5. SCS in platinum-sensitive recurrent ovarian cancer

A number of studies have assessed the two most used predictive models—that proposed by Harter (AGO) and that proposed by Tian [23, 33]. Janco et al. [38] reported that although a positive AGO score was predictive of complete SCR in 79% of patients, in 64.4% of AGO negative cases complete SCR could also be achieved—and as such the AGO score was not an independent factor associated with improved survival. Similar findings of complete cytoreduction—high positive predictive value and high false negative rates—were reported for both models in a population based study on Dutch patients [39]. In this study, 48% of patients had had chemotherapy before surgical cytoreduction but this did not impact on their results. Following on from an earlier proposal for surgical resection in ROC [40], the Memorial Sloan Kettering group compared their scoring system to the AGO and the Tian models in identifying those patients likely to benefit from secondary cytoreductive surgery—that is, those patients in whom complete surgical resection is more likely to be achieved. They proposed to offer secondary cytoreductive surgery to those with: (1) a disease-free interval of less than 6 months, if there was single site disease, (2) disease-free interval of 12–30 months, even if multiple sites of disease provided there was no carcinomatosis and (3) those with carcinomatosis, if the disease-free interval was more than 30 months. These selection criteria might be considered to be counterintuitive and are different to those of previous reports, but their assessment of the impact of carcinomatosis, is similar to that of the DESKTOP I study, albeit in the context of a longer DFI. They reported [41] that their model was more predictive of complete resection than either the AGO or Tain model. A study from two French centres [42], where initial laparoscopic assessment was common, both the AGO and Tian models were used to evaluate patients; they reported high positive predictive values for complete cytoreduction (80.6 and 74%, respectively, for each

It can been seen than that although various models have been proposed with some common criteria, the more commonly used AGO and Tian models are associated with significant false negative predictions. It is of no surprise that the factors associated with improved survival in ROC and factors associated with increased rate of CSC in ROC, are similar (Tables 1 and 3). Perhaps surprising is that in most series pre-operative CA125 is not considered relevant. Most studies do not report on or recommend an initial laparoscopic assessment, a procedure not without risks, limitations and the associated logistic problems of planning operating lists. Other than Eisenkop's early reports [43, 44], it is also surprising that in most other later models determining and evaluating criteria for surgery of ROC, tumour volume or size of recurrence were not considered relevant. An exception is the report by Onda et al. [45] in which size of recurrent disease or tumour burden was an important factor in case selection. While much emphasis has been given to the importance of complete resection in primary EOC and the positive impact on survival, some reports have emphasised that initial tumour burden in primary disease limits the gains from such surgery—the argument again about surgical skill and tumour biology [46–48]. If indeed tumour burden is important in primary disease, arguably it should be of similar if not more importance in recurrent disease, where chemotherapy is less effective. Furthermore, it is quite clear that patients treated for primary EOC by gynaecological oncologists who achieve CSC have an improved outcome when the cancer recurs, compared to patients in whom primary surgery was incomplete. The positive effects of optimum treatment of primary EOC, continue through recurrent disease. Quite evidently, the characteristics of primary

model) yet high false negative values (65.4 and 71.4%, respectively).

280 Ovarian Cancer - From Pathogenesis to Treatment

There are now numerous reports on secondary cytoreductive surgery (SCS) for recurrent ovarian cancer, with the focus on the epithelial subtype. They consistently show a benefit in overall survival—that is in ROC, complete surgical cytoreduction (with or without subsequent chemotherapy) is superior to chemotherapy only in these patients. The counter-argument is that the cases selected for surgery have more favourable features than those treated with chemotherapy alone. But as with primary disease, there is a subgroup who will not undergo surgery and be treated with chemotherapy alone, or rarely palliative care only. These treatment options should not be seen as competing for patients or as an either/or dilemma but as part of the multi-disciplinary team decision as to what is the best management for a particular patient.

The initial report by Berek et al. [50] on ROC showed a survival benefit where the surgical result was optimal (<1.5 cm residual) compared to suboptimal. In a later small study on 36 patients Eisenkop, and a subsequent study by the same authors on 106 patients [43, 44] reported a survival benefit from cytoreduction which was compromised by prior second-line chemotherapy before secondary cytoreductive surgery and where the tumour burden (maximum tumour diameter) was large (>10 cm). Their reports are unusual in that most other reports do not consider either factor as important in case selection for SCS. They also reported that the key surgical factor improving overall survival was complete cytoreduction. Other reports have found the same association and reported [51] that chemotherapy before surgical cytoreduction had a negative impact on surgery.

A common intraoperative finding in recurrent disease is carcinomatosis, which is most problematic where there is extensive involvement of the small bowel serosa and/or mesentery and often results in incomplete surgical cytoreduction. However, the DESKTOP I and II trials reported that even with carcinomatosis, if complete surgical clearance is achieved, carcinomatosis is not a negative prognostic factor in recurrent disease. Indeed, Chi et al. also consider that carcinomatosis is not a contra-indication to secondary cytoreductive surgery if the diseasefree interval is 30 months or more as there is patient benefit if CSC is achieved [40, 41]. In a retrospective review of patients with ROC treated in the CALYPSO trial [52], complete surgical cytoreduction was associated with improved survival compared to patients treated with chemotherapy alone; however, as patients who had less favourable features and who did not have complete cytoreduction derived notably less benefit from surgery, then, as noted by the authors, there is likely to be a significant selection bias in the surgical studies on ROC [52]. Most reports have not addressed quality of life (QoL) issues, but in one report [27], no difference was found to be in QoL in patients with ROC who had chemotherapy alone and those who had surgery and chemotherapy.

study [56] on a small number of patients. However, if second-line chemotherapy has been given and there has been disease progression, in general there would be a greater reluctance to operate. This sequence of management of initial chemotherapy has been proposed as a means to case select for secondary cytoreduction as only those showing a response should undergone surgery. Bulky disease has been considered an adverse factor in those undergoing surgery for ROC, but only in a few reports; Eisenkop et al. [43, 44] reported on patients with tumour mass more than and less than 10 cm and Onda et al. reported [45] a poorer outcome from surgery with tumour masses greater than 6 cm. Perhaps not surprising that amongst all patients treated initially with chemotherapy for ROC, those who do better are those who also have more favourable factors for surgery—such as longer DFI, good performance status and small volume disease. As with surgery, predictive models for response and outcome for patients treated with chemotherapy for ROC have been described. In the model proposed by Lee et al. [22], CA125 level (≤ 100 IU/l or > 100 IU/l) was assessed as was largest tumour size (<5 cm or >5 cm) but the role of secondary cytoreductive surgery was not assessed. Different managements of ROC may be appropriate in a particular patient but in patients with favourable factors, secondary cytoreductive surgery (with or without chemotherapy) results in a better outcome (overall survival) than chemotherapy alone [24, 30, 33], although level I evidence on overall survival benefit is awaited [49]. In a large retrospective study on ROC in which patients were treated with chemotherapy alone or with cytoreductive surgery and chemotherapy, the latter group had improved overall survival, but only in those with no residual disease or

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8. Surgery and IP/HIPEC chemotherapy for recurrent ovarian cancer

The Cochrane review on the use of intraperitoneal (ip) chemotherapy for primary OC [58] concluded that this treatment prolonged PFS and OS. While there is evidence of a survival benefit for IP chemotherapy/HIPEC after cytoreductive surgery in primary disease, there are fewer reports on its use and efficacy in recurrent disease [59]. No mention was made of this type of treatment in the Cochrane review on recurrent ovarian cancer [60] nor in the review by the Fifth Ovarian cancer Consensus Conference of the Gynecologic Cancer InterGroup [7].

Boisen et al. [61] reported on a retrospective study of 25 patients treated with iv/ip chemotherapy but without secondary cytoreductive surgery. The study period was over 6 years on a selected group of patients and 10 of 25 had an improved treatment-free interval. In a feasibility study of ip chemotherapy in 56 patients with platinum-sensitive recurrent disease all of whom had had prior secondary cytoreductive surgery (67.9% to <1 cm), 79% tolerated 6 cycles of ip platinum. No difference in outcome was noted related to the completeness of secondary surgery and the median overall survival was 51 months; no clinical factors associated with improved PFS or OS were identified [62]. The data from other studies report that the main indicators for response to ip chemotherapy are (1) volume of residual disease and (2) platinumsensitive disease [63, 64]. Fujiwara, in contrast reported responses in patients with suboptimal

Ansaloni et al. [66] provided one of the first reports on HIPEC following cytoreductive surgery in 30 patients with recurrent disease. In this small study, HIPEC was considered safe and there

smaller volume residual disease [57].

surgical resection [65].
