OVARIAN CANCER

Treatment
The treatment of ovarian cancer is based on the stage of the disease which is a reflection of the extent or spread of the cancer to other parts of the body. Stagingis performed by the surgeon (gynecologic oncologist) when the ovarian cancer is removed. During the surgical procedure the surgeon will obtain small pieces of tissue (biopsies) from various sites in the abdominal cavity. During this procedure, depending on the stage (extent) of the disease, the surgeon will either remove just the ovary and fallopian tube or will remove both ovaries, fallopian tubes and uterus. In addition, the surgeon will attempt to remove as much of the cancer as possible. Ovarian cancer is staged as follows: Stage I cancer is confined to one or both ovaries. The cancer is Stage II if either one or both of the ovaries is involved and has spread to the uterus and/or the fallopian tubes or other sites in the pelvis. The cancer is Stage III cancer if one or both of the ovaries is involved and has spread to lymph nodes or other sites outside of the pelvis but is still within the abdominal cavity, such as the surface of the intestine or liver. The cancer is Stage IV cancer if one or both ovaries is involved and has spread outside the abdomen or has spread to the inside of the liver. Treatment Options There are basically three forms of treatment of ovarian cancer. The primary one is surgery at which time the cancer is removed from the ovary and from as many other sites as is possible. Chemotherapy is the second important modality. This form of treatment uses drugs to kill the cancer cells. The other modality is radiation treatment, which is used in only certain instances. It utilizes high energy x-rays to kill cancer cells. Surgical treatment of ovarian cancer is best performed by a gynecologic oncologist who has been specially trained in the diagnosis and management of gynecologic malignancy. The treatment of ovarian cancer depends on the stage of the disease, the histologic cell type, and the patient's age and overall condition. The histologic cell type and the extent of disease based on the biopsies performed by the gynecologic oncologist during surgery (staging) are determined by the pathologist who analyzes tissues with a microscope. Treatment of Ovarian Epithelial Cancer Stage I Generally women with Stage I ovarian cancer have a total abdominal hysterectomy, removal of both ovaries and fallopian tubes, omentectomy, biopsy of lymph nodes and other tissues in the pelvis and abdomen. Young women whose disease is confined to one ovary are often treated by a unilateral salpingo-oophorectomy (removal of the affected ovary and fallopian tube) without a hysterectomy and removal of the opposite ovary being performed. Omentectomy and the other parts of the staging procedure are performed. Depending on the pathologist's interpretation of the tissue removed, there may be no further treatment if the cancer is low grade, or if the

tumor is high grade the patient may receive combination chemotherapy. Stage II Treatment is almost always hysterectomy and bilateral salpingooophorectomy as well as debulking of as much of the tumor as possible and sampling of lymph nodes and other tissues in the pelvis and abdomen that are suspected of harboring cancer. After the surgical procedure, treatment may be one of the following: 1) combination chemotherapy with or without radiation therapy or 2) combination chemotherapy. Stage III Treatment is the same as for Stage II ovarian cancer. Following the surgical procedure, the patient may either receive combination chemotherapy possibly followed by additional surgery to find and remove any remaining cancer. Stage IV Treatment will probably be surgery to remove as much of the tumor as possible followed by combination chemotherapy.

Recurrent Ovarian Epithelial Cancer Detection of Recurrent Disease Small tumors generally respond better to treatment, therefore early detection of recurrence may be useful. However it is important to consider that the benefits of early introduction of salvage chemotherapy are limited and may intrude upon the patient's symptom and treatment-free survival. Use of frequent clinical follow-up can detect treatment earlier. Follow-up includes bimanual pelvic examination, serial measurement of CA125 or another tumor marker, reassessment or second-look laparotomy and occasionally one or more imaging studies. However, recurrent cancer has a large spectrum of behavior making it relatively difficult to diagnose a relapse and determine the aggressiveness of the tumor. Second-Look Surgery The use of second-look surgery can help diagnose and manage ovarian cancer. In recent years there has been increasing skepticism about the benefits of this procedure. While this is the most reliable method to predict persistent cancer and prognosis, and the tumor may be resected, evidence of enhanced survival after this procedure is lacking. Patients who undergo second-look surgery usually have normal CA 125 levels. The findings of second-look surgery are: negative (defined as both grossly and microscopically negative), microscopically positive (grossly negative, but microscopically positive) and macroscopically positive (grossly and pathologically positive). Patients treated for low grade tumors, or earlier stage disease are more likely to be negative at second-look surgery than those treated for high grade or higher stage disease. Computed tomography (CT scan) of the abdomen and pelvis has been evaluated as a substitute for second look surgery, but the ability to image tumors smaller than 2cm is currently questionable. Therefore CT does not replace second look surgery, but a positive scan renders the second-look redundant. Second look surgery is only negative in 40-50% of patients with a normal CA125 level. Assessment of the size of the largest tumor during second-look surgery can help

determine volume of cancer before chemotherapy (for measurement of the subsequent response), and future treatment methods e.g. a patient with a tumor size of 0.5 cm or larger usually would not benefit from further platinum-based chemotherapy, and should consider another treatment. Alternatively, patients with tumor size of 0.5 cm or smaller can benefit from intraperitoneal chemotherapy and radiotherapy. Treatment of Recurrent Cancer Patients who develop recurrent cancer despite surgery and primary chemotherapy, and will be given salvage chemotherapy, may be placed into one of three groups (AC): Group A: are patients resistant to primary therapy and have shown tumor growth during treatment. This persisting tumor is considered to be refractory i.e. have absolute platinum-resistance. Secondary non-cross resistant chemotherapies or biological therapies should be considered. Group B: are patients who respond well to initial chemotherapy, but develop recurrent cancer within months after the end of primary care. This group with relatively platinum resistant tumor has an intermediate prognosis. Group C: are patients who showed a good response to primary chemotherapy, and did not develop recurrent cancer for more than 6 months after the end of primary treatment. This group with platinum-sensitive tumor shows the best responses to retreatment with a platinum-containing regimen. The probability of response to salvage chemotherapy is also markedly dependent upon on the number of preceding chemotherapy regimens, such that third and fourth line chemotherapies are of limited benefit. However, unique patients responding to multiple retreatments with even the same regimen of chemotherapy are sometimes observed. Tumor burden, as assessed by the size of the largest lesion and the number of disease sites and histology (serous having the best outcome) are also independent predictors of response to salvage chemotherapy. Drug Resistance The likelihood a patient will respond to salvage chemotherapy correlates with, for the most part, the cancer's degree of platinum drug resistance The Gynecological Oncology Group (GOG) defines platinum resistance as meeting any of the criteria listed below: 1. Disease progression while on a first-line platinum-based regimen 2. Tumor progression within 6 months of completion of platinum-based therapy 3. Persistent clinically measurable disease with best response as stable disease at the completion of planned first-line therapy 4. Persistent clinically measurable disease with best response as stable disease with rising CA 125 while receiving first-line non-protocol therapy. Rising CA

125 levels must be documented with two examinations where the last result being greater than or equal to 100. The most commonly used indicator of resistance is the period of time between the end of primary chemotherapy and relapse: the longer this length of time, the better the chances of responding to salvage chemotherapy. Cancer that relapses after primary treatment using a single platin analog will have less resistance to treatment than cancer that relapses after primary treatment using multi-agent treatment Generally, about 25%, 33%, and 60% respond to salvage treatment when their time between last chemotherapy and relapse is 6-12 months, 12-24 months, and greater than 24 months respectively. Treatment of Sensitive Cancer Patients with recurrent chemotherapy-sensitive disease are usually treated again with primary chemotherapy usually carboplatin/paclitaxel, but toxicity must also be taken into consideration. If carboplatin or cisplatin was used alone for primary therapy, taxol should be considered for salvage chemotherapy. For low-volume disease, intraperitoneal chemo- or radiotherapy can be considered. These patients are also candidates for trials of high dose chemotherapy with autologous bone marrow support. Treatment of Resistant Cancer The emergence of drug-resistant tumors during therapy for ovarian cancer remains an obstacle to improving long-term outcomes. Active areas of ovarian cancer research include clinical evaluation of non-cross-resistant antineoplastic agents that demonstrated single-agent activity in ovarian cancer during the 1990s: oxaliplatin, the new anthracyclines (epirubicin, liposomal doxorubicin), topotecan, oral etoposide, gemcitabine, and vinorelbine. Most of these new agents are currently being evaluated as a component of doublet and triplet combination regimens for advanced ovarian cancer, with use of sequential alternating doublet regimens gaining interest. The potential role of intraperitoneal therapy continues to be investigated. In addition, there are a variety of innovative treatment strategies on the horizon that are targeted at underlying disease processes, including anticancer vaccines, gene therapy, and antiangiogenic therapy. Based on this multitude of investigational questions and the low cure rates currently achieved, all women with advanced ovarian cancer should consider participation in clinical trials1. Taxol therapy can be considered for patients who had not received prior taxol therapy but have relatively platinum-resistant cancer. Such patients have a modest overall response rate, but may achieve relief of symptoms. A large, randomized study comparing the efficacy and safety of topotecan versus paclitaxel in patients with relapsed epithelial ovarian cancer after firstline treatment with platinum only showed that these two compounds have similar activity. In this

study, a number of patients crossed over to the alternative drug as third-line therapy, ie, from paclitaxel to topotecan and vice versa, permitting assessment of the degree of non-cross-resistance between these two compounds. Patients who had progressed after one platinum-based regimen were randomized to either topotecan (1.5 mg/m(2)/d) x 5 every 21 days (n = 112) or paclitaxel (175 mg/m(2) over 3 hours) every 21 days (n = 114). A total of 110 patients received cross-over therapy with the alternative drug (61 topotecan, 49 paclitaxel) as third-line therapy. Response rates to third-line cross-over therapy were 13.1% (8 of 61 topotecan) and 10.2% (5 of 49 paclitaxel; P =.638). Seven patients who responded to third-line topotecan and four patients who responded to paclitaxel had failed to respond to their second-line treatment. Median time to progression (from the start of third-line therapy) was 9 weeks in both groups, and median survival was 40 and 48 weeks for patients who were receiving topotecan or paclitaxel, respectively. The principal toxicity was myelosuppression; grade 4 neutropenia was more frequent with topotecan (81.4% of patients) than with paclitaxel (22.9% of patients). CONCLUSION: Topotecan and paclitaxel have similar activity as second-line therapies with regard to response rates and progression-free and overall survival2. Patients with recurrent platinum-resistance cancer can be given several secondarychemotherapy regimens by itself or in combination with other chemotherapy drugs. Secondary-Chemotherapy Drugs The response data for the secondary chemotherapy regimens was mostly generated in uncontrolled phase II trials, responses mostly in the 10-30% range. Response to treatment with secondary-chemotherapy drugs can provide the patient with temporary cancer-symptom relief from 4 months to complete cancer remission. Quality of life issues are very important in considering salvage chemotherapy options. Secondary-chemotherapy regimens include: Topotecan: Topotecan is an antitumor drug with topoisomerase I inhibitory activity. Phase I studies determined a maximum-tolerated dose of 1.5 mg/m2/d given as a 30-minute intravenous (IV) infusion on days 1 through 5 of a 21-day cycle. Phase II studies in refractory or relapsed ovarian cancers demonstrated activity that led to a phase III randomized comparison versus paclitaxel in this setting. This latter study demonstrated similar efficacy for topotecan and paclitaxel and led to marketing approval in the United States and Europe for topotecan in the treatment of metastatic carcinoma of the ovary after failure of initial or subsequent chemotherapy. An oral formulation of topotecan has been developed; it offers a more convenient treatment option than IV topotecan on the schedule of five consecutive days every 21 days. Oral topotecan was evaluated as single-agent, second-line therapy in patients with ovarian cancer previously treated with a platinum-based regimen. Patients (N = 116) with stage III or IV epithelial ovarian cancer despite prior platinum-containing chemotherapy received oral topotecan 2.3 mg/m2 daily for 5 days every 21 days. Second-line oral topotecan administered at 2.3 mg/m2 for 5 days every 21 days demonstrated activity in patients with progressive or recurrent ovarian cancer after first-line platinum-based

chemotherapy. This activity was comparable to that seen in previous studies with intravenous topotecan. Grade 4 neutropenia was less frequent with oral topotecan than previously reported for intravenous topotecan 3. Patients who had failed first line therapy with a platinum-based regimen received topotecan 0.4 mg/m(2)/day, as a 21-day infusion every 28 days. 35 patients were enrolled and evaluable for response. 3 patients (8.6%) had a partial response to treatment (95% CI 1.8%, 23.1%) with a median time to response of 8.1 weeks and a median duration of response of 17.6 weeks. Response was also evaluated by CA125 and was also found to be 8%4. Topotecan at 1.0 mg/m(2) x 5 days every 21 days is active in platinum- and paclitaxel-resistant ovarian cancer, with significant improvements in hematologic toxicity. In heavily pretreated patients-topotecan can be safely given at reduced doses without apparent loss of efficacy5. Single-agent etoposide: Oral etoposide has been studied in numerous clinical trials for the treatment of recurrent ovarian cancer. In different studies there has been a varied response rate, and it appears that the activity of this drug is dependent to a large part on the extent of prior therapy. On the basis of data from more than 270 patients in 9 different studies, the overall response rate is 20.4%. However, in the largest study performed by the Gynecologic Oncology Group (GOG), in which 82 previously treated patients received oral etoposide, the response rate was 30.5%. The GOG study categorised patients who received oral etoposide according to their response to initial therapy: patients were deemed either platinum sensitive or platinum resistant. No patients had received more than one prior regimen at the time they were entered into the oral etoposide trial. In 41 platinum-resistant patients, the overall response rate was 26.8%, including a 7.3% clinical complete remission rate. In patients who were platinum sensitive, the overall response rate was 34.1%, with a 14.6% clinical complete remission rate. Toxicity was acceptable, with myelosuppression being the dose-limiting toxicity. This GOG study confirms the activity of oral etoposide as second-line therapy both for platinum-resistant and platinum-sensitive ovarian cancer patients.Additional studies are in progress to determine how oral etoposide can be combined with paclitaxel and a platinum compound for use as initial therapy for previously untreated patients with advanced disease 6. Docetaxel: given to patients who had previously received a platinum-based primary treatment showed an overall response rate of 40%, but treatment often resulted in toxic side-effects like neutropenia. A phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in the treatment of 25 patients with platinum-refractory ovarian cancer. Docetaxel was administered at a dose of 100 mg/m2 intravenously (i.v.) over 1 hour every 21 days. Eight of 23 assessable patients (35%) had a partial response (PR; 95% confidence interval, 16% to 57%). The median response duration was 5 months. CONCLUSION: Docetaxel demonstrates significant activity in patients with platinum-refractory advanced ovarian

cancer7. A phase II study was conducted to evaluate the efficacy and toxicity of docetaxel in Japanese patients with advanced ovarian cancer. Docetaxel was administered at a dose of 70 mg/m2 intravenously to patients with platinum pretreated advanced ovarian cancer. Treatment was repeated every three weeks. No routine corticosteroid premedication was given. Ninety patients with advanced ovarian cancer were entered and sixty were assessable for response. The overall response rate was 28% in the assessable patients (95% confidence interval (95% CI): 17.54%-41.4%). CA125 responses were seen in 8 (24%) of 34 assessable patients for CA125 criteria. The 36 platinum-refractory patients had a response rate of 25% compared with 33% in the platinum-sensitive patients. The predominant toxicity was neutropenia, with 86% of the patients experiencing grade 3 or 4. Hypersensitivity reactions occurred in 37% of the patients and were not life threatening. Edema was mild and infrequent.CONCLUSION: Docetaxel at 70 mg/m2 demonstrated effectiveness as a treatment of both platinum-sensitive and platinumrefractory ovarian cancer patients, with a low incidence of severe hypersensitivity reactions and edema8. Gemcitabine: used as a single agent in platinum-resistant patients showed a response rate of 20%. Gemcitabine combined with cisplatin given to patients who had been given heavy primary-chemotherapy showed a response rate of 53%. Gemcitabine combined with paclitaxel showed a response rate of 40%. Gemcitabine combined with both carboplatin and paclitaxel resulted in 60% of patients going into complete remission, and 40% partial remission with acceptable but significant toxicity. Gemcitabine also has a mild toxicity compared with other chemotherapy drugs. Gemcitabine is a nucleoside antimetabolite with established activity against several solid tumors. The activity of the drug in patients with ovarian cancer has been reviewed both in patients who have received single drug treatment and in patients who have received combination chemotherapy. The response rates, with single agent gemcitabine, range from 13 to 24% both in previously treated and untreated patients. Doublets consisting of gemcitabine-cisplatin or gemcitabine-paclitaxel, in previously treated patients, induced response in 53% and 40% of the patients, respectively. In three studies, first-line treatment with the combination of cisplatin and gemcitabine induced remission in 53% to 71% of the patients. The triplet, including gemcitabine, paclitaxel, and cisplatin or carboplatin, has been examined in previously treated patients and a response rate of 100% was observed. In previously untreated patients the combination of gemcitabine, paclitaxel, and carboplatin has been preferred due to a more favorable toxicity profile. The activity of this combination, observed in 25 evaluable patients, was very high as all patients responded. Complete remission was observed in 60% of the patients and partial remission in 40%. Based on these promising data the triplet consisting of gemcitabine, paclitaxel, and carboplatin has been included in randomized trials both in the US and in Europe9. Oxaliplatin: given to patients with previously treated with cisplatin showed a

response rate of 29%. Neurological side-effects include acute cold-triggered dysaesthesia and cumulative sensory neural toxicity but Oxaliplatin has lesssevere toxicity than paclitaxel. Oxaliplatin (a diaminocyclohexane platinum compound) is of interest because it is only partially cross-resistant with cis- or carboplatin and devoid of severe bone marrow suppression, nephrotoxicity, or ototoxicity. Its dose-limiting toxicity is an unusual form of sensory neuropathy, which is cumulative and, contrary to cisplatin's neurotoxicity, generally reversible. Combinations with other active standard agents, as well as platinum compounds and/or taxoids, are feasible and have shown interesting activity. Similar to carboplatin and oxaliplatin, nedaplatin (cis-diammineglycolatoplatinum, only approved in Japan) can be given without hydration; its dose-limiting toxicity is myelosuppression, in particular thrombocytopenia. Although activity has been shown, no data from randomized comparative trials are available to allow a judgement on its potential advantages10. In a multicentric, open, randomized, phase II study of single-agent paclitaxel and oxaliplatin to evaluate the efficacy of oxaliplatin in a relapsing progressive ovarian cancer patient population, 86 patients with platinum-pretreated advanced ovarian cancer were randomly assigned to two arms: 41 received paclitaxel at 175 mg/m(2) over 3 hours every 3 weeks, and 45 received oxaliplatin at 130 mg/m(2) over 2 hours every 3 weeks. Seven confirmed responses were observed in each arm, for an overall response rate in the total treated population of 17% (95% confidence interval [CI], 7% to 32%) in the paclitaxel arm and 16% (95% CI, 7% to 29%) in the oxaliplatin arm. Median time to progression was 14 weeks and 12 weeks, and overall survival was 37 weeks and 42 weeks in the paclitaxel and oxaliplatin arms, respectively. Among 63 patients with a 0- to 6-month progression-free, platinum-free interval, there were five objective responses with paclitaxel in 31 patients and two objective responses with oxaliplatin in 32 patients. Nine patients (22%) in the paclitaxel arm had grade 3 or 4 neutropenia. Two patients (4%) experienced grade 3 thrombocytopenia in the oxaliplatin arm. Maximum grade (grade 3) NCIC neurosensory toxicity was experienced by three patients (7%) in the paclitaxel arm and by four patients (9%) in the oxaliplatin arm.CONCLUSION: Single-agent oxaliplatin at 130 mg/m(2) every 3 weeks is active with moderate toxicity in patients with cisplatin-/carboplatin-pretreated advanced ovarian cancer11. The activity of oxaliplatin (L-OHP) and cisplatin (CDDP) in platinum pretreated ovarian cancer patients was evaluated in 25 patients. Chemotherapy consisted of L-OHP and CDDP given sequentially as 2 h infusions on day 1 at their standard recommended dose (130 mg/m2 for oxaliplatin, 100 mg/m2 for cisplatin) every 3 weeks with a median of 3 cycles per patient. 13 and 12 patients, respectively, were considered to have platinum refractory and potentially sensitive disease. 22 patients with measurable/evaluable disease were assessable for antitumoral activity. Two complete responses (CR) (8%) (one proven histologically at laparotomy) and 8 partial responses (PR) (32%) were observed, for an overall objective response rate (ORR) of 40% (95% CI, 21-61%). The median duration of response was 4 months. Seven responses

were seen among 12 potentially platinum-sensitive tumours (58%, CI 95% 2885%), while 3/13 platinum refractory patients (23%, CI 95% 5-54%) had an objective response12. 5-FU and leucovorin: In a series 49 patients with epithelial ovarian carcinoma previously treated with platinum-based chemotherapy received leucovorin 200 mg/m2 i.v. bolus followed by 5-fluorouracil at 370 mg/m2 i.v. bolus daily for 5 days every 4 weeks for the first two courses and subsequent courses were given every 5 weeks. Of this group, 47 patients were evaluable for toxicity and 44 for response. Of the patients evaluable for response, 15 were considered platinum-sensitive and 29 were platinum-refractory. The overall response rate was 6/44 (13.6%). There were two complete responders (4.5%) and four partial responders (9.1%). In the platinum-sensitive patients, there was one complete response, yielding a response rate of 6.6%, whereas in the platinum-refractory patients, there were four partial responses and one complete response for a response rate of 17.2%. Five responses were in the pelvis and there was one response at an extrapelvic site in the abdominal mesentery. The median number of courses delivered was three (range: 1-10). The major adverse effect was myelosuppression with 16/47 (34.0%) experiencing granulocytopenia <1,000/mm3. The median white blood count nadir for the patients experiencing any leukopenia was 2,700 (range: 4003,900/mm3). There was one episode of grade 3 thrombocytopenia. Grade 3 intestinal toxicity was seen in seven patients (14.9%). There were no treatment-related deaths. In this previously treated population, 5-fluorouracil with high-dose leucovorin exhibited activity of interest in the platinumrefractory population and warrants further investigation13. Liposomal doxorubicin: given to patients with platinum and paclitaxel refractory tumor showed a response rate of 26% To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) and topotecan in patients with epithelial ovarian carcinoma that recurred after or failed to respond to first-line, platinum-based chemotherapy, patients with measurable disease were randomized to receive either PLD 50 mg/m(2) as a 1-hour infusion every 4 weeks or topotecan 1.5 mg/m(2)/d for 5 consecutive days every 3 weeks. Patients were stratified prospectively for platinum sensitivity and for the presence or absence of bulky disease. A total of 474 patients were treated (239 PLD and 235 topotecan). The overall progressionfree survival rates were similar between the two arms (P =.095). The overall response rates for PLD and topotecan were 19.7% and 17.0%, respectively. For overall survival, PLD was significantly superior to topotecan (P =.008), with a median of 108 weeks versus 71.1 weeks. The platinum-refractory subgroup demonstrated a nonstatistically significant survival trend in favor of topotecan (P =.455). Severe hematologic toxicity was more common with topotecan14. High-Dose Chemotherapy High-dose chemotherapy accompanied with Autologous Bone Marrow Transplantation (ABMT) and Peripheral Blood Stem Cell transplantation

(PBSCT) produces high response rates (70-82%) in patients with resistance to primary chemotherapy, but the responses are generally of limited duration. Such approaches are generally limited to clinical trials, and are also being tested for first line therapy.