination of paclitaxel and cisplatin has emerged as the gold standard for combination first-line chemotherapy for the treatment of epithelial ovarian carcinoma. Toxicity is much reduced with the 3-hour infusion, and the effectiveness of this infusion-rate has been proved. Cisplatin analogues such as carboplatin and iproplatin appear to have fewer marked side effects at doses equivalent to 100 mg/m2 of cisplatin (4). With respect to specific prognostic factors, clear cell and mucinous tumors have worse prognoses than other cell types. There appears to be no statistically significant evidence that the effect of cisplatin on survival is different between measurable and non-measurable suboptimal disease. Performance status, age, ascites, stage and residual tumor volume were positive prognostic factors for predicting survival. Although cisplatin appears to be the most active agent in epithelial cancer of the ovary, there is still lack of clear evidence that combining it with other agents improves outcomes.
High-Dose Chemotherapy with Autologous Bone Marrow Support:
In the last decade, high-dose chemotherapy with autologous bone marrow transplantation (ABMT) has been reported for several solid tumors, and there has been a short period of disease-free survival in most of the reports reviewed. There have been no reports of 5-year survival studies in patients with malignant ovarian tumors treated with high-dose chemotherapy followed by ABMT. Dose intensity refers to the amount of chemotherapy to which a cancer is exposed per unit of time; this is generally assumed to be reflected by the dose of drug in milligrams per square meter of body surface area per unit of time. The theory is well grounded in preclinical work showing that as the concentration of drug in culture medium increases, the fraction of surviving cancer cells decreases logarithmically. To determine whether dose intensity is important clinically, randomized trials are needed.
The toxicity of high-dose chemotherapy is a serious concern, as is the additional expense. In a report from the Bone Marrow Transplant Registry, 341 patients with ovarian cancer have undergone transplantation during the last 5 years. The reported median survival was not significantly better than that with use of paclitaxel as salvage therapy. The best response and survival were in those patients who had a complete response to pre-transplantation chemotherapy (5). High-dose therapy should be done as part of an established national protocol so that information can be obtained to increase our knowledge of this therapy.
Role of Radiation Therapy
Radiation therapy techniques include intraperitoneal instillation of radioactive chromium phosphate and external-beam radiation to the abdomen and pelvis. Patients with epithelial carcinoma of the ovary who are selected to receive postoperative irradiation should receive treatment of the entire abdomen plus additional radiation to the pelvis. This broad treatment plan is based on an analysis of post-irradiation recurrences of stage I and stage II disease, which showed that most of the recurrences were outside the pelvis. Malignant cells are shed from the primary ovarian tumor and circulate throughout the entire abdominal cavity. Lymphatic dissemination is also possible. The entire abdomen must be considered at risk, and therefore the volume that must be irradiated is large, resulting in multiple limitations for the radiotherapist. Dose restrictions are: tolerance of small intestine and kidneys, bone marrow depression, radiation enteritis caused by large volume of intestine irradiated, and adhesive peritonitis. Special problems in treatment of ovarian cancer with radiotherapy are: limits of tumor spread is often unknown, variability of radiosensitivity, total tumor burden is usually large, free mobility of tumor cells within the abdominal cavity, radiation dosage restricted by neighboring organs and infrequent detection of early disease.
Two different radiation treatment techniques have been used for abdominal irradiation. Large portals may be employed, and a dose of 2,500 -- 3000 cGy can be delivered during 4-5 weeks to the entire abdomen. The kidneys and possibly the right lobe of the liver are shielded with lead to limit the dose to 2000 -- 2500 cGy. Nausea and vomiting may be associated with this procedure, and therapy is frequently interrupted. In some centers, abdominal irradiation is delivered by the so-called moving strip technique. Both the whole-abdomen and the moving strip techniques usually finish with a pelvic boost of approximately 2000 -- 3000 cGy. The correlation of tumor size with tumoricidal dose levels in ovarian carcinoma are: Tumor size >2 treated with dose 5000-6000 cGy; between 0.5-2.0 dose needed is 4500-5000 cGy; for microscopic tumors residual dose of 2500-3000 cGy is preferred. Retrospective studies of radiation therapy in localized disease suggest that pelvic irradiation improves survival over and above the use of surgery alone. Radiation therapy as a salvage treatment in patients with chemotherapy-persistent or recurrent ovarian cancer has its advocates (6). As noted before, radiation therapy as part of initial therapy has been abandoned in favor of chemotherapy except in limited circumstances. There may be a role for whole-abdomen irradiation in patients after chemotherapy if residual tumor is small.
They have been widely used for the treatment of ovarian cancer. Both the pure beta emitter radioactive chromic phosphate (half-life of 14.2 days) and radioactive gold (10% gamma, half-life of 2.7 days) have been used. These isotopes emit radiation with an effective maximal penetration of 4-5 mm and therefore are useful only with minimal disease. Radioactive gold for intraperitoneal use is no longer available in the United States. The GOG and the Clinical Trial Group of the National Cancer Institute of Canada have compared the use of P32 with other forms of therapy, including whole-radiation and single-agent chemotherapy with melphalan with similar results. In retrospective reports the cure rates of patients with early-stage disease completely resected in combination with P32 appear to be comparable to those of patients treated with whole-abdomen irradiation, a direct comparison has never been reported.
In the last 3 decades there has been considerable interest in combining chemotherapy with immunotherapy for better results in patients with epithelial cancer of the ovary. Corynebactrium parvum, a gram-positive bacterium chosen as the immuno-modulating agent and has shown to increase non-specific tumor resistance to potentiate specific tumor rejections, to effect bone marrow proliferation, and to have additive anti-tumor effects when it is combined with alkylating agents. Ovarian cancer is a suitable model for biologic therapies. The peritoneal cavity is capable of mounting an inflammatory response to many stimuli, and this response has been shown to induce and anti-tumor effect. The identification, cloning, and mass production of the mediators of such responses are in progress (7). Albert and colleagues used a combination of doxorubicin and cyclophosphamide, with or without Pasteur Institute bacilli Calmatte-Guerin (BCG), in 121 patients with stage III and stage IV disease or recurrent ovarian carcinoma who had not previously received chemotherapy. These investigators concluded that non-specific immuno-stimulation therapy combined with chemotherapy could improve the results in advanced epithelial carcinoma of the ovary. The potential role of biologic agents in the treatment of ovarian cancer indicates that ovarian cancer is a suitable prototype tumor in which to evaluate novel immunotherapeutic and chemo-immunotherapeutic approaches.
Gene therapy is at least theoretically attractive. If the defect is identified, the gene could be replaced. This strategy is in its infancy. Many types of gene therapy are possible: immunogene, antioncogene, and tumor suppressor gene; anti-growth factor and cytokine gene drug resistance; and genes that are associated with apoptosis. Oncogenes such as K-ras are mutated in many ovarian cancers, as is the TP53 gene; erb-b2 is activated in about one third of ovarian cancers. Programmed cell senescence, probably related to reductions in telomere length, may be an important factor that may aid in our ability to increased survival. All of these are attractive, and preliminary studies have been started. Another area receiving considerable attention is anti-angiogenesis therapy. The laboratory evidence appears exciting.
Because chemotherapy resistance is major problem, new agents that have non-cross-resistance properties and novel approaches to modulations or targeting are sought. Many new drugs are in the pipe-line to be evaluated in phase II studies. It is to be hoped that a new platin drug is around the corner.
Although adenocarcinoma of the ovary remains one of the solid tumors most sensitive to chemotherapeutic regimens, the mortality from this disease remains high. The following general principles should be kept in mind. An optimal surgical procedure should be carried out whenever possible. This is defined as the removal of all bulk tumor with the intent to leave minimal residua (no individual mass >1-2 cm in diameter). Even when optimal debulking is not possible, bilateral salpingo-oopherectomy, total abdominal hysterectomy, and omentectomy may afford significant palliation for the patient. Resection of bowel should be considered only when such a resection will result in removal of all gross tumor. The conventional view of radiation therapy as the most important postoperative modality for gynecologic cancer must be re-examined with respect to adenocarcinoma of the ovary. In advanced (stage III and stage IV) disease, there is little evidence that radiation therapy has significant values over chemotherapy. A large number of reports in the literature confirm that chemotherapy with alkylating agents can produce responses in 30%-60% of patients with advanced disease. Several non-alkylating agents have been identified with considerable activity in ovarian cancer, such as hexamethylmelamine, doxorubicin, cisplatin, carboplatin, and paclitaxel.
Chemotherapy appears to be the most effective method of controlling ascites and pleural effusions. First-line chemotherapy will be effective for varying periods in 90% of patients. Intraperitoneal chemotherapy as first-line postoperative therapy appears to be effective in patients with minimal (<1cm) residual. The use of intraperitoneal colloidal isotopes such as P32 has great theoretical value for patients with microscopic residual disease after laparotomy. The use of multiple effective drugs covers more cell lines resistant to one drug.
Acknowledgement: We express special thanks to Dr. Peter A. Argenta, Assistant Professor Surgical Oncologist at University of Minnesota, MN (USA) for his assistance in preparing this document.
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- Parmar MK, Ledermann JA, Colombo N, et al. Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer. The ICON4/AGO-OVAR-2.2 trial. Lancet. 2003;361:2099-2106.
- Thigpen T. High dose chemotherapy with autologous bone marrow support in ovarian carcinoma: The bottom line, more or less (Editorial). Gynecol Oncol. 1995;57:275-276.
- Sedlack TV, Spyropoulus P, Cifaldi R et al. Whole abdomen radiation therapy as salvage-treatment for epithelial ovarian carcinoma. Cancer J Sci Am. 1997;3:358-367.
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