Surg Endosc (2015) 29:493–499 DOI 10.1007/s00464-014-3697-1
and Other Interventional Techniques
Laparoscopy mitigates adverse oncological effects of delayed adjuvant chemotherapy for colon cancer Gerald A. Gantt Jr. • Jean Ashburn • Ravi P. Kiran • Alok A. Khorana • Matthew F. Kalady
Received: 31 December 2013 / Accepted: 20 June 2014 / Published online: 12 July 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Delaying initiation of adjuvant chemotherapy more than 8 weeks after surgical resection for colorectal cancer adversely affects overall patient survival. The effect of a laparoscopic surgical approach on initiation of chemotherapy has not been studied. The goal of this study was to determine if a laparoscopic approach to colon cancer resection affects the timing of adjuvant chemotherapy and outcomes. Methods Patients who underwent curative surgery for stage II or III colon cancer and received adjuvant chemotherapy between 2003 and 2010 were identified from a prospectively maintained database. Patients were categorized according to surgical approach: open or laparoscopic. Patient demographics, clinicopathologic variables, postoperative complications, time from surgery to initiation of chemotherapy, and long-term oncologic outcomes were compared. Results Age, gender, ASA class, BMI, tumor stage, and postoperative complications were similar for laparoscopic and open cases, while length of stay was 2 days shorter for laparoscopic cases (5.4 vs 7.6 days, p \ 0.01). The proportion of patients who received adjuvant chemotherapy more than 8 weeks after surgery did not differ between the G. A. Gantt Jr. (&) J. Ashburn R. P. Kiran M. F. Kalady Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Ave A30, Cleveland, OH 44195, USA e-mail: [email protected] M. F. Kalady e-mail: [email protected] A. A. Khorana Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
groups (35.6 % open vs 38.7 % laparoscopic, p = 0.77). In the open group, delay in chemotherapy after surgery was associated with decreased disease-free and overall survival (p = 0.01, 0.01, respectively). However, delay in chemotherapy more than 8 weeks did not affect disease-free or overall survival in the laparoscopy group (p = 0.93, 0.51, respectively). Conclusions The benefits of quicker recovery after laparoscopic surgery did not translate into earlier initiation of adjuvant chemotherapy in this retrospective study. However, a laparoscopic approach negated the inferior oncologic outcomes of patients who received delayed initiation of chemotherapy. Keywords Colon cancer Adjuvant chemotherapy Laparoscopy Current treatment of stage III and select stage II colon cancer involves surgical resection followed by chemotherapy (CT) [1, 2]. Adjuvant CT has been shown to increase survival in these patients [3, 4]. Previous studies have shown that delaying initiation of adjuvant CT greater than 8 weeks after surgical resection adversely affects overall patient survival [5–8]. A number of demographic, clinical, and systemic factors have been associated with delay in the initiation of CT, including age, race, and postoperative length of stay [9, 10]. Laparoscopy has been shown to be equal to an open technique in terms of oncological outcomes for colon cancer [11, 12]. Patients who undergo a laparoscopic procedure benefit from improved cosmesis, decreased length of stay, decreased postoperative narcotic analgesia use, and quicker return of bowel function [13–15]. While it has been well established that laparoscopy is associated with decreased length of stay and recovery time, the effect of a
123
494
Surg Endosc (2015) 29:493–499 Table 1 Patient and tumor characteristics Open N = 59 (65.6 %)
Laparoscopic N = 31 (34.4 %)
60 ± 13.09
64.57 ± 12.39
25 (42.4 %)
17 (54.8 %)
1
0 (1 %)
1 (3.4 %)
2
18 (34.6 %)
11 (37.9 %)
3 4
31 (59.6 %) 3 (5.8 %)
15 (51.7 %) 2 (6.9 %)
\30
30 (52.6 %)
14 (45.2 %)
[30
27 (47.4 %)
17 (54.8 %)
II
7 (15.2 %)
4 (10.7 %)
III
52 (84.8 %)
27 (89.3 %)
pT1
2 (3.4 %)
2 (6.4 %)
pT2
9 (15.3 %)
1 (3.2 %)
pT3
42 (71.2 %)
21 (67.7 %)
pT4
6 (10.2 %)
7 (22.6 %)
pN0
7 (11.9 %)
4 (12.9 %)
pN1 pN2
34 (57.6 %) 18 (30.5 %)
13 (41.9 %) 14 (45.2 %)
59 (100 %)
31 (100 %)
19 (32.2 %)
5 (16.1 %)
Age (mean ± SD) Gender Female
0.65
BMI
0.5
Stage
1
Pathologic T stage
laparoscopic surgical approach on the time to initiation of CT has not been studied. Therefore, the aim of this study was to determine if a laparoscopic approach to colon cancer resection affected the timing of adjuvant CT and subsequently oncological outcomes.
0.12
Pathologic N stage
0.31
Pathologic M stage pM0
NA
Differentiation Poor
0.23 0.26
ASA class
Fig. 1 Algorithm for patient selection. Thousand two hundred and sixty seven patient charts with stage II or III of colorectal cancer were identified. 633 patients with rectal cancer were excluded, leaving 654 colon cancer patients. Of these, 544 patients did not receive adjuvant chemotherapy or had missing information regarding adjuvant chemotherapy use. The remaining 90 patients with stage II/III colon cancer and known adjuvant chemotherapy regimen were used in this study
p
0.14
Moderate
38 (64.4 %)
26 (83.9 %)
Well
2 (3.4 %)
0 (0 %)
Lymph nodes harvested (mean ± SD)
32.7 ± 18.4
25.6 ± 11
0.1
Patient selection
Lymph nodes involved (mean ± SD)
3.5 ± 6.3
4.6 ± 6.2
0.31
A prospectively maintained colorectal cancer database from a single institution was queried for patients with stage II or III colon cancer who underwent surgical resection between the years 2003 and 2010. The resulting patient list was then cross-referenced with a prospectively maintained oncology database of adjuvant CT regimens. Patient data present in both databases were extracted for analysis. Records without information regarding the timing of CT were excluded (Fig. 1). Patients were categorized according to surgical approach: open or laparoscopic.
Chemotherapy regimen
Materials and methods
Patient characteristics and outcomes The resulting cohort of patients was analyzed for clinicopathologic variables including age, gender, body mass
123
0.07
5-Fu/leucovorin
18
18
FOLFOX
31
11
Unknown
5
2
Capecitabine/ oxaliplatin
1
0
Capecitabine (monotherapy)
4
0
Tumor location
0.43
Right
27 (45.7 %)
15 (48.4 %)
Hepatic flexure
5 (8.5 %)
1 (3.2 %)
Transverse
5 (8.5 %)
1 (3.2 %)
Splenic flexure
3 (5.1 %)
0 (0 %)
Left
19 (32.2 %)
14 (45.2 %)
Surg Endosc (2015) 29:493–499
495
Table 1 continued Open N = 59 (65.6 %)
Laparoscopic N = 31 (34.4 %)
Right hemicolectomy
36 (61 %)
14 (45.2 %)
Left hemicolectomy
17 (28.8 %)
10 (32.2 %)
Sigmoidectomy
6 (10.2 %)
7 (22.6 %)
Operation performed
0.49
Clavien–Dindo classification I II
p
0.13 8 6
3 0
IIIa
0
0
IIIb
2
1
IVa
0
4
IVb
0
0
V
0
0
adjuvant CT was similar in both the laparoscopic and open groups (53.3 ± 19.8 vs 52.3 ± 22.0 days, p = 0.58). Of 90 patients, 33 (36.7 %) initiated CT greater than 8 weeks postoperatively. There was no difference in the proportion of patients who received adjuvant CT more than 8 weeks after surgery between the two groups (35.6 % open vs 38.7 % laparoscopic p = 0.77). Complication rates were greater for patients who received CT more than 8 weeks after surgery compared to those who received it sooner. Delay in initiation of chemotherapy was associated with higher ASA classification (Table 2). Disease-free and overall survival
Categorical variables were compared using Fisher’s exact test or Chi square as appropriate. Quantitative and ordinal variables were compared using Wilcoxon rank sum test. Kaplan–Meier curves were generated for overall and disease-free survival according to operative approach and time to initiation of CT.
Disease-free survival (DFS) was decreased in patients who began CT greater than 8 weeks following surgery (p = 0.04) (Fig. 2A). This effect varied according to the surgical approach. In patients undergoing open resection, delay in adjuvant CT was associated with a decrease in DFS (p = 0.01) (Fig. 2B). Conversely, DFS did not differ between patients who received CT sooner or later than 8 weeks postoperatively in the laparoscopic group (p = 0.93) (Fig. 2C). Overall survival in the total study population was not significantly associated with delay in CT treatment, (p = 0.08) (Fig. 3A). Similar to the DFS outcomes, for patients in the open surgery group, a delay in adjuvant CT greater than 8 weeks from surgery was associated with significantly worse survival (28 % decrease at 5 years, (p = 0.01, Fig. 3B). However, there was no difference in OS associated with initiation of CT after 8 weeks in the laparoscopic group (p = 0.51), (Fig. 3C).
Results
Discussion
Clinical and pathological data
As expected, patients with colon cancer treated by laparoscopic resection had shorter length of stay compared to open cases. However, this did not translate into earlier initiation of CT following laparoscopic cases in this nonprotocoled retrospective study. Interestingly, for those patients who had a delay in CT, there was a difference in DFS and OS depending on the approach. Patients who underwent laparoscopic resection did not have a decrease in DFS and OS when the initiation of CT was delayed. However, delayed CT was associated with decreased DFS and OS in open cases. These findings may indicate an additional benefit to laparoscopic surgery. In the literature, the proportion of patients who have delayed initiation of CT ranges from 20 to 72 % [5–8, 16]. This is consistent with our data, as approximately one third of patients received adjuvant CT greater than 8 weeks after
index (BMI), tumor stage, tumor location, tumor differentiation, and ASA class. Postoperative complications, need for reoperation, time interval from surgery to initiation of CT, and long-term oncologic outcomes were also included in the analysis. Statistical analysis
Ninety cases were included in the study, 31 (34.4 %) of which were performed laparoscopically. There was no difference in age, gender, ASA class, or BMI between the open and laparoscopic groups. Similarly, tumor stage, tumor differentiation, postoperative complications, and need for reoperation did not differ between the two cohorts (Table 1). Length of stay was approximately two days shorter in the laparoscopic group, compared to open (5.4 ± 3.7 vs 7.6 ± 5.2, p \ 0.001). Initiation of adjuvant chemotherapy Overall, the mean time to initiation of CT was less than 8 weeks (52.7 ± 21.2 days). The time to initiation of
123
496 Table 2 Factors associated with delay in chemotherapy initiation
Surg Endosc (2015) 29:493–499
Chemotherapy started \8 weeks
Chemotherapy started C8 weeks
p
6.16 ± 2.99
8.09 ± 5.4
0.13
1
0 (0 %)
1 (3.3 %)
2
20 (39.2 %)
9 (30 %)
3
29 (56.9 %)
17 (56.7 %)
2 (3.9 %)
3 (10 %)
2.65 ± 0.56
2.73 ± 0.69
Length of stay (mean ± SD) ASA
4 ASA (mean ± SD)
0.03
0.49
Complications Overall complication rate
4 (0.07 %)
10 (0.3 %)
0.05
Hemorrhage
0 (0 %)
1 (3 %)
0.37
DVT
1 (1.8 %)
0 (0 %)
1
Wound dehiscence
0 (0 %)
2 (6.1 %)
0.13
Wound infection
3 (5.3 %)
2 (6.1 %)
1
Bowel obstruction
0 (0 %)
3 (9.1 %)
0.05
Intraabdominal abscess UTI
0 (0 %) 0 (0 %)
1 (3 %) 1 (3 %)
0.37 0.37
Anastomotic leak
0 (0 %)
0 (0 %)
NA
Reoperation
0 (0 %)
2 (6.1 %)
0.13
surgery. A number of factors have been associated with delay of adjuvant CT, resulting in several confounding variables. In a study investigating the causes of delay in adjuvant CT in rectal cancer patients, Cheung et al. [10] found that the length of postoperative hospital stay, age, and race were associated with initiating CT more than three months following surgery. Postoperative complications have also been associated with delayed initiation of adjuvant CT in rectal cancer patients [17]. In addition to these patient centered factors, systematic factors also contribute to delays in adjuvant CT. Delays in referrals to medical oncologists, waiting lists for appointments, and waiting lists to initiate CT are all systematic issues associated with delays in adjuvant therapy [7]. Upon initiating this study we anticipated that patients undergoing laparoscopic surgery would be treated with adjuvant CT earlier after surgery than those undergoing open resections. This did not bear out in this retrospective study as the timing of CT relied on several uncontrolled and not recorded variables. Surprisingly, there was a slightly higher percentage of patients who received CT more than 8 weeks after laparoscopic surgery compared to open surgery (38.7 vs 35.6 %, p = 0.77). This trend was not statistically significant, and would likely disappear if a larger sample sized was used. A prospective trial that aggressively planned earlier initiation of adjuvant CT in laparoscopic patients would more appropriately determine if laparoscopy would result in improved outcomes. Decreased OS in patients who receive CT greater than 8 weeks after surgery has been demonstrated in several studies [5, 8, 9, 18]. However, none of the previous studies
123
examined the effect of laparoscopy on survival after delay in CT. In a study of 186 patients with stage II and III colon adenocarcinoma, Bayraktar et al. [5] found that delay of adjuvant CT greater than 60 days was associated with worse OS. Similarly, Czaykowski et al. [7] found a trend toward worse OS and DFS among stage III colon cancer patients who received adjuvant CT more than 56 days following surgery. Use of laparoscopy was not considered as a variable in either of these studies. Hershman et al. [6] reviewed the Surveillance, Epidemiology, and End Results (SEER)-Medicare database for patients diagnosed with stage III colon cancer between 1992 and 1999, and found that colon cancer-specific and overall mortality was higher among patients who received CT greater than 3 months following surgery. Few surgeons were performing laparoscopic colectomies during this time, and as such it is likely that few laparoscopic cases were included. The paucity of data regarding the effect of laparoscopy on timing of adjuvant CT makes the previous studies less generalizable to current surgical care, and emphasizes the relevance of our study. A relatively unexpected and novel finding of this study was that patients undergoing laparoscopic surgery did not seem to have worse outcomes if CT was delayed greater than 8 weeks after surgery. The advantages of laparoscopic colectomy are widely reported and include decreased length of stay, quicker recovery, and decreased postoperative pain [11, 14, 19]. Another advantage of laparoscopic surgery is improved immunologic response to surgical stress compared to open surgery. Several studies have shown a diminished inflammatory response for patients
Surg Endosc (2015) 29:493–499
497
Fig. 2 Kaplan–Meier plots of disease-free survival based on time to initiating chemotherapy after surgery for the total study population (p = 0.04) (A); patients treated by open approach (p = 0.01) (B); and patients treated by laparoscopic approach (p = 0.93) (C). All p values calculated using the log-rank test
undergoing laparoscopy [20, 21]. Decreased stress response to surgery may result in improved immunologic function, and oncologic benefits [22]. These findings may be a possible explanation for the relatively improved DFS and OS for laparoscopic cases with delayed CT compared to open cases. This effect on improved oncologic outcomes is particularly clinically relevant as approximately 20 % of patients have CT delayed for various reasons as discussed above. [6]. We recognize some of the limitations of this study. The retrospective nature is subject to confounding variables that may influence the timing of therapy. All of the operations in this study were performed by 15 fellowship trained colon and rectal surgeons. The majority of the surgeons performed both open and laparoscopic cases, however, five surgeons exclusively performed open operations, and three surgeons exclusively performed laparoscopic cases. Surgeon’s chose their approach based on their comfort level
performing the procedure. This may be another source of bias in our study. Also, given the quaternary referral status of our institution, many patients who undergo surgery at Cleveland Clinic receive their oncological care elsewhere. This pattern of patients receiving adjuvant therapy at outside institutions prevents the analysis of many variables that could delay CT. Systematic variables should be included in future analyses of causes of CT delay. In summary, although the benefits of quicker recovery after laparoscopic surgery did not translate into earlier initiation of adjuvant CT in this retrospective study, it is rational to test this theory in a prospective fashion. Interestingly, a laparoscopic approach negated the inferior oncologic outcomes of patients who received delayed initiation of CT. These results need to be validated in larger studies and if confirmed, underlying potential causes of the differences in oncologic outcomes warrant exploration.
123
498
Surg Endosc (2015) 29:493–499
Fig. 3 Kaplan–Meier plots of overall survival based on time to initiating chemotherapy after surgery for the total study population (p = 0.08) (A); patients treated by open approach (p = 0.01) (B); and patients treated by laparoscopic approach (p = 0.51) (C). All p values calculated using the log-rank test
Acknowledgments The authors would like to acknowledge Jeff Hammel for his statistical analysis. MFK is the Krause-Lieberman Chair in Colorectal Surgery. AAK is the Sondra and Stephen Hardis Chair in Oncology Research. Disclosures Gerald A Gantt, M.D., Jean Ashburn, M.D., Ravi P. Kiran, M.B.B.S., Alok A. Khorana, M.D., and Matthew F. Kalady, M.D. have no relevant conflict of interests or financial ties to disclose. Funding
Krause-Lieberman Endowed Chair of Colorectal Surgery.
References 1. Jessup JM, Stewart A, Greene FL, Minsky BD (2005) Adjuvant chemotherapy for stage III colon cancer: implications of race/ ethnicity, age, and differentiation. JAMA 294:2703–2711. doi:10. 1001/jama.294.21.2703 2. Benson AB III, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG (2004) American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22:3408 –3419. doi:10.1200/JCO.2004.05.063
123
3. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358. doi:10. 1056/NEJM199002083220602 4. Quasar Collaborative Group, Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ (2007) Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370:2020–2029. doi:10.1016/S0140-6736(07) 61866-2 5. Bayraktar UD, Chen E, Bayraktar S, Sands LR, Marchetti F, Montero AJ, Rocha-Lima CM (2010) Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer. doi:10.1002/cncr.25720 6. Hershman D, Hall MJ, Wang X, Jacobson JS, McBride R, Grann VR, Neugut AI (2006) Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer. Cancer 107:2581–2588. doi:10.1002/cncr.22316 7. Czaykowski PM, Gill S, Kennecke HF, Gordon VL, Turner D (2011) Adjuvant chemotherapy for stage III colon cancer: does timing matter? Dis Colon Rectum 54:1082–1089. doi:10.1097/ DCR.0b013e318223c3d6 8. Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM (2011) Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic
Surg Endosc (2015) 29:493–499
9.
10.
11.
12.
13.
14.
15.
review and meta-analysis. JAMA 305:2335–2342. doi:10.1001/ jama.2011.749 Des Guetz G, Nicolas P, Perret GY, Morere JF, Uzzan B (2010) Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. Eur J Cancer 46:1049–1055. doi:10.1016/j.ejca.2010.01.020 Cheung WY, Neville BA, Earle CC (2009) Etiology of delays in the initiation of adjuvant chemotherapy and their impact on outcomes for stage II and III rectal cancer. Dis Colon Rectum 52:1054–1063; discussion 1064. doi:10.1007/DCR.0b013e3181a51173 Clinical Outcomes of Surgical Therapy Study Group (2004) A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050–2059. doi:10.1056/NEJMo a032651 Colon Cancer Laparoscopic or Open Resection Study Group, Buunen M, Veldkamp R, Hop WC, Kuhry E, Jeekel J, Haglind E, Pahlman L, Cuesta MA, Msika S, Morino M, Lacy A, Bonjer HJ (2009) Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial. Lancet Oncol 10:44–52. doi:10.1016/S1470-2045(08)70310-3 Milsom JW, Bohm B, Hammerhofer KA, Fazio V, Steiger E, Elson P (1998) A prospective, randomized trial comparing laparoscopic versus conventional techniques in colorectal cancer surgery: a preliminary report. J Am Coll Surg 187:46–54; discussion 54–5 Abraham NS, Young JM, Solomon MJ (2004) Meta-analysis of short-term outcomes after laparoscopic resection for colorectal cancer. Br J Surg 91:1111–1124. doi:10.1002/bjs.4640 Braga M, Vignali A, Gianotti L, Zuliani W, Radaelli G, Gruarin P, Dellabona P, Di Carlo V (2002) Laparoscopic versus open colorectal surgery: a randomized trial on short-term outcome. Ann Surg 236:759–766; disscussion 767. doi:10.1097/01.SLA. 0000036269.60340.AE
499 16. Lima IS, Yasui Y, Scarfe A, Winget M (2011) Association between receipt and timing of adjuvant chemotherapy and survival for patients with stage III colon cancer in Alberta, Canada. Cancer 117:3833–3840. doi:10.1002/cncr.25954 17. Tevis SE, Kohlnhofer BM, Stringfield S, Foley EF, Harms BA, Heise CP, Kennedy GD (2013) Postoperative complications in patients with rectal cancer are associated with delays in chemotherapy that lead to worse disease-free and overall survival. Dis Colon Rectum 56:1339–1348. doi:10.1097/DCR.0b013e3182 a857eb 18. Berglund A, Cedermark B, Glimelius B (2008) Is it deleterious to delay the start of adjuvant chemotherapy in colon cancer stage III? Ann Oncol 19:400–402. doi:10.1093/annonc/mdm582 19. Hemandas AK, Abdelrahman T, Flashman KG, Skull AJ, Senapati A, O’Leary DP, Parvaiz A (2010) Laparoscopic colorectal surgery produces better outcomes for high risk cancer patients compared to open surgery. Ann Surg 252:84–89. doi:10.1097/ SLA.0b013e3181e45b66 20. Harmon GD, Senagore AJ, Kilbride MJ, Warzynski MJ (1994) Interleukin-6 response to laparoscopic and open colectomy. Dis Colon Rectum 37:754–759 21. Whelan RL, Franklin M, Holubar SD, Donahue J, Fowler R, Munger C, Doorman J, Balli JE, Glass J, Gonzalez JJ, Bessler M, Xie H, Treat M (2003) Postoperative cell mediated immune response is better preserved after laparoscopic vs open colorectal resection in humans. Surg Endosc 17:972–978. doi:10.1007/ s00464-001-8263-y 22. Allendorf JD, Bessler M, Horvath KD, Marvin MR, Laird DA, Whelan RL (1999) Increased tumor establishment and growth after open vs laparoscopic surgery in mice may be related to differences in postoperative T-cell function. Surg Endosc 13:233–235
123
and Other Interventional Techniques
Laparoscopy mitigates adverse oncological effects of delayed adjuvant chemotherapy for colon cancer Gerald A. Gantt Jr. • Jean Ashburn • Ravi P. Kiran • Alok A. Khorana • Matthew F. Kalady
Received: 31 December 2013 / Accepted: 20 June 2014 / Published online: 12 July 2014 Ó Springer Science+Business Media New York 2014
Abstract Background Delaying initiation of adjuvant chemotherapy more than 8 weeks after surgical resection for colorectal cancer adversely affects overall patient survival. The effect of a laparoscopic surgical approach on initiation of chemotherapy has not been studied. The goal of this study was to determine if a laparoscopic approach to colon cancer resection affects the timing of adjuvant chemotherapy and outcomes. Methods Patients who underwent curative surgery for stage II or III colon cancer and received adjuvant chemotherapy between 2003 and 2010 were identified from a prospectively maintained database. Patients were categorized according to surgical approach: open or laparoscopic. Patient demographics, clinicopathologic variables, postoperative complications, time from surgery to initiation of chemotherapy, and long-term oncologic outcomes were compared. Results Age, gender, ASA class, BMI, tumor stage, and postoperative complications were similar for laparoscopic and open cases, while length of stay was 2 days shorter for laparoscopic cases (5.4 vs 7.6 days, p \ 0.01). The proportion of patients who received adjuvant chemotherapy more than 8 weeks after surgery did not differ between the G. A. Gantt Jr. (&) J. Ashburn R. P. Kiran M. F. Kalady Department of Colorectal Surgery, Digestive Disease Institute, Cleveland Clinic Foundation, 9500 Euclid Ave A30, Cleveland, OH 44195, USA e-mail: [email protected] M. F. Kalady e-mail: [email protected] A. A. Khorana Department of Solid Tumor Oncology, Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
groups (35.6 % open vs 38.7 % laparoscopic, p = 0.77). In the open group, delay in chemotherapy after surgery was associated with decreased disease-free and overall survival (p = 0.01, 0.01, respectively). However, delay in chemotherapy more than 8 weeks did not affect disease-free or overall survival in the laparoscopy group (p = 0.93, 0.51, respectively). Conclusions The benefits of quicker recovery after laparoscopic surgery did not translate into earlier initiation of adjuvant chemotherapy in this retrospective study. However, a laparoscopic approach negated the inferior oncologic outcomes of patients who received delayed initiation of chemotherapy. Keywords Colon cancer Adjuvant chemotherapy Laparoscopy Current treatment of stage III and select stage II colon cancer involves surgical resection followed by chemotherapy (CT) [1, 2]. Adjuvant CT has been shown to increase survival in these patients [3, 4]. Previous studies have shown that delaying initiation of adjuvant CT greater than 8 weeks after surgical resection adversely affects overall patient survival [5–8]. A number of demographic, clinical, and systemic factors have been associated with delay in the initiation of CT, including age, race, and postoperative length of stay [9, 10]. Laparoscopy has been shown to be equal to an open technique in terms of oncological outcomes for colon cancer [11, 12]. Patients who undergo a laparoscopic procedure benefit from improved cosmesis, decreased length of stay, decreased postoperative narcotic analgesia use, and quicker return of bowel function [13–15]. While it has been well established that laparoscopy is associated with decreased length of stay and recovery time, the effect of a
123
494
Surg Endosc (2015) 29:493–499 Table 1 Patient and tumor characteristics Open N = 59 (65.6 %)
Laparoscopic N = 31 (34.4 %)
60 ± 13.09
64.57 ± 12.39
25 (42.4 %)
17 (54.8 %)
1
0 (1 %)
1 (3.4 %)
2
18 (34.6 %)
11 (37.9 %)
3 4
31 (59.6 %) 3 (5.8 %)
15 (51.7 %) 2 (6.9 %)
\30
30 (52.6 %)
14 (45.2 %)
[30
27 (47.4 %)
17 (54.8 %)
II
7 (15.2 %)
4 (10.7 %)
III
52 (84.8 %)
27 (89.3 %)
pT1
2 (3.4 %)
2 (6.4 %)
pT2
9 (15.3 %)
1 (3.2 %)
pT3
42 (71.2 %)
21 (67.7 %)
pT4
6 (10.2 %)
7 (22.6 %)
pN0
7 (11.9 %)
4 (12.9 %)
pN1 pN2
34 (57.6 %) 18 (30.5 %)
13 (41.9 %) 14 (45.2 %)
59 (100 %)
31 (100 %)
19 (32.2 %)
5 (16.1 %)
Age (mean ± SD) Gender Female
0.65
BMI
0.5
Stage
1
Pathologic T stage
laparoscopic surgical approach on the time to initiation of CT has not been studied. Therefore, the aim of this study was to determine if a laparoscopic approach to colon cancer resection affected the timing of adjuvant CT and subsequently oncological outcomes.
0.12
Pathologic N stage
0.31
Pathologic M stage pM0
NA
Differentiation Poor
0.23 0.26
ASA class
Fig. 1 Algorithm for patient selection. Thousand two hundred and sixty seven patient charts with stage II or III of colorectal cancer were identified. 633 patients with rectal cancer were excluded, leaving 654 colon cancer patients. Of these, 544 patients did not receive adjuvant chemotherapy or had missing information regarding adjuvant chemotherapy use. The remaining 90 patients with stage II/III colon cancer and known adjuvant chemotherapy regimen were used in this study
p
0.14
Moderate
38 (64.4 %)
26 (83.9 %)
Well
2 (3.4 %)
0 (0 %)
Lymph nodes harvested (mean ± SD)
32.7 ± 18.4
25.6 ± 11
0.1
Patient selection
Lymph nodes involved (mean ± SD)
3.5 ± 6.3
4.6 ± 6.2
0.31
A prospectively maintained colorectal cancer database from a single institution was queried for patients with stage II or III colon cancer who underwent surgical resection between the years 2003 and 2010. The resulting patient list was then cross-referenced with a prospectively maintained oncology database of adjuvant CT regimens. Patient data present in both databases were extracted for analysis. Records without information regarding the timing of CT were excluded (Fig. 1). Patients were categorized according to surgical approach: open or laparoscopic.
Chemotherapy regimen
Materials and methods
Patient characteristics and outcomes The resulting cohort of patients was analyzed for clinicopathologic variables including age, gender, body mass
123
0.07
5-Fu/leucovorin
18
18
FOLFOX
31
11
Unknown
5
2
Capecitabine/ oxaliplatin
1
0
Capecitabine (monotherapy)
4
0
Tumor location
0.43
Right
27 (45.7 %)
15 (48.4 %)
Hepatic flexure
5 (8.5 %)
1 (3.2 %)
Transverse
5 (8.5 %)
1 (3.2 %)
Splenic flexure
3 (5.1 %)
0 (0 %)
Left
19 (32.2 %)
14 (45.2 %)
Surg Endosc (2015) 29:493–499
495
Table 1 continued Open N = 59 (65.6 %)
Laparoscopic N = 31 (34.4 %)
Right hemicolectomy
36 (61 %)
14 (45.2 %)
Left hemicolectomy
17 (28.8 %)
10 (32.2 %)
Sigmoidectomy
6 (10.2 %)
7 (22.6 %)
Operation performed
0.49
Clavien–Dindo classification I II
p
0.13 8 6
3 0
IIIa
0
0
IIIb
2
1
IVa
0
4
IVb
0
0
V
0
0
adjuvant CT was similar in both the laparoscopic and open groups (53.3 ± 19.8 vs 52.3 ± 22.0 days, p = 0.58). Of 90 patients, 33 (36.7 %) initiated CT greater than 8 weeks postoperatively. There was no difference in the proportion of patients who received adjuvant CT more than 8 weeks after surgery between the two groups (35.6 % open vs 38.7 % laparoscopic p = 0.77). Complication rates were greater for patients who received CT more than 8 weeks after surgery compared to those who received it sooner. Delay in initiation of chemotherapy was associated with higher ASA classification (Table 2). Disease-free and overall survival
Categorical variables were compared using Fisher’s exact test or Chi square as appropriate. Quantitative and ordinal variables were compared using Wilcoxon rank sum test. Kaplan–Meier curves were generated for overall and disease-free survival according to operative approach and time to initiation of CT.
Disease-free survival (DFS) was decreased in patients who began CT greater than 8 weeks following surgery (p = 0.04) (Fig. 2A). This effect varied according to the surgical approach. In patients undergoing open resection, delay in adjuvant CT was associated with a decrease in DFS (p = 0.01) (Fig. 2B). Conversely, DFS did not differ between patients who received CT sooner or later than 8 weeks postoperatively in the laparoscopic group (p = 0.93) (Fig. 2C). Overall survival in the total study population was not significantly associated with delay in CT treatment, (p = 0.08) (Fig. 3A). Similar to the DFS outcomes, for patients in the open surgery group, a delay in adjuvant CT greater than 8 weeks from surgery was associated with significantly worse survival (28 % decrease at 5 years, (p = 0.01, Fig. 3B). However, there was no difference in OS associated with initiation of CT after 8 weeks in the laparoscopic group (p = 0.51), (Fig. 3C).
Results
Discussion
Clinical and pathological data
As expected, patients with colon cancer treated by laparoscopic resection had shorter length of stay compared to open cases. However, this did not translate into earlier initiation of CT following laparoscopic cases in this nonprotocoled retrospective study. Interestingly, for those patients who had a delay in CT, there was a difference in DFS and OS depending on the approach. Patients who underwent laparoscopic resection did not have a decrease in DFS and OS when the initiation of CT was delayed. However, delayed CT was associated with decreased DFS and OS in open cases. These findings may indicate an additional benefit to laparoscopic surgery. In the literature, the proportion of patients who have delayed initiation of CT ranges from 20 to 72 % [5–8, 16]. This is consistent with our data, as approximately one third of patients received adjuvant CT greater than 8 weeks after
index (BMI), tumor stage, tumor location, tumor differentiation, and ASA class. Postoperative complications, need for reoperation, time interval from surgery to initiation of CT, and long-term oncologic outcomes were also included in the analysis. Statistical analysis
Ninety cases were included in the study, 31 (34.4 %) of which were performed laparoscopically. There was no difference in age, gender, ASA class, or BMI between the open and laparoscopic groups. Similarly, tumor stage, tumor differentiation, postoperative complications, and need for reoperation did not differ between the two cohorts (Table 1). Length of stay was approximately two days shorter in the laparoscopic group, compared to open (5.4 ± 3.7 vs 7.6 ± 5.2, p \ 0.001). Initiation of adjuvant chemotherapy Overall, the mean time to initiation of CT was less than 8 weeks (52.7 ± 21.2 days). The time to initiation of
123
496 Table 2 Factors associated with delay in chemotherapy initiation
Surg Endosc (2015) 29:493–499
Chemotherapy started \8 weeks
Chemotherapy started C8 weeks
p
6.16 ± 2.99
8.09 ± 5.4
0.13
1
0 (0 %)
1 (3.3 %)
2
20 (39.2 %)
9 (30 %)
3
29 (56.9 %)
17 (56.7 %)
2 (3.9 %)
3 (10 %)
2.65 ± 0.56
2.73 ± 0.69
Length of stay (mean ± SD) ASA
4 ASA (mean ± SD)
0.03
0.49
Complications Overall complication rate
4 (0.07 %)
10 (0.3 %)
0.05
Hemorrhage
0 (0 %)
1 (3 %)
0.37
DVT
1 (1.8 %)
0 (0 %)
1
Wound dehiscence
0 (0 %)
2 (6.1 %)
0.13
Wound infection
3 (5.3 %)
2 (6.1 %)
1
Bowel obstruction
0 (0 %)
3 (9.1 %)
0.05
Intraabdominal abscess UTI
0 (0 %) 0 (0 %)
1 (3 %) 1 (3 %)
0.37 0.37
Anastomotic leak
0 (0 %)
0 (0 %)
NA
Reoperation
0 (0 %)
2 (6.1 %)
0.13
surgery. A number of factors have been associated with delay of adjuvant CT, resulting in several confounding variables. In a study investigating the causes of delay in adjuvant CT in rectal cancer patients, Cheung et al. [10] found that the length of postoperative hospital stay, age, and race were associated with initiating CT more than three months following surgery. Postoperative complications have also been associated with delayed initiation of adjuvant CT in rectal cancer patients [17]. In addition to these patient centered factors, systematic factors also contribute to delays in adjuvant CT. Delays in referrals to medical oncologists, waiting lists for appointments, and waiting lists to initiate CT are all systematic issues associated with delays in adjuvant therapy [7]. Upon initiating this study we anticipated that patients undergoing laparoscopic surgery would be treated with adjuvant CT earlier after surgery than those undergoing open resections. This did not bear out in this retrospective study as the timing of CT relied on several uncontrolled and not recorded variables. Surprisingly, there was a slightly higher percentage of patients who received CT more than 8 weeks after laparoscopic surgery compared to open surgery (38.7 vs 35.6 %, p = 0.77). This trend was not statistically significant, and would likely disappear if a larger sample sized was used. A prospective trial that aggressively planned earlier initiation of adjuvant CT in laparoscopic patients would more appropriately determine if laparoscopy would result in improved outcomes. Decreased OS in patients who receive CT greater than 8 weeks after surgery has been demonstrated in several studies [5, 8, 9, 18]. However, none of the previous studies
123
examined the effect of laparoscopy on survival after delay in CT. In a study of 186 patients with stage II and III colon adenocarcinoma, Bayraktar et al. [5] found that delay of adjuvant CT greater than 60 days was associated with worse OS. Similarly, Czaykowski et al. [7] found a trend toward worse OS and DFS among stage III colon cancer patients who received adjuvant CT more than 56 days following surgery. Use of laparoscopy was not considered as a variable in either of these studies. Hershman et al. [6] reviewed the Surveillance, Epidemiology, and End Results (SEER)-Medicare database for patients diagnosed with stage III colon cancer between 1992 and 1999, and found that colon cancer-specific and overall mortality was higher among patients who received CT greater than 3 months following surgery. Few surgeons were performing laparoscopic colectomies during this time, and as such it is likely that few laparoscopic cases were included. The paucity of data regarding the effect of laparoscopy on timing of adjuvant CT makes the previous studies less generalizable to current surgical care, and emphasizes the relevance of our study. A relatively unexpected and novel finding of this study was that patients undergoing laparoscopic surgery did not seem to have worse outcomes if CT was delayed greater than 8 weeks after surgery. The advantages of laparoscopic colectomy are widely reported and include decreased length of stay, quicker recovery, and decreased postoperative pain [11, 14, 19]. Another advantage of laparoscopic surgery is improved immunologic response to surgical stress compared to open surgery. Several studies have shown a diminished inflammatory response for patients
Surg Endosc (2015) 29:493–499
497
Fig. 2 Kaplan–Meier plots of disease-free survival based on time to initiating chemotherapy after surgery for the total study population (p = 0.04) (A); patients treated by open approach (p = 0.01) (B); and patients treated by laparoscopic approach (p = 0.93) (C). All p values calculated using the log-rank test
undergoing laparoscopy [20, 21]. Decreased stress response to surgery may result in improved immunologic function, and oncologic benefits [22]. These findings may be a possible explanation for the relatively improved DFS and OS for laparoscopic cases with delayed CT compared to open cases. This effect on improved oncologic outcomes is particularly clinically relevant as approximately 20 % of patients have CT delayed for various reasons as discussed above. [6]. We recognize some of the limitations of this study. The retrospective nature is subject to confounding variables that may influence the timing of therapy. All of the operations in this study were performed by 15 fellowship trained colon and rectal surgeons. The majority of the surgeons performed both open and laparoscopic cases, however, five surgeons exclusively performed open operations, and three surgeons exclusively performed laparoscopic cases. Surgeon’s chose their approach based on their comfort level
performing the procedure. This may be another source of bias in our study. Also, given the quaternary referral status of our institution, many patients who undergo surgery at Cleveland Clinic receive their oncological care elsewhere. This pattern of patients receiving adjuvant therapy at outside institutions prevents the analysis of many variables that could delay CT. Systematic variables should be included in future analyses of causes of CT delay. In summary, although the benefits of quicker recovery after laparoscopic surgery did not translate into earlier initiation of adjuvant CT in this retrospective study, it is rational to test this theory in a prospective fashion. Interestingly, a laparoscopic approach negated the inferior oncologic outcomes of patients who received delayed initiation of CT. These results need to be validated in larger studies and if confirmed, underlying potential causes of the differences in oncologic outcomes warrant exploration.
123
498
Surg Endosc (2015) 29:493–499
Fig. 3 Kaplan–Meier plots of overall survival based on time to initiating chemotherapy after surgery for the total study population (p = 0.08) (A); patients treated by open approach (p = 0.01) (B); and patients treated by laparoscopic approach (p = 0.51) (C). All p values calculated using the log-rank test
Acknowledgments The authors would like to acknowledge Jeff Hammel for his statistical analysis. MFK is the Krause-Lieberman Chair in Colorectal Surgery. AAK is the Sondra and Stephen Hardis Chair in Oncology Research. Disclosures Gerald A Gantt, M.D., Jean Ashburn, M.D., Ravi P. Kiran, M.B.B.S., Alok A. Khorana, M.D., and Matthew F. Kalady, M.D. have no relevant conflict of interests or financial ties to disclose. Funding
Krause-Lieberman Endowed Chair of Colorectal Surgery.
References 1. Jessup JM, Stewart A, Greene FL, Minsky BD (2005) Adjuvant chemotherapy for stage III colon cancer: implications of race/ ethnicity, age, and differentiation. JAMA 294:2703–2711. doi:10. 1001/jama.294.21.2703 2. Benson AB III, Schrag D, Somerfield MR, Cohen AM, Figueredo AT, Flynn PJ, Krzyzanowska MK, Maroun J, McAllister P, Van Cutsem E, Brouwers M, Charette M, Haller DG (2004) American Society of Clinical Oncology recommendations on adjuvant chemotherapy for stage II colon cancer. J Clin Oncol 22:3408 –3419. doi:10.1200/JCO.2004.05.063
123
3. Moertel CG, Fleming TR, Macdonald JS, Haller DG, Laurie JA, Goodman PJ, Ungerleider JS, Emerson WA, Tormey DC, Glick JH (1990) Levamisole and fluorouracil for adjuvant therapy of resected colon carcinoma. N Engl J Med 322:352–358. doi:10. 1056/NEJM199002083220602 4. Quasar Collaborative Group, Gray R, Barnwell J, McConkey C, Hills RK, Williams NS, Kerr DJ (2007) Adjuvant chemotherapy versus observation in patients with colorectal cancer: a randomised study. Lancet 370:2020–2029. doi:10.1016/S0140-6736(07) 61866-2 5. Bayraktar UD, Chen E, Bayraktar S, Sands LR, Marchetti F, Montero AJ, Rocha-Lima CM (2010) Does delay of adjuvant chemotherapy impact survival in patients with resected stage II and III colon adenocarcinoma? Cancer. doi:10.1002/cncr.25720 6. Hershman D, Hall MJ, Wang X, Jacobson JS, McBride R, Grann VR, Neugut AI (2006) Timing of adjuvant chemotherapy initiation after surgery for stage III colon cancer. Cancer 107:2581–2588. doi:10.1002/cncr.22316 7. Czaykowski PM, Gill S, Kennecke HF, Gordon VL, Turner D (2011) Adjuvant chemotherapy for stage III colon cancer: does timing matter? Dis Colon Rectum 54:1082–1089. doi:10.1097/ DCR.0b013e318223c3d6 8. Biagi JJ, Raphael MJ, Mackillop WJ, Kong W, King WD, Booth CM (2011) Association between time to initiation of adjuvant chemotherapy and survival in colorectal cancer: a systematic
Surg Endosc (2015) 29:493–499
9.
10.
11.
12.
13.
14.
15.
review and meta-analysis. JAMA 305:2335–2342. doi:10.1001/ jama.2011.749 Des Guetz G, Nicolas P, Perret GY, Morere JF, Uzzan B (2010) Does delaying adjuvant chemotherapy after curative surgery for colorectal cancer impair survival? A meta-analysis. Eur J Cancer 46:1049–1055. doi:10.1016/j.ejca.2010.01.020 Cheung WY, Neville BA, Earle CC (2009) Etiology of delays in the initiation of adjuvant chemotherapy and their impact on outcomes for stage II and III rectal cancer. Dis Colon Rectum 52:1054–1063; discussion 1064. doi:10.1007/DCR.0b013e3181a51173 Clinical Outcomes of Surgical Therapy Study Group (2004) A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med 350:2050–2059. doi:10.1056/NEJMo a032651 Colon Cancer Laparoscopic or Open Resection Study Group, Buunen M, Veldkamp R, Hop WC, Kuhry E, Jeekel J, Haglind E, Pahlman L, Cuesta MA, Msika S, Morino M, Lacy A, Bonjer HJ (2009) Survival after laparoscopic surgery versus open surgery for colon cancer: long-term outcome of a randomised clinical trial. Lancet Oncol 10:44–52. doi:10.1016/S1470-2045(08)70310-3 Milsom JW, Bohm B, Hammerhofer KA, Fazio V, Steiger E, Elson P (1998) A prospective, randomized trial comparing laparoscopic versus conventional techniques in colorectal cancer surgery: a preliminary report. J Am Coll Surg 187:46–54; discussion 54–5 Abraham NS, Young JM, Solomon MJ (2004) Meta-analysis of short-term outcomes after laparoscopic resection for colorectal cancer. Br J Surg 91:1111–1124. doi:10.1002/bjs.4640 Braga M, Vignali A, Gianotti L, Zuliani W, Radaelli G, Gruarin P, Dellabona P, Di Carlo V (2002) Laparoscopic versus open colorectal surgery: a randomized trial on short-term outcome. Ann Surg 236:759–766; disscussion 767. doi:10.1097/01.SLA. 0000036269.60340.AE
499 16. Lima IS, Yasui Y, Scarfe A, Winget M (2011) Association between receipt and timing of adjuvant chemotherapy and survival for patients with stage III colon cancer in Alberta, Canada. Cancer 117:3833–3840. doi:10.1002/cncr.25954 17. Tevis SE, Kohlnhofer BM, Stringfield S, Foley EF, Harms BA, Heise CP, Kennedy GD (2013) Postoperative complications in patients with rectal cancer are associated with delays in chemotherapy that lead to worse disease-free and overall survival. Dis Colon Rectum 56:1339–1348. doi:10.1097/DCR.0b013e3182 a857eb 18. Berglund A, Cedermark B, Glimelius B (2008) Is it deleterious to delay the start of adjuvant chemotherapy in colon cancer stage III? Ann Oncol 19:400–402. doi:10.1093/annonc/mdm582 19. Hemandas AK, Abdelrahman T, Flashman KG, Skull AJ, Senapati A, O’Leary DP, Parvaiz A (2010) Laparoscopic colorectal surgery produces better outcomes for high risk cancer patients compared to open surgery. Ann Surg 252:84–89. doi:10.1097/ SLA.0b013e3181e45b66 20. Harmon GD, Senagore AJ, Kilbride MJ, Warzynski MJ (1994) Interleukin-6 response to laparoscopic and open colectomy. Dis Colon Rectum 37:754–759 21. Whelan RL, Franklin M, Holubar SD, Donahue J, Fowler R, Munger C, Doorman J, Balli JE, Glass J, Gonzalez JJ, Bessler M, Xie H, Treat M (2003) Postoperative cell mediated immune response is better preserved after laparoscopic vs open colorectal resection in humans. Surg Endosc 17:972–978. doi:10.1007/ s00464-001-8263-y 22. Allendorf JD, Bessler M, Horvath KD, Marvin MR, Laird DA, Whelan RL (1999) Increased tumor establishment and growth after open vs laparoscopic surgery in mice may be related to differences in postoperative T-cell function. Surg Endosc 13:233–235
123
