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Long-term survival of a patient with primarily unresectable liver metastasis from rectal cancer after neoadjuvant chemotherapy.

Introduction

Resectability is the decisive factor for long-term survival of metastatic colorectal cancer. Unfortunately, only approximately 10% of patients with colorectal liver metastases have resectable disease. In the past decade, there has been a paradigm shift in treatment strategies. Developments in chemotherapy have led to improvements in response rates and been able to induce resectability in patients with initially unresectable metastases with the result that patients who had been regarded as non-curable have achieved long-term survival.

Here we describe the case of a 45-year-old woman with rectal cancer and initially unresectable colorectal liver metastases.

Case report

In December 2001, a 45-year-old woman [Eastern Cooperative Oncology Group (ECOG) performance status 1] with no family history of cancer presented with weight loss of 6 kg during the previous 10 weeks, perianal blood loss and changes in defecation.

The colonoscopy revealed a tumour of the rectum 4.5 cm from linea dentata with an extension of about 10 cm. The tumour was found on further examination to be stage T3N1. Leukocyte count and alkaline phosphatase levels were increased, and computed tomography (CT) scan showed a single large liver metastasis (71 x 56 mm) in contact with the portal vein branch, as well as bile duct obstruction. The metastasis was regarded as non-resectable. After having decided against a palliative resection or a colostomy, the patient received argon plasma coagulation of the rectal tumor to reduce the bleeding 'in order to keep life-qualtity for a patient with such a limited perspective' (surgical report).

The patient received cetuximab and weekly irinotecan, folinic acid and 5-FU within a clinical trial [1]. Staging examinations with CT scan after the first cycle of treatment showed a partial remission with reduction of the liver metastasis down to 51 x 33 mm, and with decreased obstruction of the intrahepatic biliary tract. After three complete cycles of chemotherapy, the liver metastasis had reduced in size to 31 x 20 mm. Colonoscopy also revealed downstaging of the primary. The levels of tumour marker carcinoembryonic antigen (CEA) normalised from 260 ng/ml in January 2002 to 2.8 ng/ml in July 2002.

The primary tumor was resected in September 2002 by anterior resection and protective colostomy [pT3pN1(2/12) G2], whereas the liver metastasis was resected in December 2002 by right hemihepatectomy. Histological examination of the liver metastasis specimen revealed necrotic material but no vital tumour tissue. Adjuvant radiotherapy was not considered because of a recto-vaginal fistula.

Today, 5 years after hepatic resection, the patient is still in complete remission.

Discussion

Our case is not unusual today--and this very normality illustrates the enormous changes of recent years and the shift in treatment of patients with potentially resectable colorectal cancer. Today, patients such as the woman described above are clearly regarded as having a chance of curative treatment; however, it may be worth remembering that this patient would have had a very poor prognosis in the era of 5-fluorouracil (5FU) monotherapy when, according to a prognostic model, life expectancy would have been only 6 months [2] and liver resections were rare [3].

In this case, the surgeon acted on the assumption that the patient had very limited options in a strictly palliative situation. The primary tumour was not resected, and the patient began chemotherapy. Retrospective analyses have shown no survival advantage for resection in patients with lack of bowel obstruction in comparison to systemic treatment [4-6]. By contrast, resection may delay systemic treatment, which is the only treatment option with proven survival benefit.

Only a few years before the start of treatment of the patient in our case report, the first larger reports of patients with liver resection after neoadjuvant chemotherapy were published by Bismuth et al. [7] and Giacchetti et al. [8], which increased the awareness of secondary resectability. However, in 2001, when colorectal liver metastases were diagnosed in our patient, neoadjuvant treatment and especially an intensive approach with chemotherapy and targeted therapy was not the standard treatment. During the following years, several single-arm studies were performed which confirmed the possibility of resecting initially non-resectable liver metastases [9-12]. This approach results in relatively favourable long-term survival. Adam and co-workers reported a 10-year survival rate of 23% [13]. However, they also reported prognostic factors that clearly showed the differences in patients without any risk factor [more than two metastases, large metastases >10 cm, elevated carbohydrate antigen (CA) 19-9 and rectal primary; calculated 5-year survival, 59%] compared to those with unfavourable factors (more than two risk factors; calculated 5-year survival, [less than or equal to] 1%) [13].

Discussions have continued regarding the optimal chemotherapy, especially as most patients in the first reports [7,8] were treated with oxaliplatin-containing schedules. Pozzo and coworkers demonstrated that irinotecan-containing schedules gave similar results to combinations with oxaliplatin in a smaller patient group [9]. Today, we know that leucovorin, 5FU and irinotecan (FOLFIRI) combined with cetuximab is an effective therapy that significantly prolongs progression-free survival and increases response rate in first-line therapy [14]. Combinations of leucovorin, 5FU and oxaliplatin (FOLFOX) with cetuximab [15] and the four-drug combination leucovorin, 5FU, oxaliplatin and irinotecan (FOLFOXIRI) [16] may also increase the response rate. When FOLFIRI/cetuximab [14] or FOLFOXIRI [16] were compared to FOLFIRI alone, the concept that increased response rates induce a higher probability of liver resection was confirmed [17].

When our patient showed a good partial response, resection of the liver metastasis was possible and took place without peri-operative complications. Early multidisciplinary discussion during chemotherapy is crucial in this group to enable the patient to undergo early liver surgery, thus avoiding unnecessary preoperative exposure to chemotherapy which is related to higher peri-operative mobidity [18]. A further reason against long-duration pre-operative chemotherapy is that even a complete remission shown on CT scan is of no advantage as approximately 85% of 'disappeared' metastases do not have pathological complete response (if resected) or recur during the first year after resection [19].

In this case, adjuvant radiotherapy was not discussed because of a recto-vaginal fistula. However, in general the value of radiochemotherapy might be reduced after resection of simultaneous liver metastases if the risk of local recurrence is weighed against the risk of systemic relapse.

Liver metastases of colorectal cancer and the management of patients with simultaneous metastases of colon and particularly rectal cancer remains a very interesting field of multidisciplinary research.

References

[1.] Folprecht G, Lutz MP, Schoffski P et al. Cetuximab and irinotecan/5-fluorouracil/folinic acid in a safe combination for the first-line treatment of patients with epidermal growth factor receptor expressing metastatic colorectal carcinoma. Ann Oncol, 2006, 17, 450-456.

[2.] Kohne CH, Cunningham D, Di Costanzo F et al. Clinical determinants of survival in patients with 5-fluorouracil-based treatment for metastatic colorectal cancer: results of a multivariate analysis of 3825 patients. Ann Oncol, 2002, 13, 308-317.

[3.] Fowler WC, Eisenberg BL and Hoffman JP. Hepatic resection following systemic chemotherapy for metastatic colorectal carcinoma. J Surg Oncol, 1992, 51, 122-125.

[4.] Tebutt NC, Norman AR, Cunningham D et al. Intestinal complications after chemotherapy for patients with primary unresected colorectal cancer and synchronous liver metastases. Gut, 2003, 52, 568-573.

[5.] Benoist S, Pautrat K, Mitry E et al. Treatment strategy for patients with colorectal cancer and synchronous irresectable liver metastases. Br J Surg, 2005, 92, 1155-1160.

[6.] Sarela AI, Guthrie JA, Seymour MT et al. Non-operative management of the primary tumour in patients with uncurable stage IV colorectal cancer. Br J Surg, 2001, 88, 1352-1358.

[7.] Bismuth H, Adam R, Levi F et al. Resection of nonresectable liver metastases from colorectal cancer after neoadjuvant chemotherapy. Ann Surg, 1996, 224, 509-522.

[8.] Giacchetti S, Itzhaki M, Gruia G 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.

[9.] Pozzo C, Basso M, Cassano A et al. Neoadjuvant treatment of unresectable liver disease with irinotecan and 5-fluorouracil plus folinic acid in colorectal cancer patients. Ann Oncol, 2004, 15, 933-939.

[10.] Alberts SR, Horvath WL, Sternfeld WC et al. 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.

[11.] De La Camara J, Rodriguez J, Rotellar F et al. Triplet therapy with oxaliplatin, irinotecan, 5-fluorouracil and folinic acid within a combined modality approach in patients with liver metastases from colorectal cancer. Proc ASCO, 2004, 23, Abstr. 3593.

[12.] Zelek L, Bugat R, Cherqui D et al. Multimodal therapy with intravenous biweekly leucovorin, 5-fluorouracil and irinotecan combined with hepatic arterial infusion pirarubicin in non-resectable hepatic metastases from colorectal cancer (a European Association for Research in Oncology trial). Ann Oncol, 2003, 14, 1537-1542.

[13.] Adam R, Delvart V, Pascal G et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg, 2004, 240, 644-657.

[14.] Van Cutsem E, Nowacki M, Lang I et al. Randomized phase III study of irinotecan and 5-FU/FA with or without cetuximab in the first-line treatment of patients with metastatic colorectal cancer (mCRC): the CRYSTAL trial. Proc ASCO, 2007, 25, Abstr. 4000.

[15.] Bokemeyer C, Bondarenko I, Makhson A et al. Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study. Proc ASCO, 2007, 25, Abstr. 4035.

[16.] Falcone A, Ricci S, Brunetti I et al. Phase III trial of infusional fluorouracil, leucovorin, oxaliplatin and irinotecan (FOLFOXIRI) compared with infusional fluorouracil, leucovorin, and irinotecan (FOLFIRI) as first-line treatment for metastatic colorectal cancer: the Gruppo Oncologico Nord Ovest. J Clin Oncol, 2007, 25, 1670-1676.

[17.] Folprecht G, Grothey A, Alberts S et al. Neoadjuvant treatment of unresectable colorectal liver metastases: correlation between tumour response and resection rates. Ann Oncol, 2005, 16, 1311-1319.

[18.] Karoui M, Penna C, Amin-Hashem M et al. Influence of preoperative chemotherapy on the risk of major hepatectomy for colorectal liver metastases. Ann Surg, 2006, 243, 1-7.

[19.] Nordlinger B, Brouquet A, Penna C et al. Complete radiological response of colorectal liver metastases (LM) after chemotherapy: does it mean cure? Proc ASCO, 2006, 24, Abstr. 3501.

Katharina Sprenger and Gunnar Folprecht

Medical Department I, University Hospital Dresden, Germany

Correspondence to: Katharina Sprenger (email: katharina.sprenger@uniklinikum-dresden.de)
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Title Annotation:Case Report
Author:Sprenger, Katharina; Folprecht, Gunnar
Publication:Advances in Gastrointestinal Cancer
Geographic Code:4EUGE
Date:Sep 1, 2007
Words:1702
Previous Article:Classification of colorectal liver metastases.
Next Article:Panitumumab with irinotecan/leucovorin/5-fluorouracil for first-line treatment of metastatic colorectal cancer.
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