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).     

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.     

Medical treatment of epithelial ovarian cancer

Epithelial ovarian carcinoma is still the most common cause of death from gynecologic cancer in the USA and Europe. Only 20-30% of patients are diagnosed at the initial stage where appropriate staging surgery can be curative. Patients with high-risk Stage I disease can benefit from adjuvant chemotherapy with platinum-based schedules. The treatment of patients with advanced disease consists of a staging surgery with maximum cytoreductive effort, followed by chemotherapy with a platinum-taxane combination. Unfortunately, the majority of patients with advanced disease will relapse and become candidates for additional chemotherapy. In those patients with recurrence over 6 months after initial therapy (platinum sensitive), combinations of paclitaxel plus carboplatin and carboplatin plus gemcitabine have shown a benefit over carboplatin alone. Patients with early relapse should be managed with supportive care and sequential monotherapy if chemotherapy is indicated.     

Medical treatment of epithelial ovarian cancer

Epithelial ovarian carcinoma is still the most common cause of death from gynecologic cancer in the USA and Europe. Only 20–30% of patients are diagnosed at the initial stage where appropriate staging surgery can be curative. Patients with high-risk Stage I disease can benefit from adjuvant chemotherapy with platinum-based schedules. The treatment of patients with advanced disease consists of a staging surgery with maximum cytoreductive effort, followed by chemotherapy with a platinum–taxane combination. Unfortunately, the majority of patients with advanced disease will relapse and become candidates for additional chemotherapy. In those patients with recurrence over 6 months after initial therapy (platinum sensitive), combinations of paclitaxel plus carboplatin and carboplatin plus gemcitabine have shown a benefit over carboplatin alone. Patients with early relapse should be managed with supportive care and sequential monotherapy if chemotherapy is indicated.     

Indications for minimally invasive surgery for ovarian cancer

Epithelial ovarian cancer is often diagnosed in advanced stages and typically managed with surgical debulking followed by chemotherapy. For patients with presumed early-stage ovarian cancer, comprehensive surgical staging is essential for management, because 31% are upstaged. Over the past 15 years, minimally invasive techniques have improved and are increasingly being used to treat patients with ovarian cancer. Currently, only retrospective data support laparoscopic staging of patients with a suspicious adnexal mass or those surgically diagnosed with presumed early-stage ovarian cancer. Laparoscopy is also used in patients undergoing second-look procedures and to help evaluate whether patients should undergo optimal tumor debulking procedures or be initially managed with neoadjuvant chemotherapy. Randomized clinical studies are needed to further support the role of minimally invasive surgery in the treatment of ovarian cancer.     

Update on the management of ovarian cancer

Ovarian cancer remains the leading gynecologic cause of death in the United States and the Western world. Progression to metastatic disease prior to diagnosis contributes to the high mortality rate associated with ovarian cancer. The current article reviews surgical and drug therapies for ovarian cancer. Prognostic factors and preventative treatment are also discussed. Surgery is essential for accurate staging of ovarian cancer and treatment. Cytoreduction, combined with chemotherapy, may relieve symptoms associated with bowel obstruction and improve survival. Management of early-stage ovarian cancer depends upon risk status determined via comprehensive staging at the time of surgical resection. High-risk, but not low-risk, patients require adjuvant chemotherapy. Studies comparing various combinations of cytotoxic agents for the treatment of advanced stage ovarian cancer are described. Despite surgery and chemotherapy, ovarian cancer recurs in approximately 50% of patients. Management of recurrent ovarian cancer and maintenance therapy following remission are discussed.     

Operative management of primary epithelial ovarian cancer

Surgery plays an integral part in the primary management of early-stage and advanced-stage epithelial ovarian cancer. Surgical staging is essential for disease grossly confined to the ovaries or pelvis. Comprehensive surgical staging often results in upstaging of patients who were presumed to be at an early stage. Accurate staging has an impact on prognosis and treatment strategies. Optimal surgical cytoreduction leads to improved outcomes in patients with advanced disease; before initiation of chemotherapy, it offers the most favorable outcome and should be offered to all patients. Intraperitoneal catheters for postoperative chemotherapy instillation may be offered and placed at the time of cytoreduction. Neoadjuvant chemotherapy and interval cytoreduction are a possibility for patients who are not amenable to an optimal cytoreduction based on preoperative findings or in those who are at extremely high risk for surgery.     

Gynecologic malignancies in older women

The aging of the population is a social phenomenon that will present a challenge to clinical practice in the 21st century. Women constitute a majority of the elderly population as they outlive males by 5 to 7 years. Ovarian, endometrial, and vulvar cancers are diseases seen more commonly in postmenopausal and elderly women. Cervical cancer continues to be a significant problem in the elderly and is usually detected at a later stage in that population than in younger patients. Accordingly, primary care clinicians ought to possess a thorough knowledge of gynecologic malignancies and should refer women who present with these disorders to a gynecologic oncologist. Ovarian cancer patients treated by a gynecologic oncologist are more likely to undergo proper surgical staging, leading to optimal debulking surgery and improved survival. Age, by itself, should not alter the diagnostic and therapeutic approach to gynecologic malignancy. Elderly patients can safely undergo radical pelvic surgery. Multiagent chemotherapy is also possible in the elderly without excess morbidity, and without compromise of response rates. Radiation therapy for cervical cancer appears to be as effective and is generally well tolerated. The Papanicolaou (Pap) test continues to be the primary screening tool for cervical cancer. Although transvaginal ultrasound seems to be useful in detecting early-stage ovarian cancer, its cost effectiveness for screening the general population remains to be demonstrated. The main considerations in the treatment of ovarian, endometrial, cervical, and vulvar cancer are discussed.     

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.     

Chemotherapy of ovarian germ cell tumors.

The development of modern surgical staging and effective chemotherapy regimens has markedly improved outcome of treatment of ovarian germ cell tumors. Almost all patients with completely resected tumors will survive their disease. Those with tumors other than dysgerminoma should all receive adjuvant chemotherapy. Patients with stage IA dysgerminoma can safely be observed, whereas those of higher stage should probably receive chemotherapy, although radiotherapy may be an option in selected patients, particularly older ones or those with other serious illness. Patients with advanced disease should all be treated with chemotherapy. Cisplatin-based regimens as developed for testicular cancer are more effective than VAC or VAC-type regimens. With such treatment, most dysgerminoma patients will be cured, as will many with other cell types. However, there is room for improvement in the latter group and continued investigation is appropriate.     

Prise en charge du cancer de l’ovaire

Ovarian carcinoma is the worst gynecologic cancer due to an advanced stage at diagnosis in two thirds of the cases. Advanced stages are usually characterized by a large tumor burden on the ovaries as well as metastatic disease in the peritoneal cavity. Early stages are more common in young women and the surgical treatment should comprise the tumor excision and a comprehensive abdominal staging to be sure that there is no extension beyond the ovaries-unilateral oophorectomy can preserve the fertility before child-bearing. No treatment is needed after surgery in stage I without poor pronostic factors. Adjuvant chemotherapy should be applied postoperatively in the other cases. The best likelihood of prolonged survival is observed after optimal debulk-ing surgery and chemotherapy in advanced stages. If possible surgery should be performed at first but in most advanced stage with large tumor volume in the upper abdomen according to clinical and CT-scan examination, the concept of chemosurgical debulking shoud be considered. Interval surgery underwent after three or four courses of front line chemotherapy but this strategy should be further evaluated by clinical trials. Currently paraplatin associated with paclitaxel is the most commonly used regimen due to its effectiveness and lower toxicity. In a near future progress can be expected with new protocols. Thank to agressive surgery and chemotherapy many patients should be able to reach a complete remission of their disease but most of them will still die of recurrent disease. At this point, two questions should be answered: 1) how to manage the residual abdominal disease in order to prevent the recurrence. No consolidation treatment demontrated any superiority but the French experience and trial with high dose chemotherapy supported by autologous stem cells transplantation showed recently positive results? 2) How to manage the recurrent disease with sometime indication for secondary surgical debulking and always chemotherapy? This is the field for testing new drugs or new strategies. A large number of patients should enter clinical trials in order to answer these questions and due to the very poor prognosis of this disease large attention should be given to the quality of life of theses patients.     

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.     

Timing for starting second-line therapy in recurrent ovarian cancer

Ovarian cancer is the leading cause of gynecologic cancer-related death in Europe and the USA. The optimal treatment strategy for this malignancy includes accurate presurgical and surgical staging, optimal debulking surgery, and first-line therapy with platinum-based chemotherapy. Unfortunately, the majority of patients diagnosed with advanced ovarian cancer will eventually relapse and die. However, an appropriate management can have a major impact on survival: salvage chemotherapy can prolong survival in the majority of cases and, in selected patients, surgical cytoreduction of recurrent disease can be beneficial. The optimal timing for starting second-line therapy should be based on symptomatic or radiologic recurrence. In fact, even though cancer antigen 125 (CA 125) elevation significantly anticipates a clinical relapse, a randomized trial failed to show a survival advantage for starting second-line therapy on the basis of CA 125 elevation. This is the most solid evidence coming from a randomized trial; however, we must take into account some limitations: in this study the role of secondary cytoreduction was not considered and, at the time of study conduction, more active salvage drugs/regimens were not yet available. In the near future, a better knowledge of ovarian cancer biology, more sensitive diagnostic techniques, more accurate and less invasive surgical procedures along with the availability of new agents will further improve prognosis. In this scenario, the anticipation of salvage therapy will probably play a different role.     

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.     

Advanced ovarian cancer

Opinion statement State-of-the-art treatment for advanced ovarian cancer requires a multimodality approach. Aggressive surgical debulking with the goal of optimal cytoreduction is the initial step. After primary cytoreductive surgery, standard treatment for patients with stage III and IV disease is systemic combination chemotherapy consisting of six cycles of paclitaxel and carboplatin. Approximately 70% of patients enter a clinical remission with this approach, yet less than 30% remain disease free. Options following primary therapy include observation or second surgical assessment if no clinical evidence of disease is present. Novel strategies for consolidation are needed. Second-look surgery can be performed safely and effectively laparoscopically, and this is the most accurate means of identifying patients who appear to be clinically free of disease but actually harbor persistent cancer. Although this procedure is an extremely accurate means of identifying these patients, women who have pathologically negative second-look surgery are still at risk for relapse. Patients can receive additional treatment following second-look surgical assessment via the intraperitoneal route if they are pathologically negative or if they have microscopic or small volume disease. Alternatively, additional systemic chemotherapy can be given with non-cross-resistant systemic agents, but no current standard approach for consolidation therapy exists for patients following the completion of primary treatment. Unfortunately, most patients relapse. Multiple agents with similar activity in phase II trials are available to treat patients with advanced recurrent disease. Combination therapy in this setting has not been shown to have significantly superior progressionfree or overall survival compared with single agents. The selection of treatment for patients with recurrent disease is currently based on a determination of the treatmentfree interval since last treatment, as well as the route, schedule, and expected side effects of the agent.     

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

Ovarian cancer is the second most common cause of gynecologic cancer death in women around the world. The outcomes are complicated, because the disease is often diagnosed late and composed of several subtypes with distinct biological and molecular properties (even within the same histological subtype), and there is inconsistency in availability of and access to treatment. Upfront treatment largely relies on debulking surgery to no residual disease and platinum-based chemotherapy, with the addition of antiangiogenic agents in patients who have suboptimally debulked and stage IV disease. Major improvement in maintenance therapy has been seen by incorporating inhibitors against poly (ADP-ribose) polymerase (PARP) molecules involved in the DNA damage-repair process, which have been approved in a recurrent setting and recently in a first-line setting among women with BRCA1/BRCA2 mutations. In recognizing the challenges facing the treatment of ovarian cancer, current investigations are enlaced with deep molecular and cellular profiling. To improve survival in this aggressive disease, access to appropriate evidence-based care is requisite. In concert, realizing individualized precision medicine will require prioritizing clinical trials of innovative treatments and refining predictive biomarkers that will enable selection of patients who would benefit from chemotherapy, targeted agents, or immunotherapy. Together, a coordinated and structured approach will accelerate significant clinical and academic advancements in ovarian cancer and meaningfully change the paradigm of care.     

The role of interval debulking surgery in ovarian cancer

The mainstay of treatment for advanced ovarian cancer is the multimodality approach of debulking surgery and paclitaxel— platinum chemotherapy. The size of residual lesions after primary surgery remains the most important prognostic factor for survival. Optimal primary debulking surgery can be performed in approximately 40% of patients and up to 80% if it is done by gynecologic oncologists, but sometimes at the cost of considerable morbidity and even mortality. Based on a trial conducted by the European Organization for Research and Treatment of Cancer, optimal as well as suboptimal interval debulking surgery increases overall (P=0.0032) and progression-free survival (P=0.0055). However, not all patients who have undergone suboptimal primary debulking surgery seem to benefit from interval debulking surgery. Preliminary data from the Gynecologic Oncology Group interval debulking study (GOG-152) indicate that, if the gynecologic oncologist makes a maximal effort to resect the tumor, patients who have undergone suboptimal debulking surgery probably gain little benefit from interval debulking surgery.     

Surgical management of ovarian cancer.

Ovarian cancer affects over 25,000 women each year in the United States. The performance of appropriate surgery for ovarian cancer is critical in directing further therapies and improving survival. Systematic surgical staging must be performed in patients who appear to have early stage ovarian cancer because a significant proportion of these women have occult metastases. A marked improvement in survival has been demonstrated in patients with bulky disease if all masses larger than 2 cm can be surgically removed. Despite the dramatic effect of surgery on the subsequent course of the disease, recent studies show that only a minority of women with ovarian cancer receive appropriate initial surgery. We review the evidence and rationale for systematic surgical treatment of ovarian cancer.     

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.     

Cancers de l’endomètre de stades avancés : chirurgie première ou chimiothérapie néoadjuvante ?

Endometrial cancers with peritoneal spread are stage IVB of FIGO classification. Their pattern is similar to that of ovarian cancer. Optimal debulking surgery and chemotherapy are predictor of better overall and disease free survival. Despite the poor outcome, there is a need for new treatment options. Recommended management for this group of patients should consist of surgical cytoreduction followed by chemotherapy. There may be a role for neoadjuvant chemotherapy followed by interval surgery in selected subgroups of patients.