Neoadjuvant chemotherapy in ovarian cancer revisited

Neoadjuvant chemotherapy in ovarian cancer revisited

symposium article Annals of Oncology 27 (Supplement 1): i30–i32, 2016 doi:10.1093/annonc/mdw092 Neoadjuvant chemotherapy in ovarian cancer revisited...

110KB Sizes 0 Downloads 93 Views

symposium article

Annals of Oncology 27 (Supplement 1): i30–i32, 2016 doi:10.1093/annonc/mdw092

Neoadjuvant chemotherapy in ovarian cancer revisited S. Mahner1,†*, F. Trillsch1,†, D. Chi2, P. Harter3, J. Pfisterer4, F. Hilpert5, A. Burges1, T. Weissenbacher1 & A. du Bois3 Department of Gynaecology and Obstetrics, Ludwig-Maximilians-University, Munich; 2Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, USA; 3Department of Gynaecolgy and Gynaecolgic Oncology, Kliniken Essen-Mitte, Essen; 4Gynaecologic Oncology Center, Kiel; 5Department of Gynaecolgy and Obstetrics, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Germany

Despite the recent publication of two randomized controlled phase III trials addressing neoadjuvant chemotherapy in advanced ovarian cancer, the optimal timing of multimodal management in primary therapy is still under debate. As both studies met their primary end point by demonstrating non-inferiority, neoadjuvant chemotherapy followed by interval debulking surgery has been proposed to be an alternative standard for primary ovarian cancer treatment. Nevertheless, significant questions remain unanswered in both trials. Especially, the radicality of surgical therapy was below expectation with the median operating times of <3 h and complete gross resection in <20% of the patients. Consecutively, survival rates of patients undergoing primary debulking surgery were low. Since the primarily surgical question of ‘primary versus interval-surgery’ can only be answered if the key criteria ‘complete gross resection’ are present in a considerable percentage of patients, additional studies are needed and neoadjuvant chemotherapy should not be used to reduce surgical radicality for ovarian cancer treatment. Key words: ovarian cancer, surgery, chemotherapy, neoadjuvant, interval debulking

Following the publication of the first randomized controlled phase III trial addressing neoadjuvant chemotherapy in advanced ovarian cancer by Vergote et al. in 2010 [1], a discussion on the optimal timing of multimodal management has emerged. Since then, some authors claim neoadjuvant chemotherapy followed by interval debulking surgery (IDS) to be an alternative for primary ovarian cancer surgical treatment with the possible advantage of reduced surgical morbidity. Recently, this tendency was further supported when the results of the multicentre phase III CHORUS trial were published in July 2015 [2]. Nevertheless, due to significant questions in both studies, especially in terms of surgical quality, evidence regarding neoadjuvant chemotherapy for primary ovarian cancer is still insufficient to define the optimal sequence of the treatment modalities. Consequently, this topic needs to be revisited. Over decades, the standard management of patients with advanced ovarian cancer has been primary cytoreductive debulking surgery (PDS) followed by chemotherapy. Griffiths [3] initially demonstrated that survival depends on residual disease which was confirmed by many other authors and two meta-analyses [4–13]. Although these data arise mainly from retrospective analyses, the observation of improved patient

*Correspondence to: Sven Mahner, Department of Gynaecology and Obstetrics, LudwigMaximilians-University Munich, Marchioninistr. 15, Munich 81377, Germany. Tel: +49-894400-54101; Fax: +49-89-4400-54143; E-mail: [email protected]

outcome with more extensive surgical debulking has been consistent and led to the primary surgical aim of no macroscopic visible tumour after surgery. To achieve complete resection, cytoreductive surgery consists of salpingo-oophorectomy, hysterectomy, and omentectomy, but can also include additional surgical procedures like bowel surgery and upper abdominal surgery as well as systematic pelvic and paraaortic lymphadenectomy in patients with advanced ovarian cancer [14]. The impact of debulking on patient survival has been shown to be equivalent whether complete debulking is attained with easily resectable disease solely affecting the omentum and ovaries or whether it requires more extensive surgery involving the peritoneal diaphragm, rectosigmoid colon, or paraaortic lymph nodes [13, 15]. Furthermore, contemporary studies have demonstrated that the impact of potentially negative biological factors such as grade and histology can be overcome by surgical debulking [13]. Residual disease after surgery is (apart from which systemic treatment is selected) the only prognostic factor which can be influenced by the treating physician. The first prospective randomized phase III trial concentrating on the alternative approach with neoadjuvant chemotherapy was reported in 2010 by the European Organization for Research and Treatment of Cancer-Gynecologic Cancer Group (EORTC-GCG) and the National Cancer Institute of Canada (NCIC) Clinical Trials Group [1]. In this international study, 670 patients with stage IIIC or IV ovarian cancer were randomized to PDS followed by platinum-based chemotherapy or to neoadjuvant platinum-



These authors contributed equally.

© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

Downloaded from http://annonc.oxfordjournals.org/ by guest on June 6, 2016

symposium article

1

Annals of Oncology

Volume 27 | Supplement 1 | April 2016

to death or progressive disease during the first three cycles of neoadjuvant chemotherapy [2]. As this seems to represent a positive selection for the cohort undergoing surgery in the NACT arm, this might have had a significant impact on the results. Accordingly, only 88% of patients assigned to NACT actually underwent IDS in the EORTC/NCIC trial [1]. This has to be accounted for when perioperative morbidity is discussed and claimed as a main advantage of NACT. Due to the significant drawbacks in these two studies, the question whether PDS or NACT followed by IDS should be the standard approach for patients with advanced ovarian cancer has not yet been answered. Although PFS and OS for the NACT arm are consistent with those of other neoadjuvant studies in the literature [20], survival outcomes in the PDS arm were alarmingly low. Rates for complete gross resection at PDS in both trials were also very low (19% and 16%) and consecutively called the findings of both studies into question. As several studies and meta-analyses have shown that complete cytoreduction with no residual disease after surgery is most beneficial for patients with advanced ovarian cancer [12, 13], the comparison of the approaches upfront surgical debulking versus interval debulking apparently needs to account for this factor. This can hardly be drawn from trials in which this factor was only present in <20% of the population. As a comparison, rates for complete resection of unselected patients with advanced stage ovarian cancer in surgically specialized gynaecologic cancer centres ranges between 50% and 70% [21–24]. Accordingly, the median surgical times of 120 and 165 min urgently put the question of surgical radicality into focus as this time appears hardly sufficient to have a thorough exploration of the abdomen and carry out at least the standard procedures for ovarian cancer treatment, no mention of more advanced surgical procedures as upper abdominal resections. We therefore believe that the mainly surgical question ‘primary versus interval-surgery’ can only be answered if the key criteria ‘complete gross resection’ are present in a considerable percentage of patients. Consequently, this has been incorporated in the study protocol of the envisaged open randomized prospective multicentre trial of the international TRUST collaboration (TRUST, trial on radical upfront surgery in advanced ovarian Documentation of all patients with suspected advanced ovarian cancer at trial center

In-/exclusion criteria met

Informed consent

Randomization

Upfront surgery

3 cycles neoadjuvant chemo Interval debulking

6 cycles postoperative chemotherapy

3 cycles postoperative chemo

Figure 1. Design of the TRUST study.

doi:10.1093/annonc/mdw092 | i

Downloaded from http://annonc.oxfordjournals.org/ by guest on June 6, 2016

based chemotherapy (NACT) followed by IDS and postoperative platinum-based chemotherapy. The rate of complete tumour resection after debulking surgery was 19.4% in patients in the PDS arm, and 51.2% in the NACT arm. Progression-free survival (PFS) and overall survival (OS) were comparable between the two arms, so that the primary aim demonstrating non-inferiority of NACT was reached. Complete resection of all macroscopic disease, at PDS or after NACT, was the strongest independent variable in predicting OS [1]. However, a closer look on the treatment characteristics and the survival rates reveals important details possibly influencing the presented results. In general, the complete resection rates of only 19.4% with large differences between the participating countries (e.g. 3.9% in the Netherlands and 6.3% in Italy versus 62.9% in Belgium) challenge the question if surgical radicality of the participating centres was high enough to generate reliable results. The median operating time of only 165 min appears insufficient for comprehensive surgical evaluation and treatment of advanced ovarian cancer. In addition, the reported median OS of 29 months for the PDS and 30 months for the NACT group are remarkably low [1]. Compared with previously reported randomized phase III studies which included patients undergoing combination chemotherapy with carboplatin and paclitaxel exhibiting median OS between 41 and 52 months [16–19], these rates are significantly impaired. Furthermore, only 78.4% in the PDS arm compared 87.9% in the NACT arm received platinum-based combination chemotherapy which might represent an additional factor influencing interpretation of the results [1]. Of note, despite these possible bias, preplanned per-protocol analyses already revealed remarkable differences in subgroups of patients with no macroscopic residual tumour (45 versus 38 months) and residual tumour below 1 cm (32 versus 27 months) following surgery favouring PDS compared with NACT [1]. As a consequence, German treatment guidelines did not change the sequence of the current treatment standard consisting of PDS followed by platinum-based chemotherapy [14]. A second randomized phase III trial (CHORUS) comparing PDS followed by platinum-based chemotherapy with NACT and IDS was more recently reported by the National Cancer Research Institute (NCRI) Gynecological Cancer Studies Group [2]. This trial had a comparable design to the previous EORTC/ NCIC study but also included patients with FIGO stage IIIB. After debulking surgery, rates for complete tumour resection were even lower with 16% in patients in the PDS arm, and 40% in the NACT arm. Again, PFS and OS were similar between the two arms implying non-inferiority of NACT compared with PDS with a hazard ratio (HR) of 0.87 (0.71, 1.05). However, similar to the EORTC/NCIC trial, OS was again very low with 22.8 months for PDS and 24.5 months for NACT compared with previously reported results of other studies [13]. The median operating times were even lower than in the previous trial with a median of 120 min for both arms. Of interest, postoperative morbidity and deaths were significantly higher in patients undergoing PDS. Grade III and IV postoperative adverse events were noted in 24% versus 14% favouring NACT (P = 0.007) as it was reported for postoperative deaths within 28 days (14 of 255 patients versus 1 of 219 patients, P < 0.001). In this context, it is important to note that 18 patients of the perprotocol population in the NACT arm did not undergo IDS due

symposium article

symposium article cancer, Figure 1) which is aimed to generate a definitive and reliable answer for this important question. The study protocol includes qualification criteria for participating centres to allow for highest surgical quality within the trial. With these criteria, TRUST will hopefully help to define the optimal timing of radical surgery in advanced ovarian cancer. Until then, PDS remains gold standard in ovarian cancer care and the currently available evidence regarding NACT should not be used as an excuse to reduce surgical radicality for surgical therapy of this challenging disease.

disclosure The authors have declared no conflicts of interest.

references

i | Mahner et al.

12. Bristow RE, Tomacruz RS, Armstrong DK et al. Survival effect of maximal cytoreductive surgery for advanced ovarian carcinoma during the platinum era: a meta-analysis. J Clin Oncol 2002; 20: 1248–1259. 13. du Bois A, Reuss A, Pujade-Lauraine E et al. Role of surgical outcome as prognostic factor in advanced epithelial ovarian cancer: a combined exploratory analysis of 3 prospectively randomized phase 3 multicenter trials: by the Arbeitsgemeinschaft Gynaekologische Onkologie Studiengruppe Ovarialkarzinom (AGO-OVAR) and the Groupe d’Investigateurs Nationaux Pour les Etudes des Cancers de l’Ovaire (GINECO). Cancer 2009; 115: 1234–1244. 14. Wagner U, Harter P, Hilpert F et al. S3-guideline on diagnostics, therapy and follow-up of malignant ovarian tumours: short version 1.0—AWMF registration number: 032/035OL, June 2013. Geburtshilfe Frauenheilkd 2013; 73: 874–889. 15. du Bois A, Reuss A, Harter P et al. Potential role of lymphadenectomy in advanced ovarian cancer: a combined exploratory analysis of three prospectively randomized phase III multicenter trials. J Clin Oncol 2010; 28: 1733–1739. 16. du Bois A, Luck HJ, Meier W et al. A randomized clinical trial of cisplatin/paclitaxel versus carboplatin/paclitaxel as first-line treatment of ovarian cancer. J Natl Cancer Inst 2003; 95: 1320–1329. 17. du Bois A, Weber B, Rochon J et al. Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens. J Clin Oncol 2006; 24: 1127–1135. 18. Pfisterer J, Weber B, Reuss A et al. Randomized phase III trial of topotecan following carboplatin and paclitaxel in first-line treatment of advanced ovarian cancer: a gynecologic cancer intergroup trial of the AGO-OVAR and GINECO. J Natl Cancer Inst 2006; 98: 1036–1045. 19. du Bois A, Herrstedt J, Hardy-Bessard AC et al. Phase III trial of carboplatin plus paclitaxel with or without gemcitabine in first-line treatment of epithelial ovarian cancer. J Clin Oncol 2010; 28: 4162–4169. 20. Bristow RE, Chi DS. Platinum-based neoadjuvant chemotherapy and interval surgical cytoreduction for advanced ovarian cancer: a meta-analysis. Gynecol Oncol 2006; 103: 1070–1076. 21. Woelber L, Jung S, Eulenburg C et al. Perioperative morbidity and outcome of secondary cytoreduction for recurrent epithelial ovarian cancer. Eur J Surg Oncol 2010; 36: 583–588. 22. Harter P, Muallem ZM, Buhrmann C et al. Impact of a structured quality management program on surgical outcome in primary advanced ovarian cancer. Gynecol Oncol 2011; 121: 615–619. 23. Chekerov R, Braicu I, Castillo-Tong DC et al. Outcome and clinical management of 275 patients with advanced ovarian cancer International Federation of Obstetrics and Gynecology II to IV inside the European Ovarian Cancer Translational Research Consortium-OVCAD. Int J Gynecol Cancer 2013; 23: 268–275. 24. Chi DS, Eisenhauer EL, Zivanovic O et al. Improved progression-free and overall survival in advanced ovarian cancer as a result of a change in surgical paradigm. Gynecol Oncol 2009; 114: 26–31.

Volume 27 | Supplement 1 | April 2016

Downloaded from http://annonc.oxfordjournals.org/ by guest on June 6, 2016

1. Vergote I, Trope CG, Amant F et al. Neoadjuvant chemotherapy or primary surgery in stage IIIC or IV ovarian cancer. N Engl J Med 2010; 363: 943–953. 2. Kehoe S, Hook J, Nankivell M et al. Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label, randomised, controlled, non-inferiority trial. Lancet 2015; 386: 249–257. 3. Griffiths CT. Surgical resection of tumor bulk in the primary treatment of ovarian carcinoma. Natl Cancer Inst Monogr 1975; 42: 101–104. 4. Eisenkop SM, Friedman RL, Wang HJ. Complete cytoreductive surgery is feasible and maximizes survival in patients with advanced epithelial ovarian cancer: a prospective study. Gynecol Oncol 1998; 69: 103–108. 5. Heintz AP, Hacker NF, Berek JS et al. Cytoreductive surgery in ovarian carcinoma: feasibility and morbidity. Obstet Gynecol 1986; 67: 783–788. 6. Piver MS, Lele SB, Marchetti DL et al. The impact of aggressive debulking surgery and cisplatin-based chemotherapy on progression-free survival in stage III and IV ovarian carcinoma. J Clin Oncol 1988; 6: 983–989. 7. Bertelsen K. Tumor reduction surgery and long-term survival in advanced ovarian cancer: a DACOVA study. Gynecol Oncol 1990; 38: 203–209. 8. Hoskins WJ, Bundy BN, Thigpen JT, Omura GA. The influence of cytoreductive surgery on recurrence-free interval and survival in small-volume stage III epithelial ovarian cancer: a Gynecologic Oncology Group study. Gynecol Oncol 1992; 47: 159–166. 9. Hacker NF, Berek JS, Lagasse LD et al. Primary cytoreductive surgery for epithelial ovarian cancer. Obstet Gynecol 1983; 61: 413–420. 10. Guidozzi F, Ball JH. Extensive primary cytoreductive surgery for advanced epithelial ovarian cancer. Gynecol Oncol 1994; 53: 326–330. 11. Allen DG, Heintz AP, Touw FW. A meta-analysis of residual disease and survival in stage III and IV carcinoma of the ovary. Eur J Gynaecol Oncol 1995; 16: 349–356.

Annals of Oncology