Palliative primary tumor resection provides survival benefits for the patients with metastatic colorectal cancer and low circulating levels of dehydrogenase and carcinoembryonic antigen
- Wen-Zhuo He†1, 2,
- Yu-Ming Rong†1, 2,
- Chang Jiang1, 2,
- Fang-Xin Liao1, 2,
- Chen-Xi Yin1, 2,
- Gui-Fang Guo1, 2,
- Hui-Juan Qiu1, 2,
- Bei Zhang1, 2 and
- Liang-Ping Xia1, 2Email author
© The Author(s) 2016
Received: 23 June 2015
Accepted: 15 June 2016
Published: 29 June 2016
It remains controversial whether palliative primary tumor resection (PPTR) can provide survival benefits to the patients with metastatic colorectal cancer (mCRC) who have unresectable metastases. The aim of this study was to evaluate whether PPTR could improve the survival of patients with mCRC.
We conducted a retrospective study on consecutive mCRC patients with unresectable metastases who were diagnosed at Sun Yat-sen University Cancer Center in Guangzhou, Guangdong, China, between January 2005 and December 2012. Overall survival (OS) and progression-free survival (PFS) after first-line chemotherapy failure were compared between the PPTR and non-PPTR patient groups.
A total of 387 patients were identified, including 254 who underwent PPTR and 133 who did not. The median OS of the PPTR and non-PPTR groups was 20.8 and 14.8 months (P < 0.001), respectively. The median PFS after first-line chemotherapy was 7.3 and 4.8 months (P < 0.001) in the PPTR and non-PPTR groups, respectively. A larger proportion of patients in the PPTR group (219 of 254, 86.2%) showed local progression compared with that of patients in the non-PPTR group (95 of 133, 71.4%; P < 0.001). Only patients with normal lactate dehydrogenase (LDH) levels and with carcinoembryonic antigen (CEA) levels <70 ng/mL benefited from PPTR (median OS, 22.2 months for the PPTR group and 16.2 months for the non-PPTR group; P < 0.001).
For mCRC patients with unresectable metastases, PPTR can improve OS and PFS after first-line chemotherapy and decrease the incidence of new organ involvement. However, PPTR should be recommended only for patients with normal LDH levels and with CEA levels <70 ng/mL.
KeywordsMetastatic colorectal cancer Palliative primary tumor resection Overall survival Lactate dehydrogenase Carcinoembryonic antigen
Summary of studies that evaluated the role of PPTR
First author and reference number
Period of patient involvement
No. of patients
Median OS (months)
Oxaliplatin, irinotecan, and 5-FU
Irinotecan, oxaliplatin, and capecitabine
Oxaliplatin and capecitabine
5-FU + CF, 5-FU, or raltitrexed
FOLFOX, FOLFIRI, XELOX, or 5-FU
5-FU, raltitrexed, capecitabine, or uracil tegafur
The specific benefits of PPTR remain undefined, because all the published studies are retrospective and have reported contradictory results; no randomized controlled studies have been reported. In addition, in a previous study, the effect of palliative surgery on survival was confounded by the differential use of chemotherapy drugs . Furthermore, some studies did not provide details about the chemotherapy used [9–11]. Other studies included patients who were treated between 1980 and 2000 ; during this period, chemotherapy for metastatic colorectal cancer (mCRC) changed from 5-fluorouracil-based two-agent regimens to oxaliplatin- or irinotecan-based three-agent regimens. Similarly, the principles underlying the management of metastatic lesions also changed during this period. Also, the reliability of comparing one study with another is inevitably challenged by patient selection bias.
Apart from the ongoing randomized clinical trials, an alternative way to resolve the question is to identify a method or index for selecting patients who are likely to benefit from PPTR. To date, only one study has indicated that patients with rectal cancer or with low levels of carcinoembryonic antigen (CEA) are likely to benefit from PPTR . Accordingly, in the age of modern chemotherapy, we investigated the effect of PPTR on the survival of patients with synchronous mCRC. Additionally, we determined which patients are likely to benefit from PPTR.
We reviewed the database from Sun Yat-sen University Cancer Center and selected patients who met the following criteria: (1) between 2005 and 2012, they were diagnosed with mCRC at first diagnosis; (2) they had an Eastern Cooperative Oncology Group status ≤2; and (3) their follow-up information was available. The following patients were excluded: (1) those who had evidence of intestinal obstruction, enterobiasis, or bleeding at the time of first presentation; (2) those who had a second primary tumor; and (3) those who had all visible tumors removed. Informed consent was obtained from all patients involved in this study, which was approved by the ethical committee of Sun Yat-sen University Cancer Center.
Detection of CEA
CEA level was evaluated using electrochemiluminescence with the Roche Elecsys 2010 Chemistry Analyzer (Basel, Switzerland).
Patient follow-up and statistical analysis
Overall survival (OS) was defined as the time from diagnosis to death or the last follow-up; progression-free survival (PFS) after first-line chemotherapy was defined as the time from the initiation of first-line chemotherapy to disease progression or death. The calculation date was October 31, 2014.
SPSS version 13.0 software (Statistical Product and Service Solutions, Chicago, IL, USA) was used to perform statistical analyses. The Kaplan–Meier method was used to plot the survival curves, and the differences were compared using the log-rank test. Multivariate analysis and the Cox proportional hazards model were used to determine independent significance. A P value less than or equal to 0.05 was considered significant.
Characteristics of the 387 colorectal cancer patients with unresectable metastasis
Among the 387 patients studied, 109 refused surgery, 254 underwent PPTR, and 24 underwent an exploratory celiotomy. Of the patients who underwent a celiotomy, 16 had their abdomen closed immediately because peritoneal metastases and other organ involvement were found; the remaining eight patients underwent a prophylactic enterostomy because of the advanced stage of the primary tumor. Both the patients who refused surgery and those who underwent an exploratory celiotomy were included in the non-PPTR group.
None of the 254 patients who underwent PPTR died as a result of surgery. The median interval between PPTR and systemic chemotherapy was 24 days (range, 13–58 days). Of these patients, 221 underwent PPTR followed by chemotherapy, and 33 underwent chemotherapy followed by PPTR. All 133 patients in the non-PPTR group accepted palliative chemotherapy, either oxaliplatin-based or irinotecan-based.
The effect of PPTR on OS
Multivariate analysis of prognostic factors in 387 patients with metastatic colorectal cancer
95% CI for exp(B)
Next, we studied the distribution of clinicopathologic characteristics at baseline in the PPTR group and non-PPTR group patients (Table 2). Elevated LDH level was observed in 51.1% (68 of 133) of patients in the non-PPTR group, but only 24.4% (62 of 254) of patients in the PPTR group had high LDH level (P < 0.001). The other factors, including age, sex, primary tumor location, metastatic site, regimen of first-line chemotherapy, and ALP and CEA levels, were similar between the two groups.
The effect of PPTR followed by first-line chemotherapy on PFS
The median PFS after first-line chemotherapy of patients in the PPTR and non-PPTR groups were 7.3 and 4.8 months, respectively (P < 0.001). Among the factors listed in Table 2, ALP (P < 0.001), LDH (P < 0.001), and CEA (P < 0.001) levels could all be used to distinguish patients with different PFS after the first-line chemotherapy. A multivariate analysis including PPTR and ALP, LDH, and CEA levels indicated that PPTR (P = 0.014) and LDH level (P = 0.036) were independent factors.
The effect of PPTR on first-line chemotherapy failure
In this study, all patients accepted first-line chemotherapy; each of them accepted at least four cycles of chemotherapy. We classified the patients into two groups according to the nature of first-line chemotherapy failure. If new organs were involved in the progression, it was defined as systematic progression; if only the primary tumor was enlarged or new lesions were emerged only in organs that had already been involved, it was defined as local progression. We found local progression in a larger proportion of PPTR group patients compared with non-PPTR group patients (86.2% [219/254] vs. 71.4% [95/133], P < 0.001).
LDH and CEA levels could identify patients who may benefit from PPTR
Characteristics of the 257 colorectal cancer patients with unresectable metastasis who had normal LDH levels
Overall survival of the patients grouped by LDH levels
LDH level (U/mL)
Overall survival (months)
Overall survival of the patients with colorectal cancer grouped by CEA levels
CEA level (ng/mL)
Overall survival (months)
Overall survival of the patients grouped by the combination of LDH and CEA levels
In the present study, we analyzed the role of PPTR from the following aspects: its effect on intestinal complications, its effect on patient survival, and its safety. We found that only patients with normal LDH levels and CEA levels <70 ng/mL gained survival benefits from PPTR.
The first potential advantage of PPTR is to reduce the incidence of potential intestinal complications during chemotherapy. However, the incidence of death and major complications, including those associated with surgical intervention, was reported to be 14% among patients treated with folinic acid (or leucovorin), 5-fluorouracil, and oxaliplatin, a combination better known as FOLFOX6, plus bevacizumab . Reports from Memorial Sloan Kettering Cancer Center  and Fox Chase Cancer Center  showed that only 7% and 9.8% of patients, respectively, needed surgical intervention for intestinal complications experienced during chemotherapy. Furthermore, a meta-analysis that included seven studies involving 850 patients showed that the incidences of intestinal obstruction and hemorrhage were 13.9% and 3.0%, respectively . Thus, these data suggest that prophylactic primary cancer resection before chemotherapy is not necessary.
The second indication for PPTR is that it may extend patient survival. However, these survival benefits are controversial, and previous studies have had several drawbacks, including unknown or outdated chemotherapy regimens and patient selection biases. The patients in our study were diagnosed after 2005 and were given either the standard mFOLFOX6 regimen (folinic acid, 5-fluorouracil, and oxaliplatin) or FOLFIRI (folinic acid, 5-fluorouracil, and irinotecan) as first-line chemotherapy. Efforts were also made to limit patient selection bias. First, we compared the age distribution, performance status score, tumor location, and metastasis site between the PPTR and non-PPTR groups. Second, the distribution of the potential prognostic factors, including ALP, LDH, and CEA levels, was also compared. All the mentioned indexes except LDH levels were balanced between the two groups. We found that PFS after first-line chemotherapy was significantly extended in the PPTR group, which could be important in understanding the advantage of PPTR; we do not think that patient selection bias influenced this PFS. In addition, chemotherapy discontinuation did not occur in our study, which suggests that patients in both groups tolerated chemotherapy well. However, the mechanism of how PPTR can extend PFS remains unclear.
Although the indications for PPTR are not established, short life expectancy, terminal stage, and poor general patient condition are usually considered contraindications for surgery. To determine which patients can benefit from PPTR, we investigated whether the three prognostic factors found in our study—ALP, LDH, and CEA levels—could identify these patient populations. First, we found that only patients with normal LDH could get survival benefit from PPTR. We further classified patients with elevated LDH levels into the upper and lower halves and confirmed that neither benefited from PPTR. A one-pool analysis reported at the American Society of Clinical Oncology annual meeting in 2012 indicated that patients with low CEA levels can benefit from PPTR , but the benefit was lost once CEA levels increased to greater than 600 ng/mL. We found similar results; however, the cutoff of CEA level in our study was 70 ng/mL. Finally, the combination of LDH and CEA levels was a better predictor of patient benefit than either LDH or CEA levels alone. This superiority was reflected in three aspects. The first aspect is that the combination of the two indexes can be used to select patients in the normal LDH group with relatively poor prognosis and patients in the elevated LDH group with relatively good prognosis; both of these were defined as moderate-risk groups, as shown in Fig. 1. The second aspect is that patients in the moderate-risk groups do not benefit from PPTR. The third and most important aspect is that only patients with a very good prognosis, as opposed to those with a moderate or poor prognosis, benefit from PPTR.
The safety of PPTR was another unresolved question. No surgery-related deaths were found in our study. The average interval between chemotherapy and surgery was 24 days, which is very similar to the 3-week interval usually required for adjuvant chemotherapy. However, a recent meta-analysis found 2.7% of postoperative mortality rate and 11.8% of overall serious complications , indicating that PPTR should only be undertaken with caution.
Our study had several limitations. First, the retrospective nature limited its power. Second, we did not further divide LDH into subtypes, such as LDH-1 and LDH-5. Third, some elderly patients might have had cardiovascular disease, which could also affect LDH levels. Further prospective studies are needed to validate the results of our study.
Although the distributions of CEA were balanced between the PPTR group and non-PPTR group, it is noteworthy that there were significant metastatic organ differences between the PPTR and non-PPTR groups in our study. The unbalanced distribution of metastasis organs may reflect the fact that patients with a smaller tumor burden are more likely to implement PPTR in clinical practice. We acknowledge that this is a potential weakness of our study. We think that close attention should be paid to tumor burden and metastasis organs when future investigations are designed.
In conclusion, we found that PPTR could extend OS and PFS after first-line chemotherapy and decrease the incidence of new organ involvement in patients with mCRC who had unresectable metastases. Although no serious surgery-related complications occurred, PPTR should be recommended only for patients with normal LDH levels and CEA levels <70 ng/mL. However, further validation studies are needed.
WZH, YMR, and LPX designed the study. CJ, YMR, FXL, CXY, XYC, and GFG collected the data. HJQ, XXC, and BZ analyzed the data. WZH, CJ, and LPX wrote the manuscript. All authors read and approved the final manuscript.
This work was supported by grants from the Natural Science Foundation of Guangdong, China (2015A030313010), Science and Technology Program of Guangzhou, China (1563000305) and National Natural Science Foundation of China (81272641 and 81572409).
The authors declare that they have no competing interests.
Consent to publish
The patients involved in this study provided consent for publication.
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- Scheer MG, Sloots CE, van der Wilt GJ, Ruers TJ. Management of patients with asymptomatic colorectal cancer and synchronous irresectable metastases. Ann Oncol. 2008;19(11):1829–35. doi:https://doi.org/10.1093/annonc/mdn398mdn398.View ArticlePubMedGoogle Scholar
- Zhou Q, Li K, Lin GZ, Shen JC, Dong H, Gu YT, et al. Incidence trends and age distribution of colorectal cancer by subsite in Guangzhou, 2000–2011. Chin J Cancer. 2015;34:34. doi:https://doi.org/10.1186/s40880-015-0026-610.1186/s40880-015-0026-6.View ArticlePubMed CentralGoogle Scholar
- Sarela AI, Guthrie JA, Seymour MT, Ride E, Guillou PJ, O’Riordain DS. Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg. 2001;88(10):1352–6. doi:https://doi.org/10.1046/j.0007-1323.2001.01915.x.View ArticlePubMedGoogle Scholar
- Seo GJ, Park JW, Yoo SB, Kim SY, Choi HS, Chang HJ, et al. Intestinal complications after palliative treatment for asymptomatic patients with unresectable stage IV colorectal cancer. J Surg Oncol. 2010;102(1):94–9. doi:https://doi.org/10.1002/jso.21577.View ArticlePubMedGoogle Scholar
- Ahmed S, Leis A, Fields A, Chandra-Kanthan S, Haider K, Alvi R, et al. Survival impact of surgical resection of primary tumor in patients with stage IV colorectal cancer: results from a large population-based cohort study. Cancer. 2014;120(5):683–91. doi:https://doi.org/10.1002/cncr.28464.View ArticlePubMedGoogle Scholar
- Bajwa A, Blunt N, Vyas S, Suliman I, Bridgewater J, Hochhauser D, et al. Primary tumour resection and survival in the palliative management of metastatic colorectal cancer. Eur J Surg Oncol. 2009;35(2):164–7. doi:https://doi.org/10.1016/j.ejso.2008.06.View ArticlePubMedGoogle Scholar
- Chan TW, Brown C, Ho CC, Gill S. Primary tumor resection in patients presenting with metastatic colorectal cancer: analysis of a provincial population-based cohort. Am J Clin Oncol. 2010;33(1):52–5. doi:https://doi.org/10.1097/COC.0b013e31819e902d.View ArticlePubMedGoogle Scholar
- Gonsalves WI, Wolpert J, Tashi T, Ganti AK, Subbiah S, Ternent C, et al. Assessment of prognostic factors after primary tumor resection in metastatic colon cancer patients: a Veteran’s Affairs Central Cancer Registry (VACCR) analysis, 1995–2008. J Surg Oncol. 2012;106(4):486–90. doi:https://doi.org/10.1002/jso.23102.View ArticlePubMedGoogle Scholar
- 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, 1988–2000. Ann Surg Oncol. 2005;12(8):637–45. doi:https://doi.org/10.1245/ASO.2005.06.012.View ArticlePubMedGoogle Scholar
- Kaufman MS, Radhakrishnan N, Roy R, Gecelter G, Tsang J, Thomas A, et al. Influence of palliative surgical resection on overall survival in patients with advanced colorectal cancer: a retrospective single institutional study. Colorectal Dis. 2008;10(5):498–502. doi:https://doi.org/10.1111/j.1463-1318.2007.01384.x.View ArticlePubMedGoogle Scholar
- Michel P, Roque I, Di Fiore F, Langlois S, Scotte M, Teniere P, et al. Colorectal cancer with non-resectable synchronous metastases: should the primary tumor be resected? Gastroenterol Clin Biol. 2004;28(5):434–7.View ArticlePubMedGoogle Scholar
- Faron M, Pignon JP, Bouche O, Douillard JY, Adenis A, Elias D, Ducreux M. Impact on survival of primary tumor resection in patients with colorectal cancer and unresectable metastasis: pooled analysis of individual patients’ data from four randomized trials. J Clin Oncol. 2012; suppl(30): 3507. http://meeting.ascopubs.org/cgi/content/abstract/34/4_suppl/704?sid=520abd27-681f-482c-bc25-b580007b9d54
- McCahill LE, Yothers G, Sharif S, Petrelli NJ, Lai LL, Bechar N, et al. Primary mFOLFOX6 plus bevacizumab without resection of the primary tumor for patients presenting with surgically unresectable metastatic colon cancer and an intact asymptomatic colon cancer: definitive analysis of NSABP trial C-10. J Clin Oncol. 2012;30(26):3223–8. doi:https://doi.org/10.1200/JCO.2012.42.4044.View ArticlePubMedPubMed CentralGoogle Scholar
- Poultsides GA, Servais EL, Saltz LB, Patil S, Kemeny NE, Guillem JG, et al. Outcome of primary tumor in patients with synchronous stage IV colorectal cancer receiving combination chemotherapy without surgery as initial treatment. J Clin Oncol. 2009;27(20):3379–84. doi:https://doi.org/10.1200/JCO.2008.20.9817.View ArticlePubMedPubMed CentralGoogle Scholar
- Nitzkorski JR, Farma JM, Watson JC, Siripurapu V, Zhu F, Matteotti RS, et al. Outcome and natural history of patients with stage IV colorectal cancer receiving chemotherapy without primary tumor resection. Ann Surg Oncol. 2012;19(2):379–83. doi:https://doi.org/10.1245/s10434-011-2028-1.View ArticlePubMedGoogle Scholar
- Venderbosch S, de Wilt JH, Teerenstra S, Loosveld OJ, van Bochove A, Sinnige HA, et al. Prognostic value of resection of primary tumor in patients with stage IV colorectal cancer: retrospective analysis of two randomized studies and a review of the literature. Ann Surg Oncol. 2011;18(12):3252–60. doi:https://doi.org/10.1245/s10434-011-1951-5.View ArticlePubMedPubMed CentralGoogle Scholar
- Ruo L, Gougoutas C, Paty PB, Guillem JG, Cohen AM, Wong WD. Elective bowel resection for incurable stage IV colorectal cancer: prognostic variables for asymptomatic patients. J Am Coll Surg. 2003;196(5):722–8. doi:https://doi.org/10.1016/S1072-7515(03)00136-4.View ArticlePubMedGoogle Scholar
- Ferrand F, Malka D, Bourredjem A, Allonier C, Bouche O, Louafi S, et al. Impact of primary tumour resection on survival of patients with colorectal cancer and synchronous metastases treated by chemotherapy: results from the multicenter, randomised trial Federation Francophone de Cancerologie Digestive 9601. Eur J Cancer. 2013;49(1):90–7. doi:https://doi.org/10.1016/j.ejca.2012.07.006.View ArticlePubMedGoogle Scholar
- Karoui M, Roudot-Thoraval F, Mesli F, Mitry E, Aparicio T, Des Guetz G, 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(8):930–8. doi:https://doi.org/10.1097/DCR.0b013e31821cced0.View ArticlePubMedGoogle Scholar
- Tebbutt NC, Norman AR, Cunningham D, Hill ME, Tait D, Oates J, et al. Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut. 2003;52(4):568–73.View ArticlePubMedPubMed CentralGoogle Scholar
- Evans MD, Escofet X, Karandikar SS, Stamatakis JD. Outcomes of resection and non-resection strategies in management of patients with advanced colorectal cancer. World J Surg Oncol. 2009;7:28. doi:https://doi.org/10.1186/1477-7819-7-281477-7819-7-28.View ArticlePubMedPubMed CentralGoogle Scholar