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The Role of Secondary Surgery in Recurrent Ovarian Cancer

The Role of Secondary Surgery in Recurrent Ovarian Cancer Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 613980, 6 pages doi:10.1155/2012/613980 Review Article D. Lorusso,M.Mancini,R.DiRocco,R.Fontanelli, andF.Raspagliesi Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy Correspondence should be addressed to D. Lorusso, kettalorusso@libero.it Received 31 March 2012; Accepted 30 May 2012 Academic Editor: Constantine P. Karakousis Copyright © 2012 D. Lorusso et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite optimal treatment (complete cytoreduction and adjuvant chemotherapy), 5-year survival for advanced ovarian cancer is approximately 30% and most patients succumb to their disease. Cytoreductive surgery is accepted as a major treatment of primary ovarian cancer but its role in recurrent disease is controversial and remains a field of discussion mainly owing to missing data from prospective randomized trials. A critical review of literature evidence on secondary surgery in recurrent ovarian cancer will be described. 1. Introduction Moreover, given the long time span of most studies (>5–10 years), the pre- and postoperative chemotherapy Despite optimal treatment (complete cytoreduction and treatments varied widely between patients thus increasing adjuvant platinum-paclitaxel chemotherapy), 5-year survival the difficulties in the interpretation of data. for advanced ovarian cancer is approximately 30% [1]and None of the studies details how recurrence was detected, most patients succumb to their disease. Overall, 85% of the type of followup adopted after primary treatment, and ovarian cancer patients will experience recurrent disease, the selection criteria used for secondary cytoreduction which with virtually no long-term survival after recurrence. Cytore- broadly differ between studies. ductive surgery is accepted as a major treatment of primary Although the recently published MRC OVO5/EORTC ovarian cancer but its role in recurrent disease is contro- 55955 trial [4] concluded that early intervention with versial and remains a field of discussion mainly owing to chemotherapy for recurrent ovarian cancer detected only missing data from prospective randomized trials and to the on the basis of serum CA 125 rising does not alter overall broad variety of definitions of surgical procedures. Moreover, survival with respect to waiting for the appearance of different studies include different groups of patients ranging symptomatic disease, Tanner et al. [5] found that survival from patients with persistent disease at the end of first line after ovarian cancer recurrence was greater in asymptomatic treatment (which possibly includes patients with persisting patients than in those with symptoms (45 versus 29.4 and/or progressing disease at the completion of carboplatin- months, P = 0.006), and this was due to the rate of successful paclitaxel chemotherapy) to patients with recurrent disease secondary cytoreductive surgery which was higher in the after a disease-free period variable from some weeks to asymptomatic group (90% versus 57%, P = 0.053). Even if several years [2, 3]. retrospective in nature, this study seems to suggest that early In addition, all but one series are represented by ret- surgery in asymptomatic patients with recurrent ovarian rospective studies and obviously suffer from selection bias. cancer may be of benefit thus underling the opportunity of Generally, the rate of patients not offered secondary surgery continuous clinical and radiological followup at the end of at recurrence varied from 7 to 64% among different trials first line treatment. but unfortunately informations about selection criteria and Unfortunately, the only prospective randomized trial outcomes of nonsurgery selected populations are lacking. addressing the role of secondary surgery in recurrent ovarian 2 International Journal of Surgical Oncology cancer, the LOROCSON trial, sponsored by European Orga- the subgroup with “absence of visible disease” consistently nization for Research and Treatment of Cancer (EORTC), demonstrate superior results in this group [6, 7, 10–13, 15, aborted prematurely due to low recruitment. 17, 20] with respect to all the other residual disease cutoff Since the publication by Berek et al. in 1983, which first groups. introduced the term “secondary cytoreduction,” the clinical The large multicenter prospective trial DESKTOP I scenarios and indications of repeated tumor cytoreductive (Descriptive Evaluation of Preoperative Selection Criteria operations for recurrent ovarian cancer have been more pre- for Operability) [24] has clearly demonstrated that only cisely defined [21]. According to most clinicians, secondary complete debulking has prognostic influence and that the cytoreductive surgery for recurrent ovarian cancer is defined “so-called” optimal debulking with residuals up to 1 cm as an operative procedure performed at some time remote plays no role in surgery for recurrent ovarian cancer. The (generally disease free interval of more than 6 months) DESKTOP I trial identified residual disease after surgery as from the completion of primary therapy with the intended the strongest independent prognostic factor for survival in purpose of tumor reduction. Although usually not curative, combination with the absence of ascites and platinum-based this kind of surgery aims at prolongation of survival by reinduction chemotherapy. reducing tumor burden and at improvement of quality of life Most studies document approximately 50% of patients and cancer-related symptoms. being cytoreducted to absence of residual disease, but the The only 2 studies looking at secondary cytoreduction complete debulking rate varied from 9% to 85% [13, 16] in patients with suboptimal response to primary treatment likely being these differences expression of variances in showed a marginal benefit of surgery at the cost of high patients selection criteria, definitions of optimal cytoreduc- morbidity (24%) and limited long-term benefit with a tion, surgical techniques, and aggressiveness of surgeons. median survival of 9 months [6, 22] so, at present, there is no evidence that secondary surgery is of significant benefit 4. How to Identify Patients Who Most in this population. Likely Benefit? The DESKTOP I trial [24] identified an independently 2. Rationale for Surgery predictive score for complete resection (AGO score) com- The rationale of surgical removal or recurrent tumor is prehensive of good performance status (Eastern Cooperative high and it is supported by the mathematical model of Oncology Group 0), complete resection at primary surgery Goldie and Coldman predicting drug resistance in cancer (or alternatively, International Federation of Gynecology [23] and suggesting that the likelihood of chemotherapy and Obstetrics stage I/II), and the absence of ascites. If all being curable is related to the number of tumor cells the 3 factors were contemporarily present (positive AGO present (10 tumor cells are likely to be curable with score), complete resection was feasible in 79% of patients. 6 7 chemotherapy, but 1 cm tumor nodules contain 10 –10 The subsequent international multicenter trial DESKTOP cells). Other theoretical benefits are the removal of a poorly II prospectively validated this score [25]: 129 patients with vascularized tumor which may represent pharmacologic positive AGO score submitted to secondary surgery for sanctuaries of drug resistance; a higher growth fraction in ovarian cancer recurrence were enrolled with a confirmed the better perfuse small residual tumor masses which favors complete resection rate of 76%. the action of cytotoxic therapy; the potentially fewer number Several studies have been published addressing the role of chemotherapy cycles required by small tumor masses of radiological evaluation in predicting successful secondary limiting the probability of inducing drug resistance; finally surgery but all of the series were retrospective evaluations, the enhancement of host immunocompetence generated by never prospectively validated [26]. Laparoscopic evaluation the removal of large tumor bulk. of successful surgery was published by an Italian group with percentages of complete resections comparable to what obtained with AGO score but at higher price in terms of 3. Definition of Residual Disease complications and feasibility of the procedure [27]. None of the published series reported age as a predictor Almost all series reported a relationship between survival of resectability but most of them excluded patients older than and surgical outcome in univariate analysis and complete 70 years old from secondary surgery. debulking is one of the strongest predictors for survival in all The presence of cancer-related symptoms, tumor burden, multivariate analyses (Table 1). At present what is considered presurgical serum CA 125 values, localizations of disease, “optimal cytoreduction”? The definition of optimal residual and treatment-free interval (TFI) were inconstantly reported disease widely varies across studies; while some authors argue as predictive factors of tumor resectability in univariate and that optimal cytoreduction can only be described as “absence multivariate analysis. of visible disease” at the end of the operation, others use less than 0.5 cm [10, 13], less than 1 cm [16, 17, 19, 20], less than 1.5 cm [21], or less than 2 cm cutoff [6–9, 12, 14]. 5. Prognostic Factors for Survival All the studies report superior overall survival in optimally cytoreducted patients, regardless of the discrepancy in how Complete debulking was the strongest predictor for survival “optimal cytoreduction” was defined. The studies stratifying in all the multivariate analyses performed across the studies International Journal of Surgical Oncology 3 Table 1: Published results on secondary cytoreduction for recurrent ovarian cancer. Median survival after secondary surgery Reference n Definition used Cytoreduced (%) (months) Berek [3]21 RD<o>1.5 cm; 6/21 (29); 15/21 (71) <1.5, (20); >1.5 (5) P< 0.01 Morris [6]30 NVD;RD<o>2 cm 9/30 (30); 8/30 (27); 13/30 (43) <2 (18.8); > 2(13.3) ns Janicke [7]28 NVD;RD<o> 2 cm 14/28 (50); 12/28 (43); 2/28 (7) NVD, (29); RD, (9) P = 0.0000 Segna [8] 100 RD<o>2 cm 61/100 (61); 39/100 (39) <2,(27.1); >2, (9) P = 0.0001 3/5 stage I (60); 2/5 stage I (40); Pecorelli [9] 270 NVD; RD RD<o>2cm <2 (20); >2 (12) P = 0.045 13/22 stage III (58); 9/22 stage III ( 41) Vaccarello [10]57 RD<o>0.5 cm 38/57 (67); 23/38 <0.5, NYR; >0.5 (23) Cormio [11] 21 NVD; no cytoreduction 15/21 (71); 6/21 (25) NVD, (32); RD (9) P = 0.029) Gadducci [12]30 NVDRD<o>2 cm 17/30 (57); 8/30 (27); 5/30 (17) NVD (37); RD (19) P = 0.04 Eisenkop [13] 106 NVD; RD<o>2 cm 87/106 (82); 3/106 (3); 16/106 (15) NVD (44.4); RD (19.3) P = 0.0007 Munkarah [14]25 NVD;RD<o>2 cm 12/25 (48); 6/25 (24); 7/25 (28) NVD (56.9); RD (25.1) P = 0.08 Tay [15] 46 NVD; RD 19/46 (41); 27/46 (59) NVD (38); RD (11) P = 0.002 Zang [16] 107 NVD; RD<o>1 cm 11/107 (10); 61/107 (57); 35/107 (33) NVD nyr; RD < 1 (26); >1(14.5) Onda [17]44 NVD;RD<o>1 cm 26/44 (59); 11/44 (25); 7/44 (16) NVD (52); RD<1 (23) P = 0.0007; >1 (20) Gung ¨ or ¨ [18] 44 Surgery; chemo only; NVD 44/75 (59); 31/75 (41); 34/44 (77) NVD (19); RD (9) P = 0.007 Pfisterer [19] 267 NVD; RD<o>1 cm 133/267 (50); 69/267 (26); 65/267 (24) NVD (45.3); RD (19) P< 0.0001 Ayhan [20]64 NVD;RD<o>1 cm 28/64 (44); 25/64 (39); 11/64 (17) <1 (28); >1 (18) P = 0.004 RD: residual disease, NVD: no visible disease, NS: not significant, NYR: not yet reached. (Table 2). All the other analyzed factors provided conflicting arms which is generally poorer than the median overall results. Treatment free interval before secondary surgery did survival reported by the majority of trials of optimally not show any significant impact on outcome in univariate debulked recurrent ovarian cancer patients [32]. Moreover, a analysis in approximately half of the published series and meta-analysis on the role of secondary surgery for recurrent even where reported did not retain independent prognostic ovarian cancer on 40 studies in 2019 patients reported significance in multivariate analysis. Of note, a very poor that each 10% increase in optimally cytoreducted patients percentage of enrolled patients presented TFI less than 6 translates into a 3-month increase of overall survival [33]. months (0–13.5%) suggesting that data addressing a possible Gung ¨ or ¨ et al. [18] reported in a retrospective review that impact of TFI on survival are mainly valid for different patients who underwent successful secondary cytoreductive periods beyond 6 months. surgery had an improved survival over patients who had The absence of ascites and the reintroduction of platinum chemotherapy as exclusive treatment at recurrence. Unfor- as adjuvant treatment after surgery are generally asso- tunately, in absence of a prospective randomized trial, such ciate with prolonged survival. On the contrary, unfavorable conclusions may represent the result of selection bias rather outcome was reported for patients receiving preoperative than the effect of surgery. chemotherapy possibly for the emergence and selections A recently published Cochrane Review [34] found no of chemotherapy resistant foci. The impact of preoperative evidence from randomized clinical trials to inform decisions tumor load remains controversial: an exploratory analysis of about secondary surgical cytoreduction and chemotherapy DESKTOP 1 trial showed that peritoneal carcinomatosis is a compared to chemotherapy alone for women with recurrent significant negative predictor for complete resection, but if epithelial ovarian cancer. The author concluded that ideally, complete resection is still possible there is no difference in a large randomized controlled trial or, at the very least, survival compared to completely debulked patients without well-designed nonrandomized studies that use multivariate peritoneal carcinomatosis [28]. analysis to adjust for baseline imbalances are needed to compare these two treatment modalities. The AGO group started with the DESKTOP III trial in 6. Comparison with Chemotherapy Q3 2011. This study is a randomized phase III trial com- Platinum-based combinations appear as the most suit- paring cytoreductive surgery followed by platinum-based chemotherapy versus chemotherapy alone in a population of able and active treatments for recurrent platinum-sensitive (platinum-free interval >6 months) ovarian cancer patients. 408 recurrent platinum sensitive ovarian cancer with positive Combinations with taxanes [29], gemcitabine [30], and AGO score at first event of disease recurrence. A similar study, the GOG 213 study, is ongoing in the pegylated liposomal doxorubicin [31] reported a median survival of 29, 18, and 31.5 months in the respective superior United States addressing two different questions: the role of 4 International Journal of Surgical Oncology Table 2: Multivariate analysis for survival. Zang Eisenkop Tay Zang Onda Pfisterer Ayhan [16][13][15][16][17][19][20] n 60 106 46 107 44 267 64 Age Ns Ns Ns Ns PS Ns Ns Ns Initial FIGO Ns Ns Ns Ns Ns Grade Ns Ns Ns Ns Histology Ns 0.017 Ns 0.005 RD after primary surgery Ns Ns 0.003 DFI 0.0116 0.005 0.001 <0.001 0.003 RD after secondary surgery 0.0041 0.007 0.002 <0.001 0.04 Disease localization Ns 0.013 No disease sites <0.001 Largest tumor diameter Ns 0.04 <0.001 Ascites 0.0191 Ns Ns 0.012 Ca 125 Ns No cycles chemo Ns Chemo Ns 0.001 Ns: not significant, RD: residual disease, DFI: disease-free interval. At secondary surgery. Prior to secondary surgery. secondary surgery in recurrent platinum-sensitive ovarian reviewed the oncologic outcome, morbidity and mortality of cancer and the inclusion of bevacizumab in combination or cytoreductive surgery, and HIPEC of 19 retrospective obser- not to standard carboplatin-paclitaxel treatment as adjuvant vational studies from 10 high volume specialized treatment chemotherapy. centers and reported a severe morbidity rate ranging from 12% to 63%, a treatment-related mortality ranging from 0.9% to 10%, and a median overall survival ranging from 22 7. Morbidity and Quality of Life to 64 months. Such a broad variability in reported oncologic outcomes and toxicities represents the clear expression of the Due to the retrospective nature of most studies, reliable extreme heterogeneity in enrolled population, the different information on QOL and postoperative morbidity are often time point of HIPEC administration during the natural not available. Most studies reported around 30–40% post- history of ovarian cancer (published data are a miscellanea operative morbidity with severe morbidity (including sepsis, of interval debulking surgery, second-look surgery, and sec- hemorrhage, adult respiratory distress syndrome, bowel ondary cytoreduction of mixed platinum-sensitive and resis- obstruction, and disseminated intravascular coagulation) tant patients), the variability of chemotherapy employed, quoted around 10% and up to 2% postoperative mortality the center expertise, and also possibly may represent the registered [12, 13, 15]. expression of a wide different clinicians’ interpretation and Very little is known about quality of life (QOL) after reporting of data which make it exceptionally difficult to secondary cytoreduction. Wenzel et al. [35]reportedno draw definitive conclusions. difference in QOL in a randomized multicenter trial compar- ing FIGO stage III-IV ovarian cancer patients who did and The absence of valuable alternative treatment option, did not undergo interval debulking surgery after incomplete as suggested by few authors, is not an acceptable criteria primary cytoreduction and 3 cycles of platinum-paclitaxel “per se” for further promoting this concept: the high level chemotherapy thus suggesting that additional surgical inter- of perioperative morbidity and mortality might be consid- ventions in ovarian cancer may not have any significant ered acceptable when no other alternate therapy has been impact (positive or negative) on QOL. shown to be effective in curing or controlling the disease but this is not the case of ovarian cancer recurrence in which surgery and platinum-based chemotherapy represent 8. Cytoreductive Surgery and Hyperthermic accepted, evidence-based, valuable options. Intraperitoneal Chemotherapy (HIPEC) Ovarian cancer moreover is quite a different disease Cytoreductive surgery and HIPEC have yielded promising with respect to colon cancer in which only one random- results in malignant disease for which no other systemic ized trial comparing HIPEC versus palliative surgery plus therapies have been shown to be beneficial [36–38]. As far as chemotherapy has ratified HIPEC as the new standard ovarian cancer is concerned, Chua et al. [39]systematically treatment of peritoneal colon cancer carcinomatosis [40], International Journal of Surgical Oncology 5 and conclusions derived from one type of malignancy should [2] F. Sharp, A. D. Blackett, R. E. Leake, and J. S. 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The Role of Secondary Surgery in Recurrent Ovarian Cancer

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Hindawi Publishing Corporation
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Copyright © 2012 D. Lorusso et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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10.1155/2012/613980
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Hindawi Publishing Corporation International Journal of Surgical Oncology Volume 2012, Article ID 613980, 6 pages doi:10.1155/2012/613980 Review Article D. Lorusso,M.Mancini,R.DiRocco,R.Fontanelli, andF.Raspagliesi Fondazione IRCCS Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy Correspondence should be addressed to D. Lorusso, kettalorusso@libero.it Received 31 March 2012; Accepted 30 May 2012 Academic Editor: Constantine P. Karakousis Copyright © 2012 D. Lorusso et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Despite optimal treatment (complete cytoreduction and adjuvant chemotherapy), 5-year survival for advanced ovarian cancer is approximately 30% and most patients succumb to their disease. Cytoreductive surgery is accepted as a major treatment of primary ovarian cancer but its role in recurrent disease is controversial and remains a field of discussion mainly owing to missing data from prospective randomized trials. A critical review of literature evidence on secondary surgery in recurrent ovarian cancer will be described. 1. Introduction Moreover, given the long time span of most studies (>5–10 years), the pre- and postoperative chemotherapy Despite optimal treatment (complete cytoreduction and treatments varied widely between patients thus increasing adjuvant platinum-paclitaxel chemotherapy), 5-year survival the difficulties in the interpretation of data. for advanced ovarian cancer is approximately 30% [1]and None of the studies details how recurrence was detected, most patients succumb to their disease. Overall, 85% of the type of followup adopted after primary treatment, and ovarian cancer patients will experience recurrent disease, the selection criteria used for secondary cytoreduction which with virtually no long-term survival after recurrence. Cytore- broadly differ between studies. ductive surgery is accepted as a major treatment of primary Although the recently published MRC OVO5/EORTC ovarian cancer but its role in recurrent disease is contro- 55955 trial [4] concluded that early intervention with versial and remains a field of discussion mainly owing to chemotherapy for recurrent ovarian cancer detected only missing data from prospective randomized trials and to the on the basis of serum CA 125 rising does not alter overall broad variety of definitions of surgical procedures. Moreover, survival with respect to waiting for the appearance of different studies include different groups of patients ranging symptomatic disease, Tanner et al. [5] found that survival from patients with persistent disease at the end of first line after ovarian cancer recurrence was greater in asymptomatic treatment (which possibly includes patients with persisting patients than in those with symptoms (45 versus 29.4 and/or progressing disease at the completion of carboplatin- months, P = 0.006), and this was due to the rate of successful paclitaxel chemotherapy) to patients with recurrent disease secondary cytoreductive surgery which was higher in the after a disease-free period variable from some weeks to asymptomatic group (90% versus 57%, P = 0.053). Even if several years [2, 3]. retrospective in nature, this study seems to suggest that early In addition, all but one series are represented by ret- surgery in asymptomatic patients with recurrent ovarian rospective studies and obviously suffer from selection bias. cancer may be of benefit thus underling the opportunity of Generally, the rate of patients not offered secondary surgery continuous clinical and radiological followup at the end of at recurrence varied from 7 to 64% among different trials first line treatment. but unfortunately informations about selection criteria and Unfortunately, the only prospective randomized trial outcomes of nonsurgery selected populations are lacking. addressing the role of secondary surgery in recurrent ovarian 2 International Journal of Surgical Oncology cancer, the LOROCSON trial, sponsored by European Orga- the subgroup with “absence of visible disease” consistently nization for Research and Treatment of Cancer (EORTC), demonstrate superior results in this group [6, 7, 10–13, 15, aborted prematurely due to low recruitment. 17, 20] with respect to all the other residual disease cutoff Since the publication by Berek et al. in 1983, which first groups. introduced the term “secondary cytoreduction,” the clinical The large multicenter prospective trial DESKTOP I scenarios and indications of repeated tumor cytoreductive (Descriptive Evaluation of Preoperative Selection Criteria operations for recurrent ovarian cancer have been more pre- for Operability) [24] has clearly demonstrated that only cisely defined [21]. According to most clinicians, secondary complete debulking has prognostic influence and that the cytoreductive surgery for recurrent ovarian cancer is defined “so-called” optimal debulking with residuals up to 1 cm as an operative procedure performed at some time remote plays no role in surgery for recurrent ovarian cancer. The (generally disease free interval of more than 6 months) DESKTOP I trial identified residual disease after surgery as from the completion of primary therapy with the intended the strongest independent prognostic factor for survival in purpose of tumor reduction. Although usually not curative, combination with the absence of ascites and platinum-based this kind of surgery aims at prolongation of survival by reinduction chemotherapy. reducing tumor burden and at improvement of quality of life Most studies document approximately 50% of patients and cancer-related symptoms. being cytoreducted to absence of residual disease, but the The only 2 studies looking at secondary cytoreduction complete debulking rate varied from 9% to 85% [13, 16] in patients with suboptimal response to primary treatment likely being these differences expression of variances in showed a marginal benefit of surgery at the cost of high patients selection criteria, definitions of optimal cytoreduc- morbidity (24%) and limited long-term benefit with a tion, surgical techniques, and aggressiveness of surgeons. median survival of 9 months [6, 22] so, at present, there is no evidence that secondary surgery is of significant benefit 4. How to Identify Patients Who Most in this population. Likely Benefit? The DESKTOP I trial [24] identified an independently 2. Rationale for Surgery predictive score for complete resection (AGO score) com- The rationale of surgical removal or recurrent tumor is prehensive of good performance status (Eastern Cooperative high and it is supported by the mathematical model of Oncology Group 0), complete resection at primary surgery Goldie and Coldman predicting drug resistance in cancer (or alternatively, International Federation of Gynecology [23] and suggesting that the likelihood of chemotherapy and Obstetrics stage I/II), and the absence of ascites. If all being curable is related to the number of tumor cells the 3 factors were contemporarily present (positive AGO present (10 tumor cells are likely to be curable with score), complete resection was feasible in 79% of patients. 6 7 chemotherapy, but 1 cm tumor nodules contain 10 –10 The subsequent international multicenter trial DESKTOP cells). Other theoretical benefits are the removal of a poorly II prospectively validated this score [25]: 129 patients with vascularized tumor which may represent pharmacologic positive AGO score submitted to secondary surgery for sanctuaries of drug resistance; a higher growth fraction in ovarian cancer recurrence were enrolled with a confirmed the better perfuse small residual tumor masses which favors complete resection rate of 76%. the action of cytotoxic therapy; the potentially fewer number Several studies have been published addressing the role of chemotherapy cycles required by small tumor masses of radiological evaluation in predicting successful secondary limiting the probability of inducing drug resistance; finally surgery but all of the series were retrospective evaluations, the enhancement of host immunocompetence generated by never prospectively validated [26]. Laparoscopic evaluation the removal of large tumor bulk. of successful surgery was published by an Italian group with percentages of complete resections comparable to what obtained with AGO score but at higher price in terms of 3. Definition of Residual Disease complications and feasibility of the procedure [27]. None of the published series reported age as a predictor Almost all series reported a relationship between survival of resectability but most of them excluded patients older than and surgical outcome in univariate analysis and complete 70 years old from secondary surgery. debulking is one of the strongest predictors for survival in all The presence of cancer-related symptoms, tumor burden, multivariate analyses (Table 1). At present what is considered presurgical serum CA 125 values, localizations of disease, “optimal cytoreduction”? The definition of optimal residual and treatment-free interval (TFI) were inconstantly reported disease widely varies across studies; while some authors argue as predictive factors of tumor resectability in univariate and that optimal cytoreduction can only be described as “absence multivariate analysis. of visible disease” at the end of the operation, others use less than 0.5 cm [10, 13], less than 1 cm [16, 17, 19, 20], less than 1.5 cm [21], or less than 2 cm cutoff [6–9, 12, 14]. 5. Prognostic Factors for Survival All the studies report superior overall survival in optimally cytoreducted patients, regardless of the discrepancy in how Complete debulking was the strongest predictor for survival “optimal cytoreduction” was defined. The studies stratifying in all the multivariate analyses performed across the studies International Journal of Surgical Oncology 3 Table 1: Published results on secondary cytoreduction for recurrent ovarian cancer. Median survival after secondary surgery Reference n Definition used Cytoreduced (%) (months) Berek [3]21 RD<o>1.5 cm; 6/21 (29); 15/21 (71) <1.5, (20); >1.5 (5) P< 0.01 Morris [6]30 NVD;RD<o>2 cm 9/30 (30); 8/30 (27); 13/30 (43) <2 (18.8); > 2(13.3) ns Janicke [7]28 NVD;RD<o> 2 cm 14/28 (50); 12/28 (43); 2/28 (7) NVD, (29); RD, (9) P = 0.0000 Segna [8] 100 RD<o>2 cm 61/100 (61); 39/100 (39) <2,(27.1); >2, (9) P = 0.0001 3/5 stage I (60); 2/5 stage I (40); Pecorelli [9] 270 NVD; RD RD<o>2cm <2 (20); >2 (12) P = 0.045 13/22 stage III (58); 9/22 stage III ( 41) Vaccarello [10]57 RD<o>0.5 cm 38/57 (67); 23/38 <0.5, NYR; >0.5 (23) Cormio [11] 21 NVD; no cytoreduction 15/21 (71); 6/21 (25) NVD, (32); RD (9) P = 0.029) Gadducci [12]30 NVDRD<o>2 cm 17/30 (57); 8/30 (27); 5/30 (17) NVD (37); RD (19) P = 0.04 Eisenkop [13] 106 NVD; RD<o>2 cm 87/106 (82); 3/106 (3); 16/106 (15) NVD (44.4); RD (19.3) P = 0.0007 Munkarah [14]25 NVD;RD<o>2 cm 12/25 (48); 6/25 (24); 7/25 (28) NVD (56.9); RD (25.1) P = 0.08 Tay [15] 46 NVD; RD 19/46 (41); 27/46 (59) NVD (38); RD (11) P = 0.002 Zang [16] 107 NVD; RD<o>1 cm 11/107 (10); 61/107 (57); 35/107 (33) NVD nyr; RD < 1 (26); >1(14.5) Onda [17]44 NVD;RD<o>1 cm 26/44 (59); 11/44 (25); 7/44 (16) NVD (52); RD<1 (23) P = 0.0007; >1 (20) Gung ¨ or ¨ [18] 44 Surgery; chemo only; NVD 44/75 (59); 31/75 (41); 34/44 (77) NVD (19); RD (9) P = 0.007 Pfisterer [19] 267 NVD; RD<o>1 cm 133/267 (50); 69/267 (26); 65/267 (24) NVD (45.3); RD (19) P< 0.0001 Ayhan [20]64 NVD;RD<o>1 cm 28/64 (44); 25/64 (39); 11/64 (17) <1 (28); >1 (18) P = 0.004 RD: residual disease, NVD: no visible disease, NS: not significant, NYR: not yet reached. (Table 2). All the other analyzed factors provided conflicting arms which is generally poorer than the median overall results. Treatment free interval before secondary surgery did survival reported by the majority of trials of optimally not show any significant impact on outcome in univariate debulked recurrent ovarian cancer patients [32]. Moreover, a analysis in approximately half of the published series and meta-analysis on the role of secondary surgery for recurrent even where reported did not retain independent prognostic ovarian cancer on 40 studies in 2019 patients reported significance in multivariate analysis. Of note, a very poor that each 10% increase in optimally cytoreducted patients percentage of enrolled patients presented TFI less than 6 translates into a 3-month increase of overall survival [33]. months (0–13.5%) suggesting that data addressing a possible Gung ¨ or ¨ et al. [18] reported in a retrospective review that impact of TFI on survival are mainly valid for different patients who underwent successful secondary cytoreductive periods beyond 6 months. surgery had an improved survival over patients who had The absence of ascites and the reintroduction of platinum chemotherapy as exclusive treatment at recurrence. Unfor- as adjuvant treatment after surgery are generally asso- tunately, in absence of a prospective randomized trial, such ciate with prolonged survival. On the contrary, unfavorable conclusions may represent the result of selection bias rather outcome was reported for patients receiving preoperative than the effect of surgery. chemotherapy possibly for the emergence and selections A recently published Cochrane Review [34] found no of chemotherapy resistant foci. The impact of preoperative evidence from randomized clinical trials to inform decisions tumor load remains controversial: an exploratory analysis of about secondary surgical cytoreduction and chemotherapy DESKTOP 1 trial showed that peritoneal carcinomatosis is a compared to chemotherapy alone for women with recurrent significant negative predictor for complete resection, but if epithelial ovarian cancer. The author concluded that ideally, complete resection is still possible there is no difference in a large randomized controlled trial or, at the very least, survival compared to completely debulked patients without well-designed nonrandomized studies that use multivariate peritoneal carcinomatosis [28]. analysis to adjust for baseline imbalances are needed to compare these two treatment modalities. The AGO group started with the DESKTOP III trial in 6. Comparison with Chemotherapy Q3 2011. This study is a randomized phase III trial com- Platinum-based combinations appear as the most suit- paring cytoreductive surgery followed by platinum-based chemotherapy versus chemotherapy alone in a population of able and active treatments for recurrent platinum-sensitive (platinum-free interval >6 months) ovarian cancer patients. 408 recurrent platinum sensitive ovarian cancer with positive Combinations with taxanes [29], gemcitabine [30], and AGO score at first event of disease recurrence. A similar study, the GOG 213 study, is ongoing in the pegylated liposomal doxorubicin [31] reported a median survival of 29, 18, and 31.5 months in the respective superior United States addressing two different questions: the role of 4 International Journal of Surgical Oncology Table 2: Multivariate analysis for survival. Zang Eisenkop Tay Zang Onda Pfisterer Ayhan [16][13][15][16][17][19][20] n 60 106 46 107 44 267 64 Age Ns Ns Ns Ns PS Ns Ns Ns Initial FIGO Ns Ns Ns Ns Ns Grade Ns Ns Ns Ns Histology Ns 0.017 Ns 0.005 RD after primary surgery Ns Ns 0.003 DFI 0.0116 0.005 0.001 <0.001 0.003 RD after secondary surgery 0.0041 0.007 0.002 <0.001 0.04 Disease localization Ns 0.013 No disease sites <0.001 Largest tumor diameter Ns 0.04 <0.001 Ascites 0.0191 Ns Ns 0.012 Ca 125 Ns No cycles chemo Ns Chemo Ns 0.001 Ns: not significant, RD: residual disease, DFI: disease-free interval. At secondary surgery. Prior to secondary surgery. secondary surgery in recurrent platinum-sensitive ovarian reviewed the oncologic outcome, morbidity and mortality of cancer and the inclusion of bevacizumab in combination or cytoreductive surgery, and HIPEC of 19 retrospective obser- not to standard carboplatin-paclitaxel treatment as adjuvant vational studies from 10 high volume specialized treatment chemotherapy. centers and reported a severe morbidity rate ranging from 12% to 63%, a treatment-related mortality ranging from 0.9% to 10%, and a median overall survival ranging from 22 7. Morbidity and Quality of Life to 64 months. Such a broad variability in reported oncologic outcomes and toxicities represents the clear expression of the Due to the retrospective nature of most studies, reliable extreme heterogeneity in enrolled population, the different information on QOL and postoperative morbidity are often time point of HIPEC administration during the natural not available. Most studies reported around 30–40% post- history of ovarian cancer (published data are a miscellanea operative morbidity with severe morbidity (including sepsis, of interval debulking surgery, second-look surgery, and sec- hemorrhage, adult respiratory distress syndrome, bowel ondary cytoreduction of mixed platinum-sensitive and resis- obstruction, and disseminated intravascular coagulation) tant patients), the variability of chemotherapy employed, quoted around 10% and up to 2% postoperative mortality the center expertise, and also possibly may represent the registered [12, 13, 15]. expression of a wide different clinicians’ interpretation and Very little is known about quality of life (QOL) after reporting of data which make it exceptionally difficult to secondary cytoreduction. Wenzel et al. [35]reportedno draw definitive conclusions. difference in QOL in a randomized multicenter trial compar- ing FIGO stage III-IV ovarian cancer patients who did and The absence of valuable alternative treatment option, did not undergo interval debulking surgery after incomplete as suggested by few authors, is not an acceptable criteria primary cytoreduction and 3 cycles of platinum-paclitaxel “per se” for further promoting this concept: the high level chemotherapy thus suggesting that additional surgical inter- of perioperative morbidity and mortality might be consid- ventions in ovarian cancer may not have any significant ered acceptable when no other alternate therapy has been impact (positive or negative) on QOL. shown to be effective in curing or controlling the disease but this is not the case of ovarian cancer recurrence in which surgery and platinum-based chemotherapy represent 8. Cytoreductive Surgery and Hyperthermic accepted, evidence-based, valuable options. Intraperitoneal Chemotherapy (HIPEC) Ovarian cancer moreover is quite a different disease Cytoreductive surgery and HIPEC have yielded promising with respect to colon cancer in which only one random- results in malignant disease for which no other systemic ized trial comparing HIPEC versus palliative surgery plus therapies have been shown to be beneficial [36–38]. As far as chemotherapy has ratified HIPEC as the new standard ovarian cancer is concerned, Chua et al. [39]systematically treatment of peritoneal colon cancer carcinomatosis [40], International Journal of Surgical Oncology 5 and conclusions derived from one type of malignancy should [2] F. Sharp, A. D. Blackett, R. E. Leake, and J. S. 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