Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice

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Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice S. Karim a,b, S. Nanji b,c, K. Brennan a, C.S. Pramesh e, C.M. Booth a,b,d,* a

Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, Canada b Department of Oncology, Queen’s University, Kingston, Canada c Department of Surgery, Queen’s University, Kingston, Canada d Department of Public Health Sciences, Queen’s University, Kingston, Canada e Department of Surgical Oncology, Tata Memorial Centre, Mumbai, India Accepted 5 May 2017 Available online - - -

Abstract Background: The role of chemotherapy in the setting of resected colorectal cancer pulmonary metastases (CRCPM) is not well defined. Here we describe utilization of peri-operative chemotherapy and outcomes among patients with resected CRCPM in the general population. Methods: All cases of CRCPM who underwent resection from 2002 to 2009 were identified using the Ontario Cancer Registry (OCR). Electronic treatment records identified peri-operative chemotherapy delivered within 16 weeks before or after pulmonary metastasectomy (PM). Modified Poisson regression was used to evaluate factors associated with chemotherapy delivery. Cox proportional models were used to explore the association between post-operative chemotherapy and cancer-specific (CSS) and overall survival (OS). Results: The study population included 420 patients. Thirty-six percent of patients (151/420) received peri-operative chemotherapy. Among these patients, 75% (113/151) received post-operative chemotherapy. Factors that were independently associated with use of post-operative chemotherapy included higher socioeconomic status (SES) and no prior adjuvant chemotherapy (p < 0.01). In adjusted analyses postoperative chemotherapy was not associated with improved CSS (HR 0.99, 95% CI 0.67e1.47) or OS (HR 0.93 95% CI 0.66e1.31). In exploratory analyses, among those patients who did not receive previous adjuvant therapy for the primary colorectal cancer, postoperative chemotherapy following lung metastasectomy was associated with HR 0.50 (95% CI 0.27e0.95) for OS and HR 0.59 (95% CI 0.27e1.27) for CSS. Conclusion: One third of patients with resected CRCPM in routine practice receive peri-operative chemotherapy. A randomized controlled trial is warranted to evaluate whether chemotherapy following resection of CRCPM is associated with improved survival. Ó 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Keywords: Colon cancer; Metastasectomy; Adjuvant chemotherapy; Pulmonary metastases

Introduction The lungs are the second most common site of metastases from colorectal cancer (CRC) with approximately 10e15% of patients developing pulmonary recurrence after * Corresponding author. Division of Cancer Care and Epidemiology, Queen’s University Cancer Research Institute, 10 Stuart St, Kingston, ON K7L 3N6, Canada. Fax: þ1 613 533 6794. E-mail address: [email protected] (C.M. Booth).

curative resection.1,2 Despite no randomized evidence to support it, the practice of pulmonary metastasectomy (PM) has become widespread based on data from retrospective studies that suggest that long-term survival is achieved for some patients. A recent meta-analysis reported that fiveyear survival for patients with resected colorectal cancer pulmonary metastases (CRCPM) is 27e68%.3 A number of factors have been associated with poor survival including shorter disease-free interval, multiple lung metastases, involvement of mediastinal and hilar lymph nodes and

http://dx.doi.org/10.1016/j.ejso.2017.05.003 0748-7983/Ó 2017 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved. Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003

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S. Karim et al. / EJSO xx (2017) 1e7

elevated pre-operative carcinoembryonic antigen level (CEA).4e6 While guidelines recommend peri-operative chemotherapy for patients with resectable colorectal liver metastases (CRCLM),7e9 little data support its use in resectable CRCPM. No randomized controlled trials have evaluated peri-operative chemotherapy versus surgery alone in this patient population. Some guidelines have extrapolated evidence for resectable CRCLM and recommend perioperative chemotherapy for liver and/or lung metastases.10,11 Most large retrospective studies describing management and outcome of patients with resected CRCPM have not evaluated the potential survival benefit of perioperative chemotherapy. Two recent single institution studies of patients have reported conflicting results regarding the potential survival benefit of chemotherapy in this setting.12,13 To address this gap in knowledge, we undertook a population-based study of patients with resected CRCPM to describe utilization and outcomes of peri-operative chemotherapy in routine practice. Methods Study design and population We performed a population-based, retrospective cohort study to describe utilization of chemotherapy and outcome of resected CRCPM in the Canadian province of Ontario. Ontario has a population of approximately 13.5 million people and a single-payer universal health insurance program. The study cohort was defined using the Ontario Cancer Registry (OCR) to identify all incident cases of colorectal adenocarcinoma with pulmonary resection during 2002e2009. Electronic records of treatment were linked to the OCR. Extent of pulmonary metastases was not available in the existing data sources; therefore, we obtained surgical pathology reports for all cases. The study was approved by the Research Ethics Board of Queen’s University. Data sources and linkage The OCR is a passive, population-based cancer registry that captures diagnostic and demographic information on at least 98% of all incident cases of cancer in the province of Ontario.14 The OCR also provides information about vital status and cause of death. Records of hospitalization from the Canadian Institute for Health Information (CIHI) provided information about surgical interventions and are known to be complete.15 Provincial physician billing records from the Ontario Health Insurance Plan (OHIP), treatment records [Activity Level Reporting (ALR)] from regional cancer centers, and provincial records of chemotherapy delivery [New Drug Funding Program (NDFP) and Ontario Drug Benefits (ODB)] were used to identify chemotherapy utilization. These datasets were linked using

unique encoded identifiers and analyzed at the Institute of Clinical and Evaluative Sciences (ICES). Surgical pathology reports were obtained from the OCR. A team of trained data abstractors reviewed the pathology reports and entered information about extent of disease and surgical procedure into an electronic database. Measures and outcomes Indicators of the socioeconomic status (SES) of the community in which patients resided at diagnosis were linked as described previously.16 Quintiles (Q) of the median household income were based on the household income distribution for the full province of Ontario. Q1 represents the communities where the poorest 20% of the Ontario population resided. Geographic regions reflect the catchment areas for Ontario’s regional cancer centers.16 Co-morbidity was classified using the Charlson Index modified for administrative data.17 Pre-operative chemotherapy was defined as chemotherapy given within 16 weeks before resection of CRCPM; post-operative chemotherapy was defined as treatment initiated within 16 weeks after surgery for CRCPM. Cancer-specific (CSS) and overall survival (OS) were measured from resection of CRCPM. To account for possible cause of death miscoding, CSS included death from any cancer. Complete information about vital status in the OCR was available up to December 31, 2012; cause of death was available up to December 31, 2010. Analyses of factors associated with treatment and chemotherapy comparative effectiveness were restricted to patients who did not receive pre-operative chemotherapy. This was done for two reasons. First, administrative data sources do not distinguish between down staging chemotherapy for unresectable disease and peri-operative chemotherapy delivered to patients with resectable disease. Second, the extent of pulmonary metastases (i.e. size and number of lesions) would not be reliably known from surgical pathology reports among patients already treated with chemotherapy. Because these factors are known to be strongly associated with both chemotherapy utilization and outcome, subsequent analyses would be substantially limited by unmeasured confounding. Because the survival measure began before the chemotherapy exposure window ended (i.e. at 16 weeks) our results were vulnerable to immortal person-time bias whereby patients dying during the exposure window have a lower chance of receiving treatment; this would artificially worsen survival of the no chemotherapy group. We therefore excluded patients dying within 16 weeks of surgery from survival analyses. Statistical analysis Comparisons of proportions between study groups were made using the chi-square test. CSS and OS were determined using the KaplaneMeier method. Factors associated

Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003

S. Karim et al. / EJSO xx (2017) 1e7

with post-operative chemotherapy were evaluated using modified Poisson regression. Factors associated with CSS/ OS were evaluated using the Cox proportional hazards regression model. Results were considered statistically significant at p-value < 0.05. All analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC). Results Study population As shown in eFigure 1, we identified 526 patients who underwent resection for CRCPM during 2002e2009. Pathology reports were available for 420 (80%) cases; these patients comprise the study population. There were no important differences in case mix or survival between patients with and without surgical pathology reports (Supplemental eTable and eFigure 2). Table 1 describes the characteristics of the cohort. The median age was 64 years and 60% were male. The majority of patients (75%) had no significant co-morbidity. Nearly half of patients underwent lung resection more than 2 years from the time of their primary colorectal resection. Chemotherapy practice patterns Thirty-six percent of patients (151/420) received perioperative chemotherapy. The majority of these patients (75%, 113/151) were treated in the post-operative setting. Pre-operative chemotherapy was administered to 12% (18/151) of patients; 13% (20/151) received both pre- and post-operative treatment. Temporal trends in chemotherapy utilization rates are shown in Fig. 1. Overall utilization remained stable over the study period (32% in 2002 and 38% in 2009, p ¼ 0.541). Chemotherapy regimens were identified for 80% (121/ 151) of patients who received it. Of these, 45% (54/121) of patients received oxaliplatin-based chemotherapy, 35% (42/121) received irinotecan-based therapy and 21% (25/ 121) received 5-flurouracil (5-FU) monotherapy. Five percent of patients (6/121) received bevacizumab in combination with chemotherapy. Between 2002 and 2009, there was an increase in the use of oxaliplatin-based therapy [0% (0/17) in 2002 to 65% (13/20) in 2009, p < 0.001], and a decrease in the use of both irinotecan-based therapy [53% (9/17) 2002 to 20% (4/20) 2009, p ¼ 0.003] and 5FU monotherapy [29% (5/17) 2002 to 10% (2/20) 2009, p ¼ 0.167].

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Table 1 Characteristics of patients treated with surgical resection of colorectal cancer lung metastases in Ontario 2002 to 2009 (n ¼ 420). Patient-related Age (years) Median age (range) <65 65-74 75þ Sex Male Female SES by quintile 1 2 3 4 5 Charlson co-morbidity score 0 1 2þ Disease-related Timing of lung resectiona 0e6 mos 07e12 mos 13e24 mos 24 þ mos Extent of disease Mean number of lesionsb Mean size largest lesionc Involved surgical margind Treatment-related Surgical proceduree Wedge Lobectomy Multiple wedges Lobectomy and wedge(s) Pneumonectomy Peri-operative chemotherapy Pre-op Post-op Both None

64 (17e87) 211 (50%) 143 (34%) 66 (16%) 251 (60%) 169 (40%) 69 (16%) 100 (24%) 93 (22%) 75 (18%) 83 (20%) 313 (75%) 66 (16%) 41 (10%)

51 (13%) 45 (12%) 103 (27%) 186 (48%) 1.9 2.4 27 (6%)

127 (30%) 121 (29%) 112 (27%) 43 (10%) 14 (3%) 18 (4%) 113 (27%) 20 (5%) 269 (64%)

a

Defined as time from resection of primary CRC; only reported for n ¼ 385 cases with identified date of primary CRC resection. b Number of lesions not stated for <6 cases. c Lesion size not stated for 11 cases. d Margin status not stated for 37 cases. e Surgical procedure unknown for <6 cases.

adjuvant chemotherapy (RR 0.57, 95% CI 0.39e0.83 for prior chemotherapy, p ¼ 0.007). Statistical trends suggested greater utilization in young patients and those with no comorbidities (p ¼ 0.068 and p ¼ 0.089, respectively). Outcomes

Factors associated with chemotherapy utilization Factors associated with chemotherapy utilization are shown in Table 2. Factors that were independently associated with greater utilization of post-operative chemotherapy included higher SES (RR 0.45, 95% CI 0.25e0.81 for lowest SES, p ¼ 0.002) and no prior

Unadjusted five year CSS and OS for the entire cohort was 41% and 40%, respectively. Among patients treated with peri-operative chemotherapy, five year CSS and OS was 44% and 42%. In patients who received postoperative chemotherapy, CSS and OS at 5 years was 43% and 44%, respectively.

Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003

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S. Karim et al. / EJSO xx (2017) 1e7 100% 90% 80% 70% 60%

None Post-op

50%

Pre-op 40%

Both

30% 20% 10% 0% 2002

2003

2004

2005

2006

2007

2008

2009

Figure 1. Temporal trends in peri-operative chemotherapy for resected colorectal cancer pulmonary metastases in Ontario 2002e2009.

Factors associated with long-term survival in patients who did not receive pre-operative chemotherapy are listed in Table 3. CSS and OS were associated with the number of lesions, size of the largest lesion and lymph node status (p < 0.05). CSS but not OS was associated with gender, and OS but not CSS was associated with co-morbidity. Postoperative chemotherapy was not associated with improved CSS (HR 0.99, 95% CI 0.67e1.47) or OS (HR 0.93, 95% CI 0.66e1.31). In an exploratory analysis we explored for potential interaction between previous (remote) adjuvant chemotherapy and post-operative chemotherapy. The interaction term was significant in the OS model (p ¼ 0.022) and approached significance in the CSS model (p ¼ 0.012). Among those patients who did not receive previous adjuvant therapy for the primary colorectal cancer, post-operative chemotherapy following lung metastasectomy was associated with HR 0.50 (95%CI 0.27e0.95) for OS and HR 0.59 (95%CI 0.27e1.27) for CSS. Discussion This study describes utilization and outcome of perioperative chemotherapy in patients with resected CRCPM in routine clinical practice. Several important findings have emerged. First, one-third of patients with resected CRCPM receive peri-operative chemotherapy. Second, while overall utilization of peri-operative chemotherapy has not significantly changed over time, oxaliplatin-based chemotherapy has increased. Third, higher SES and no prior adjuvant therapy were associated with receipt of post-operative chemotherapy. Finally, our results did not find an association between post-operative chemotherapy and improved survival. Exploratory analyses suggest there may be a survival benefit among chemo-na€ıve patients.

Previous studies of patients undergoing resection of CRCPM have shown variation in use of peri-operative chemotherapy. Among 354 patients with resected CRCPM at five centers in Europe during 2005e2009, Pages et al. reported that 8% received pre-operative and 35% received post-operative chemotherapy.18 Conversely, among 221 patients treated during 2002e2013 at a single institution study in Korea, 80% received post-operative chemotherapy.12 High utilization of post-operative chemotherapy (93%) was also reported among 176 patients at another single center study in Korea.5 Compared to the studies in Asia, utilization rates in Ontario are substantially lower. This substantial geographic variation in practice likely reflects the lack of strong evidence to guide decision-making in this context. To our knowledge, temporal trends in utilization of perioperative chemotherapy for CRCPM have not been previously described. This study shows that there has been no significant change in the utilization of peri-operative chemotherapy during 2002e2009. However, there has been an increase in oxaliplatin-based peri-operative chemotherapy with a corresponding decrease in use of irinotecanbased therapy and 5-FU monotherapy. This is consistent with the evolution of evidence to support the use of FOLFOX chemotherapy in high-risk stage II/stage III colon cancer as well as in resected colorectal cancer liver metastases.19,20 Conversely, clinical trials failed to show that FOLFIRI was superior to 5-FU monotherapy for early-stage colon cancer21 or resected CRCLM.22 The preferred use of oxaliplatin-based chemotherapy in this study is consistent with other studies that describe chemotherapy utilization for CRCPM.12,13 Previous literature has identified low SES as a risk factor for not receiving adjuvant chemotherapy for early-stage

Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003

S. Karim et al. / EJSO xx (2017) 1e7 Table 2 Factors associated with post-operative chemotherapy among patients treated with surgical resection of colorectal cancer pulmonary metastases in Ontario 2002e2009 who did not receive pre-operative chemotherapy (n ¼ 382). Co-variate

Patient-related Age, years <65 years (n ¼ 189) 65e74 years (n ¼ 130) 75þ years (n ¼ 63) Sex Male (n ¼ 226) Female (n ¼ 156) SES by quintile 1 (n ¼ 61) 2 (n ¼ 91) 3 (n ¼ 83) 4 (n ¼ 73) 5 (n ¼ 74) Charlson score 0 (n ¼ 280) 1þ(n ¼ 102) Disease-related Timing of lung resectiona 0e6 mos (n ¼ 46) 7e12 mos (n ¼ 33) 13e24 mos (n ¼ 91) 24þ mos (n ¼ 182) Mean number lesionsb 1 (n ¼ 239) >1 (n ¼ 142) Mean size largest lesionc 2 cm (n ¼ 202) >2 cm (n ¼ 170) Treatment-related Previous chemotherapye Yes (n ¼ 296) No (n ¼ 86) System-related Regiond A (n ¼ 196) B (n ¼ 54) C (n ¼ 16) D (n ¼ 29) E (n ¼ 7) F (n ¼ 6) G (n ¼ 20) H (n ¼ 52)

% Post-op Chemo

Multivariate analysis

33% 32% 16%

Ref 0.87 (0.62e1.21) 0.51 (0.27e0.98)

30% 29%

Ref 0.89 (0.65e1.22)

20% 35% 17% 27% 47%

0.45 0.80 0.39 0.64 Ref

32% 23%

Ref 0.72 (0.48e1.08)

41% 48% 24% 28%

1.26 (0.81e1.96) 1.52 (1.00e2.31) 0.82 (0.52e1.27) Ref

27% 34%

Ref 1.15 (0.84e1.57)

34% 24%

Ref 0.78 (0.56e1.09)

27% 38%

0.57 (0.39e0.83) Ref

27% 26% 56% 28% N/R N/R N/R 35%

Ref 1.23 2.18 1.34 1.84 0.90 0.94 1.38

RR (95%CI)

P 0.068

0.464

0.002 (0.25e0.81) (0.53e1.20) (0.23e0.66) (0.40e1.01) 0.089

0.158

0.392

0.139

0.007

0.248 (0.75e2.03) (1.38e3.43) (0.74e2.43) (1.00e3.38) (0.16e5.10) (0.41e2.17) (0.89e2.13)

a

Date of primary resection not available for 30 cases. Lesion number not stated for <6 cases. c Lesion size not stated for 10 cases. d Region data not available for 2 cases. N/R: not reportable due to small cell size. e Previous chemotherapy is defined as any chemotherapy within 72 months before lung resection but not within 16 weeks before lung resection. b

colon cancer, even in countries with universal health care.23 A recently published study from our group demonstrated similar findings, although the effect size was smaller.24 In addition, SES was shown to be a significant factor for

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utilization of adjuvant chemotherapy for breast cancer in Ontario.25 Our study showed a very strong association between higher SES and receipt of post-operative chemotherapy after resection of CRCPM (Q5 vs Q1: 47% vs 20%, RR 0.45). Our study suggests that post-operative chemotherapy may not be associated with improved outcomes in resected CRCPM. This is consistent with other retrospective series. In a pooled analysis of 146 patients, Salah and colleagues did not find that post-operative chemotherapy was associated with improved survival in patients with resected CRCPM.26 A recent French multi-center study of 354 patients who underwent PM between 2005 and 2010 suggested a trend toward reduced recurrence rates with postoperative chemotherapy (p ¼ 0.06). However, there was no noted benefit in overall survival.18 To our knowledge, the only large study (n ¼ 615) to date that has shown an overall survival benefit with post-operative chemotherapy comes from a single institution in Korea. Cho et al. reported a HR of 1.77 (95% CI 1.25e2.47) for OS among patients that did not receive post-operative chemotherapy.27 Specific chemotherapy regimens were not described. The conflicting results from these observational studies points to the need for a clinical trial to evaluate whether chemotherapy can improve the survival of patients with resected CRCPM. Exploratory analyses in our study suggest there may be benefit to post-operative therapy among chemo-na€ıve patients. The observation that female gender is associated with inferior cancer-specific survival warrants further investigation. In contrast to these results, other studies have shown that women with CRC have superior survival compared to men.28,29 Although our study provides data regarding the uptake and outcomes of chemotherapy for CRCPM, several methodological limitations warrant comment. While the study datasets provide comprehensive information about various cancer therapies, granular patient-level details (i.e. stage of primary cancer, CEA level, performance status) are not available. Finally, as with any observational study, our comparative survival analysis may be limited by residual confounding. The strengths of our study include the relatively large sample size and the fact that by virtue of the Ontario Cancer Registry our cohort includes all cases of resected CRCPM. This reduces the referral and selection bias that may be present in institution-based observational studies. To our knowledge, this is the largest population-based study evaluating the utilization and outcomes of perioperative chemotherapy for resected CRCPM. Regimen use has shifted based on emerging data in other settings of colorectal cancer. Given the lack of robust data to support its use, peri-operative chemotherapy for resected CRCPM should be evaluated in the context of a randomized controlled trial.

Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003

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S. Karim et al. / EJSO xx (2017) 1e7

Table 3 Factors Associated with Cancer Specific and Overall Survival among patients treated with surgical resection of colorectal cancer pulmonary metastases in Ontario 2002e2009 who did not receive pre-operative chemotherapy (n ¼ 382). Co-Variate

Patient-related Age, years <65 years (n ¼ 187) 65e74 years (n ¼ 130) >75 years (n ¼ 60) Sex Male (n ¼ 224) Female (n ¼ 153) Charlson co-morbidity score 0 (n ¼ 277) 1þ (n ¼ 100) Disease free intervala 0e6 months (n ¼ 46) 7e12 months (n ¼ 32) 13e24 months (n ¼ 90) 24 þ months (n ¼ 180) Disease-related Mean number lesionsb 1 (n ¼ 236) >1 (n ¼ 140) Mean size largest lesionc 2 cm (n ¼ 200) >2 cm (n ¼ 167) Lymph node statusd Negative (n ¼ 186) Positive (n ¼ 47) No nodes (n ¼ 142) Margin Statuse No (n ¼ 317) Yes (n ¼ 24) Post-operative chemotherapy Yes (n ¼ 113) No (n ¼ 264) Previous chemotherapyf Yes (n ¼ 292) No (n ¼ 85)

Cancer-specific survival 5 yr CSS

Multivariable analysis

%

HR (95%CI)

41 40 40

Ref 1.11 (0.75e1.64) 1.59 (0.98e2.57)

43 35

Ref 1.44 (1.01e2.06)

44 29

Ref 1.32 (0.90e1.94)

42 26 42 44

1.38 (0.84e2.27) 1.36 (0.78e2.40) 1.21 (0.79e1.85) Ref

47 29

Ref 1.91 (1.35e2.70)

46 34

Ref 1.59 (1.10e2.29)

46 12 41

Ref 2.23 (1.41e3.52) 1.16 (0.77e1.74)

43 27

Ref 0.90 (0.49e1.68)

40 40

0.99 (0.67e1.47) Ref

39 44

1.19 (0.77e1.84) Ref

Overall survival

P

5 yr OS

Multivariable analysis

%

HR (95%CI)

42 41 41

Ref 1.10 (0.79e1.54) 1.53 (1.00e2.34)

45 36

Ref 1.31 (0.96e1.79)

45 29

Ref 1.41 (1.01e1.95)

41 24 46 43

1.15 (0.74e1.80) 1.32 (0.81e2.18) 1.01 (0.69e1.47) Ref

49 28

Ref 1.76 (1.30e2.38)

48 34

Ref 1.44 (1.05e1.97)

48 17 40

Ref 2.24 (1.47e3.41) 1.32 (0.94e1.86)

44 24

Ref 0.99 (0.58e1.70)

43 41

0.93 (0.66e1.31) Ref

41 42

0.97 (0.67e1.41) Ref

0.172

P 0.144

0.046

0.085

0.158

0.041

0.491

0.688

<0.001

<0.001

0.013

0.022

0.002

0.001

0.751

0.972

0.976

0.672

0.432

0.886

Patients who died within 16 weeks of surgery are excluded to account for immortal time bias. a Date of primary resection not available for 29 cases. b Lesion number not stated for <6 cases. c Lesion size not stated for 10 cases. d Lymph node status not stated for <6 cases. e Margin status not stated for 36 cases. f Previous chemotherapy is defined as any chemotherapy within 72 months before lung resection but not within 16 weeks before lung resection.

Funding

Acknowledgments

Dr. Booth is supported as a Canada Research Chair in Population Cancer Care. This work was also supported by the Canada Foundation for Innovation and Queen’s University Department of Surgery.

Parts of this material are based on data and information provided by Cancer Care Ontario. However, the analysis, conclusions, opinions and statements expressed herein are those of the authors and not necessarily those of Cancer Care Ontario. This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which is funded by an annual grant from the Ontario Ministry of Health and Long-Term

Disclosure The authors report no conflicts of interest.

Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003

S. Karim et al. / EJSO xx (2017) 1e7

Care (MOHLTC). The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Dr. Booth had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Appendix A. Supplementary data Supplementary data related to this article can be found at http://dx.doi.org/10.1016/j.ejso.2017.05.003. References 1. Pihl E, Hughes ES, McDermott FT, Johnson WR, Katrivessis H. Lung recurrence after curative surgery for colorectal cancer. Dis Colon Rectum 1987;30(6):417–9. 2. Lee W, Yun S, Chun H, Lee W, Yun H. Clinical usefulness of chest radiography in detection of pulmonary metastases after curative resection for colorectal cancer. World J Surg 2007;31(7):1502–6. 3. Gonzalez M, Poncet A, Combescure C, Robert J, Ris HB, Gervaz P. Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis. Ann Surg Oncol 2012;20(2):572–9. 4. Embun R, Rivas de Andres JJ, Call S, et al. Causal model of survival after pulmonary metastasectomy of colorectal cancer: a nationwide prospective registry. Ann Thorac Surg 2016;101:1883–90. 5. Ihn MH, Kim D-W, Cho S, et al. Curative resection for metachronous pulmonary metastases from colorectal cancer: analysis of survival rates and prognostic factors. Cancer Res Treat 2017;49(1):104–15. 6. Lumachi F, Chiara GB, Tozzoli R, Contea ADEL, Basso SMM. Factors affecting survival in patients with lung metastases from colorectal cancer. A short meta-analysis. Anticancer Res 2016;20:13–9. 7. Schmoll HJ, Van Cutsem E, Stein A, et al. ESMO consensus guidelines for management of patients with colon and rectal cancer. A personalized approach to clinical decision making. Ann Oncol 2012; 23(10):2479–516. 8. Van De Velde CJH, Boelens PG, Borras JM, et al. EURECCA colorectal: multidisciplinary management: European consensus conference colon & rectum. Eur J Cancer 2014;50(1):e1–e34. 9. Gallinger S, Biagi JJ, Fletcher GG, Nhan C, Ruo L, McLeod RS. Liver resection for colorectal cancer metastases. Curr Oncol 2013;20(3): e255–65. 10. van Cutsem E, Nordlinger B, Cervantes A. Advanced colorectal cancer: ESMO clinical practice guidelines for treatment. Ann Oncol 2010; 21(Suppl. 5):93–7. 11. National Comprehensive Cancer Network (NCCN). NCCN clinical practice guidelines in oncology. Version 2. J Natl Compr Canc Netw 2017;15(3):370–98. 12. Park HS, Jung M, Shin SJ, et al. Benefit of adjuvant chemotherapy after curative resection of lung metastasis in colorectal cancer. Ann Surg Oncol 2016;23(3):928–35. 13. Hawkes EA, Ladas G, Cunningham D, et al. Peri-operative chemotherapy in the management of resectable colorectal cancer pulmonary metastases. BMC Cancer 2012;12(1):326.

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Please cite this article in press as: Karim S, et al., Chemotherapy for resected colorectal cancer pulmonary metastases: Utilization and outcomes in routine clinical practice, Eur J Surg Oncol (2017), http://dx.doi.org/10.1016/j.ejso.2017.05.003