Neoadjuvant chemotherapy in ovarian cancer

Primary radical tumor debulking followed by platinum/taxane-based chemotherapy is considered standard for advanced stage ovarian carcinomas. The extent of postoperative residual disease is the most important prognostic factor. However, complete tumor resection is achieved in only 40–50% of advanced ovarian cancers. For the remaining patients, who have an unfavorable prognosis, the concept of neoadjuvant or primary chemotherapy followed by interval laparotomy has emerged. Two different strategies are pursued. One is to administer several courses of neoadjuvant chemotherapy in order to downstage the tumor prior to primary debulking surgery. The other is to administer chemotherapy after suboptimal debulking surgery to optimize cytoreduction during interval laparotomy. Numerous retrospective studies demonstrated that neoadjuvant chemotherapy followed by primary debulking surgery is a feasible and safe approach. It is becoming increasingly evident that the selection of appropriate patients is crucial. Some studies demonstrated that the volume of ascites proved to be an easily measurable biomarker that allowed prediction of tumor resectability. However, further investigations are needed to better define patients who will benefit from neoadjuvant chemotherapy. Despite promising results, neoadjuvant chemotherapy must still be considered experimental. Therefore, the potential advantages of neoadjuvant chemotherapy need to be confirmed in prospective randomized studies.     

Neoadjuvant chemotherapy for ovarian cancer

Primary debulking surgery by a gynecologic oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumor load. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of future randomized trials to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in stage IIIC and IV patients. Interval debulking is defined as an operation performed after a short course of induction chemotherapy. Based on the randomized European Organization for Research and Treatment of Cancer-Gynecological Cancer Group (EORTC-GCG) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on Gynecologic Oncology Group (GOG) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery.     

Primary surgery or neoadjuvant chemotherapy followed by interval debulking surgery in advanced ovarian cancer

Advanced ovarian cancer has a poor prognosis. De-bulking surgery and platinum-based chemotherapy are the cornerstones of the treatment. Primary debulking surgery has been the standard of care in advanced ovarian cancer. Recently a new strategy with neoadjuvant chemotherapy followed by interval debulking surgery has been developed. In a recently published randomised trial of the EORTC-NCIC (European Organisation for Research and Treatment of Cancer - National Cancer Institute Canada) in patients with extensive stage IIIc and IV ovarian cancer it was shown that the survival was similar for patients randomised to neoadjuvant chemotherapy followed by interval debulking compared to primary debulking surgery, followed by chemotherapy. The post-operative complications and mortality rates were lower after interval debulking than after primary debulking surgery. The most important independent prognostic factor for overall survival was no residual tumour after primary or interval debulking surgery. In some patients obtaining the goal of no residual tumour at interval debulking is difficult due to chemotherapy-induced fibrosis. On the other hand the patients randomised had very extensive stage IIIc and IV disease and in patients with metastases smaller than 5 cm the survival tended to be better after primary debulking surgery. Hence, selection of the correct patients with stage IIIc or IV ovarian cancer for primary debulking or neoadjuvant chemotherapy followed by interval debulking surgery is important. Besides imaging with CT, diffusion MRI and/or PET-CT, also laparoscopy can play an important role in the selection of patients. It should be emphasised that the group of patients included in this study had extensive stage IIIc or IV disease. Surgical skills, especially in the upper abdomen, remain pivotal in the treatment of advanced ovarian cancer. However, very aggressive surgery should be tailored according to the general condition and extent of the disease of the patients. Otherwise, this type of aggressive surgery will result in unnecessary postoperative morbidity and mortality without improving survival. Hence, neoadjuvant chemotherapy should not be an easy way out, but is in some patients with stage IIIc or IV ovarian cancer a better alternative treatment option than primary debulking. According to the current treatment algorithm at the University Hospitals Leuven about 50% of the patients with stage IIIc or IV ovarian cancer are selected for neoadjuvant chemotherapy.     

The role of neoadjuvant chemotherapy in the treatment of advanced ovarian cancer

Primary cytoreductive surgery followed by chemotherapy represents the current standard treatment for patients with advanced ovarian cancer. Neoadjuvant chemotherapy followed by interval debulking surgery has been proposed as an alternative approach for the initial management of bulky ovarian cancer, aiming at the improvement of surgical efficiency and patients' quality of life. According to the hitherto published studies, consisting mainly of retrospective observations, neoadjuvant chemotherapy followed by interval cytoreduction appears to improve the prognosis and quality of life in selected groups of patients. The survival outcome in these patients is similar to that of the conventional approach, or even better in some of the cases. Moreover, patients undergoing debulking surgery after having received neoadjuvant chemotherapy had a reduced perioperative morbidity compared to patients undergoing primary cytoreduction. Concurrently, neoadjuvant chemotherapy provides preoperative knowledge of tumor chemosensitivity, hence allowing the surgeon to choose appropriately aggressive treatment. However, until the results of prospective randomized trials become available, neoadjuvant chemotherapy followed by interval surgery should be applied only to individual cases and primarily in the context of clinical trials.     

卵巢癌的新辅助化疗与间隔减瘤术

在过去10年中,晚期卵巢癌的新辅助化疗和间隔减瘤术一直是人们关注的焦点,全文回顾了近年来的有关文献,认为对于那些预计首次手术无法切除的晚期卵巢癌,由于缺乏随机对照研究证实新辅助化疗能够改善生存,尚不能作为常规治疗手段来使用。同时,探讨了欧洲和美国的两项有关卵巢癌间隔减瘤术的随机对照研究。     

Neoadjuvant chemotherapy and ovarian cancer

Primary surgical cytoreduction followed by chemotherapy usually is the preferred management of advanced (stage III or IV) ovarian cancer. The presence of residual disease after surgery is one of the most important adverse prognostic factors for survival. Neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery as initial management of bulky ovarian cancer, with the goal of improving surgical quality. Retrospective analyses suggest that a subgroup of patients with Stage III and IV ovarian carcinoma can be treated with neoadjuvant chemotherapy followed by interval debulking surgery. The absolute indications for neoadjuvant chemotherapy appear to be Stage IV disease (excluding pleural fluid) or metastases of more than 1 g at sites where resection is impossible. Interval debulking surgery in patients with suboptimal primary debulking surgery has been proven effective in increasing overall survival and progression-free survival in a large prospective, randomized trial of the European Organization for Research and Treatment of Cancer (EORTC). GOG evaluated the effect of adding secondary cytoreductive surgery to postoperative chemotherapy. Unfortunately in this study, for patients with advanced ovarian carcinoma in whom primary cytoreductive surgery was considered to be maximal, the addition of secondary cytoreductive surgery to postoperative chemotherapy with paclitaxel plus cisplatin does not improve progression-free survival or overall survival. The strategy of neoadjuvant chemotherapy, followed by interval debulking surgery, should be confirmed in a prospective randomized trial. The EORTC55971 trial is currently addressing this issue.     

Controversies in surgery in ovarian cancer — what is its real role?

Rupture of an ovarian malignant tumour should be avoided at the time of surgery for an early ovarian cancer. Laparoscopic removal of ovarian cysts should be restricted to patients with preoperative evidence that the cyst is benign. Degree of differentiation is the most important independent prognostic factor in stage I disease and should be used in decisions on therapy in clinical practice and the future FIGO (International Federation of Gynecology and Obstetrics) classification of stage 1. In early ovarian cancer, staging adequacy and tumour grade were the only two statistically significant prognostic factors for survival in the multivariate analysis of the EORTC (European Organisation for Research and Treatment of Cancer) ACTION (Adjuvant ChemoTherapy In Ovarian Neoplasms) trial. According to the present data there is no scientific basis to rely only on adjuvant chemotherapy or on optimal staging procedure in medium and high risk stage I ovarian cancer.Primary debulking surgery by a gynaecological oncologist remains the standard of care in advanced ovarian cancer. Optimal debulking surgery should be defined as no residual tumour load. Interval debulking is defined as an operation performed after a short course of induction chemotherapy, usually 2 or 3 cycles. Based on the randomised EORTC GCG (Gynaecological Cancer Group) trial, interval debulking by an experienced surgeon improves survival in some patients who did not undergo optimal primary debulking surgery. Based on the GOG (Gynecologic Oncology Group) 152 data, interval debulking surgery does not seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynaecological oncologist. Open laparoscopy is probably the most valuable tool for evaluating the operability primarily or at the time of interval debulking surgery. In retrospective analyses, neoadjuvant chemotherapy followed by interval debulking surgery does not seem to worsen prognosis compared to primary debulking surgery followed by chemotherapy. However, we will have to wait for the results of the EORTC-GCG/NCI (National Cancer Institute) Canada randomised trial to know whether neoadjuvant chemotherapy followed by interval debulking surgery is as good as primary debulking surgery in some or all stage IIIc and IV patients.The most suitable candidates for secondary debulking surgery are those who had an initial complete response to chemotherapy, a long treatment-free interval (e.g. more than 12 months), and resectable disease (without diffuse carcinomatosis).     

Clinical Trials of Neoadjuvant Chemotherapy for Ovarian Cancer: What Do We Gain After an EORTC Trial and After Two Additional Ongoing Trials Are Completed?

The aim of neoadjuvant chemotherapy is to reduce the tumor volume or spread of the disease before the main treatment, and it could possibly make the main procedures easier or less invasive. Although the standard therapeutic strategy for advanced ovarian cancer is a maximum primary debulking surgery followed by chemotherapy, a European Organisation for Research and Treatment of Cancer (EORTC) prospective randomized trial demonstrated that neoadjuvant chemotherapy followed by interval debulking surgery was not inferior to the standard procedure. This study raised a number of controversies, particularly regarding the quality of debulking surgery. To solve the questions, we need to wait for the results of two additional ongoing randomized trials. However, the results of those two trials must be carefully assessed, because the quality of debulking surgery would significantly affect survival, and may make the interpretation of the trial results more confusing and difficult.     

Feasibility and outcome of complete secondary tumor resection for patients with advanced ovarian cancer

From November 1981 to July 1985, 124 women with International Federation of Gynecology and Obstetrics (FIGO) stage III ovarian cancer were treated in prospective studies of surgery and chemotherapy in our institution. Patients with no macroscopic cancer after primary surgery (n = 16) received five cycles of adjuvant cis-platinum; those with residual cancer after primary laparotomy (n = 108) underwent a second surgical debulking after three or five cycles of cis-platinum-based cytoreductive chemotherapy. Total macroscopic tumor clearance was achieved in 26 of these 108 patients. Fourteen patients with total tumor excision at primary laparotomy remain in complete clinical remission a minimum of 36 months after diagnosis, but the median progression-free interval for the other two groups was 9 and 17 months, respectively. The survival for women who have total tumor clearance only at secondary surgery after chemotherapy is inferior to that for women with primary macroscopic tumor excision followed by chemotherapy.     

新辅助化疗结合间隔减瘤术治疗晚期卵巢癌的探讨

目的：探讨新辅助化疗结合间隔减瘤术治疗晚期卵巢癌的效果。方法：对我院在1998年1月至2003年12月间收治的51例晚期卵巢癌进行回顾性分析,先行新辅助化疗,CP方案全身化疗3疗程后行间隔减瘤术,术后继续化疗6疗程,分析3年及5年生存率。结果：明显提高肿瘤细胞减灭术的满意率,3年生存率80．4％,5年生存率58．8％。结论：新辅助化疗结合间隔减瘤术治疗晚期卵巢癌可以明显提高晚期卵巢癌患者手术满意率和生存率。     

Neoadjuvant chemotherapy for advanced epithelial ovarian cancer]

Primary surgical cytoreduction followed by paclitaxel/carboplatin combination chemotherapy currently is the treatment of choice for advanced epithelial ovarian cancer. Aggressive surgery is widely accepted as a valid approach to initial cytoreduction of stage III disease, but suboptimal residual disease following primary surgical resection is one of the most important adverse prognostic factors in these patients. Neoadjuvant chemotherapy has been proposed as an alternative approach to conventional surgery for initial management of bulky ovarian cancer, with the goal of improving surgical quality. General acceptance of neoadjuvant chemotherapy as an alternative to primary surgery for patients who are not ideal surgical candidates remains limited, because equivalent or superior survival has not yet been demonstrated in a prospective randomized study. A large-scale, prospective, randomized study is being conducted by the European Organization for Research and Treatment of Cancer (EORTC) Gynecologic Cancer Cooperative Group and Gynecologic Oncology Group (GOG) to compare outcomes (overall and progression-free survival, quality of life, treatment complications) of neoadjuvant chemotherapy/interval debulking surgery versus primary cytoreductive surgery/adjuvant chemotherapy in patients with advanced epithelial ovarian carcinoma.     

Clinical Outcome of Iranian Patients with Advanced Ovarian Cancer with Neoadjuvant Chemotherapy versus Primary Debulking Surgery

Objective: The aim of this study is to evaluate the results of neoadjuvant chemotherapy (NACT) and theimpact of interval debulking surgery (IDS) on clinical outcomes of patients with advanced-stage ovarian cancer.Methods: We performed a retrospective analysis on 92 patients with advanced ovarian cancer admitted to Vali-Asr Gynecologic oncology departments during 1996–2002. Comparison was made with results of neoadjuvantchemotherapy of 24 patients with unresectable advanced epithelial ovarian cancer treated with platinum- basedNACT followed by IDS and clinical outcomes of 68 consecutive stage III and IV ovarian cancer patients treatedwith primary cytoreduction followed by platinum-based adjuvant chemotherapy. Results: Primary cytoreductivesurgery caused longer survival compared to neoadjuvant chemotherapy. Patients who underwent optimal intervaldebulking surgery (IDS) had a better progression free survival (PFS) (p=0.002) and overall survival (p=0.03)than those who did not. There were not significant differences between the two groups in complications ofsurgery. Conclusion: NACT followed by successful IDS can lead to high survival percentage in patients withchemoresponsive advanced ovarian cancer; although the result is more effective in those with optimal primarycytoreduction, we still got the same results with those with suboptimal primary cytoreduction.     

Neoadjuvant chemotherapy followed by tumor debulking prolongs survival for patients with poor prognosis in International Federation of Gynecology and Obstetrics Stage IIIC ovarian carcinoma.

BACKGROUND: Patients with advanced ovarian carcinoma of International Federation of Gynecology and Obstetrics (FIGO) Stage IIIC should be treated by radical surgical tumor debulking with the goal of complete tumor resection. Prolonged median survival can be achieved in those patients entirely free of tumor after surgery by the administration of postsurgical platinum/taxane-based chemotherapy regimens. However, residual tumor is present in the majority of patients, which limits survival prognosis. Different therapy approaches should be utilized to improve prognosis in these patients. Neoadjuvant chemotherapy could induce "downstaging" of the tumor and thus improve operability. Here, evidence of large ascites volume (>500 mL) can be used to identify those patients who could benefit from neoadjuvant chemotherapy. METHODS: In a prospective, nonrandomized Phase II study, 31 patients with advanced FIGO Stage IIIC ovarian carcinoma and large ascites volume (>500 mL) received 3 cycles of platinum/taxane-based combination chemotherapy, followed by tumor debulking surgery and 3 additional cycles of platinum/taxane-based combination chemotherapy. During the same period, 32 patients with advanced FIGO Stage IIIC ovarian carcinoma and large ascites volume (>500 mL) received conventional therapy (tumor debulking surgery followed by 6 cycles of platinum/taxane-based combination chemotherapy). The two groups were investigated and compared with respect to tumor resection rates, blood transfusion requirements, morbidity, and mortality during surgery, duration of surgery, and median survival. RESULTS: The tumor resection rate in the patient group receiving neoadjuvant chemotherapy was significantly higher (P = 0.04) than that of the conventionally treated group; the median survival time of 42 months versus 23 months also was significantly longer (P = 0.007). Time spent in surgery, blood transfusion requirements, morbidity, and mortality during surgery were not significantly different. CONCLUSIONS: Patients with advanced ovarian carcinoma of FIGO Stage IIIC who will benefit only marginally from conventional therapy can be identified by evidence of large ascites volume. Higher tumor resection rates and longer median survival can be achieved in these patients by the use of neoadjuvant chemotherapy. A prospective randomized multicenter study currently is being performed by the Society for Gynecological Oncology in Germany to confirm these findings.     

Neoadjuvant chemotherapy for advanced ovarian cancer: overview of outcomes and unanswered questions

Neoadjuvant chemotherapy for advanced ovarian cancer was initially administered as an alternative treatment for patients not suitable for primary debulking surgery (PDS) because of unresectable tumor or poor performance status. Accumulation of favorable outcomes of this treatment compared with standard treatment starting with PDS made this strategy a candidate for prospective, randomized Phase III studies without limiting the subjects to patients who were unsuitable for PDS. Among the four Phase III studies to date, the earliest study from the European Organization for Research and Treatment of Cancer (EORTC) has revealed noninferior survival with less-serious morbidity in the neoadjuvant chemotherapy arm. These data suggest that neoadjuvant chemotherapy followed by surgical cytoreduction is an acceptable management strategy for patients with advanced ovarian cancer. In this article, we review the treatment outcomes and discuss some unanswered questions, as well as possible future research in this area.     

Interval debulking surgery: an alternative for primary surgical debulking?

Retrospective analyses suggest that a subgroup of patients with Stage III and IV ovarian carcinoma can be treated with neo-adjuvant chemotherapy followed by interval debulking surgery. The absolute indications for neo-adjuvant chemotherapy appear to be Stage IV disease (excluding pleural fluid) or metastases of more than 1 g at sites where resection is impossible. In patients with an estimated total metastatic tumor load of >100 g, the presence of at least two of the following relative indications for neo-adjuvant chemotherapy are considered to be necessary: 1) uncountable (>100) peritoneal metastases, 2) estimated metastatic tumor load of >1000 g, 3) presence of large (>10 g) peritoneal metastatic plaques, 4) large volume ascites, and 5) World Health Organization (WHO) status II or III. Interval debulking surgery in patients with suboptimal primary debulking surgery has been proven effective in increasing overall survival and progression-free survival in a large prospective, randomized trial of the European Organization for Research and Treatment of Cancer (EORTC). The strategy of neo-adjuvant chemotherapy, followed by interval debulking surgery, should be confirmed in a prospective randomized trial. The EORTC 55971 trial is currently addressing this issue. We will review the studies on primary chemotherapy, interval debulking surgery, and the indications for primary chemotherapy followed by interval debulking surgery, and ongoing trials.     

Contemporary considerations for neoadjuvant chemotherapy in primary ovarian cancer

Surgery is essential for the successful treatment of patients with advanced ovarian cancer. Recent reports have raised questions about the best time to perform surgery with regard to administering chemotherapy. A prospective randomized clinical trial comparing neoadjuvant chemotherapy (ie, platinum-based chemotherapy before attempting cytoreductive surgery) and conventional treatment (ie, aggressive cytoreductive surgery followed by platinum-based chemotherapy) demonstrated no difference in progression-free and overall survival between the two treatment groups. The trial demonstrated the need for optimum surgical cytoreduction regardless of whether surgery is performed before or after neoadjuvant chemotherapy. As the postoperative morbidity and mortality was lower in the neoadjuvant treatment group, neoadjuvant chemotherapy should be considered a standard treatment for women with advanced ovarian cancer, particularly those unlikely to be surgically cytoreduced to no residual tumor. This article reviews contemporary considerations in the use of neoadjuvant chemotherapy in the treatment of primary ovarian cancer.     

新辅助化疗结合间隔减瘤术治疗晚期卵巢癌的探讨

目的:探讨新辅助化疗结合间隔减瘤术治疗晚期卵巢癌的效果.方法: 对我院在1998年1月至2003年12月间收治的51例晚期卵巢癌进行回顾性分析,先行新辅助化疗,CP方案全身化疗3疗程后行间隔减瘤术,术后继续化疗6疗程,分析3年及5年生存率.结果: 明显提高肿瘤细胞减灭术的满意率,3年生存率80.4%,5年生存率58.8%.结论: 新辅助化疗结合间隔减瘤术治疗晚期卵巢癌可以明显提高晚期卵巢癌患者手术满意率和生存率.     

Outcome of Interval Debulking in Advanced Ovarian Cancer Patients

Interval debulking and neoadjuvant chemotherapy have been used in management of advanced epithelialovarian cancer for many years in order to achieve optimal residual disease and reduce surgical morbidity. Thepresent study was conducted to evaluate the outcomes of advanced ovarian cancer patients treated with thesetwo approaches prior to cytoreductive surgery in Chiang Mai University Hospital between January 2001 andDecember 2006. The medical records of 29 patients who met the criteria were retrospectively reviewed. Mosthad stage IIIC serous cystadenocarcinomas. We found that the 5 year progression free survival and overallsurvival were 10% and 22% while the median values were 13 months and 34 months, respectively. Multivariateanalysis showed that a suboptimal residual tumor volume was a statistically significant adverse prognosticfactor for overall survival. In conclusion, interval debulking surgery and neoadjuvant chemotherapy beforecytoreductive surgery lead to a more favorable outcome with advanced epithelial ovarian cancers.     

Neoadjuvant chemotherapy for unresectable ovarian carcinoma: a French multicenter study.

BACKGROUND: Initial debulking surgery followed by chemotherapy is the current treatment for International Federation of Gynecology and Obstetrics Stage IIIC/IV ovarian carcinoma but has a limited efficacy when optimal cytoreduction is not achieved at the end of the surgical procedure. An alternative treatment for these patients could be neoadjuvant chemotherapy. The purpose of this retrospective study was to report the results of neoadjuvant chemotherapy in operable patients (no medical contraindication to surgery) presenting with primary unresectable tumors. METHODS: Between January 1996 and March 1999, operable patients presenting with Stage IIIC or IV ovarian carcinoma underwent, in six French gynecologic oncology departments, surgical staging to evaluate tumor resectability. When the tumor was deemed unresectable by standard surgery, the patient received three to six cycles of platinum-based neoadjuvant chemotherapy according to the response and the center's usual protocol. Patients were surgically explored after completion of neoadjuvant chemotherapy when the tumor did not progress during treatment. Debulking was performed during this secondary surgery when a response to chemotherapy was observed. RESULTS: Fifty-four patients were treated by neoadjuvant chemotherapy. The first surgical staging procedure was laparoscopy in 33 patients (61%) and laparotomy in 21 patients (39%). The median number of neoadjuvant chemotherapy cycles was 4 (range, 0-6). Forty-three patients (80%) responded to neoadjuvant chemotherapy and then tumors were debulked. Optimal cytoreduction was obtained in 39 patients (91% of the patients who underwent debulking) and with standard surgery in 32 patients (82%). For patients whose tumors were optimally debulked, blood transfusions were administered to 17 patients (43%), median intensive care unit stay was 0 days (range, 0-7 days), and median postoperative hospital stay was 10 days (range, 4-62 days). Median overall survival for the total series was 22 months. Survival was better for patients debulked after neoadjuvant chemotherapy compared with patients with nondebulked tumors (P < 0.001). CONCLUSIONS: Neoadjuvant chemotherapy for primary unresectable ovarian carcinoma leads to the selection of a subset of patients sensitive to chemotherapy in whom optimal cytoreduction can be achieved after chemotherapy by standard surgery in a high proportion of cases. Conversely, aggressive surgery can be avoided in patients with initial chemoresistance, in whom the prognosis is known to be poor regardless of treatment.     

Cytoreductive surgery for advanced ovarian cancer: quo vadis?

Two-thirds of women who are newly diagnosed with invasive epithelial ovarian cancer present with stage III or IV disease.The preferred initial treatment has traditionally consisted of primary surgical debulking followed by platinum-based chemotherapy. However, recent data suggesting comparable efficacy for neoadjuvant chemotherapy and interval debulking have challenged this conventional dogma. Most patients with advanced ovarian cancer will achieve remission regardless of initial treatment, but 80% to 90% of patients will ultimately relapse. The timing and clinical benefit of a second debulking operation for recurrent disease is even more contentious. This article focuses on the recent debate regarding when--or whether--patients with ovarian cancer should undergo aggressive surgical resection.