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10.1245/s10434-006-9146-1
Annals of Surgical Oncology 14:766-770 (2007)
© 2007 Society of Surgical Oncology
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Original Article

Asymptomatic Colorectal Cancer with Un-Resectable Liver Metastases: Immediate Colorectal Resection or Up-Front Systemic Chemotherapy?

Andrea Muratore, MD1, Daria Zorzi, MD1, Hedayat Bouzari, MD1, Marco Amisano, MD1, Paolo Massucco, MD1, Elisa Sperti, MD2 and Lorenzo Capussotti, MD1

1 Division of Surgical Oncology, Istituto per la Ricerca e la Cura del Cancro, Candiolo (TO), Italy
2 Division of Medical Oncology, Istituto per la Ricerca e la Cura del Cancro, Candiolo (TO), Italy

Correspondence: Address correspondence and reprint requests to: Andrea Muratore, MD, Via Muratori 2C, 10126, Torino, Italy; E-mail: andrea.muratore{at}ircc.it


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: About 20% of patients with colorectal cancer have synchronous unresectable liver metastases. Resection of colorectal cancer in patients with moderate-severe symptoms is mandatory before starting chemotherapy. Surgical treatment of asymptomatic colorectal cancers is still a matter of discussion.

Methods: From January 2000 to December 2004, we prospectively collected data on 35 consecutive patients who were treated straightaway by chemotherapy without primary tumor resection. All patients underwent FOLFOX6 as first-line chemotherapy. The aim of the study was to evaluate the rate of surgical complications related to unresected colorectal tumor.

Results: The mean interval between diagnosis and start of chemotherapy was 23.1 days (95% CI: 17.3–28.8). Fifteen of the 35 patients (42.9% ) were down-staged to surgery; the mean interval between chemotherapy start and colon-rectum cancer resection was 6.5 months (95% CI: 5.5–7.5). None of them developed complications related to the primary tumor during chemotherapy. Of the other 20 patients who did not undergo any curative surgery, 16 received a second line chemotherapy and 10 a third line: six patients are alive and without intestinal symptoms (mean follow up 22.5 months, 95% CI: 11.2–33.9). Only one patient (2.8% ) developed clinical signs of intestinal occlusion 5.6 months from the start of chemotherapy and required urgent colostomy.

Conclusions: The rate of complications related to the non-resected colorectal tumor is very low using oxaliplatin as first line chemotherapy. Non-operative management of asymptomatic colorectal cancers with un-resectable liver metastases is a safe approach.

Key Words: Colorectal cancer • Liver metastases • Surgical management • Chemotherapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
About 20% of patients with colorectal cancer have synchronous liver metastases at the time of diagnosis. Up to 90% of these patients have un-resectable disease. There is no doubt that chemotherapy is effective in prolonging survival.1 Moreover, oxaliplatin-based chemotherapy downstages to surgery in up to 38% of treated patients.2 Resection of colorectal cancer in patients with moderate or severe symptoms (i.e., rectal bleeding and anaemia or intestinal obstruction) is mandatory before starting chemotherapy. However, surgical treatment of relatively asymptomatic colorectal cancers is still a matter of discussion. In the past, some investigators have recommended routine resection of the primary tumor to prevent the need for urgent surgical procedures because of local complications.3,4 More recently, some authors have suggested elective resection of asymptomatic colorectal cancers at least in the subset of patients with less advanced stage IV disease.5,6 Other authors have suggested deferring resection of minimally symptomatic colorectal tumors because most of these patients succumb to progressive systemic disease instead of complications related to the intact primary lesion.7–9

In the current study, we sought to prospectively observe patients with asymptomatic colorectal cancer and synchronous unresectable liver metastases who underwent oxaliplatin-based chemotherapy as first line treatment in order to determine the rate of primary tumor-specific complications.


   MATERIAL AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
From January 2000 to December 2004, 236 consecutive patients with stage IV colorectal cancer underwent systemic chemotherapy at the Institute for Research and Cure of Cancer. Thirty-five patients had biopsy-proven colorectal cancer and unresectable synchronous liver metastases. All of these patients had no or minimal symptoms (i.e., hematochezia, rectal tenesmus, or mild bowel dysfunction) due to colorectal cancer. In accord with medical oncologists, all 35 patients were treated straightaway by oxaliplatin-based chemotherapy without primary tumor resection or any other local treatment (i.e., endoscopic stenting).

Liver metastases were considered unresectable when, based on the site or on the number of the hepatic lesions, resection with tumor-free margins was precluded.

Carcinoembryonic antigen (CEA), abdominal Ultrasound, and contrast-enhanced computed tomography (CT) were routinely performed for pre-operative staging. Spiral-CT scan was performed with a single slice spiral CT system (High Speed Cti, GE Medical System, Milwaukee, Wisconsin) using dual-phase scanning. A 5 mm reconstruction interval was used in the upper abdomen, whereas a 7 mm interval was used in the lower abdomen and in the chest.

First-line chemotherapy consisted of FOLFOX6 (oxaliplatin 100 mg/m2, folinic acid 200 mg/m2/d, bolus 5 fluorouracil 400 mg/m2 on day 1 followed by 48-hour infusion of 5 fluorouracil 1200 mg/m2/d). All the patients had performance status Eastern Cooperative Oncology Group (ECOG) ≤ 1. Response to chemotherapy was assessed by spiral-CT scan according to the RECIST criteria.10

All patients were periodically reviewed by a hepatobiliary surgeon, an oncologist, and a radiologist. Surgery was performed as soon as metastases became technically resectable. Standard second line chemotherapy for progressive disease was FOLFIRI (irinotecan 180 mg/m2 on day 1, folinic acid 200 mg/m2/d, bolus 5 fluorouracil 400 mg/m2 on day 1 and 2, and 48-hour infusion of 5 fluorouracil 600 mg/m2/d). Capecitabine schedules represented the third line chemotherapy.

The end-point of the study was to evaluate the rate of complications related to un-resected colorectal tumors and necessary surgical treatment.

Continuous variables were compared using the Student T-test; categorical variables were compared using the Chi-square or Fisher exact tests, as appropriate. Statistical tests were performed using Statistica for Windows (Stat Soft, Inc. 2003).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
From January 2000 to December 2004, we prospectively collected data on 35 consecutive patients. The sites of the primary lesion were the right colon in 8 cases, the left or sigmoid colon in 13, and the rectum in 14. The reasons for initial non-resectability were the presence of multiple bilateral liver metastases in 26 cases (74.3% ), the presence of associated unresectable extra-hepatic disease in 7 (20% ), and the location of the tumor (involving hepatic vein confluence) in 2 (5.7% ). The sites of extra-hepatic disease were the lung in 4 patients (multiple, bilateral lesions), the paraaortic lymph nodes in 2, and peritoneal in 1. The mean interval between diagnosis and start of chemotherapy was 23.1 days (95% CI: 17.3–28.8).

The overall response rate to oxaliplatin-based chemotherapy was 68.6% (complete response in 1 patient, partial response in 23 patients). The disease control rate at the colorectal cancer site was partial response in 20 patients (57.1% ), stable disease in 14 (40% ), and unavailable in 1 (2.9% ). The last patient had small colon cancer that was undetectable by CT scan.

Fifteen patients (42.9% ) were downstaged to surgery by oxaliplatin-based first line chemotherapy. Of these thirteen underwent resection for colon-rectum cancer (the location of the primary cancer was rectal in 10 patients, the left colon in 1 patient, and the right colon in 2 patients) and of the liver metastases (synchronous resection in 8 cases). None of the 5 patients who underwent delayed liver resection had chemotherapy after resection of the primary tumor. The remaining two patients had resection for rectal cancer. The pre-planned delayed liver resection was not performed due to progression of the liver metastases. In-hospital mortality was nil. The mean interval between chemotherapy start and colon-rectum cancer resection was 6.5 months (95% CI: 5.5–7.5 months). No patients developed clinical signs of complications due to colorectal tumor during chemotherapy. On December 2005 (mean follow up 30 months, 95% CI: 21.7–39), 10 patients were alive (5 without evidence of disease) and 5 were dead of disease.

Of the other 20 patients who remained unresectable, 16 received second line chemotherapy and 10 a third line treatment. The mean interval between chemotherapy start and end of the follow-up was 17.7 months (95% CI: 14–21.5 months). On December 2005, 6 patients were alive with a mean follow up of 22.5 months (95% CI: 11.2–33.9). None of them has developed symptoms related to colorectal cancer. The remaining 14 patients are dead because of progression of the metastatic disease (mean survival 15.5 months 95% CI: 12–18.9); three of them developed complications related to the primary tumor during systemic chemotherapy.

Surgery occurred in only 1 case (2.8% of the entire cohort). The patient required a colostomy to treat acute large bowel obstruction. This patient developed clinical signs of intestinal occlusion 5.6 months from the start of chemotherapy and died 14 months after surgery. Another patient received radiotherapy to control rectal pain and bleeding. Symptoms developed 2.2 months after chemotherapy start and were controlled by radiotherapy; the patient died 4 months after the end of radiotherapy treatment. The remaining patient developed intestinal obstruction 11.6 months after chemotherapy. He was treated conservatively because of his advanced-illness status and died 3 days after symptoms onset.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Patients with colorectal carcinoma and synchronous unresectable liver metastases have a dismal 5-year survival without treatment.5,11–14 A recent meta-analysis has clearly shown that chemotherapy prolongs overall survival.1

There are no doubts that among patients with moderate-severe intestinal symptoms, resection is mandatory before starting systemic chemotherapy. If the colorectal tumor is asymptomatic, chemotherapy can be performed after resection of the colorectal cancer or d’emblée. Many authors have recommended resection of the colorectal tumor as the first step of treatment in order to prevent the complications related to colorectal tumors.3–5,15 Ruo has reported that 30 (29% ) of the 103 patients who initially managed without bowel resection required a subsequent operation for palliation of complications.6 However, other authors have strongly supported up-front chemotherapy as the optimal approach, reporting a low risk of complications before death from systemic disease progression.7–9,16 Despite these conclusions, the reported rate of complications related to colorectal tumors and required surgery still ranged from 9% to 21% (Table 1Go). In contrast, the rate of complications observed in the present study was very low: only one patient out of thirty-five (2.8% ) required surgery to treat intestinal occlusion. Two other patients developed complications related to the primary tumor but did not require surgery. It is important to highlight that all three patients belonged to a group who never became resectable because of disease progression during chemotherapy.


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  		TABLE 1. Studies analysing the impact of up-front systemic chemotherapy in stage IV colorectal cancers
 
Our low rate of surgical complications can be explained by the different chemotherapy regimens used. Most of the patients in the previously mentioned studies received a de Gramont regimen comprising leucovorin plus bolus and infusional fuorouracil every 2 weeks (LV5FU2),7,9,16–18, whereas in the present series all patients underwent FOLFOX6 as a first-line treatment. To date, the fluouracil-oxaliplatin combination has been shown to be superior to the de Gramont regimen: response rates have increased from 20% to 50–60% .19,20 Moreover, all the patients of the present series requiring a second-line chemotherapy received FOLFIRI regimen. A recent study has confirmed its efficacy.21

To our knowledge, the present study is the largest series to report on patients with relatively asymptomatic colorectal cancers and synchronous unresectable liver metastases who immediately underwent oxaliplatin-based chemotherapy without resection of the colorectal cancer. Our data strongly support the management algorithm of stage IV colorectal cancer recently reported by Cohen.22 Up-front chemotherapy approach in this subset of patients is safe, provided that efficient chemotherapy regimens can be used.

Moreover, this type of approach has some advantages: first, the interval between diagnosis and chemotherapy start is reduced. In Benoist’s paper, the mean period was 44 days in the resection group versus 15 days in the chemotherapy group.8 In the present study, most of the patients started chemotherapy within one month from the diagnosis. Starting of chemotherapy early is particularly relevant since the most important predictor of survival is the extension of the hepatic disease and not of the colorectal cancer.6,7 Second, not only the liver metastases but the primary tumor can be downsized by chemotherapy. In the present study, CT scan showed reduction of colorectal cancer or of metastatic regional lymph nodes in about two-thirds of the patients (Fig. 1Go). Shrinkage of the colorectal cancer may also change the surgical strategy. One patient in our series was planned to undergo an abdominoperineal resection because of anal sphincter infiltration. After oxaliplatin-based chemotherapy, she was radically operated with a sphincter-saving resection, and final pathology did not show residual neoplastic cells. Third, the absence of the postoperative immune dysfunction may reduce the theoretical risk of meta-static disease growth.23,24


Figure 1
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  		FIG. 1. (A) Pre-chemotherapy CT scan image shows a large sigmoid cancer. (B) Post-chemotherapy CT scan image shows an impressive reduction of the sigmoid mass.

 
The present study did not focus on survival since it has been clearly shown that no survival advantage is gained by resection of colorectal cancer in stage IV patients.7,8 Long-term outcome is determined largely by the metastatic tumor burden.6

In conclusion, our data show that oxaliplatin first-line chemotherapy is associated with a low rate of complications related to the non-resected colorectal cancer. Less than 3% of the patients will need surgery because of complications. Therefore, in select cases, a non-operative management of asymptomatic colorectal cancers with unresectable liver metastases should be advised.

Received for publication May 28, 2006. Accepted for publication June 14, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIAL AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Colorectal Cancer Collaborative Group Palliative chemotherapy for advanced colorectal cancer: systematic review and meta-analysis. BMJ 2000; 321:531–5.[Abstract/Free Full Text]
  2. Giacchetti S, Itzhaki M, Gruia G, Adam R, Zidani R, Kunstlinger F, et al. Long-term survival of patients with unresectable colorectal cancer liver metastases following infusional chemotherapy with 5-fluorouracil, leucovorin, oxaliplatin and surgery. Ann Oncol 1999; 10:663–669.[Abstract/Free Full Text]
  3. Joffe J, Gordon PH. Palliative resection for colorectal carcinoma. Dis Colon rectum 1981; 24:355–360.[Medline]
  4. Longo WE, Ballantyne GH, Bilchik AJ, Modlin IM. Advanced rectal cancer. What is the best palliation ?. Dis Colon Rectum 1988; 31:842–847.[CrossRef][Medline]
  5. Rosen SA, Buell JF, Yoshida A, Kazsuba S, Hurst R, Michelassi F, Millis M, Posner MC. Initial presentation with stage IV colorectal cancer. How aggressive should we be?. Arch Surg 2000; 135:530–535.[Abstract/Free Full Text]
  6. 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; 196:722–728; DOI: 10.1016/S1072-7515(03)00136-4.[CrossRef][Medline]
  7. Scoggins CR, Meszoely IM, Blanke CD, Beauchamp RD, Leach SD. Nonoperative management of primary colorectal cancer in patients with stage IV disease. Ann Surg Oncol 1999; 6:651–657.[Abstract]
  8. Benoist S, Pautrat K, Mitry E, Rougier P, Penna C, Nordlinger B. Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg 2005; 92:1155–1160; DOI: 10.1002/bjs.5060.[CrossRef][Medline]
  9. Sarela AI, Guthrie JA, Seymourt MT, Ride E, Guillou PJ, O’Riordain S. Non-operative management of the primary tumour in patients with incurable stage IV colorectal cancer. Br J Surg 2001; 88:1352–1356.[CrossRef][Medline]
  10. Therasse P, Arbuck SG, Eisenhauer E, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205–216.[Abstract/Free Full Text]
  11. Steinberg SM, Barkin JS, Kaplan RS, Stablein DM. Prognostic indicators of colon tumors. The Gastrointestinal Tumor Study Group experience. Cancer 1986; 57:1866–1870.[CrossRef][Medline]
  12. Finan PJ, Marshall RJ, Cooper EH, Giles GR. Factors affecting survival in patients presenting with synchronous hepatic metastases from colorectal cancer: a clinical and computer analysis. Br J Surg 1985; 72:373–7.[Medline]
  13. Goslin R, Steele G Jr, Zamcheck N, Mayer R, MacIntyre J. Factors influencing survival in patients with hepatic metastases from adenocarcinoma of the colon or rectum. Dis Colon Rectum 1982; 25:749–54.[Medline]
  14. Bengtsson G, Carlsson G, Hafstrom L, Jonsson PE. Natural history of patients with untreated liver metastases from colorectal cancer. Am J Surg 1981; 141:586–9.[CrossRef][Medline]
  15. Moran MR, Rothenberger DA, Lahr CJ, Buls JG, Goldberg SM. Palliation for rectal cancer. Resection? Anastomosis?. Arch Surg 1987; 122:640–643.[Abstract/Free Full Text]
  16. Michel P, Roque I, Di Fiore F, Langlois S, Scotte M, Teniere P, Paillot B. Colorectal cancer with non-resectable synchronous metastases: should the primari tumor be resected?. Gastroenterol Clin Biol 2004; 28:434–437.[Medline]
  17. Stelzner S, Hellmich G, Koch R, Ludwig K. Factors predicting survival in stage IV colorectal carcinoma patients after palliative treatment: a multivariate analysis. J Surg Oncol 2005; 89:211–217.[CrossRef][Medline]
  18. Tebbutt NC, Norman AR, Cunningham D, Hill ME, Tait D, Oates J, Livingstone S, Andreyev J. Intestinal complications after chemotherapy for patients with unresected primary colorectal cancer and synchronous metastases. Gut 2003; 52:568–573.[Abstract/Free Full Text]
  19. de Gramont A, Figer A, Seymour M, Homerin M, Hmissi A, Cassidy J, Boni C, Cortes-Funes H, Cervantes A, Freqyer G, Papamichael D, Le Bail N, Louvet C, Hendler D, de Braud F, Wilson C, Morvan F, Bonetti A. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18:2938–2947.[Abstract/Free Full Text]
  20. Alberts SR, Horvath WL, Sternfeld WC, Goldberg RM, Mahoney MR, Dakhil SR, Levitt R, Rowland K, Nair S, Sargent DJ, Donohue JH. Oxaliplatin, fluorouracil, and leucovorin for patients with unresectable liver-only metastases from colorectal cancer: a North Central Cancer Treatment Group phase II study. J Clin Oncol 2005; 23:9243–9249; DOI: 10.1200/JCO.2005.07.740.[Abstract/Free Full Text]
  21. Tournigand C, Andrè T, Achille E, Lledo G, Flesh M, Mery-Mignard D, Quinaux E, Couteau C, Buyse M, Ganem G, landi B, Colin P, Louvet C, de Gramont A. FOLFIRI follone by FOLFOX6 or the riverse sequenze in advanced colorectal cancer: a randomized GERCOR study. J Clin Oncol 2004; 22:229–237; DOI: 10.1200/JCO.2004.05.113.[Abstract/Free Full Text]
  22. Cohen AM. What is the best treatment for stage IV colorectal cancer?. Ann Surg Oncol 2005; 12:581–582; DOI: 10.1245/ASO.2005.03.901.[Free Full Text]
  23. Wichmann MW, Huttl TP, Winter H, Spelsberg F, Angele MK, Heiss MM, Jauch KW. Immunological effects of laparoscopic vs open colorectal surgery. Arch Surg 2005; 140:692–697.[Abstract/Free Full Text]
  24. Jarnagin WR, Delman K, Kooby D, Mastorides S, Zager J, Brennan MF, Blumgart LH, Federoff H, Fong Y. Neoadjuvant interleukin-12 immunogene therapy protects against cancer recurrence after liver resection in an animal model. Ann Surg 2000; 231:762–71.[CrossRef][Medline]



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