- Email: [email protected]
or Metastatic Colorectal Cancer—Predictive Factors and Prognosis
Accepted Manuscript Conversion to resection in patients receiving systemic chemotherapy for unresectable and/or metastatic colorectal cancer - predictive factors and prognosisHiroaki Nozawa, Soichiro Ishihara, Kazushige Kawai, Keisuke Hata, Tomomichi Kiyomatsu, Toshiaki Tanaka, Takeshi Nishikawa, Kensuke Otani, Koji Yasuda, Kazuhito Sasaki, Manabu Kaneko, Koji Murono, Toshiaki Watanabe PII:
S1533-0028(17)30057-9
DOI:
10.1016/j.clcc.2017.10.002
Reference:
CLCC 396
To appear in:
Clinical Colorectal Cancer
Received Date: 4 February 2017 Revised Date:
27 September 2017
Accepted Date: 10 October 2017
Please cite this article as: Nozawa H, Ishihara S, Kawai K, Hata K, Kiyomatsu T, Tanaka T, Nishikawa T, Otani K, Yasuda K, Sasaki K, Kaneko M, Murono K, Watanabe T, Conversion to resection in patients receiving systemic chemotherapy for unresectable and/or metastatic colorectal cancer - predictive factors and prognosis-, Clinical Colorectal Cancer (2017), doi: 10.1016/j.clcc.2017.10.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Conversion to resection in patients receiving systemic chemotherapy for unresectable and/or metastatic colorectal cancer - predictive factors and prognosis-
RI PT
Hiroaki Nozawa, Soichiro Ishihara, Kazushige Kawai, Keisuke Hata, Tomomichi Kiyomatsu, Toshiaki Tanaka, Takeshi Nishikawa, Kensuke Otani, Koji Yasuda, Kazuhito Sasaki, Manabu
SC
Kaneko, Koji Murono, Toshiaki Watanabe
M AN U
Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
Address for correspondence: Hiroaki Nozawa, MD, PhD, Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan,
AC C
EP
TE D
Phone: +81-3-5800-8653, FAX: +81-3-3811-6822, email: [email protected]
1
ACCEPTED MANUSCRIPT Abstract
Background: Systemic chemotherapy increases the possibility of resection in patients with initially unresectable colorectal cancer (mCRC), particularly with hepatic metastasis.
RI PT
However, predictive factors and the prognosis of conversion to resection after chemotherapy
in patients with various organ metastases remain largely unknown. Patients and Methods:
SC
We reviewed mCRC patients who received oxaliplatin- or irinotecan-based systemic
M AN U
chemotherapy between 2005 and 2016. Predictors for conversion to surgery were assessed by multivariate analyses. Cancer-free and overall survivals after the initiation of treatment in patients were compared between patients who underwent successful conversion therapy and those who underwent surgery first for resectable stage IV colorectal
TE D
cancer (CRC). Results: Among 99 mCRC patients receiving first-line chemotherapy, 23 underwent secondary surgical resection. Single organ metastasis, the presence of liver
EP
metastases, and usage of biologics were independent predictors of successful conversion
AC C
therapy. The long-term survival of patients who underwent successful secondary surgery did not differ significantly from that of 112 patients with resectable stage IV CRC treated by
surgery first. Conclusion: Liver metastases and single organ metastasis were more likely to be resected after chemotherapy than other situations in mCRC. Biologics contributed to increasing the conversion rate. Successful conversion resulted in similar outcomes to resectable stage IV CRC. 2
ACCEPTED MANUSCRIPT MicroAbstract
Conversion to resection after chemotherapy in metastatic colorectal cancer patients with
RI PT
various organ metastases has not yet been investigated in detail. Multivariate analyses showed that single organ metastasis and liver metastasis as well as the usage of biologics
correlated with successful conversion therapy. Kaplan-Meier analyses suggested that the
SC
survival of patients who received successful conversion therapy was similar to that of stage
Clinical Practice Points
M AN U
IV colorectal cancer patients initially treated with curative surgery.
Conversion to resection after chemotherapy was mainly investigated in initially unresectable
TE D
colorectal cancer patients with liver-limited metastasis.
On the other hand, conversion therapy in metastatic colorectal cancer patients with various
EP
organ metastases has yet to be characterized in detail.
AC C
We demonstrated that single organ metastasis and liver metastasis as well as the usage of biologics correlated with an increased probability of conversion to resection in metastatic colorectal cancer patient with various organ metastases.
Moreover, Kaplan-Meier survival analyses showed that the survival of patients who received successful conversion therapy was similar to that of initially resectable stage IV colorectal 3
ACCEPTED MANUSCRIPT cancer patients who underwent curative surgery first.
Therefore, conversion therapy may reverse the progression of metastatic colorectal cancer.
AC C
EP
TE D
M AN U
SC
RI PT
Keywords: Colorectal cancer, Conversion, Chemotherapy, Predictive factors, Prognosis
4
ACCEPTED MANUSCRIPT Introduction
Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality
RI PT
worldwide [1]. Approximately 25% of CRC patients have metastatic diseases at the initial diagnosis and 50% will develop metastatic disease metachronously [2]. Unless resection is feasible, systemic chemotherapy constitutes the main therapeutic option for these
SC
patients. In the last decade, prominent advances in chemotherapy by cytotoxic drugs in
M AN U
combination with molecular targeting agents have contributed to the prolonged survival of patients with initially unresectable/metastatic CRC (mCRC) [2,3], and further render metastases resectable in a subset of patients [4,5]. Previous studies investigating
TE D
“conversion” to resection mostly focused on CRC with liver-limited metastasis [4,5]. In contrast, fewer studies have examined conversion therapy for CRC patients with unresectable lesions involving extrahepatic and/or multiple distant organs. Moreover,
EP
factors associated with conversion and the long-term outcomes of conversion therapy have
AC C
not yet been investigated in detail.
We herein analyzed clinicopathological parameters in patients who received systemic
chemotherapy for mCRC with the aim of identifying the factors associated with conversion to resection. We also compared the prognosis of patients who underwent secondary surgery with that of resectable stage IV colorectal cancer patients. 5
ACCEPTED MANUSCRIPT
Patients and methods
RI PT
Patients and data retrieval
We retrospectively reviewed stage IV CRC patients who were treated in our
SC
department between June 2005 and April 2016. Of these, we selected mCRC patients who were initially diagnosed with unresectable disease and received FOLFOX
M AN U
(5-fluorouracil (5-FU), folinic acid, and oxaliplatin), CapeOX (capecitabine and oxaliplatin), SOX (S-1 and oxaliplatin), or FOLFIRI (5-FU, folinic acid, and irinotecan) as first-line chemotherapy. As their counterparts, stage IV CRC patients with resectable metastases
TE D
were also analyzed. Patients who received neoadjuvant chemotherapy for resectable disease were excluded. In all eligible patients, data regarding age, sex, the Eastern
EP
Cooperative Oncology Group (ECOG) performance status (PS), serum tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 just before the
AC C
initiation of chemotherapy, the location (the right-sided colon, left-sided colon, or rectum) and histological grade of the primary tumor, and metastasized organs were documented. The KRAS status in exon 2 was analyzed when available.
The study protocol was approved by the local ethics committees in the University of Tokyo (reference number: 3252-(3)), and thus meets the standards of the Declaration of 6
ACCEPTED MANUSCRIPT Helsinki in its revised version of 1975 and its later amendments. All patients provided
Chemotherapy regimen and radiological evaluation
RI PT
written informed consent.
SC
mFOLFOX6 (oxaliplatin 85 mg/m2 and folinic acid 200 mg/m2, followed by 5-FU, as a 400 mg/m2 intravenous bolus and a 2,400 mg/m2 infusion over 46 hours) was administered
M AN U
every two weeks [6]. CapeOX (oxaliplatin 130 mg/m2 over two hours on day one plus oral capecitabine 1,000 mg/m2 twice daily on days 1-14) was repeated every three weeks [7]. SOX (oxaliplatin 130 mg/m2 over two hours on day one plus oral S-1 40 mg/m2 twice daily
TE D
on days 1-14) was repeated every three weeks [8]. FOLFIRI (150 mg/m2 irinotecan, the dose approved in Japan, and 200 mg/m2 folinic acid, followed by 5-FU, as a 400 mg/m2
EP
intravenous bolus and a 2,400 mg/m2 infusion over 46 hours) was administered every two
AC C
weeks [9]. Targeted biologics such as bevacizumab (anti-vascular endothelial growth factor (VEGF)) as well as cetuximab and panitumumab (anti-epidermal growth factor receptor (EGF-R)) may be added to one of the aforementioned backbone regimens as recommended by the guidelines [10-12]. The choice of cytotoxic drugs and targeted agents depended on doctors’ discretion; however, cetuximab and panitumumab were exclusively used for CRC with wild-type KRAS. Dose reductions and the cessation of 7
ACCEPTED MANUSCRIPT chemotherapy were considered based on the patient’s condition and preference.
In order to evaluate tumor responses, computed tomography (CT) scans were
RI PT
performed before chemotherapy, and every two to three months thereafter during the treatment. When elevations in serum tumor markers were noted in an accelerated manner, or symptoms suggesting disease progression newly appeared, CT scans and other imaging
SC
modalities such as magnetic resonance imaging and positron emission tomography were
M AN U
additionally performed. In each case, the best response was graded according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 [13].
TE D
Resectability, conversion, and follow-up
Resectability was dependent on whether it was possible to completely resect
EP
metastatic lesions while preserving the adequate function of the target organ and without
AC C
sacrificing the adjacent critical organs. In our institute, resectability was assessed jointly in conferences or cancer board meetings by multiple doctors who specialized in gastrointestinal, hepatobiliary, or pulmonary surgery and/or radiology. Conversion was defined as macroscopically complete removal (R0 or R1 resection) for all lesions disseminated from CRC and/or the primary tumor per se that was initially deemed unresectable. Surgical complications were graded by the Clavien-Dindo classification [14]. 8
ACCEPTED MANUSCRIPT Postoperative treatments such as adjuvant chemotherapy, palliative chemotherapy, radiotherapy, surgical resection and other local treatments for recurrent disease were reviewed from the medical charts. Recurrence-free survival (RFS) was defined between
RI PT
the time of the complete removal of cancer and the date of recurrence. Overall survival (OS) was the time between the initiation of any treatment and death due to any reason.
SC
Surviving patients were censored at the last time point of patient contact either directly or
Results
TE D
Profiles of mCRC patients
M AN U
indirectly.
Ninety-nine patients (59 men and mean age: 61 years old) received systemic
EP
chemotherapy for mCRC during the study period. The baseline characteristics of patients
AC C
are shown in Table 1. Most patients had a good PS. Rectal cancer was predominant (55%). A differentiated histology was noted in 86% of patients. Multiple organs were involved in more than 50% of cases; the most frequently involved organ was the liver (62%), followed by the lung (39%) and distant lymph nodes (35%). Asymptomatic primary tumors were not resected in 40% of patients before chemotherapy. Approximately 80% of patients had elevated CEA levels (> 5 ng/mL), whereas CA 19-9 showed an elevation (> 37 U/mL) in 9
ACCEPTED MANUSCRIPT 57% of patients before chemotherapy. The KRAS status in exon 2 was analyzed in 68
RI PT
patients (69%); of these, 26 harbored mutations in the gene.
Chemotherapy regimen
SC
Table 2 depicts the regimen selected as first-line chemotherapy. Most patients (97%) received an oxaliplatin-based cytotoxic drug combination as backbone chemotherapy.
M AN U
Targeted biologics were employed for 60% of patients. Bevacizumab was administered to 28 patients, whereas cetuximab or panitumumab was given to 31 patients with CRC
TE D
carrying wild-type KRAS.
EP
Best response, conversion, and details of surgery
AC C
As the best response, tumor volumes were reduced from the baseline in 54 patients, including seven showing stable disease according to RECIST. Of these, responses were deemed sufficient to be resectable in 23 patients (43%), who underwent surgical resection after a median of 4.6 months (range: 1.5-30.4 months) of systemic chemotherapy. Forty surgical procedures were performed on these patients including primary tumor resection (13), hepatic resection (21), pulmonary resection (5), and peritoneal resection (1). Among 10
ACCEPTED MANUSCRIPT these procedures, 12 (30%) were accompanied by postoperative complications classified as Clavien-Dindo system grade II and comprised six surgical site infections, five systemic
RI PT
non-infectious complications, and one non-surgical infection.
SC
Predictive factors for conversion
In order to identify the clinicopathological predictors of successful conversion in mCRC,
M AN U
we first conducted a univariate analysis using the logistic regression model. Single organ metastasis, the existence of liver metastasis, no lung metastasis, no peritoneal metastasis, and the usage of biologics were associated with a greater possibility of conversion (Table 3).
TE D
We then performed multivariate analyses to identify independent predictors of conversion using these parameters. As shown in Table 4, single organ metastasis, the existence of
EP
liver metastasis, and the usage of biologics were independent predictive factors of
AC C
conversion (single organ metastasis: odds ratio 22.64, p<0.0001; liver metastasis: odds ratio 60.60, p<0.0001; biologics: odds ratio 56.86, p<0.0001).
Comparisons of prognosis between mCRC patients undergoing conversion therapy and resectable stage IV CRC patients
11
ACCEPTED MANUSCRIPT In order to elucidate the prognostic impact of conversion, we compared the long-term outcomes of patients who underwent secondary surgery with those of resectable stage IV CRC patients treated by surgery first. Table 5 shows the profiles of the two groups. The
RI PT
surgery-first group had fewer patients with multiple organ metastases (11% vs 30%,
p=0.013) and those with distant lymph nodal involvement (6% vs 22%, p=0.048) than the
SC
conversion group. Moreover, fewer patients in the conversion group received adjuvant
M AN U
chemotherapy than in the surgery-first group (43% vs 67%, p=0.034, Table 6). The combination of oxaliplatin and 5-FU was the major common regimen in both groups (60% and 67%, respectively). In patients with recurrence, similar treatments were administered
TE D
to the surgery-first and conversion groups (Table 6).
As shown in Figure 1, 44% of patients undergoing secondary surgery after chemotherapy were estimated to survive recurrence-free for two years after the complete
EP
removal of cancer, and this was not significantly different from surgery-first CRC patients
AC C
(28%, p=0.79). OS after the start of the treatment was also similar between the two groups (three-year OS rate: conversion group 66% vs surgery-first group 77%, p=0.22, Figure 2).
Discussion
In the era of cytotoxic drug combinations and biologics, the sequential integration of 12
ACCEPTED MANUSCRIPT effective chemotherapy and surgical resection has emerged as a new strategy for improving the prognosis of patients with mCRC. In the current treatment paradigm, the characterization of patients with a high possibility of conversion to resection is an important
RI PT
issue. Predictive factors for conversion to hepatectomy were previously addressed in patients with initially unresectable colorectal liver metastases [15]. We attempted to
M AN U
organ involvement using multivariate analyses.
SC
investigate the predictive factors of successful conversion therapy in mCRC with various
A recent study reported that higher conversion rates to resectability may be achieved by intensified chemotherapy using triplet cytotoxic drugs, namely, FOLFOXIRI (5-FU, folinic acid, oxaliplatin, and irinotecan) in liver-limited mCRC [16,17]. In targeted biologics
TE D
associations, BOXER and first BEAT studies showed that the addition of bevacizumab to key cytotoxic drug combinations increased conversion rates in liver-limited mCRC [18,19].
EP
Similarly, anti-EGF-R targeting biologics were shown to contribute to an increased
AC C
conversion rate in patients with KRAS wild-type colorectal liver-limited metastases [5,20]. However, when disseminated lesions are not confined to the liver, there is a paucity of clinical trials to demonstrate the superior conversion rates of anti-EGF-R antibody-including therapy to backbone cytotoxic drugs alone [21]. A combined analysis on data of the First BEAT and NO16966 trials failed to show additional effects of bevacizumab in the resectability of CRC with any distant metastases [18]. Hence, the effects of biologics have 13
ACCEPTED MANUSCRIPT been controversial in conversion therapy for mCRC. Our findings showing that the usage of bevacizumab, cetuximab, or panitumumab predicted high resectability may usher in these
RI PT
targeted antibodies as key components of conversion therapy in mCRC.
In the present study, liver metastasis and single organ metastasis were significant
predictive factors of secondary surgical resection after first-line chemotherapy in mCRC.
SC
These results appear to reflect the liver being the predominant target organ in previous
M AN U
studies on conversion therapy for mCRC.
In analyses of long-term prognosis, mCRC patients undergoing surgery after first-line systemic chemotherapy exhibited more advanced disease such as multiple organ and
TE D
distant lymph node metastases than resectable stage IV CRC patients treated by surgery first, as shown in Table 5. Nevertheless, the conversion group showed similar RFS and OS
EP
to the surgery-first group, as shown in Figures 1 and 2. Therefore, our results emphasize
AC C
the long-term substantial benefits of conversion.
Our study had several limitations. Due to its retrospective nature, potential biases
existed in the selection of chemotherapy regimens. Our study cohort comprised patients lacking information on the KRAS status because the cost of the gene analysis was not covered by the national health insurance system in Japan until 2010. Moreover, the extended RAS status and other genetic mutations such as BRAF were not examined in 14
ACCEPTED MANUSCRIPT many patients for similar reasons. In addition, we did not assess cases of conversion after second-line chemotherapy or other treatment modalities. We did not take into account the number, size, or anatomical site of lesions within metastasized organs. Furthermore, the
RI PT
backgrounds and postoperative chemotherapy of patients were not matched in the
SC
comparison of prognoses between the conversion therapy and surgery-first groups.
M AN U
Conclusion
We demonstrated that single organ metastasis and liver metastasis were significant factors associated with a high conversion rate to secondary resection by systemic
TE D
chemotherapy for initially unresectable CRC. In combination with cytotoxic drugs, appropriate types of biologics need to be considered in order to increase the possibility of
AC C
EP
resection. Successful conversion therapy is expected to reverse the progression of CRC.
Acknowledgements
This study was supported by Grants-in-Aid for Scientific Research from Japan Society
for the promotion of Science (A : grant number;16H02672, C: grant number;16K07143, C: grant number;16K07161,C: grant number; 17K10620, C: grant number;17K10621 and C: 15
ACCEPTED MANUSCRIPT grant number;17K10623), and the Project for Cancer Research And Therapeutic Evolution
RI PT
(P-CREATE) from the Japan Agency for Medical Research and development (AMED).
Disclosure
SC
Dr. Watanabe has received fees for lectures, and grants and endowments for research from Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Bristol-Myers
M AN U
Squibb, and Merck Serono Japan. He has also received fees for writing manuscripts outside the submitted work from Takeda Pharmaceutical Co. Ltd. and Merck Serono Japan.
TE D
For the remaining authors, none were declared.
1.
EP
References
Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates
AC C
and Trends--An Update. Cancer Epidemiol Biomarkers Prev. 2016;25:16-27. 2. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386-1422.
16
ACCEPTED MANUSCRIPT 3.
Jawed I, Wilkerson J, Prasad V, et al. Colorectal cancer survival gains and novel treatment regimens: a systematic review and analysis. JAMA Oncol. 2015;1:787-795.
4.
Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection
RI PT
for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2005;23:2038–2048.
Nordlinger B, Van Cutsem E, Gruenberger T, et al. Combination of surgery and
SC
5.
M AN U
chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol. 2009;20:985-992. 6.
Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse
2004;22:229-237.
Díaz-Rubio E, Evans TR, Tabemero J, et al. Capecitabine (Xeloda) in combination with
EP
7.
TE D
sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol.
AC C
oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol. 2002;13:558-565.
8.
Hong YS, Park YS, Lim HY, et al. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012;13:1125-1132.
17
ACCEPTED MANUSCRIPT 9.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-1047.
RI PT
10. Benson AB 3rd, Venook AP, Bekaii-Saab T, et al. Colon cancer, version 3.2014. J Natl Compr Canc Netw. 2014;12:1028-1059.
SC
11. Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO
M AN U
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25:iii1-iii9.
12. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin
TE D
Oncol. 2015;20:207-239.
13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
EP
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
AC C
14. Dindo D, Demartines N, Clavien PA. Classification of surgical complications.A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213.
15. Beppu T, Miyamoto Y, Sakamoto Y, et al. Chemotherapy and targeted therapy for patients with initially unresectable colorectal liver metastases, focusing on conversion hepatectomy and long-term survival. Ann Surg Oncol. 2014;21:S405-S413. 18
ACCEPTED MANUSCRIPT 16. Ychou M, Rivoire M, Thezenas S, et al. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann Surg
RI PT
Oncol. 2013;20:4289-4297.
17. Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus mFOLFOX-6 or
SC
FOLFOXIRI in patients with initially unresectable liver metastases from colorectal
M AN U
cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015;26:702-708.
18. Okines A, Puerto OD, Cunningham D, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer
TE D
First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101:1033-1038.
EP
19. Wong R, Cunningham D, Barbachano Y, et al. A multicentre study of capecitabine,
AC C
oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol.
2011;22:2042-2048.
20. Petrlli F, Barni S. Anti-EGFR agents for liver metastases. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis. 2012;27:997-1004. 19
ACCEPTED MANUSCRIPT 21. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol.
AC C
EP
TE D
M AN U
SC
RI PT
2011;29:2011-2019.
20
ACCEPTED MANUSCRIPT Figure legends
Figure 1 Estimated RFS curves for mCRC patients who underwent surgery after
RI PT
chemotherapy (bold line) and stage IV CRC patients who underwent surgery as the first treatment (dotted line). The survival time was counted from the complete removal of
SC
cancer.
Figure 2 Estimated OS curves for mCRC patients who underwent surgery after
M AN U
chemotherapy (bold line) and stage IV CRC patients who underwent surgery as the first
AC C
EP
TE D
treatment (dotted line). The survival time was counted from the initiation of treatment.
21
ACCEPTED MANUSCRIPT
Table 1 Profiles of unresectable CRC patients who received systemic chemotherapy
n=99
Male
Age (years)
Mean ± SD
ECOG PS
0
M AN U
EP
93 (94%) 5 ( 5%)
2
1 ( 1%)
Right-sided colon
35 (45%)
Left-sided colon
10 (45%)
Rectum
54 (56%)
Diff. adenoca.
85 (86%)
Others
14 (14%)
AC C
*
60.9 ± 12.5
1
TE D
Location of tumor
Histological type *
59 (60%)
SC
Gender
RI PT
Variable
Histology of major component was shown.
Abbreviations: SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; PS = performance status; Diff. adenoca. = well or moderately differentiated adenocarcinoma.
1
ACCEPTED MANUSCRIPT
Table 1 (continued) Profiles of unresectable CRC patients who received systemic chemotherapy
n=99
Number of metastasized organs
RI PT
Variable
1
47 (48%)
36 (36%)
M AN U
3 or more
SC
2
Primary tumor
59 (60%)
Liver
61 (62%)
Lung
39 (39%)
Distant lymph nodes
35 (35%)
Peritoneum
23 (23%)
Others
11 (11%)
Normal
19 (19%)
Elevated
76 (77%)
AC C
CEA
EP
TE D
Target organs *
*
16 (16%)
Not evaluated
Multiple organs could be involved.
Abbreviation: CEA = carcinoembryonic antigen.
2
4 ( 4%)
ACCEPTED MANUSCRIPT
Table 1 (continued) Profiles of unresectable CRC patients who received systemic chemotherapy
CA 19-9
Normal Elevated
39 (39%)
56 (57%)
M AN U
Not evaluated
RI PT
n=99
SC
Variable
KRAS exon 2
4 ( 4%)
Wild-type
42 (43%)
Mutant
26 (26%)
Not evaluated
31 (31%)
AC C
EP
TE D
Abbreviation: CA = carbohydrate antigen.
3
ACCEPTED MANUSCRIPT
Table 2 Chemotherapy regimen
n=99
Cytotoxic drug combination
FOLFOX CapeOX
SC
SOX
M AN U
FOLFIRI
AC C
EP
TE D
Biologics
4
84 (85%)
RI PT
Regimen
11 (11%) 1 (1%)
3 ( 3%)
None
39 (40%)
Bevacizumab
28 (28%)
Cetuximab
22 (22%)
Panitumumab
9 ( 9%)
ACCEPTED MANUSCRIPT
Table 3 Univariate analysis for conversion to resection in patients receiving chemotherapy for initially unresectable CRC
Odds ratio
Gender
Male
0.67
> 60 ≤ 60
ECOS PS
0 1 or more
1.55
0.29-1.90
0.53
0.23-30.50
0.68
Right-sided colon
1.23
0.30-5.06
0.78
Left-sided colon
0.36
0.12-1.08
0.068
0.83-84.82
0.088
EP
AC C
*
0.41
1
Rectum
Histological type *
0.26-1.74
1
TE D
Location of tumor
0.74
M AN U
Age (years)
1
p value
SC
Female
95% CI
RI PT
Variable
Diff. adenoca.
1
4.54
Others
1
Histology of major component was analyzed.
Abbreviations: CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; PS = performance status; Diff. adenoca. = well or moderately differentiated adenocarcinoma.
5
ACCEPTED MANUSCRIPT
Table 3 (continued) Univariate analysis for conversion to resection in patients
Variable
Odds ratio
organs
Multiple
1
Present
1.07
Absent
1
Present
9.45
Absent
1
TE D
Liver metastasis
Present
0.34
Absent
1
EP
Lung metastasis
3.32
M AN U
Primary tumor
Single
Distant lymph node
AC C
metastasis
Peritoneal dissemination
*
95% CI
p value
1.26-9.52
0.015
SC
Number of metastasized
RI PT
receiving chemotherapy for initially unresectable CRC
Present
0.43
Absent
1
Present
0.25
Absent
1
excluding cases in which data were not available
Abbreviation: CI = confidence interval.
6
0.42-2.86
0.89
2.53-61.69
0.0003
0.10-0.96
0.042
0.13-1.20
0.11
0.04-0.95
0.042
ACCEPTED MANUSCRIPT
Table 3 (continued) Univariate analysis for conversion to resection in patients receiving chemotherapy for initially unresectable CRC
Odds ratio
CEA *
Elevated
3.04
CA 19-9 *
KRAS exon 2 *
Wild-type Mutant
2.05
0.12
0.38-2.72
0.99
0.70-6.59
0.19
0.05-13.14
0.69
4.28-403.67
<0.0001
1
0.59
Irinotecan-based
1
TE D
Oxaliplatin-based
Yes
22.00 1
AC C
None
*
0.77-20.22
1
EP
Chemotherapy regimen
1.01
M AN U
Elevated Normal
Biologics
1
p value
SC
Normal
95% CI
RI PT
Variable
excluding cases in which data were not available
Abbreviations: CI = confidence interval; CEA = carcinoembryonic antigen; CA = carbohydrate antigen.
7
ACCEPTED MANUSCRIPT
Table 4 Multivariate analysis for conversion to resection in patients receiving chemotherapy for initially unresectable CRC
Odds ratio
Liver metastasis
Multiple
1
Present
60.60
Absent
Lung metastasis
Present Absent
1.67
<0.0001
8.05-842.97
<0.0001
0.32-9.82
0.54
0.12-7.71
0.93
7.84-1314.95
<0.0001
1
Present
1.09
Absent
1
Yes
EP
Biologics
3.56-232.07
1
TE D
Peritoneal dissemination
22.64
p value
SC
organs
Single
M AN U
Number of metastasized
95% CI
RI PT
Variable
1
AC C
None
56.86
Abbreviation: CI = confidence interval.
8
ACCEPTED MANUSCRIPT
Table 5 Patient profiles of conversion and surgery-first groups
64 (57%)
0.66
Female
11 (48%)
0
57.1 ± 12.7
48 (43%)
62.4 ± 11.6
0.054
22 (96%)
105 (94%)
0.72
1 or more
1 ( 4%)
7 ( 6%)
Rectum
9 (39%)
45 (40%)
Colon
14 (61%)
67 (60%)
Diff. adenoca.
22 (96%)
105 (94%)
1 ( 4%)
7 ( 6%)
TE D
M AN U
ECOS PS
EP
Others
0.93
0.71
Histology of major component was shown.
AC C
*
p value
12 (52%)
Mean ± SD
Histological type *
(n=112)
Male
Age (years)
Location of tumor
(n=23)
SC
Gender
Surgery-first
RI PT
Variable
Conversion
Abbreviations: SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; PS = performance status; Diff. adenoca. = well or moderately differentiated adenocarcinoma.
9
ACCEPTED MANUSCRIPT
Table 5 (continued) Patient profiles of conversion and surgery-first groups
Surgery-first
(n=23)
(n=112)
p value
100 (89%)
0.013
Variable
Organs
Metastasis
Multiple
7 (30%)
Present
21 (91%)
AC C
CEA *
*
81 (72%)
2 ( 9%)
31 (28%)
Present
5 (22%)
11 (10%)
Absent
18 (78%)
101 (90%)
Present
5 (22%)
7 ( 6%)
Absent
18 (78%)
105 (94%)
Present
2 ( 9%)
22 (20%)
Absent
21 (91%)
90 (80%)
Elevated
20 (91%)
87 (78%)
2 ( 9%)
25 (22%)
EP
Peritoneal dissemination
12 (11%)
Absent
TE D
Lung metastasis
Distant lymph node
16 (70%)
M AN U
Liver metastasis
Single
SC
Number of metastasized
RI PT
Conversion
Normal
excluding cases in which data were not available
Abbreviation: CEA = carcinoembryonic antigen.
10
0.064
0.11
0.048
0.21
0.16
ACCEPTED MANUSCRIPT
Table 5 (continued) Patient profiles of conversion and surgery-first groups
p value
55 (49%)
0.39
Elevated
13 (59%)
Normal
9 (41%)
Wild-type
16 (73%)
Mutant *
(n=112)
57 (51%)
SC
KRAS exon 2 *
(n=23)
M AN U
CA 19-9 *
Surgery-first
RI PT
Variable
Conversion
6 (27%)
excluding cases in which data were not available
AC C
EP
TE D
Abbreviation: CA = carbohydrate antigen.
11
27 (56%) 21 (44%)
0.19
ACCEPTED MANUSCRIPT
Table 6 Postoperative treatments in conversion and surgery-first groups
Adjuvant chemotherapy
(n=23)
(n=112)
p value
75 (67%)
0.034
8.4 ± 5.9
0.43
10 (43%) Mean ± SD
7.4 ± 4.8
SC
Duration (months)
Surgery-first
RI PT
Variable
Conversion
Variable
Palliative chemotherapy
Radiotherapy
RFA (liver)
(n=14)
(n=90)
p value
12 (86%)
56 (62%)
0.13
1 ( 7%)
6 ( 7%)
1.00
1.1 ± 1.9
0.9 ± 1.2
0.66
0
2 ( 2%)
1.00
Only recurrent patients were analyzed. ** Number of procedures per patient was
AC C
displayed.
EP
*
Mean ± SD
TE D
Surgical resections **
Surgery-first *
M AN U
Conversion *
Abbreviations: SD = standard deviation; RFA = radiofrequency ablation.
12
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
S1533-0028(17)30057-9
DOI:
10.1016/j.clcc.2017.10.002
Reference:
CLCC 396
To appear in:
Clinical Colorectal Cancer
Received Date: 4 February 2017 Revised Date:
27 September 2017
Accepted Date: 10 October 2017
Please cite this article as: Nozawa H, Ishihara S, Kawai K, Hata K, Kiyomatsu T, Tanaka T, Nishikawa T, Otani K, Yasuda K, Sasaki K, Kaneko M, Murono K, Watanabe T, Conversion to resection in patients receiving systemic chemotherapy for unresectable and/or metastatic colorectal cancer - predictive factors and prognosis-, Clinical Colorectal Cancer (2017), doi: 10.1016/j.clcc.2017.10.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Conversion to resection in patients receiving systemic chemotherapy for unresectable and/or metastatic colorectal cancer - predictive factors and prognosis-
RI PT
Hiroaki Nozawa, Soichiro Ishihara, Kazushige Kawai, Keisuke Hata, Tomomichi Kiyomatsu, Toshiaki Tanaka, Takeshi Nishikawa, Kensuke Otani, Koji Yasuda, Kazuhito Sasaki, Manabu
SC
Kaneko, Koji Murono, Toshiaki Watanabe
M AN U
Department of Surgical Oncology, The University of Tokyo, Tokyo, Japan
Address for correspondence: Hiroaki Nozawa, MD, PhD, Department of Surgical Oncology, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan,
AC C
EP
TE D
Phone: +81-3-5800-8653, FAX: +81-3-3811-6822, email: [email protected]
1
ACCEPTED MANUSCRIPT Abstract
Background: Systemic chemotherapy increases the possibility of resection in patients with initially unresectable colorectal cancer (mCRC), particularly with hepatic metastasis.
RI PT
However, predictive factors and the prognosis of conversion to resection after chemotherapy
in patients with various organ metastases remain largely unknown. Patients and Methods:
SC
We reviewed mCRC patients who received oxaliplatin- or irinotecan-based systemic
M AN U
chemotherapy between 2005 and 2016. Predictors for conversion to surgery were assessed by multivariate analyses. Cancer-free and overall survivals after the initiation of treatment in patients were compared between patients who underwent successful conversion therapy and those who underwent surgery first for resectable stage IV colorectal
TE D
cancer (CRC). Results: Among 99 mCRC patients receiving first-line chemotherapy, 23 underwent secondary surgical resection. Single organ metastasis, the presence of liver
EP
metastases, and usage of biologics were independent predictors of successful conversion
AC C
therapy. The long-term survival of patients who underwent successful secondary surgery did not differ significantly from that of 112 patients with resectable stage IV CRC treated by
surgery first. Conclusion: Liver metastases and single organ metastasis were more likely to be resected after chemotherapy than other situations in mCRC. Biologics contributed to increasing the conversion rate. Successful conversion resulted in similar outcomes to resectable stage IV CRC. 2
ACCEPTED MANUSCRIPT MicroAbstract
Conversion to resection after chemotherapy in metastatic colorectal cancer patients with
RI PT
various organ metastases has not yet been investigated in detail. Multivariate analyses showed that single organ metastasis and liver metastasis as well as the usage of biologics
correlated with successful conversion therapy. Kaplan-Meier analyses suggested that the
SC
survival of patients who received successful conversion therapy was similar to that of stage
Clinical Practice Points
M AN U
IV colorectal cancer patients initially treated with curative surgery.
Conversion to resection after chemotherapy was mainly investigated in initially unresectable
TE D
colorectal cancer patients with liver-limited metastasis.
On the other hand, conversion therapy in metastatic colorectal cancer patients with various
EP
organ metastases has yet to be characterized in detail.
AC C
We demonstrated that single organ metastasis and liver metastasis as well as the usage of biologics correlated with an increased probability of conversion to resection in metastatic colorectal cancer patient with various organ metastases.
Moreover, Kaplan-Meier survival analyses showed that the survival of patients who received successful conversion therapy was similar to that of initially resectable stage IV colorectal 3
ACCEPTED MANUSCRIPT cancer patients who underwent curative surgery first.
Therefore, conversion therapy may reverse the progression of metastatic colorectal cancer.
AC C
EP
TE D
M AN U
SC
RI PT
Keywords: Colorectal cancer, Conversion, Chemotherapy, Predictive factors, Prognosis
4
ACCEPTED MANUSCRIPT Introduction
Colorectal cancer (CRC) is one of the leading causes of morbidity and mortality
RI PT
worldwide [1]. Approximately 25% of CRC patients have metastatic diseases at the initial diagnosis and 50% will develop metastatic disease metachronously [2]. Unless resection is feasible, systemic chemotherapy constitutes the main therapeutic option for these
SC
patients. In the last decade, prominent advances in chemotherapy by cytotoxic drugs in
M AN U
combination with molecular targeting agents have contributed to the prolonged survival of patients with initially unresectable/metastatic CRC (mCRC) [2,3], and further render metastases resectable in a subset of patients [4,5]. Previous studies investigating
TE D
“conversion” to resection mostly focused on CRC with liver-limited metastasis [4,5]. In contrast, fewer studies have examined conversion therapy for CRC patients with unresectable lesions involving extrahepatic and/or multiple distant organs. Moreover,
EP
factors associated with conversion and the long-term outcomes of conversion therapy have
AC C
not yet been investigated in detail.
We herein analyzed clinicopathological parameters in patients who received systemic
chemotherapy for mCRC with the aim of identifying the factors associated with conversion to resection. We also compared the prognosis of patients who underwent secondary surgery with that of resectable stage IV colorectal cancer patients. 5
ACCEPTED MANUSCRIPT
Patients and methods
RI PT
Patients and data retrieval
We retrospectively reviewed stage IV CRC patients who were treated in our
SC
department between June 2005 and April 2016. Of these, we selected mCRC patients who were initially diagnosed with unresectable disease and received FOLFOX
M AN U
(5-fluorouracil (5-FU), folinic acid, and oxaliplatin), CapeOX (capecitabine and oxaliplatin), SOX (S-1 and oxaliplatin), or FOLFIRI (5-FU, folinic acid, and irinotecan) as first-line chemotherapy. As their counterparts, stage IV CRC patients with resectable metastases
TE D
were also analyzed. Patients who received neoadjuvant chemotherapy for resectable disease were excluded. In all eligible patients, data regarding age, sex, the Eastern
EP
Cooperative Oncology Group (ECOG) performance status (PS), serum tumor markers such as carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 just before the
AC C
initiation of chemotherapy, the location (the right-sided colon, left-sided colon, or rectum) and histological grade of the primary tumor, and metastasized organs were documented. The KRAS status in exon 2 was analyzed when available.
The study protocol was approved by the local ethics committees in the University of Tokyo (reference number: 3252-(3)), and thus meets the standards of the Declaration of 6
ACCEPTED MANUSCRIPT Helsinki in its revised version of 1975 and its later amendments. All patients provided
Chemotherapy regimen and radiological evaluation
RI PT
written informed consent.
SC
mFOLFOX6 (oxaliplatin 85 mg/m2 and folinic acid 200 mg/m2, followed by 5-FU, as a 400 mg/m2 intravenous bolus and a 2,400 mg/m2 infusion over 46 hours) was administered
M AN U
every two weeks [6]. CapeOX (oxaliplatin 130 mg/m2 over two hours on day one plus oral capecitabine 1,000 mg/m2 twice daily on days 1-14) was repeated every three weeks [7]. SOX (oxaliplatin 130 mg/m2 over two hours on day one plus oral S-1 40 mg/m2 twice daily
TE D
on days 1-14) was repeated every three weeks [8]. FOLFIRI (150 mg/m2 irinotecan, the dose approved in Japan, and 200 mg/m2 folinic acid, followed by 5-FU, as a 400 mg/m2
EP
intravenous bolus and a 2,400 mg/m2 infusion over 46 hours) was administered every two
AC C
weeks [9]. Targeted biologics such as bevacizumab (anti-vascular endothelial growth factor (VEGF)) as well as cetuximab and panitumumab (anti-epidermal growth factor receptor (EGF-R)) may be added to one of the aforementioned backbone regimens as recommended by the guidelines [10-12]. The choice of cytotoxic drugs and targeted agents depended on doctors’ discretion; however, cetuximab and panitumumab were exclusively used for CRC with wild-type KRAS. Dose reductions and the cessation of 7
ACCEPTED MANUSCRIPT chemotherapy were considered based on the patient’s condition and preference.
In order to evaluate tumor responses, computed tomography (CT) scans were
RI PT
performed before chemotherapy, and every two to three months thereafter during the treatment. When elevations in serum tumor markers were noted in an accelerated manner, or symptoms suggesting disease progression newly appeared, CT scans and other imaging
SC
modalities such as magnetic resonance imaging and positron emission tomography were
M AN U
additionally performed. In each case, the best response was graded according to Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.1 [13].
TE D
Resectability, conversion, and follow-up
Resectability was dependent on whether it was possible to completely resect
EP
metastatic lesions while preserving the adequate function of the target organ and without
AC C
sacrificing the adjacent critical organs. In our institute, resectability was assessed jointly in conferences or cancer board meetings by multiple doctors who specialized in gastrointestinal, hepatobiliary, or pulmonary surgery and/or radiology. Conversion was defined as macroscopically complete removal (R0 or R1 resection) for all lesions disseminated from CRC and/or the primary tumor per se that was initially deemed unresectable. Surgical complications were graded by the Clavien-Dindo classification [14]. 8
ACCEPTED MANUSCRIPT Postoperative treatments such as adjuvant chemotherapy, palliative chemotherapy, radiotherapy, surgical resection and other local treatments for recurrent disease were reviewed from the medical charts. Recurrence-free survival (RFS) was defined between
RI PT
the time of the complete removal of cancer and the date of recurrence. Overall survival (OS) was the time between the initiation of any treatment and death due to any reason.
SC
Surviving patients were censored at the last time point of patient contact either directly or
Results
TE D
Profiles of mCRC patients
M AN U
indirectly.
Ninety-nine patients (59 men and mean age: 61 years old) received systemic
EP
chemotherapy for mCRC during the study period. The baseline characteristics of patients
AC C
are shown in Table 1. Most patients had a good PS. Rectal cancer was predominant (55%). A differentiated histology was noted in 86% of patients. Multiple organs were involved in more than 50% of cases; the most frequently involved organ was the liver (62%), followed by the lung (39%) and distant lymph nodes (35%). Asymptomatic primary tumors were not resected in 40% of patients before chemotherapy. Approximately 80% of patients had elevated CEA levels (> 5 ng/mL), whereas CA 19-9 showed an elevation (> 37 U/mL) in 9
ACCEPTED MANUSCRIPT 57% of patients before chemotherapy. The KRAS status in exon 2 was analyzed in 68
RI PT
patients (69%); of these, 26 harbored mutations in the gene.
Chemotherapy regimen
SC
Table 2 depicts the regimen selected as first-line chemotherapy. Most patients (97%) received an oxaliplatin-based cytotoxic drug combination as backbone chemotherapy.
M AN U
Targeted biologics were employed for 60% of patients. Bevacizumab was administered to 28 patients, whereas cetuximab or panitumumab was given to 31 patients with CRC
TE D
carrying wild-type KRAS.
EP
Best response, conversion, and details of surgery
AC C
As the best response, tumor volumes were reduced from the baseline in 54 patients, including seven showing stable disease according to RECIST. Of these, responses were deemed sufficient to be resectable in 23 patients (43%), who underwent surgical resection after a median of 4.6 months (range: 1.5-30.4 months) of systemic chemotherapy. Forty surgical procedures were performed on these patients including primary tumor resection (13), hepatic resection (21), pulmonary resection (5), and peritoneal resection (1). Among 10
ACCEPTED MANUSCRIPT these procedures, 12 (30%) were accompanied by postoperative complications classified as Clavien-Dindo system grade II and comprised six surgical site infections, five systemic
RI PT
non-infectious complications, and one non-surgical infection.
SC
Predictive factors for conversion
In order to identify the clinicopathological predictors of successful conversion in mCRC,
M AN U
we first conducted a univariate analysis using the logistic regression model. Single organ metastasis, the existence of liver metastasis, no lung metastasis, no peritoneal metastasis, and the usage of biologics were associated with a greater possibility of conversion (Table 3).
TE D
We then performed multivariate analyses to identify independent predictors of conversion using these parameters. As shown in Table 4, single organ metastasis, the existence of
EP
liver metastasis, and the usage of biologics were independent predictive factors of
AC C
conversion (single organ metastasis: odds ratio 22.64, p<0.0001; liver metastasis: odds ratio 60.60, p<0.0001; biologics: odds ratio 56.86, p<0.0001).
Comparisons of prognosis between mCRC patients undergoing conversion therapy and resectable stage IV CRC patients
11
ACCEPTED MANUSCRIPT In order to elucidate the prognostic impact of conversion, we compared the long-term outcomes of patients who underwent secondary surgery with those of resectable stage IV CRC patients treated by surgery first. Table 5 shows the profiles of the two groups. The
RI PT
surgery-first group had fewer patients with multiple organ metastases (11% vs 30%,
p=0.013) and those with distant lymph nodal involvement (6% vs 22%, p=0.048) than the
SC
conversion group. Moreover, fewer patients in the conversion group received adjuvant
M AN U
chemotherapy than in the surgery-first group (43% vs 67%, p=0.034, Table 6). The combination of oxaliplatin and 5-FU was the major common regimen in both groups (60% and 67%, respectively). In patients with recurrence, similar treatments were administered
TE D
to the surgery-first and conversion groups (Table 6).
As shown in Figure 1, 44% of patients undergoing secondary surgery after chemotherapy were estimated to survive recurrence-free for two years after the complete
EP
removal of cancer, and this was not significantly different from surgery-first CRC patients
AC C
(28%, p=0.79). OS after the start of the treatment was also similar between the two groups (three-year OS rate: conversion group 66% vs surgery-first group 77%, p=0.22, Figure 2).
Discussion
In the era of cytotoxic drug combinations and biologics, the sequential integration of 12
ACCEPTED MANUSCRIPT effective chemotherapy and surgical resection has emerged as a new strategy for improving the prognosis of patients with mCRC. In the current treatment paradigm, the characterization of patients with a high possibility of conversion to resection is an important
RI PT
issue. Predictive factors for conversion to hepatectomy were previously addressed in patients with initially unresectable colorectal liver metastases [15]. We attempted to
M AN U
organ involvement using multivariate analyses.
SC
investigate the predictive factors of successful conversion therapy in mCRC with various
A recent study reported that higher conversion rates to resectability may be achieved by intensified chemotherapy using triplet cytotoxic drugs, namely, FOLFOXIRI (5-FU, folinic acid, oxaliplatin, and irinotecan) in liver-limited mCRC [16,17]. In targeted biologics
TE D
associations, BOXER and first BEAT studies showed that the addition of bevacizumab to key cytotoxic drug combinations increased conversion rates in liver-limited mCRC [18,19].
EP
Similarly, anti-EGF-R targeting biologics were shown to contribute to an increased
AC C
conversion rate in patients with KRAS wild-type colorectal liver-limited metastases [5,20]. However, when disseminated lesions are not confined to the liver, there is a paucity of clinical trials to demonstrate the superior conversion rates of anti-EGF-R antibody-including therapy to backbone cytotoxic drugs alone [21]. A combined analysis on data of the First BEAT and NO16966 trials failed to show additional effects of bevacizumab in the resectability of CRC with any distant metastases [18]. Hence, the effects of biologics have 13
ACCEPTED MANUSCRIPT been controversial in conversion therapy for mCRC. Our findings showing that the usage of bevacizumab, cetuximab, or panitumumab predicted high resectability may usher in these
RI PT
targeted antibodies as key components of conversion therapy in mCRC.
In the present study, liver metastasis and single organ metastasis were significant
predictive factors of secondary surgical resection after first-line chemotherapy in mCRC.
SC
These results appear to reflect the liver being the predominant target organ in previous
M AN U
studies on conversion therapy for mCRC.
In analyses of long-term prognosis, mCRC patients undergoing surgery after first-line systemic chemotherapy exhibited more advanced disease such as multiple organ and
TE D
distant lymph node metastases than resectable stage IV CRC patients treated by surgery first, as shown in Table 5. Nevertheless, the conversion group showed similar RFS and OS
EP
to the surgery-first group, as shown in Figures 1 and 2. Therefore, our results emphasize
AC C
the long-term substantial benefits of conversion.
Our study had several limitations. Due to its retrospective nature, potential biases
existed in the selection of chemotherapy regimens. Our study cohort comprised patients lacking information on the KRAS status because the cost of the gene analysis was not covered by the national health insurance system in Japan until 2010. Moreover, the extended RAS status and other genetic mutations such as BRAF were not examined in 14
ACCEPTED MANUSCRIPT many patients for similar reasons. In addition, we did not assess cases of conversion after second-line chemotherapy or other treatment modalities. We did not take into account the number, size, or anatomical site of lesions within metastasized organs. Furthermore, the
RI PT
backgrounds and postoperative chemotherapy of patients were not matched in the
SC
comparison of prognoses between the conversion therapy and surgery-first groups.
M AN U
Conclusion
We demonstrated that single organ metastasis and liver metastasis were significant factors associated with a high conversion rate to secondary resection by systemic
TE D
chemotherapy for initially unresectable CRC. In combination with cytotoxic drugs, appropriate types of biologics need to be considered in order to increase the possibility of
AC C
EP
resection. Successful conversion therapy is expected to reverse the progression of CRC.
Acknowledgements
This study was supported by Grants-in-Aid for Scientific Research from Japan Society
for the promotion of Science (A : grant number;16H02672, C: grant number;16K07143, C: grant number;16K07161,C: grant number; 17K10620, C: grant number;17K10621 and C: 15
ACCEPTED MANUSCRIPT grant number;17K10623), and the Project for Cancer Research And Therapeutic Evolution
RI PT
(P-CREATE) from the Japan Agency for Medical Research and development (AMED).
Disclosure
SC
Dr. Watanabe has received fees for lectures, and grants and endowments for research from Chugai Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co. Ltd., Bristol-Myers
M AN U
Squibb, and Merck Serono Japan. He has also received fees for writing manuscripts outside the submitted work from Takeda Pharmaceutical Co. Ltd. and Merck Serono Japan.
TE D
For the remaining authors, none were declared.
1.
EP
References
Torre LA, Siegel RL, Ward EM, Jemal A. Global Cancer Incidence and Mortality Rates
AC C
and Trends--An Update. Cancer Epidemiol Biomarkers Prev. 2016;25:16-27. 2. Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann Oncol. 2016;27:1386-1422.
16
ACCEPTED MANUSCRIPT 3.
Jawed I, Wilkerson J, Prasad V, et al. Colorectal cancer survival gains and novel treatment regimens: a systematic review and analysis. JAMA Oncol. 2015;1:787-795.
4.
Leonard GD, Brenner B, Kemeny NE. Neoadjuvant chemotherapy before liver resection
RI PT
for patients with unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2005;23:2038–2048.
Nordlinger B, Van Cutsem E, Gruenberger T, et al. Combination of surgery and
SC
5.
M AN U
chemotherapy and the role of targeted agents in the treatment of patients with colorectal liver metastases: recommendations from an expert panel. Ann Oncol. 2009;20:985-992. 6.
Tournigand C, André T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse
2004;22:229-237.
Díaz-Rubio E, Evans TR, Tabemero J, et al. Capecitabine (Xeloda) in combination with
EP
7.
TE D
sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol.
AC C
oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors. Ann Oncol. 2002;13:558-565.
8.
Hong YS, Park YS, Lim HY, et al. S-1 plus oxaliplatin versus capecitabine plus oxaliplatin for first-line treatment of patients with metastatic colorectal cancer: a randomised, non-inferiority phase 3 trial. Lancet Oncol. 2012;13:1125-1132.
17
ACCEPTED MANUSCRIPT 9.
Douillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet. 2000;355:1041-1047.
RI PT
10. Benson AB 3rd, Venook AP, Bekaii-Saab T, et al. Colon cancer, version 3.2014. J Natl Compr Canc Netw. 2014;12:1028-1059.
SC
11. Van Cutsem E, Cervantes A, Nordlinger B, et al. Metastatic colorectal cancer: ESMO
M AN U
Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014;25:iii1-iii9.
12. Watanabe T, Itabashi M, Shimada Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) Guidelines 2014 for treatment of colorectal cancer. Int J Clin
TE D
Oncol. 2015;20:207-239.
13. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid
EP
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228-247.
AC C
14. Dindo D, Demartines N, Clavien PA. Classification of surgical complications.A new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205–213.
15. Beppu T, Miyamoto Y, Sakamoto Y, et al. Chemotherapy and targeted therapy for patients with initially unresectable colorectal liver metastases, focusing on conversion hepatectomy and long-term survival. Ann Surg Oncol. 2014;21:S405-S413. 18
ACCEPTED MANUSCRIPT 16. Ychou M, Rivoire M, Thezenas S, et al. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases. The METHEP trial. Ann Surg
RI PT
Oncol. 2013;20:4289-4297.
17. Gruenberger T, Bridgewater J, Chau I, et al. Bevacizumab plus mFOLFOX-6 or
SC
FOLFOXIRI in patients with initially unresectable liver metastases from colorectal
M AN U
cancer: the OLIVIA multinational randomised phase II trial. Ann Oncol. 2015;26:702-708.
18. Okines A, Puerto OD, Cunningham D, et al. Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer
TE D
First BEAT and the randomised phase-III NO16966 trial. Br J Cancer. 2009;101:1033-1038.
EP
19. Wong R, Cunningham D, Barbachano Y, et al. A multicentre study of capecitabine,
AC C
oxaliplatin plus bevacizumab as perioperative treatment of patients with poor-risk colorectal liver-only metastases not selected for upfront resection. Ann Oncol.
2011;22:2042-2048.
20. Petrlli F, Barni S. Anti-EGFR agents for liver metastases. Resectability and outcome with anti-EGFR agents in patients with KRAS wild-type colorectal liver-limited metastases: a meta-analysis. Int J Colorectal Dis. 2012;27:997-1004. 19
ACCEPTED MANUSCRIPT 21. Van Cutsem E, Köhne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol.
AC C
EP
TE D
M AN U
SC
RI PT
2011;29:2011-2019.
20
ACCEPTED MANUSCRIPT Figure legends
Figure 1 Estimated RFS curves for mCRC patients who underwent surgery after
RI PT
chemotherapy (bold line) and stage IV CRC patients who underwent surgery as the first treatment (dotted line). The survival time was counted from the complete removal of
SC
cancer.
Figure 2 Estimated OS curves for mCRC patients who underwent surgery after
M AN U
chemotherapy (bold line) and stage IV CRC patients who underwent surgery as the first
AC C
EP
TE D
treatment (dotted line). The survival time was counted from the initiation of treatment.
21
ACCEPTED MANUSCRIPT
Table 1 Profiles of unresectable CRC patients who received systemic chemotherapy
n=99
Male
Age (years)
Mean ± SD
ECOG PS
0
M AN U
EP
93 (94%) 5 ( 5%)
2
1 ( 1%)
Right-sided colon
35 (45%)
Left-sided colon
10 (45%)
Rectum
54 (56%)
Diff. adenoca.
85 (86%)
Others
14 (14%)
AC C
*
60.9 ± 12.5
1
TE D
Location of tumor
Histological type *
59 (60%)
SC
Gender
RI PT
Variable
Histology of major component was shown.
Abbreviations: SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; PS = performance status; Diff. adenoca. = well or moderately differentiated adenocarcinoma.
1
ACCEPTED MANUSCRIPT
Table 1 (continued) Profiles of unresectable CRC patients who received systemic chemotherapy
n=99
Number of metastasized organs
RI PT
Variable
1
47 (48%)
36 (36%)
M AN U
3 or more
SC
2
Primary tumor
59 (60%)
Liver
61 (62%)
Lung
39 (39%)
Distant lymph nodes
35 (35%)
Peritoneum
23 (23%)
Others
11 (11%)
Normal
19 (19%)
Elevated
76 (77%)
AC C
CEA
EP
TE D
Target organs *
*
16 (16%)
Not evaluated
Multiple organs could be involved.
Abbreviation: CEA = carcinoembryonic antigen.
2
4 ( 4%)
ACCEPTED MANUSCRIPT
Table 1 (continued) Profiles of unresectable CRC patients who received systemic chemotherapy
CA 19-9
Normal Elevated
39 (39%)
56 (57%)
M AN U
Not evaluated
RI PT
n=99
SC
Variable
KRAS exon 2
4 ( 4%)
Wild-type
42 (43%)
Mutant
26 (26%)
Not evaluated
31 (31%)
AC C
EP
TE D
Abbreviation: CA = carbohydrate antigen.
3
ACCEPTED MANUSCRIPT
Table 2 Chemotherapy regimen
n=99
Cytotoxic drug combination
FOLFOX CapeOX
SC
SOX
M AN U
FOLFIRI
AC C
EP
TE D
Biologics
4
84 (85%)
RI PT
Regimen
11 (11%) 1 (1%)
3 ( 3%)
None
39 (40%)
Bevacizumab
28 (28%)
Cetuximab
22 (22%)
Panitumumab
9 ( 9%)
ACCEPTED MANUSCRIPT
Table 3 Univariate analysis for conversion to resection in patients receiving chemotherapy for initially unresectable CRC
Odds ratio
Gender
Male
0.67
> 60 ≤ 60
ECOS PS
0 1 or more
1.55
0.29-1.90
0.53
0.23-30.50
0.68
Right-sided colon
1.23
0.30-5.06
0.78
Left-sided colon
0.36
0.12-1.08
0.068
0.83-84.82
0.088
EP
AC C
*
0.41
1
Rectum
Histological type *
0.26-1.74
1
TE D
Location of tumor
0.74
M AN U
Age (years)
1
p value
SC
Female
95% CI
RI PT
Variable
Diff. adenoca.
1
4.54
Others
1
Histology of major component was analyzed.
Abbreviations: CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; PS = performance status; Diff. adenoca. = well or moderately differentiated adenocarcinoma.
5
ACCEPTED MANUSCRIPT
Table 3 (continued) Univariate analysis for conversion to resection in patients
Variable
Odds ratio
organs
Multiple
1
Present
1.07
Absent
1
Present
9.45
Absent
1
TE D
Liver metastasis
Present
0.34
Absent
1
EP
Lung metastasis
3.32
M AN U
Primary tumor
Single
Distant lymph node
AC C
metastasis
Peritoneal dissemination
*
95% CI
p value
1.26-9.52
0.015
SC
Number of metastasized
RI PT
receiving chemotherapy for initially unresectable CRC
Present
0.43
Absent
1
Present
0.25
Absent
1
excluding cases in which data were not available
Abbreviation: CI = confidence interval.
6
0.42-2.86
0.89
2.53-61.69
0.0003
0.10-0.96
0.042
0.13-1.20
0.11
0.04-0.95
0.042
ACCEPTED MANUSCRIPT
Table 3 (continued) Univariate analysis for conversion to resection in patients receiving chemotherapy for initially unresectable CRC
Odds ratio
CEA *
Elevated
3.04
CA 19-9 *
KRAS exon 2 *
Wild-type Mutant
2.05
0.12
0.38-2.72
0.99
0.70-6.59
0.19
0.05-13.14
0.69
4.28-403.67
<0.0001
1
0.59
Irinotecan-based
1
TE D
Oxaliplatin-based
Yes
22.00 1
AC C
None
*
0.77-20.22
1
EP
Chemotherapy regimen
1.01
M AN U
Elevated Normal
Biologics
1
p value
SC
Normal
95% CI
RI PT
Variable
excluding cases in which data were not available
Abbreviations: CI = confidence interval; CEA = carcinoembryonic antigen; CA = carbohydrate antigen.
7
ACCEPTED MANUSCRIPT
Table 4 Multivariate analysis for conversion to resection in patients receiving chemotherapy for initially unresectable CRC
Odds ratio
Liver metastasis
Multiple
1
Present
60.60
Absent
Lung metastasis
Present Absent
1.67
<0.0001
8.05-842.97
<0.0001
0.32-9.82
0.54
0.12-7.71
0.93
7.84-1314.95
<0.0001
1
Present
1.09
Absent
1
Yes
EP
Biologics
3.56-232.07
1
TE D
Peritoneal dissemination
22.64
p value
SC
organs
Single
M AN U
Number of metastasized
95% CI
RI PT
Variable
1
AC C
None
56.86
Abbreviation: CI = confidence interval.
8
ACCEPTED MANUSCRIPT
Table 5 Patient profiles of conversion and surgery-first groups
64 (57%)
0.66
Female
11 (48%)
0
57.1 ± 12.7
48 (43%)
62.4 ± 11.6
0.054
22 (96%)
105 (94%)
0.72
1 or more
1 ( 4%)
7 ( 6%)
Rectum
9 (39%)
45 (40%)
Colon
14 (61%)
67 (60%)
Diff. adenoca.
22 (96%)
105 (94%)
1 ( 4%)
7 ( 6%)
TE D
M AN U
ECOS PS
EP
Others
0.93
0.71
Histology of major component was shown.
AC C
*
p value
12 (52%)
Mean ± SD
Histological type *
(n=112)
Male
Age (years)
Location of tumor
(n=23)
SC
Gender
Surgery-first
RI PT
Variable
Conversion
Abbreviations: SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; PS = performance status; Diff. adenoca. = well or moderately differentiated adenocarcinoma.
9
ACCEPTED MANUSCRIPT
Table 5 (continued) Patient profiles of conversion and surgery-first groups
Surgery-first
(n=23)
(n=112)
p value
100 (89%)
0.013
Variable
Organs
Metastasis
Multiple
7 (30%)
Present
21 (91%)
AC C
CEA *
*
81 (72%)
2 ( 9%)
31 (28%)
Present
5 (22%)
11 (10%)
Absent
18 (78%)
101 (90%)
Present
5 (22%)
7 ( 6%)
Absent
18 (78%)
105 (94%)
Present
2 ( 9%)
22 (20%)
Absent
21 (91%)
90 (80%)
Elevated
20 (91%)
87 (78%)
2 ( 9%)
25 (22%)
EP
Peritoneal dissemination
12 (11%)
Absent
TE D
Lung metastasis
Distant lymph node
16 (70%)
M AN U
Liver metastasis
Single
SC
Number of metastasized
RI PT
Conversion
Normal
excluding cases in which data were not available
Abbreviation: CEA = carcinoembryonic antigen.
10
0.064
0.11
0.048
0.21
0.16
ACCEPTED MANUSCRIPT
Table 5 (continued) Patient profiles of conversion and surgery-first groups
p value
55 (49%)
0.39
Elevated
13 (59%)
Normal
9 (41%)
Wild-type
16 (73%)
Mutant *
(n=112)
57 (51%)
SC
KRAS exon 2 *
(n=23)
M AN U
CA 19-9 *
Surgery-first
RI PT
Variable
Conversion
6 (27%)
excluding cases in which data were not available
AC C
EP
TE D
Abbreviation: CA = carbohydrate antigen.
11
27 (56%) 21 (44%)
0.19
ACCEPTED MANUSCRIPT
Table 6 Postoperative treatments in conversion and surgery-first groups
Adjuvant chemotherapy
(n=23)
(n=112)
p value
75 (67%)
0.034
8.4 ± 5.9
0.43
10 (43%) Mean ± SD
7.4 ± 4.8
SC
Duration (months)
Surgery-first
RI PT
Variable
Conversion
Variable
Palliative chemotherapy
Radiotherapy
RFA (liver)
(n=14)
(n=90)
p value
12 (86%)
56 (62%)
0.13
1 ( 7%)
6 ( 7%)
1.00
1.1 ± 1.9
0.9 ± 1.2
0.66
0
2 ( 2%)
1.00
Only recurrent patients were analyzed. ** Number of procedures per patient was
AC C
displayed.
EP
*
Mean ± SD
TE D
Surgical resections **
Surgery-first *
M AN U
Conversion *
Abbreviations: SD = standard deviation; RFA = radiofrequency ablation.
12
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT