Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive surgery for advanced ovarian cancer

Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive surgery for advanced ovarian cancer

YGYNO-977760; No. of pages: 5; 4C: Gynecologic Oncology xxx (xxxx) xxx Contents lists available at ScienceDirect Gynecologic Oncology journal homepa...

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YGYNO-977760; No. of pages: 5; 4C: Gynecologic Oncology xxx (xxxx) xxx

Contents lists available at ScienceDirect

Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno

Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive surgery for advanced ovarian cancer K. Bixel a,b,⁎, M. Vetter a,b, B. Davidson c,d, A. Berchuck c,d, D. Cohn a,b, L. Copeland a,b, J.M. Fowler a,b, L. Havrilesky c,d, P.S. Lee c,d, D.M. O'Malley a,b, R. Salani a,b, F. Valea e, A. Alvarez Secord c,d, F. Backes a,b a

Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America The Ohio State University Comprehensive Cancer Center, Arthur G James Cancer Hospital and Richard J Solove Research institute, Columbus, OH, United States of America Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, United States of America d Duke Cancer Institute, Duke University Medical Center, Durham, NC, United States of America e Division of Gynecologic Oncology, Virginia Tech Carilion School of Medicine, Roanoke, VA, United States of America b c

H I G H L I G H T S • Intraperitoneal (IP) chemotherapy after neoadjuvant chemotherapy (NACT)/interval tumor reductive surgery (TRS) improved PFS. • Overall survival did not differ by route of administration of chemotherapy following NACT and interval TRS. • There were no significant differences in grade 3 or 4 toxicities for women receiving IP or intravenous (IV) chemotherapy.

a r t i c l e

i n f o

Article history: Received 30 September 2019 Received in revised form 10 December 2019 Accepted 16 December 2019 Available online xxxx Keywords: Neoadjuvant chemotherapy Intraperitoneal chemotherapy Ovarian cancer

a b s t r a c t Objectives. Intraperitoneal (IP) chemotherapy following neoadjuvant chemotherapy (NACT) and interval tumor reductive surgery (TRS) for advanced ovarian cancer is feasible, however, the impact on disease outcomes remains unclear. We compare outcomes of patients treated with IP chemotherapy versus intravenous (IV) chemotherapy following NACT and interval TRS. Methods. In this retrospective review, patients with advanced ovarian cancer were included if they received NACT followed by optimal interval TRS between 1/2004 and 4/2017. Patients were excluded if they had an ECOG PS N1, received N6 cycles of NACT or postoperative chemotherapy, and/or received bevacizumab during primary therapy. Primary outcomes were progression free survival (PFS) and overall survival (OS). Results. There were 134 patients included in this study, 37 (28%) received IP and 97 (72%) received IV chemotherapy postoperatively. Patients in the IV group were older (median 66.3 vs 59.7 years, p = 0.0039) though there were no differences in BMI, race, BRCA status, stage, or histology. Median PFS was 3 months longer in the IP group (14.5 versus 11.5 months, p = 0.028) however there was no significant difference in OS. On univariate analysis, increasing number of NACT cycles (HR 1.914, 95% CI 1.024–3.497) and residual disease at completion of TRS (HR 1.541, 95% CI 1.042–2.248) were associated with decreased PFS; IP chemotherapy was associated with increased PFS (HR 0.633, 95% CI 0.414–0.944). These associations remained on multivariate analysis. Toxicity was comparable between the groups. Conclusions. IP after NACT and optimal interval TRS was associated with in improved PFS compared to IV chemotherapy without significant differences in toxicity. © 2019 Elsevier Inc. All rights reserved.

1. Introduction Epithelial ovarian cancer (EOC) is associated with the highest mortality of all gynecologic malignancies because the majority of patients ⁎ Corresponding author at: 320 W 10th Ave, M210 Starling Loving, Columbus, OH 43210, United States of America. E-mail address: [email protected] (K. Bixel).

present with advanced disease; recurrence rates remain high despite aggressive therapy. Primary tumor reductive surgery (TRS) followed by platinum based chemotherapy has long been the preferred treatment [1]. The vast majority of patients with EOC have disease limited to the peritoneal cavity making this an attractive target for drug delivery. Pharmacokinetic and pharmacodynamics studies have demonstrated that intraperitoneal (IP) delivery results in increased peritoneal to plasma ratios for cisplatin, carboplatin, and paclitaxel,

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Please cite this article as: K. Bixel, M. Vetter, B. Davidson, et al., Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.016

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three of the most commonly utilized agents in the management of advanced ovarian cancer [2]. Three large randomized controlled trials have demonstrated the survival benefit of IP chemotherapy after optimal (≤1 cm residual disease) TRS. While these studies differed in their regimens, each found IP chemotherapy to be superior to intravenous (IV) chemotherapy, with a survival advantage ranging from 8 to 16 months [3–5]. These findings ultimately led to a rare clinical announcement by the National Cancer Institute (NCI) in 2006 encouraging the use of IP chemotherapy. The most contemporary trial designed to determine the optimal adjuvant treatment strategy, GOG 252, compared IV carboplatin and paclitaxel to two different IP regimens, with all treatment arms including bevacizumab. While this study failed to demonstrate an improvement in progression free survival (PFS) and overall survival (OS) with IP chemotherapy, these results may have been influenced by the IP regimens chosen and/or the use of bevacizumab in all patients enrolled [6]. Neoadjuvant chemotherapy (NACT) with interval TRS has become an accepted alternative to primary TRS in patients with advanced disease based on several large randomized controlled trials [7–9]. IP chemotherapy was not utilized in the postoperative setting in these studies and thus the role of IP chemotherapy after NACT has been questioned. There are a limited number of retrospective and prospective studies that suggest feasibility and potential survival benefit to IP after NACT and interval TRS [10–13]. Additionally, a recent randomized controlled trial found that hyperthermic intraperitoneal chemotherapy (HIPEC) following NACT and optimal interval TRS was associated with improved PFS and OS adding to the body of evidence supporting the role of IP chemotherapy in the management of this disease [14]. Given the established survival benefit of IP chemotherapy after primary TRS in the absence of bevacizumab and the limited data suggesting its potential benefit after NACT and interval TRS, we aimed to compare disease outcomes for patients receiving IP chemotherapy to those patients receiving IV chemotherapy following NACT and optimal interval TRS.

2. Methods This study was approved by the Institutional Review Board at The Ohio State University Wexner Medical Center and Duke University Health System. Patients diagnosed with stage III–IV ovarian, fallopian tube, or primary peritoneal cancer between January 2004 and April 2017 were retrospectively identified by medical record review at each institution. We included women who were treated with NACT (up to 6 cycles) followed by optimal interval TRS as long as they received at least 1 but not N6 additional cycles of chemotherapy in the postoperative setting. Patients were excluded if they had an Eastern Cooperative Oncology Group (ECOG) performance status (PS) N1 as these patients would be unlikely to be offered or tolerate IP therapy. Additionally, we excluded patients who received bevacizumab with primary therapy. IP chemotherapy was defined as having one or more cycles of an IP regimen administered after interval TRS. Patients receiving IP chemotherapy following interval TRS were compared to those receiving IV only chemotherapy. Patient charts were reviewed for demographic variables, disease characteristics, treatment course, and disease outcomes. The primary outcomes of interest were PFS and OS. PFS was defined as the time from surgery to first radiographic and/or pathologic evidence of disease recurrence or death from any cause. OS was defined as the time from surgery to death from any cause. Patients not experiencing disease recurrence or death were censored at the date of their last known visit. Baseline characteristics were compared using chi-square, Fisher's exact, or 2-sided t-test depending on their distribution. PFS and OS were estimated using the Kaplan-Meier method and compared using the log rank test. Univariate and multivariate logistic regression analyses were performed to identify factors associated with progression

free survival. A p-value of ≤0.05 was considered statistically significant. Statistical analysis was performed using the JMP 14.0.0 software. 3. Results One hundred thirty-four patients met inclusion criteria with a median follow-up time of 29.5 months. The median age at diagnosis was 64.3 years (range 21–87 years). The median BMI was 28.1 kg/m2 (range 16–52.5 kg/m2). The majority of patients were white (n = 110, 82%) and of the 65 patients who had BRCA testing, 13 (20%) carried a deleterious mutation. Most patients had high grade tumors (n = 123, 92%) and the most common histology was serous carcinoma (n = 112, 83%). Patients received a median of 4 (range 2–6) cycles of neoadjuvant chemotherapy which nearly always consisted of a platinum/ taxane doublet (n = 133, 99%). Eighty-nine (66%) patients had no gross residual disease at completion of interval TRS. At the time of TRS surgery, 32 (24%) patients underwent a bowel resection and 15 (11%) underwent extensive upper abdominal debulking procedures. Postoperatively, patients received a median of 3 (range 1–6) cycles of chemotherapy. Patients were grouped according to the route of administration of chemotherapy in the postoperative setting with 37 (28%) patients receiving IP and 97 (72%) patients receiving IV chemotherapy. As shown in Table 1, patients in the IV chemotherapy group were older with a median age of 66.3 years compared to 59.7 years in the IP group (p = 0.013). There were however no significant differences with respect to body mass index, race, BRCA status, stage, histology, or grade between the 2 groups. Table 2 illustrates the treatment characteristics of each group which differed only in number of postoperative cycles of chemotherapy with a median of 4 (range 2–6) cycles in the IP group and 3 cycles (range 1–6) in the IV group (p b 0.0001). Importantly, there were no significant differences in the extent of surgery and the rate of complete cytoreduction was not significantly different between the groups (70% vs 65%, p = 0.683). Of the 34 patients receiving IP chemotherapy, 29 (85%) received a modified GOG 172 regimen with an IV taxane + IP cisplatin/taxane and 5 (15%) received IV paclitaxel with IP carboplatin/ paclitaxel. The vast majority of patients in the IV arm (87.6%) received a platinum/taxane doublet. There were 5 patients in each group that received maintenance therapy following completion of planned chemotherapy (7 received paclitaxel and 3 received another agent on clinical trial). There were no significant differences in treatment delays, dose reductions, early discontinuation of therapy, grade 3–4 toxicities, or death Table 1 Patient characteristics (n = 134).

Age [median (range)] BMI [median (range)] Race White Black Asian Other BRCA status Negative Positive Unknown Stage III IV Advanceda Histology Serous Other Grade Low High Unknown a

IP (n = 37)

IV (n = 97)

p

59.7 (40–81) 28.7 (18–36.2)

66.3 (21–87) 28.0 (16–52.5)

0.004 0.847 0.070

35 (94%) 1 (3%) 0 1 (3%)

75 (77%) 13 (13%) 2 (2%) 7 (7%)

14 (38%) 3 (8%) 20 (54%)

38 (39%) 10 (10%) 49 (51%)

15 (41%) 19 (51%) 3 (8%)

34 (35%) 35 (36%) 28 (29%)

31 (84%) 6 (16%)

81 (84%) 16 (16%)

0 36 (97%) 1 (3%)

3 (3%) 87 (90%) 7 (7%)

1

0.678

1

0.557

Not otherwise specified.

Please cite this article as: K. Bixel, M. Vetter, B. Davidson, et al., Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.016

K. Bixel et al. / Gynecologic Oncology xxx (xxxx) xxx Table 2 Treatment characteristics.

Chemotherapy NACT regimen Platinum/taxane Platinum/other Cycles NACT [median (range)] Adjuvant regimen Platinum/taxane Platinum/other Non-platinum Cycles adjuvant chemotherapy [median (range)] Maintenance therapy Yes No Surgery Bowel resection Yes No Ostomy Yes No Extensive upper abdominal debulking Yes No Residual disease NGR Optimal (b1 cm)

IP (n = 37)

IV (n = 97)

37 (100%) 0 4 (2–6)

96 (99%) 1(1%) 4 (2–6)

37 (100%) 0 0 4 (2–6)

85 (88%) 3 (3%) 9 (9%) 3 (1–6)

5 (14%) 32 (86%)

5 (5%) 92 (95%)

p

1

0.781 0.070

b0.001 0.138

0.167 6 (16%) 31 (84%)

26 (27%) 61 (73%)

1 (3%) 36 (97%)

0 97 (100%)

5 (14%) 32 (86%)

10 (10%) 87 (90%)

26 (70%) 11 (30%)

63 (65%) 34 (35%)

0.276

0.760

0.683

NGR, no gross residual.

during treatment based on the route of postoperative chemotherapy administration (Table 3). There were, however, more treatment modifications as defined by change in drug(s) used or route of administration in the IP group compared to the IV group (44% vs 6%, p b 0.001). Two patients died during treatment; one patient in the IP group died from a myocardial infarction and one patient in the IV group died as a result of sepsis with resulting complications. Overall, 117 patients (87%) experienced disease recurrence. The median PFS was 12.2 months (95% CI 11.3–13.7) and the median OS was 35.3 months (95% CI 28.6–42.9). The median PFS was 3 months longer in the IP compared to the IV cohort (14.5 months versus 11.5 months, p = 0.028; Fig. 1a) however there was no significant difference in OS Table 3 Toxicity associated with adjuvant chemotherapy.

Treatment delay Yes No Unk Dose reduction Yes No Unk Treatment modificationa Yes No Unk Early discontinuation Yes No Unk Grade 3–4 toxicity Yes No Unk Death during treatment Yes No a

IP/IV (n = 37)

IV (n = 97)

8 (22%) 20 (54%) 9 (24%)

23 (24%) 64 (66%) 10 (10%)

10 (27%) 27 (73%) 0

24 (25%) 62 (64%) 11 (11%)

15 (41%) 22 (59%) 0

6 (6%) 83 (86%) 8 (8%)

1 (3%) 36 (97%) 0

11 (11%) 86 (89%) 0

9 (24%) 18 (49%) 10 (27%)

17 (18%) 68 (70%) 12 (12%)

1 (3%) 36 (97%)

1 (1%) 96 (99%)

p value 1

1

b0.001

0.209

0.245

1

Change in agent or route of administration.

3

(35.6 months versus 33.1 months, p = 0.5051; Fig. 1b). When the survival analysis was restricted to patients with only high grade serous carcinoma who had no gross residual disease, the median PFS was 14.7 months in the IP group vs 12 months in the IV group (p = 0.0290). There again was no difference in overall survival (median PFS 35.6 months vs 34.7 months, p = 0.1687). On univariate analysis, increasing number of NACT cycles (HR 1.914, 95% CI 1.024–3.497) and residual disease at completion of TRS (HR 1.541, 95% CI 1.042–2.248) were associated with decreased PFS whereas postoperative administration of IP chemotherapy was associated with increased PFS (HR 0.633, 95% CI 0.414–0.944). These associations remained consistent at multivariate analysis (Table 4). 4. Discussion The impact of IP chemotherapy following NACT and interval TRS remains under studied. The current study is amongst only a few retrospective reports on the use of IP chemotherapy in this patient population and the only one that has included patients from multiple institutions. Here we demonstrate that IP chemotherapy after optimal interval TRS was associated with improved progression free survival and a trend towards improved overall survival. Importantly, toxicity was not significantly increased in the IP/IV group, and the majority of patients were able to complete the planned treatment. Intraperitoneal disease spread is one of the most characteristic features of EOC, making the peritoneal cavity an attractive target for drug delivery. Perhaps the best clinical data to support the use of IP chemotherapy arises from GOG 172, a randomized controlled trial comparing IV paclitaxel plus cisplatin with IV paclitaxel plus IP cisplatin and paclitaxel in women with optimally debulked stage III ovarian cancer. While only 42% of patients in the IP arm of that trial were able to complete all 6 cycles of assigned therapy, the median PFS and OS were significantly improved (18.3 vs 23.8 months (p = 0.05) and 49.7 vs 65.6 months 9 (p = 0.03) respectively) when analyzed by intention to treat. Importantly, despite increased toxicity and worse QOL during and immediately following treatment in the IP arm, there were no significant QOL differences between the groups 1 year following completion of treatment [4]. Despite this, IP chemotherapy was never widely adopted; fewer than 50% of eligible patients received IP chemotherapy at National Comprehensive Cancer Network (NCCN) centers between 2006 and 2012 [15]. Barriers to the use of IP chemotherapy include a lack of facilities for administration, treatment related toxicities, and patient preferences [16]. In our study, the majority of patients received a modified IP/ IV regimen consisting of a slightly lower dose of cisplatin with treatment administered on day 1 and 8, rather than on day 1, 2 and 8. This likely contributed to increased tolerability and completion of the planned treatment but perhaps also reduced the magnitude of benefit. Only two prospective studies have evaluated the use of IP chemotherapy following NACT. A single arm phase II study demonstrated the safety and feasibility of IP chemotherapy in women with stage III/IV EOC. In this study, patients were treated with IV paclitaxel and IP carboplatin/paclitaxel following NACT and optimal TRS. Of the 26 eligible patients who were optimally debulked and treated with IP chemotherapy, 18 (69%) completed the planned therapy. When comparing the toxicities associated with therapy to other IP studies, this modified regimen resulted in less neurologic, gastrointestinal, and hematologic toxicity [4,5,13]. These results are consistent with findings in the current study that support the tolerability of IP chemotherapy after NACT. Though treatment modifications were common, the majority of patients included were able to complete IP chemotherapy as planned and early discontinuation of therapy was rare. The OV21/PETROC trial is the only randomized trial in this patient population to date where a comparison of outcomes can be made. Women with stage IIB-IVA EOC treated with NACT were randomly assigned to an IP (carboplatin vs cisplatin) or an IV regimen following optimal interval TRS. This trial was multi-staged and adaptive resulting

Please cite this article as: K. Bixel, M. Vetter, B. Davidson, et al., Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.016

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Fig. 1. a, b: A: Progression free survival. Red, IP; Blue, IV. b: Overall survival. Red, IP; Blue, IV. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

in the elimination of the cisplatin containing IP arm after failing to meet the pre-set superiority rule in the first stage. The final analysis therefore included 101 patients in the IV arm (IV carboplatin/paclitaxel) and 102 patients in the IP arm (IP carboplatin + IV/IP paclitaxel). IP chemotherapy resulted in a statistically significant improvement in the rate of disease progression at 9 months (23.3% vs 42.2%, p = 0.03) which was the primary endpoint. Additionally, there was a non-significant improvement in OS (59.3 vs 38.1 months, p = 0.4) [12]. Our results are consistent with this study demonstrating a 3-month improvement in PFS with IP/IV when compared to IV chemotherapy alone, thus supporting a potential role for its use. It is unclear why previous retrospective studies have failed to show improvement in clinical outcomes with IP chemotherapy after interval TRS. Perhaps this is due to selection bias, to which all retrospective studies are subjected. We tried to limit this by creating strict inclusion criteria to include an ECOG performance status of 0–1 and receipt of no more than 6 cycles of neoadjuvant or adjuvant Table 4 Univariate and multivariate analysis of factors associated with progression free survival. Univariate HR (95% CI) Age BMI Race White AA Asian Other BRCA Negative Positive Stage III IV NACT cycles Adjuvant cycles Residual disease NGR b1cm Route of admin IV IP Maintenance therapy No Yes

P value

Multivariate HR (95% CI)

P value

0.769 (0.245–2.415) 0.652 1.497 (0.551–3.948) 0.424 Ref 1.624 (0.885–2.758) 0.112 6.799 0.1513 (0.371–35.346) 0.605 (0.236–1.271) 0.2006 Ref 0.982 (0.492–1.815) 0.9556 Ref 1.141 (0.754–1.733) 0.5316 1.914 (1.024–3.497) 0.0419 1.179 (1.006–1.373) 0.561(0.256–1.204) 0.1393

0.0415

Ref 1.541 (1.042–2.248) 0.0307 1.564 (1.055–2.287)

0.264

Ref 0.633 (0.414–0.944) 0.0246 0.655 (0.428–0.978)

0.0384

chemotherapy. Additionally, we excluded women who received bevacizumab as part of their primary therapy given the speculation that the results of GOG 252 may have been influenced by the use of bevacizumab in all three arms. IP chemotherapy seems to have fallen further out of favor with the recent results GOG 252, a randomized trial comparing two IP regimens to IV chemotherapy, where no survival advantage was seen with IP therapy [6]. It should be recognized that the intraperitoneal chemotherapy regimens in this study differed from those in GOG 172, GOG 114, and GOG 104 which may account for the lack of benefit observed. Additionally, all patients received bevacizumab in this study and it is not clear how this may have influenced the results. Perhaps bevacizumab has a beneficial effect when added to IV therapy or a detrimental effect when added to IP regimens. Unlike IP therapy however, bevacizumab has not been shown to improve overall survival in the adjuvant setting and thus caution should be used in interpreting these results [17]. The limitations of this retrospective review are recognized including a relatively small sample size, incomplete records (especially for those diagnosed prior to 2010), and a relatively low rate of BRCA testing (b50% overall). While the groups were balanced with respect to those who had testing completed, they may not be balanced overall. There is some data to suggest that patients with BRCA mutations may derive the greatest benefit from IP therapy and thus this is a possible weakness in our dataset. In addition, though not statistically significant, the proportion of patients receiving maintenance therapy was higher in the IP group. Given the small sample size, it is difficult to comment on how this may have impacted the results. While the future of IP chemotherapy remains uncertain and as other treatment strategies emerge, our current study supports the consideration of IP chemotherapy following NACT and optimal interval TRS. While it is impossible to draw definitive conclusions without a phase III trial, this study in addition to the OV21/PETROC study suggests this a tolerable treatment strategy with a potential progression-free survival benefit. Author contribution Conceptualization: KB, FB Data collection: KB, MV, BD Data analysis: KB Writing - Original draft preparation: KB Writing - Reviewing &Editing: All authors Financial support

Ref 0.604 (0.284–1.129) 0.1204

None.

Please cite this article as: K. Bixel, M. Vetter, B. Davidson, et al., Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.016

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Declaration of competing interest The authors report no conflicts of interest.

[8] [9]

Appendix A. Supplementary data

[10]

Supplementary data to this article can be found online at https://doi. org/10.1016/j.ygyno.2019.12.016.

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Please cite this article as: K. Bixel, M. Vetter, B. Davidson, et al., Intraperitoneal chemotherapy following neoadjuvant chemotherapy and optimal interval tumor reductive..., Gynecologic Oncology, https://doi.org/10.1016/j.ygyno.2019.12.016