Neoadjuvant Chemotherapy for Ovarian Cancer

The importance of cytoreductive surgery in the treatment of advanced ovarian cancer (International Federation of Gynecology and Obstetrics [FIGO] stage III and IV) was first suggested as early as 1934 by Meigs.[1] But this procedure was long disputed until, in the 1970s, Aure et al[2] and Griffiths et al[3] showed that the amount of residual tumor following primary surgery was an important prognostic factor in advanced ovarian carcinoma. Unfortunately, no prospective randomized controlled trials have investigated the role of primary cytoreductive surgery in advanced ovarian carcinoma. Despite this lack of randomized controlled trials, primary cytoreductive surgery should be the standard of care in advanced ovarian cancer.[4] In the 1980s, the European Organization for Research and Treatmentof Cancer-Gynecological Cancer Group (EORTC-GCG) launched a randomized study of the role of interval debulking surgery in women who did not or could not have a successful primary debulking operation (reduction of disease to < 1 cm). During the same time period, several institutions started using neoadjuvant chemotherapy in patients with advanced ovarian cancer (without a primary attempt at debulking) followed by an interval debulking surgery. We will try to define the current role of primary or neoadjuvant chemotherapy followed by interval debulking surgery in the primary management of advanced ovarian cancer. Definitions Agreement about the terminology for surgical procedures is essential for a clear understanding. The following standard definitions were recommended during the 1998 consensus meeting on advanced ovarian cancer[5]: Primary cytoreductive surgery: an operation to remove as much of the tumor and its metastases as possible before subsequent therapy is initiated. Interval cytoreductive surgery: an operation performed in patients after a short course of induction chemotherapy- usually two or three cycles of chemotherapy-to remove as much primary and metastatic disease as possible, in order to facilitate response to subsequent chemotherapy and to improve survival. Secondary cytoreductive surgery: an operation performed in patients who have either persistent disease at the completion of a planned course of chemotherapy or who subsequently experienced clinical relapse. Surgery in Primary Management of Advanced Ovarian Cancer Primary Debulking Surgery

• Biologic Basis of Cytoreductive Surgery-In contrast to its limited use in other abdominal malignancies, cytoreductive surgery has an important role in the treatment of advanced ovarian cancer. This is mainly due to the relatively good resectability of ovarian cancer. Metastatic disease is usually confined to the abdominal cavity, and despite an extraordinarily large tumor burden, resection of metastatic tumor masses may be feasible as well as efficacious in these circumstances.
There is also a biologic explanation for the success of cytoreductive surgery.[6,7] Large tumors have a relatively small percentage of blood vessels compared to their volume and more often have hypoxic or necrotic areas. Small tumors have more central blood perfusion and seem to have a higher percentage of dividing or proliferating cells. In the latter group, the increased blood flow will favor the transport and diffusion of the cytotoxic drugs to the tumor cells, andsince rapidly dividing cells are more sensitive to the action of cytotoxic drugs, the impact of these drugs on the cells will be greater. Cytoreductive surgery will therefore increase the susceptibility of smaller lesions to chemotherapy. Skipper[6] coined the "fractional cell kill" hypothesis postulating that the proportion of tumor cells killed with each treatment is constant. Since the number of tumor cells is reduced by cytoreductive surgery, these smaller lesions will also require fewer chemotherapy cycles. Fewer cycles also reduces the chance of developing drugresistance during the course of therapy.
• Optimal vs Suboptimal Cytoreductive Surgery-It has become clear that primary debulking surgery is only advantageous to the patient if the primary cytoreductive surgery results in a minimal residual tumor load. In studies conducted in the 1970s, and even in more recent multicentric trials investigating different chemotherapeutic regimens, the rate of optimal primary cytoreductive surgery was only 20% to 30%.[2,8-12] A metaanalysis of surgery in advanced ovarian cancer by Hunter et al[12] suggested that cytoreductive surgery only had a small improvement in median survival, but this meta-analysis has been criticized for two reasons. First, the rate of optimally debulked patients was low, and second, a large number of patients were not treated with optimal platinumbased chemotherapy.
More recently, during the platinum era, Bristow et al[13] performed a new meta-analysis on the survival effect of maximal debulking surgery for advanced ovarian carcinoma. In this meta-analysis, 81 cohorts of patients with stage III or IV ovarian carcinoma were included (6,885 patients in total). The analysis showed a statistically significant positive correlation between percent maximal cytoreduction and median survival time, even after controlling for all other variables. In addition, each 10% increase in maximal cytoreduction was associated with a 5.5% increase in median survival time. They concluded that maximal debulking surgery is one of the most powerful determinants of cohortsurvival among patients with advanced ovarian cancer. The definition of "optimal" or "maximal" debulking surgery remains controversial. The definition of optimal debulking has changed many times in the past 20 years, from a largest residual tumor mass of 2 cm to no residual tumor, and even recent trials often differ in the definition they use for optimal debulking. Griffiths et al[3] originally proposed that the residual tumor mass for an optimal debulking should be less than 1.5 cm. Later, many studies showed that patients without residual tumor had a better survival than those with a largest residual tumor mass less than 0.5 cm, and the latter group had a better prognosis than patients with residual tumor of 0.5 to 1.5 cm.[14-20] Vergote et al[21] suggested that optimal cytoreductive surgery should be defined as no macroscopic residual tumor, and this proposal was endorsed by the meta-analysis of Bristow at al.[13] Despite this clear evolution toward a more radical approach during primary debulking surgery, a questionnaire among US gynecologic oncologists showed that only 12% of the responders regarded optimal debulking surgery as no residual tumor, 13.7% as ≤ 0.5 cm, 60.8% as ≤ 1 cm, and 12.3% as ≤ 1.5 or 2 cm.[22]
• Variables Influencing Cytoreductive Surgery-Whether the observed survival benefits for optimally cytoreduced patients are a function of tumor biology or surgical skill remains a fiercely debated issue. Indirect evidence is available that inherent tumor biology relates to resectability. For example, Heintz et al[14] observed that cytoreduction was easier to achieve in patients with low-grade tumors, small metastases, and no ascites. Burghardt et al[23] showed that women in whom optimal debulking was impossible had a higher number of positive pelvic and para-aortic lymph node metastases.
In addition, Friedlander et al[24] reported that the size of the largest residual tumor mass was not an independent factor when newer prognostic variables such as DNA ploidy were included in the multivariate analyses.Recently, microarrays were used to screen for differences in gene expression profiles between optimally and suboptimally debulked ovarian cancers.[ 25] Microarrays were able to differentiate between optimal and suboptimal debulking with 72.7% accuracy. The authors concluded that the achievement of optimal cytoreduction is, at least in part, linked to tumor biology. Apart from this finding, however, the importance of surgical expertise cannot be underestimated. Comparison of overall survival of patients treated by surgeons with or without subspecialist training in gynecologic oncology showed a survival benefit for patients treated by a surgeon trained in this type of operation.[26] This result may not be solely attributed to the skills of the surgeon but also to the qualifications of the whole team with which the surgeon is working. The interdisciplinary approach and the continuous education and self-evaluation required at "expert" centers is of great importance. The suggested requirement for an "expert" center is an optimal resection rate of at least 75%.[14] Even in patients with advanced ovarian carcinoma initially thought to be unresectable by less experienced surgeons, an optimal cytoreductive debulking can be achieved in 71% to 76% by gynecologic oncologists, who play an integral role at such centers.[14,18] Not only is the residual tumor load of prognostic significance, but so too is the initial metastatic tumor load. In an analysis of data from the University of California, Los Angeles, Hacker et al[18] first observed that patients with extensive metastatic disease prior to cytoreduction (> 10 cm in diameter) or with clinical ascites had a poor prognosis, even if the disease was cytoreduced to an optimal status. A later study from the same center showed that the only prognostic factors influencing resectability to optimal status were metastatic disease larger than 5 cm and the presence of more than 1 L of ascites.[14] Furthermore, in a study from The Netherlands, Heintz et al[19] observed that prognosis was influenced by the diameter of the largest metastasis before cytoreduction and the presence of ascites or peritoneal carcinomatosis. In a Gynecologic Oncology Group (GOG) study of 349 patients with optimally resected (≤ 1 cm) disease, multivariate analyses revealed that the presence of 20 or more residual lesions was an independent unfavorable prognostic variable.[20] Potter et al[15] analyzed 302 patients with ovarian carcinoma and concluded that the role of bowel resection should be questioned when residual disease remains at the completion of the operative procedure. Vergote et al[21] reported that patients with more than 1,000 g of total metastatic tumor load treated with primary debulking surgery had a poor survival despite optimal surgery. In addition, Farias-Eisner et al[27] found that the extent of peritoneal carcinomatosis before surgery was the most important prognostic factor in patients with less than 0.5 cm residual tumor. On the other hand, some studies suggested that a complete excision of all peritoneal implants is feasible, even in the presence of an initial extensive peritoneal carcinomatosis, and that this excision will still improve survival.[28,29] Patient variables also influence the resectability of widespread disease. Indeed, patients with good prognostic variables may be easier to debulk than patients with poor prognosis. For example, Heintz et al[14] observed that cytoreduction was easier to achieve in young patients. Age is an important prognostic factor for patients with ovarian cancer. Older patients often have multiple medical comorbidities, and often only those patients with good performance status are selected for exploration. Moreover, these patients are very often treated less aggressively than younger patients. However, patients should not be offered less aggressive treatment based upon age alone. Carefully selected elderly patients tolerate surgical cytoreduction remarkably well, with a complication and recovery rate similar to that of younger women.[30] The role of cytoreductive surgery in FIGO stage IV disease remains controversial. Some studies have reported an improved survival in optimally debulked stage IV ovarian cancer patients,even when liver or lung metastases were present.[31,32] In contrast, Vergote et al[21] reported that patients with stage IV disease treated with primary debulking surgery had a poor survival despite optimal surgery. During the consensus meeting in 1998, it was agreed that patients with only a pleural effusion, or a supraclavicular node or a single cutaneous metastasis can be treated as having stage III disease. Extensive primary debulking in patients with liver or lung metastases was regarded as most likely of no benefit.[5] This was confirmed by Zang et al in a retrospective study reviewing 71 patients with stage IV ovarian cancer.[33] Optimal cytoreductive surgery was an important prognostic factor of survival, but mainly in those with malignant pleural effusion or positive supraclavicular lymph node pathology.
• Conclusion-Primary debulking surgery is currently a cornerstone in the standard care of patients with advanced- stage ovarian cancer. This operation should be performed in expert centers by surgeons or gynecologists with a certain degree of subspecialization in the field of gynecologic oncology, in order to obtain a high percentage of optimal debulking (approximately 75% or higher). The goal of cytoreductive surgery should be no residual disease, or, when this is impossible, minimal residual disease. FIGO stage IV ovarian cancer can be treated similarly to FIGO stage III disease, in case of a malignant pleural effusion or a supraclavicular lymph node metastasis. In our experience, only a few categories of patients are considered unsuitable for primary debulking surgery and are candidates for neoadjuvant chemotherapy followed by interval debulking:
  (1) Poor general condition (eg, > 80 years old) making a "maximal surgical effort" to no residual tumor impossible
  (2) Intrahepatic multiple metastases larger than 2 cm
  (3) Extra-abdominal metastatic disease (> 2-cm diameter), excluding supraclavicular and inguinal node metastases
  (4) Metastatic disease, > 2-cm diameter, at the level of the porta hepatis
  (5) Metastatic disease, > 2-cm diameter, at the level of the superior mesenteric artery
  (6) Extensive serosal invasion (plaques) of the intestines necessitating multiple bowel resections totalling > 1.5 m of bowel resection. Neoadjuvant Chemotherapy and Interval Debulking Surgery
  
• Interval Debulking Surgery After Suboptimal Primary Debulking-If optimal debulking cannot be achieved, either an immediate reoperation by an experienced surgeon can be performed or the operation can be completed after several cycles of chemotherapy. Interval debulking surgery after suboptimal primary debulking followed by three courses of platinum-based chemotherapy has been investigated in two prospective randomized trials.[34,35] The firststudy was performed by the EORTCGCG, and the second, by the GOG. The EORTC study design is summarized in Figure 1. This study included patients with FIGO stage IIB-IV epithelial ovarian carcinoma, suboptimally debulked, with residual disease > 1 cm. In the group of patients randomized to the interval debulking surgery arm, there was a 49% observed reduction in risk of death. At the time of a study update in 2001, after a median follow-up of 6.3 years, survival remained improved up to 9 years after randomization (P = .0032). Of note, the overall survival of patients with less than 1 cm of tumor at the time of interval debulking surgery was exactly the same as that of patients who were debulked to less than 1 cm during this procedure. Furthermore, no patient subgroups (eg, stage, age, grading, presence of peritoneal carcinomatosis, number of lesions, or tumor size at the time of interval debulking surgery) failed to show an improved survival. The outline of the GOG 152 trial is summarized in Figure 2. In this trial, patients with suboptimal (residual tumor > 1 cm) stage III/IV ovarian carcinoma were included. One important difference between the EORTC trial and the GOG trial is that one criterion for eligibility was appropriate ovarian cancer surgery, defined as a laparotomy with an adequate excision to explore the entire abdominal cavity, with a maximal effort to resect the uterus, tubes, ovaries, omentum, and all gross residual ovarian cancer, at the time of primary surgery. The main differences between the two trials are summarized in Table 1. In the EORTC study, more patients had stage IV disease, poor WHO performance status, and a higher residual tumor load after primary surgery.
• Conclusion-Based on the EORTC trial, interval debulking surgery by an experienced gynecologic oncologist appears to improve survival in some patients who have not been optimally operated primarily (poor medical condition, inexperienced surgeon, and so forth). On the other hand, based on the GOG 152 trial, interval debulking surgery doesnot seem to be indicated in patients who underwent primarily a maximal surgical effort by a gynecologic oncologist.
• Neoadjuvant Chemotherapy Followed by Interval Debulking Surgery-As an alternative to primary debulking surgery, neoadjuvant chemotherapy can be administered before attempting cytoreductive surgery. This approach has been advocated by some authors, especially for the treatment of stage IV ovarian cancer, for patients with a very high metastatic tumor load (eg, more than 1 kg), or for patients with a poor general condition. From several retrospective phase II studies, it appears that the outcome for these women, after treatment with neoadjuvant chemotherapy followed by interval debulking surgery, is essentially the same as for patients treated with primary debulking surgery followed by chemotherapy. These studies are summarized in Table 2.[21,36-52]
In most studies, interval debulking surgery was performed after three or four courses of neoadjuvant chemotherapy. The arguments for this timing of the interval surgery are, first, that chemotherapy-induced fibrosis is less extensive after three than after six courses; second, that more patients might be chemoresistant after six courses than after three courses; and last, that earlier studies investigating the role of debulking surgery at the time of second-look surgery after six courses of chemotherapy did not improve survival. Summarizing the published data, the survival results for 872 patients with stage III and/or stage IV ovarian cancer treated with neoadjuvant chemotherapy (usually followed by interval debulking surgery) are similar or better than for those treated with primary debulking surgery, but no firm conclusions can be drawn because all these studies were retrospective. To illustrate the confounding factors, we observed a better overall survival when selecting 45% of our patients for neoadjuvant chemotherapy and 55% for primary debulking surgery compared with a historical series treated with very aggressivedebulking (82% < 0.5 cm residual tumor).[21] However, in the historical series, only 76% of patients were treated with platinum and none with paclitaxel, while in the group treated with neoadjuvant chemotherapy, 94% were treated with platinum (and 30% with platinum and paclitaxel).
• Conclusion-Although evidence from retrospective studies suggests that neoadjuvant chemotherapy followed by interval debulking surgery is a valid alternative in a selected group of patients with stage III or IV ovarian carcinoma, this needs to beconfirmed in a prospective randomized trial. Therefore, the EORTCGCG, in cooperation with the National Cancer Institute of Canada, launched a prospective randomized trial to compare primary debulking surgery with neoadjuvant chemotherapy (Figure 3). To be eligible, patients must have biopsy- proven stage IIIC or IV epithelial ovarian cancer or peritoneal or fallopian tube carcinoma (with the biopsy taken at laparoscopy or laparotomy, or image-guided). The study is expected to close in the summer of 2006, with a target accrual of 704 patients.

• Conclusion-Open laparoscopy is an important tool in the evaluation of the operability of patients with ovarian cancer. To date, this technique has produced no proven detrimental effects on the prognosis of these patients.