ORIGINAL ARTICLE
Laparoscopic Surgery for Stage IV Colorectal Cancer Katsuya Ohta, MD, Ichiro Takemasa, PhD, MD, Mamoru Uemura, PhD, MD, Junichi Nishimura, PhD, MD, Tsunekazu Mizushima, PhD, MD, Masataka Ikeda, PhD, MD, Hirofumi Yamamoto, PhD, MD, Mitsugu Sekimoto, PhD, MD, Yuichiro Doki, PhD, MD, FACS, and Masaki Mori, PhD, MD, FACS
Abstract: Laparoscopic surgery (Lap) is a feasible therapy in advanced colorectal cancer (CRC) without distant metastasis. Resection of primary lesion in stage IV CRC is now recognized as part of multimodal therapy. However, technical safety and invasiveness of Lap in stage IV CRC remain controversial. The feasibility of Lap in stage IV CRC was determined. Clinical outcomes were compared in primary colorectal resection using Lap, open surgery (Opn), and radical Lap for stages I to III CRC. No difference was observed regarding estimated blood loss and operative time between procedures. Postoperative recovery time and time to subsequent secondary therapy in the stage IV Lap group were significantly shorter than those in the Opn group. Similar results were observed for the 3-year overall survival rate. Lap for stage IV CRC is feasible and preferable in terms of technical safety and invasiveness. It may be useful in multimodal therapy for stage IV CRC. Key Words: colorectal cancer, laparoscopic surgery, stage IV, technical safety, invasiveness
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aparoscopic surgery (Lap) has been widely indicated for advanced colorectal cancer (CRC) without distant metastasis because of improvements in devices and technical advances. The oncological safety and minimal invasiveness of this procedure have been confirmed in several randomized controlled trials.1–4 Detailed visualization of membrane reorganization using laparoscopic techniques minimizes damage compared with open surgery (Opn). The indications of Lap for CRC are increasing; this procedure has been reported to protect nerves and preserve sexual and urinary tract functions better than Opn because of its ability to maintain the total mesorectal excision layer by membrane recognition.5,6 Recent advances in chemotherapy for CRC with unresectable distant metastasis have caused a dramatic (50%) increase in the response rate. Changes from single agent to multidrug therapy, such as folinic acid/fluorouracil/irinotecan hydrochloride or folinic acid/fluorouracil/ oxaliplatin,7–9 have also contributed to this improvement. Moreover, the median survival time (MST) reportedly reached 30 months in patients using multidrug therapy with molecular targeted agents.10–12 These multidrug therapies aid the control of distant metastasis. Received for publication June 11, 2012; accepted October 16, 2012. From the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. The author declares no conflicts of interest. Reprints: Ichiro Takemasa, PhD, MD, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka E2-2, Suita-City, Osaka 565-0871, Japan (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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Various treatment strategies are available for resectable stage IV CRC, such as surgery alone, neoadjuvant chemotherapy followed by surgery, and resection of the primary lesion followed by adjuvant chemotherapy.13,14 For the symptomatic patients of stage IV CRC, to control symptoms such as bleeding or obstruction caused by the primary tumor, resection of primary lesion has priority than neoadjuvant chemotherapy.15,16 Because of the aforementioned recent advances in chemotherapy, resection of primary lesion has gained recognition as leading to better conversion to subsequent secondary therapy and a prolonged improved prognosis than has been observed in previous palliative resection. Therefore, resection of primary lesion is now recognized not only as palliative therapy but also as an important part of multimodal therapy. According to the guidelines, resection of primary lesion for stage IV CRC is recommended to be performed by Opn.15,16 Superior oncological safety and minimal invasiveness of radical Lap for CRC compared with those of Opn has been proven, but the use of Lap in stage IV CRC (Lap-IV) remains controversial. The aim of the present study is to evaluate the feasibility of Lap in stage IV CRC by examining the procedure in terms of technical safety and invasiveness compared with radical Lap for stages I to III CRC (Lap-I to Lap-III) and Opn for stage IV CRC (Opn-IV).
MATERIALS AND METHODS Subjects This retrospective study reviewed charts of patients in whom primary colorectal resection was performed at our institute from September 2006 to December 2010. The study comprised patients with nonsymptomatic stage IV CRC in whom resection of the primary lesion was performed followed by chemotherapy. For the selection of surgical procedure for stage IV CRC, we informed sufficient description about various advantages and disadvantages of both laparoscopic and open, and then received the consent of patient’s own will, not included surgeon’s bias. Radical surgery for patients with stages I to III CRC was performed using Lap with complete mesocolic excision (CME) and central vascular ligation (CVL), as the surgical procedure involved systematic lymph node dissection.17 CME-CVL has been established as an exact procedure, which provides operative safety and oncological clearance.17 Resection of the primary lesion for stage IV cancer was performed using surgical procedures similar to that in CME-CVL. Patients with tumor infiltration to other organs (Si/Ai) or synchronous resection of other organ metastases were excluded because of inability to maintain the membrane structure for CME.
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TABLE 1. Comparison of Baseline Characteristics Between Groups Age (y) [mean (range)] Sex ratio (M:F) BMI (kg/m2) [mean (range)] ASA Physical Status (1/2/3) PNI* Depth of tumor T1 T2 T3 T4 Operation procedure Right colectomy Left-sigmoid colectomy Rectal surgery
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
63 (42-77) 11:10 21.9 (16.6-31.2) 14/7/0 45.3 (40.3-51.3)
66 (50-90) 11:8 22.5 (17.4-27.3) 10/9/0 43.8 (40.5-55.9)
NS NS NS NS NS 0
67 (34-93) 86:69 21.9 (15.1-32.0) 116/39/0 48.5 (40.3-57.2)
NS NS NS NS NS < 0.001
0 0 21 0
0 0 21 0
3 9 9
8 7 4
48 32 75 0 NS
NS 39 72 44
*Prognostic Nutritional Index: lymphocyte (/mL) 0.005 + Alb (g/dL) 10. ASA indicates American Society of Anesthesiologists; NS, not significant.
Patients in this study were categorized as American Society of Anesthesiologists (ASA) Physical Status Class I or II and had a Prognostic Nutrition Index (PNI) score of Z40.18–21 In total, 195 patients met the inclusion criteria. They were divided into the following 3 groups depending upon the surgical procedure: Lap-IV (Lap and stage IV CRC; group A, n = 21), Opn-IV (Opn and stage IV CRC; group B, n = 19), and radical Lap-I to Lap-III (radical Lap and stages I to III CRC; group C, n = 155), all similar in terms of baseline characteristics (Table 1).
Parameters This study analyzed the technical safety and invasiveness of the procedure used in group A compared with those used in groups B and C. Technical safety was evaluated using intraoperative data (operative time, estimated blood loss, and rate of conversion to Opn) and data regarding postoperative complications. Invasiveness was evaluated based on the length of hospital stay after surgery, conversion to subsequent secondary treatment (rate and interval period), and survival rate.
Statistical Analysis Categorical variables in all groups were compared using the w2 test. Continuous variables were presented as median values and interquartile range and were compared using the Wilcoxon test. Survival was analyzed using the Kaplan-Meier method. Factors were compared using the log-rank test. Statistical analyses were performed using the JMP software (JMP version 8.01; SAS Institute, Cary, NC). Differences with P values >0.05 were considered statistically significant.
RESULTS Baseline Characteristics Table 1 shows patient background, activity levels, and nutritional status. The median age of patients was 66 years (range, 34 to 93 y), median body mass index (BMI) was 22.0 kg/m2, and median PNI was 46.8. No significant difference was observed in age, male/female ratio, BMI, ASA physical status, PNI, and operative approach between the groups. Although a significant difference was observed between groups A and C in terms of cancer staging, no significant difference in the depth of tumor invasion between groups A and B was observed.
Technical Safety Table 2 shows the outcomes of the operative factors in the 3 groups. No significant difference was observed in the operative time (group A: 243 min vs. group C: 222 min) or estimated blood loss (group A: 50 mL vs. group C: 40 mL) between groups A and C. However, blood loss in group B was significantly higher because of ruptures of the paraaortic lymph node, splenic artery, and splenic vein. A shift to Opn was necessary in 3 patients (9.5%) in group A because of 2 adhesions and 1 case of uncontrollable blood loss. A shift to Opn was necessary in 7 patients in group C because of 5 adhesions and 2 cases of uncontrollable blood loss (4.5%; P = 0.11). This study also compared the estimated blood loss and operative time between groups of patients in which Lap was performed according to tumor localization. Surgical procedures included right hemicolectomy and ileocecum colectomy in Lap performed on the right side, left hemicolectomy and sigmoidectomy in Lap performed on the left side, and high and
TABLE 2. Intraoperative Data for Each Group Duration of operation (min) [median (range)] Estimated blood loss (mL) [median (range)] Conversion rate to open [n (%)]
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
243 (160-420) 50 (10-200) 3 (9.8)
175 (78-590) 300 (20-3420) —
NS* < 0.001* —
222 (110-540) 40 (5-1010) 7 (4.5)
NSw NSw NSw
*Statistical comparison between groups A and B. wStatistical comparison between groups A and C. NS indicates not significant.
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Laparoscopic Surgery for Stage IV CRC
FIGURE 1. Comparison of operative variables in laparoscopic surgery (groups A and C) in terms of operative time (A) and estimated blood loss (B) according to the operative procedure. LtG indicates left side group; RecG, rectal surgery group; RtG, right side group.
low anterior resection in Lap performed rectally. In these 3 surgical approaches, no difference in the operative time and estimated blood loss was observed (Fig. 1). Complications developed in 9.5% of patients in group A, 15.8% of patients in group B (P = 0.54), and 11.6% in group C (P = 0.77). Types of complications are shown in Table 3. Significantly fewer intestinal obstructions were observed in group A. Anastomotic leakage, which is a fatal surgical complication, was not observed in groups A and B. No mortality was observed in any group.
Invasiveness Details of perioperative recovery are presented in Table 4. The median duration of hospital stay after surgery (group A: 12 d vs. group B: 13 d; P = 0.04) and interval to subsequent secondary therapy (group A: 32 d vs. group B: 48 d; P = 0.03) was significantly longer in group B than in group A. Most stage IV patients underwent postoperative therapy (group A: 90.5%, group B: 84.2%, P = 0.54). Subsequent secondary therapy for patients with
distant metastasis was as follows: 16 cases of chemotherapy and 3 cases of surgery in group A (90.3%) and 14 cases of chemotherapy and 2 cases of surgery in group B (84.2%). Liver metastasis was most commonly observed, occurring in 16 patients in group A (76.1%) and 12 patients in group B (63.1%).
Survival Rates The survival curve in Figure 2 shows no significant difference in the 3-year overall survival rate in groups A (60.1%) and B (43.1%). This study examined secondary treatment in the stage IV groups. MST was 20.8 months in the 35 patients in whom secondary treatment was administered and 10.9 months in the 5 patients who did not receive secondary treatment.
DISCUSSION Approximately 20% of patients with CRC are diagnosed with distant metastasis.22 Most of these patients
TABLE 3. Postoperative Complications Within Each Group
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
0 0 1 1 0 0 2 (9.5)
0 3 0 0 0 0 3 (15.8)
— 0.03* NS* NS* — — NS*
3 5 5 1 1 1 18 (11.6)
NSw NSw NSw NSw NSw NSw NSw
Anastomotic leakage Intestinal obstruction Surgical site infection Thrombosis Acute myocardial infarction Pneumonia Overall [n (%)]
*Statistical comparison between groups A and B. wStatistical comparison between groups A and C. NS indicates not significant.
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TABLE 4. Perioperative Recovery and Prognosis Hospital stay after surgery (d) [median (range)] Rate to following treatment (d) [n (%)] Chemotherapy Surgery Interval to following therapy (d) [median (range)] 1 y survival (%) 3 y survival (%)
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
12 (8-36) 19 (90.5) 16 3 32 (20-203) 86.7 60.1
13 (9-29) 16 (84.2) 14 2 48 (15-424) 82.1 43.1
0.046* NS*
12 (5-74) — — — — — —
NSw —
0.034* NS*
— — —
*Statistical comparison between groups A and B. wStatistical comparison between groups A and C. NS indicates not significant.
undergo primary colorectal resection by Opn. The surgical benefits of combined therapy (primary colorectal resection and chemotherapy) for stage IV CRC have been shown to contribute to a better prognosis than chemotherapy alone.23 Radical Lap with CME-CVL for CRC has been established as a standard surgical procedure in Japan because of its technical safety and oncological clearance.17 This procedure has resulted in better prognosis and lower morbidity rates than with Opn. Fukunaga et al24 reported a perioperative outcome for CRC patients undergoing palliative surgery similar to that for patients undergoing radical surgery. Other studies on Lap for patients with distant metastasis have shown similar postoperative complication rates compared with Lap-I to Lap-III surgery.25,26 These reports demonstrated technical safety of palliative surgery through Lap similar to that of radical procedures. In a large multicenter cohort study of consecutive CRC patients, Hida et al27 reported Lap to be superior to Opn for stage IV CRC in the short term. Previous studies have reported postoperative complication and mortality rates in Opn-IV of 9% to 43.5% and 0% to 6.4%, respectively,22,28–30 and rates in Lap-IV of 12.3% to 19.5% and 0% to 2.7%, respectively.24,25,31,32 Postoperative recovery time and duration of hospital stay were shorter for Lap-IV patients (6 to 10 d)24,25,31 than for Opn-IV patients (13 to 14 d).22,28,29 Several reports have also shown shorter intervals to secondary treatment with Lap-IV compared with Opn-IV.23,29,33 These reports have investigated the procedures in terms of invasiveness. Our study demonstrated technical safety of Lap for stage IV CRC similar to radical Lap for CRC stages I to III based on operative factors and postoperative complications.
Operative time and estimated blood loss were similar in LapIV and Lap-I to Lap-III. Lap-IV was less invasive than OpnIV based on results for postoperative recovery time. In our study, postoperative hospital stay and interval to subsequent secondary therapy were also shorter for Lap-IV patients than for those treated with Opn-IV. In addition, Lap-IV patients experienced easier transitions into subsequent secondary therapy than those in whom Opn-IV was performed. This study is the first to report data for both technical safety and invasiveness of these procedures in CRC. Analysis of survival rates is necessary for determining the value of Lap in multimodal treatment for stage IV CRC. Previous studies reported similar results for Lap-IV and Opn-IV for 1-year overall survival.22,27–29 This study showed similar survival rates between Lap-IV and Opn-IV at 20.4 months, which is a longer median follow-up period than that in previous studies.22,27,31 To determine the efficacy of multimodal therapy, data for patients with or without secondary treatment after surgery were examined. MST was twice as high in patients who received subsequent secondary therapy compared with those who did not. Multimodal therapy may therefore contribute to long-term survival because of its lack of invasiveness, which was clearly demonstrated in this study of Lap for patients with stage IV CRC. Adequate technical safety and minimal invasiveness associated with laparoscopic resection improved postoperative outcomes and quality of life in CRC patients in this study. Although this study was the case-matched control retrospective study showing the clinical feasibility of Lap for patients with stage IV CRC, the results were examined which showed that patient selections did not affect the baseline characteristics and surgical outcomes between Lap-IV and Opn-IV. Therefore, the conclusions are not considered to influence for patient’s selection. However, there are selection bias by patients own selection of surgical procedure for stage IV CRC. Further studies are necessary to consider the randomized prospective study and to assess more patients and accrue more long-term survival results.
CONCLUSIONS Our study demonstrated the feasibility of Lap for stage IV CRC by comparing it with Opn for stage IV and Lap for stages I to III CRC. Lap is a promising procedure with an important role in multimodal therapy for CRC patients. REFERENCES FIGURE 2. Survival rates of patients with laparoscopic and open resection for stage IV colorectal cancer.
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1. Lacy AM, Garcia-Valdecasas JC, Delgado S, et al. Laparoscopy-assisted colectomy versus open colectomy for treatment r
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of non-metastatic colon cancer: a randomised trial. Lancet. 2002;359:2224–2229. Nelson H, Sargent D, Wieand HS, et al. A comparison of laparoscopically assisted and open colectomy for colon cancer. N Engl J Med. 2004;350:2050–2059. Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of conventional versus laparoscopic-assisted surgery in patients with colorectal cancer (MRC CLASICC trial): multicentre, randomised controlled trial. Lancet. 2005;365:1718–1726. Bonjer HJ, Haglind E, Jeekel I, et al. Laparoscopic surgery versus open surgery for colon cancer: short-term outcomes of a randomised trial. Lancet Oncol. 2005;6:477–484. Lujan J, Valero G, Hernandez Q, et al. Randomized clinical trial comparing laparoscopic and open surgery in patients with rectal cancer. Br J Surg. 2009;96:982–989. Li S, Chi P, Lin H, et al. Long-term outcomes of laparoscopic surgery versus open resection for middle and lower rectal cancer: an NTCLES study. Surg Endosc. 2011;25:3175–3182. De Gramont A, Figer A, Seymour M, et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol. 2000;18: 2938–2947. Goldberg RM, Sargent DJ, Morton RF, et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol. 2004;22:23–30. Fuchs CS, Marshall J, Barrueco J. Randomized, controlled trial of irinotecan plus infusional, bolus, or oral fluoropyrimidines in first- line treatment of metastatic colorectal cancer: Updated results from the BICC-C study. J Clin Oncol. 2008; 26:689–690. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350:2335–2342. Saltz. Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol. 2008; 26:2013–2019. Tournigand C, Andre T, Achille E, et al. FOLFIRI followed by FOLFOX6 or the reverse sequence in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol. 2004;22:229–237. Cellini C, Hunt SR, Fleshman JW, et al. Stage IV rectal cancer with liver metastases: is there a benefit to resection of the primary tumor? World J Surg. 2010;34:1102–1108. Ronnekleiv-Kelly SM, Kennedy GD. Management of stage IV rectal cancer: palliative options. World J Gastroenterol. 2011;17:835–847. Stillwell AP, Buettner PG, Siu SK, et al. Predictors of postoperative mortality, morbidity, and long-term survival after palliative resection in patients with colorectal cancer. Dis Colon Rectum. 2011;54:535–544. Cook AD, Single R, McCahill LE. Surgical resection of primary tumors in patients who present with stage IV colorectal cancer: an analysis of surveillance, epidemiology, and end results data, 1988 to 2000. Ann Surg Oncol. 2005;12:637–645.
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17. West NP, Hohenberger W, Weber K, et al. Complete mesocolic excision with central vascular ligation produces an oncologically superior specimen compared with standard surgery for carcinoma of the colon. J Clin Oncol. 2010; 28:272–278. 18. Cullen DJ, Apolone G, Greenfield S, et al. Asa physical status and age predict morbidity after 3 surgical-procedures. Ann Surg. 1994;220:3–9. 19. Haynes SR, Lawler PGP. An assessment of the consistency of asa physical status classification allocation. Anaesthesia. 1995;50:195–199. 20. Buzby GP, Mullen JL, Matthews DC, et al. Prognostic nutritional index in gastrointestinal surgery. Am J Surg. 1980; 139:160–167. 21. Denis L, Quinonez M. Nutritional assessment in intensive care unit. Nutrition Clinique Et Metabolisme. 2008;22:20–26. 22. Lun Law W, Fan JKM, Poon JTC, et al. Laparoscopic bowel resection in the setting of metastatic colorectal cancer. Ann Surg Oncol. 2008;15:1424–1428. 23. Karoui M, Roudot-Thoraval F, Mesli F, et al. Primary colectomy in patients with stage IV colon cancer and unresectable distant metastases improves overall survival: results of a multicentric study. Dis Colon Rectum. 2011;54:930–938. 24. Fukunaga Y, Higashino M, Tanimura S, et al. Laparoscopic surgery for stage IV colorectal cancer. Surg Endosc. 2009;24: 1353–1359. 25. Moloo H, Be´dard ELR, Poulin EC, et al. Palliative laparoscopic resections for stage IV colorectal cancer. Dis Colon Rectum. 2006;49:213–218. 26. Verheijen P, Stevenson A, Lumley J, et al. Laparoscopic resection of advanced colorectal cancer. Br J Surg. 2011;98: 427–430. 27. Hida K, Hasegawa S, Kinjo Y, et al. Open versus laparoscopic resection of primary tumor for incurable stage IV colorectal cancer: a large multicenter consecutive patients cohort study. Ann Surg. 2012;255:929–934. 28. Feliciotti F, Guerrieri M, Paganini AM, et al. Long-term results of laparoscopic vs open resections for rectal cancer for 124 unselected patients. Surg Endosc. 2003;17:1530–1535. 29. Akagi T, Inomata M, Etoh T, et al. Laparoscopic Versus conventional palliative resection for incurable, symptomatic stage IV colorectal cancer: impact on short-term results. Surg Laparosc Endosc Percutan Tech. 2011;21:184–187. 30. Sun J, Jiang T, Qiu Z, et al. Short-term and medium-term clinical outcomes of laparoscopic-assisted and open surgery for colorectal cancer: a single center retrospective casecontrol study. BMC Gastroenterol. 2011;11:85–97. 31. Verheijen PM, Stevenson ARL, Lumley JW, et al. Laparoscopic resection of advanced colorectal cancer. Br J Surg. 2011;98:427–430. 32. Gonzalez R, Smith CD, Ritter EM, et al. Laparoscopic palliative surgery for complicated colorectal cancer. Surg Endosc. 2004;19:43–46. 33. Allaix ME, Degiuli M, Giraudo G, et al. Laparoscopic versus open colorectal resections in patients with symptomatic stage IV colorectal cancer. Surg Endosc. 2012;26:2609–2616.
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Laparoscopic Surgery for Stage IV Colorectal Cancer Katsuya Ohta, MD, Ichiro Takemasa, PhD, MD, Mamoru Uemura, PhD, MD, Junichi Nishimura, PhD, MD, Tsunekazu Mizushima, PhD, MD, Masataka Ikeda, PhD, MD, Hirofumi Yamamoto, PhD, MD, Mitsugu Sekimoto, PhD, MD, Yuichiro Doki, PhD, MD, FACS, and Masaki Mori, PhD, MD, FACS
Abstract: Laparoscopic surgery (Lap) is a feasible therapy in advanced colorectal cancer (CRC) without distant metastasis. Resection of primary lesion in stage IV CRC is now recognized as part of multimodal therapy. However, technical safety and invasiveness of Lap in stage IV CRC remain controversial. The feasibility of Lap in stage IV CRC was determined. Clinical outcomes were compared in primary colorectal resection using Lap, open surgery (Opn), and radical Lap for stages I to III CRC. No difference was observed regarding estimated blood loss and operative time between procedures. Postoperative recovery time and time to subsequent secondary therapy in the stage IV Lap group were significantly shorter than those in the Opn group. Similar results were observed for the 3-year overall survival rate. Lap for stage IV CRC is feasible and preferable in terms of technical safety and invasiveness. It may be useful in multimodal therapy for stage IV CRC. Key Words: colorectal cancer, laparoscopic surgery, stage IV, technical safety, invasiveness
(Surg Laparosc Endosc Percutan Tech 2014;24:153–157)
L
aparoscopic surgery (Lap) has been widely indicated for advanced colorectal cancer (CRC) without distant metastasis because of improvements in devices and technical advances. The oncological safety and minimal invasiveness of this procedure have been confirmed in several randomized controlled trials.1–4 Detailed visualization of membrane reorganization using laparoscopic techniques minimizes damage compared with open surgery (Opn). The indications of Lap for CRC are increasing; this procedure has been reported to protect nerves and preserve sexual and urinary tract functions better than Opn because of its ability to maintain the total mesorectal excision layer by membrane recognition.5,6 Recent advances in chemotherapy for CRC with unresectable distant metastasis have caused a dramatic (50%) increase in the response rate. Changes from single agent to multidrug therapy, such as folinic acid/fluorouracil/irinotecan hydrochloride or folinic acid/fluorouracil/ oxaliplatin,7–9 have also contributed to this improvement. Moreover, the median survival time (MST) reportedly reached 30 months in patients using multidrug therapy with molecular targeted agents.10–12 These multidrug therapies aid the control of distant metastasis. Received for publication June 11, 2012; accepted October 16, 2012. From the Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan. The author declares no conflicts of interest. Reprints: Ichiro Takemasa, PhD, MD, Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka E2-2, Suita-City, Osaka 565-0871, Japan (e-mail: [email protected]). Copyright r 2014 by Lippincott Williams & Wilkins
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Various treatment strategies are available for resectable stage IV CRC, such as surgery alone, neoadjuvant chemotherapy followed by surgery, and resection of the primary lesion followed by adjuvant chemotherapy.13,14 For the symptomatic patients of stage IV CRC, to control symptoms such as bleeding or obstruction caused by the primary tumor, resection of primary lesion has priority than neoadjuvant chemotherapy.15,16 Because of the aforementioned recent advances in chemotherapy, resection of primary lesion has gained recognition as leading to better conversion to subsequent secondary therapy and a prolonged improved prognosis than has been observed in previous palliative resection. Therefore, resection of primary lesion is now recognized not only as palliative therapy but also as an important part of multimodal therapy. According to the guidelines, resection of primary lesion for stage IV CRC is recommended to be performed by Opn.15,16 Superior oncological safety and minimal invasiveness of radical Lap for CRC compared with those of Opn has been proven, but the use of Lap in stage IV CRC (Lap-IV) remains controversial. The aim of the present study is to evaluate the feasibility of Lap in stage IV CRC by examining the procedure in terms of technical safety and invasiveness compared with radical Lap for stages I to III CRC (Lap-I to Lap-III) and Opn for stage IV CRC (Opn-IV).
MATERIALS AND METHODS Subjects This retrospective study reviewed charts of patients in whom primary colorectal resection was performed at our institute from September 2006 to December 2010. The study comprised patients with nonsymptomatic stage IV CRC in whom resection of the primary lesion was performed followed by chemotherapy. For the selection of surgical procedure for stage IV CRC, we informed sufficient description about various advantages and disadvantages of both laparoscopic and open, and then received the consent of patient’s own will, not included surgeon’s bias. Radical surgery for patients with stages I to III CRC was performed using Lap with complete mesocolic excision (CME) and central vascular ligation (CVL), as the surgical procedure involved systematic lymph node dissection.17 CME-CVL has been established as an exact procedure, which provides operative safety and oncological clearance.17 Resection of the primary lesion for stage IV cancer was performed using surgical procedures similar to that in CME-CVL. Patients with tumor infiltration to other organs (Si/Ai) or synchronous resection of other organ metastases were excluded because of inability to maintain the membrane structure for CME.
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TABLE 1. Comparison of Baseline Characteristics Between Groups Age (y) [mean (range)] Sex ratio (M:F) BMI (kg/m2) [mean (range)] ASA Physical Status (1/2/3) PNI* Depth of tumor T1 T2 T3 T4 Operation procedure Right colectomy Left-sigmoid colectomy Rectal surgery
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
63 (42-77) 11:10 21.9 (16.6-31.2) 14/7/0 45.3 (40.3-51.3)
66 (50-90) 11:8 22.5 (17.4-27.3) 10/9/0 43.8 (40.5-55.9)
NS NS NS NS NS 0
67 (34-93) 86:69 21.9 (15.1-32.0) 116/39/0 48.5 (40.3-57.2)
NS NS NS NS NS < 0.001
0 0 21 0
0 0 21 0
3 9 9
8 7 4
48 32 75 0 NS
NS 39 72 44
*Prognostic Nutritional Index: lymphocyte (/mL) 0.005 + Alb (g/dL) 10. ASA indicates American Society of Anesthesiologists; NS, not significant.
Patients in this study were categorized as American Society of Anesthesiologists (ASA) Physical Status Class I or II and had a Prognostic Nutrition Index (PNI) score of Z40.18–21 In total, 195 patients met the inclusion criteria. They were divided into the following 3 groups depending upon the surgical procedure: Lap-IV (Lap and stage IV CRC; group A, n = 21), Opn-IV (Opn and stage IV CRC; group B, n = 19), and radical Lap-I to Lap-III (radical Lap and stages I to III CRC; group C, n = 155), all similar in terms of baseline characteristics (Table 1).
Parameters This study analyzed the technical safety and invasiveness of the procedure used in group A compared with those used in groups B and C. Technical safety was evaluated using intraoperative data (operative time, estimated blood loss, and rate of conversion to Opn) and data regarding postoperative complications. Invasiveness was evaluated based on the length of hospital stay after surgery, conversion to subsequent secondary treatment (rate and interval period), and survival rate.
Statistical Analysis Categorical variables in all groups were compared using the w2 test. Continuous variables were presented as median values and interquartile range and were compared using the Wilcoxon test. Survival was analyzed using the Kaplan-Meier method. Factors were compared using the log-rank test. Statistical analyses were performed using the JMP software (JMP version 8.01; SAS Institute, Cary, NC). Differences with P values >0.05 were considered statistically significant.
RESULTS Baseline Characteristics Table 1 shows patient background, activity levels, and nutritional status. The median age of patients was 66 years (range, 34 to 93 y), median body mass index (BMI) was 22.0 kg/m2, and median PNI was 46.8. No significant difference was observed in age, male/female ratio, BMI, ASA physical status, PNI, and operative approach between the groups. Although a significant difference was observed between groups A and C in terms of cancer staging, no significant difference in the depth of tumor invasion between groups A and B was observed.
Technical Safety Table 2 shows the outcomes of the operative factors in the 3 groups. No significant difference was observed in the operative time (group A: 243 min vs. group C: 222 min) or estimated blood loss (group A: 50 mL vs. group C: 40 mL) between groups A and C. However, blood loss in group B was significantly higher because of ruptures of the paraaortic lymph node, splenic artery, and splenic vein. A shift to Opn was necessary in 3 patients (9.5%) in group A because of 2 adhesions and 1 case of uncontrollable blood loss. A shift to Opn was necessary in 7 patients in group C because of 5 adhesions and 2 cases of uncontrollable blood loss (4.5%; P = 0.11). This study also compared the estimated blood loss and operative time between groups of patients in which Lap was performed according to tumor localization. Surgical procedures included right hemicolectomy and ileocecum colectomy in Lap performed on the right side, left hemicolectomy and sigmoidectomy in Lap performed on the left side, and high and
TABLE 2. Intraoperative Data for Each Group Duration of operation (min) [median (range)] Estimated blood loss (mL) [median (range)] Conversion rate to open [n (%)]
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
243 (160-420) 50 (10-200) 3 (9.8)
175 (78-590) 300 (20-3420) —
NS* < 0.001* —
222 (110-540) 40 (5-1010) 7 (4.5)
NSw NSw NSw
*Statistical comparison between groups A and B. wStatistical comparison between groups A and C. NS indicates not significant.
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FIGURE 1. Comparison of operative variables in laparoscopic surgery (groups A and C) in terms of operative time (A) and estimated blood loss (B) according to the operative procedure. LtG indicates left side group; RecG, rectal surgery group; RtG, right side group.
low anterior resection in Lap performed rectally. In these 3 surgical approaches, no difference in the operative time and estimated blood loss was observed (Fig. 1). Complications developed in 9.5% of patients in group A, 15.8% of patients in group B (P = 0.54), and 11.6% in group C (P = 0.77). Types of complications are shown in Table 3. Significantly fewer intestinal obstructions were observed in group A. Anastomotic leakage, which is a fatal surgical complication, was not observed in groups A and B. No mortality was observed in any group.
Invasiveness Details of perioperative recovery are presented in Table 4. The median duration of hospital stay after surgery (group A: 12 d vs. group B: 13 d; P = 0.04) and interval to subsequent secondary therapy (group A: 32 d vs. group B: 48 d; P = 0.03) was significantly longer in group B than in group A. Most stage IV patients underwent postoperative therapy (group A: 90.5%, group B: 84.2%, P = 0.54). Subsequent secondary therapy for patients with
distant metastasis was as follows: 16 cases of chemotherapy and 3 cases of surgery in group A (90.3%) and 14 cases of chemotherapy and 2 cases of surgery in group B (84.2%). Liver metastasis was most commonly observed, occurring in 16 patients in group A (76.1%) and 12 patients in group B (63.1%).
Survival Rates The survival curve in Figure 2 shows no significant difference in the 3-year overall survival rate in groups A (60.1%) and B (43.1%). This study examined secondary treatment in the stage IV groups. MST was 20.8 months in the 35 patients in whom secondary treatment was administered and 10.9 months in the 5 patients who did not receive secondary treatment.
DISCUSSION Approximately 20% of patients with CRC are diagnosed with distant metastasis.22 Most of these patients
TABLE 3. Postoperative Complications Within Each Group
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
0 0 1 1 0 0 2 (9.5)
0 3 0 0 0 0 3 (15.8)
— 0.03* NS* NS* — — NS*
3 5 5 1 1 1 18 (11.6)
NSw NSw NSw NSw NSw NSw NSw
Anastomotic leakage Intestinal obstruction Surgical site infection Thrombosis Acute myocardial infarction Pneumonia Overall [n (%)]
*Statistical comparison between groups A and B. wStatistical comparison between groups A and C. NS indicates not significant.
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TABLE 4. Perioperative Recovery and Prognosis Hospital stay after surgery (d) [median (range)] Rate to following treatment (d) [n (%)] Chemotherapy Surgery Interval to following therapy (d) [median (range)] 1 y survival (%) 3 y survival (%)
Group A (n = 21)
Group B (n = 19)
P
Group C (n = 155)
P
12 (8-36) 19 (90.5) 16 3 32 (20-203) 86.7 60.1
13 (9-29) 16 (84.2) 14 2 48 (15-424) 82.1 43.1
0.046* NS*
12 (5-74) — — — — — —
NSw —
0.034* NS*
— — —
*Statistical comparison between groups A and B. wStatistical comparison between groups A and C. NS indicates not significant.
undergo primary colorectal resection by Opn. The surgical benefits of combined therapy (primary colorectal resection and chemotherapy) for stage IV CRC have been shown to contribute to a better prognosis than chemotherapy alone.23 Radical Lap with CME-CVL for CRC has been established as a standard surgical procedure in Japan because of its technical safety and oncological clearance.17 This procedure has resulted in better prognosis and lower morbidity rates than with Opn. Fukunaga et al24 reported a perioperative outcome for CRC patients undergoing palliative surgery similar to that for patients undergoing radical surgery. Other studies on Lap for patients with distant metastasis have shown similar postoperative complication rates compared with Lap-I to Lap-III surgery.25,26 These reports demonstrated technical safety of palliative surgery through Lap similar to that of radical procedures. In a large multicenter cohort study of consecutive CRC patients, Hida et al27 reported Lap to be superior to Opn for stage IV CRC in the short term. Previous studies have reported postoperative complication and mortality rates in Opn-IV of 9% to 43.5% and 0% to 6.4%, respectively,22,28–30 and rates in Lap-IV of 12.3% to 19.5% and 0% to 2.7%, respectively.24,25,31,32 Postoperative recovery time and duration of hospital stay were shorter for Lap-IV patients (6 to 10 d)24,25,31 than for Opn-IV patients (13 to 14 d).22,28,29 Several reports have also shown shorter intervals to secondary treatment with Lap-IV compared with Opn-IV.23,29,33 These reports have investigated the procedures in terms of invasiveness. Our study demonstrated technical safety of Lap for stage IV CRC similar to radical Lap for CRC stages I to III based on operative factors and postoperative complications.
Operative time and estimated blood loss were similar in LapIV and Lap-I to Lap-III. Lap-IV was less invasive than OpnIV based on results for postoperative recovery time. In our study, postoperative hospital stay and interval to subsequent secondary therapy were also shorter for Lap-IV patients than for those treated with Opn-IV. In addition, Lap-IV patients experienced easier transitions into subsequent secondary therapy than those in whom Opn-IV was performed. This study is the first to report data for both technical safety and invasiveness of these procedures in CRC. Analysis of survival rates is necessary for determining the value of Lap in multimodal treatment for stage IV CRC. Previous studies reported similar results for Lap-IV and Opn-IV for 1-year overall survival.22,27–29 This study showed similar survival rates between Lap-IV and Opn-IV at 20.4 months, which is a longer median follow-up period than that in previous studies.22,27,31 To determine the efficacy of multimodal therapy, data for patients with or without secondary treatment after surgery were examined. MST was twice as high in patients who received subsequent secondary therapy compared with those who did not. Multimodal therapy may therefore contribute to long-term survival because of its lack of invasiveness, which was clearly demonstrated in this study of Lap for patients with stage IV CRC. Adequate technical safety and minimal invasiveness associated with laparoscopic resection improved postoperative outcomes and quality of life in CRC patients in this study. Although this study was the case-matched control retrospective study showing the clinical feasibility of Lap for patients with stage IV CRC, the results were examined which showed that patient selections did not affect the baseline characteristics and surgical outcomes between Lap-IV and Opn-IV. Therefore, the conclusions are not considered to influence for patient’s selection. However, there are selection bias by patients own selection of surgical procedure for stage IV CRC. Further studies are necessary to consider the randomized prospective study and to assess more patients and accrue more long-term survival results.
CONCLUSIONS Our study demonstrated the feasibility of Lap for stage IV CRC by comparing it with Opn for stage IV and Lap for stages I to III CRC. Lap is a promising procedure with an important role in multimodal therapy for CRC patients. REFERENCES FIGURE 2. Survival rates of patients with laparoscopic and open resection for stage IV colorectal cancer.
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