Pre-Operative Chemotherapy for Colorectal Cancer with Liver Metastases and Conversion Therapy

WCRJ 2015; 2 (1): e473

PRE-OPERATIVE CHEMOTHERAPY FOR COLORECTAL CANCER WITH LIVER METASTASES AND CONVERSION THERAPY

C. DE DIVITIIS 1, M. BERRETTA 2,3 , F. DI BENEDETTO 4, R.V. IAFFAIOLI 1, S. TAFUTO 1, C. ROMANO 1, A. CASSATA 1, R. CASARETTI 1, A. OTTAIANO 1, G. NASTI 1

1Medical Oncology, Abdominal Department, National Cancer Institute G. Pascale Foundation, Naples, Italy. 2Department of Medical Oncology, National Cancer Institute of Aviano, Aviano (PN), Italy. 3Euro-Mediterranean Institute of Science and Technology (IEMEST), Palermo, Italy. 4Hepato-Pancreato-Biliary Surgery and Liver Transplantation Unit, University of Modena and Reggio Emilia, Modena, Italy.

Abstract: Preoperative treatment of resectable liver metastases from colorectal cancer (CRC) is a matter of debate. More than 50% of patients with colorectal cancer develop liver metastases. Surgical resection is the only available treatment that improves survival in patients with colorectal liver metas - tases (CRLM). Neoadjuvant and conversion chemotherapy may lead to improved response rates in this population of patients and increase the proportion of patients eligible for surgical resection. The pres - ent review discusses the available data for chemotherapy in this setting.

Keywords: Colorectal cancer, Pre-operative chemotherapy, Liver metastases.

INTRODUCTION acquired that surgery is the first therapeutic which must follow a systemic adjuvant chemotherapy 5. Colorectal cancer (CRC) is the third tumor inci - The standard treatment of CRC patients with dence in the world with over 940,000 new cases LM is systemic chemotherapy; however, despite and nearly 500,000 deaths annually worldwide 1. recent advances, the 5-year survival is poor. About 50% of CRC patients has, diagnosis, dis - About a third of patients with CRC with extensive tant metastases, and overall survival (OS) does liver disease presents ab initio resectable metas - not exceed two years 2,3 . The liver is involved in tases, and it recently acquired that surgery is the 80-90% of cases, and in almost half of patients at first therapeutic which must follow a systemic ad - stage IV, is the only site of metastasis. The inte - juvant chemotherapy 5. On the other hand, in pa - gration of chemotherapy and surgery in the treat - tients who undergo immediate radical surgical ment of liver metastases (LM) represents the more resection of LM, the 5-year survival reaches 30- modern approach and is able to increase the sur - 40%. vival in this subgroup of patients 4 with an approx - Retrospective studies show an advantage in imately 10% of patients cured. terms of OS in patients who undergo hepatic re - About a third of patients with CRC extensive section with respect to patients treated only with LM resectable presents ab initio , and it recently chemotherapy 6,7 , but it is commonly felt that the

Corresponding Author : Guglielmo Nasti, MD; e-mail: [email protected] 1 advantage evidenced with surgery is at least par - erative chemotherapy could eradicate micro- tially due to patient selection (better performance metastases, offering a test of in vivo chemosensi - status and smaller disease extension in patients tivity which could possibly be useful for the treated with surgery). determination of an optimal post-operative med - ical approach. Regarding the neoadjuvant chemotherapy, the Patient selection for primary liver optimal regimen has not yet been determined. resection of CRC metastases However, as in the metastatic setting, the combi - nation of chemotherapy with biological agents ap - In most cases, the patients with LM are not eligi - pears to offers the best results. ble for radical surgical resection. Historically, the Nasti and others 15 investigated the feasibility main contraindications for a surgical approach and activity of bevacizumab plus FOLFIRI in this have been: > 4 metastases, presence of extra-he - setting. patic disease and resection margins < 1 cm 8. Bis - A single-stage, single-arm phase 2 study de - muth et al 9 have extended these criteria allowing sign was applied with 1-year progression-free rate resection of more metastases and of multinodular as the primary end point, and 39 patients required. or hilar metastases. A consensus group has pro - From October 2007 to December 2009, 39 pa - posed new guidelines for the evaluation of re - tients aged 18-75 years, PS 0-1, with resectable sectability of LM. Their unresectability criteria liver-confined metastases from CRC received be - are: 1) hepatic disease that involves more than vacizumab 5 mg/kg, followed by irinotecan 180 50% of liver parenchyma or six segments, 2) ex - mg/m 2, leucovorin 200 mg/m 2, 5-fluorouracil 400 tra-hepatic disease, 3) unfit patients 10 . However, mg/m 2 bolus and 5-fluorouracil 2400 mg/m 2 46-h consensus on the definition of resectability crite - infusion, biweekly, for 7 cycles. Bevacizumab ria varies considerably among centres. The pa - (Beva) was stopped at cycle 6. The objective re - tients candidated for radical hepatic resection can sponse rate was 66.7% (95% exact CI: 49.8-80.9). be stratified into risk groups on the basis of clini - Of these, 37 patients (94.9%) underwent surgery, cal scoring systems 11-13 , which use prognostic fac - with a R0 rate of 84.6%. Five patients had a patho - tors identified with multivariate analysis, such as logical complete remission (14%). Out of 37 pa - the presence of positive lymph nodes, a < 12 tients, 16 (43.2%) had at least one surgical month disease-free survival, the presence of more complication (most frequently biloma). At 1 year than one tumour, high preoperative CEA, a > 5 cm of follow-up, 24 patients were alive and free from tumour. According to the above factors, the 5-year disease progression (61.6%, 95% CI: 44.6-76.6). survival has been shown to range between 14 and Median PFS and OS were 14 (95% CI: 11-24) and 60%. The validity of these guidelines needs to be 38 (95% CI: 28-NA) months, respectively. The confirmed in further trials before becoming a authors concluded that the preoperative treatment standard approach to patients with liver metas - of patients with resectable LM from CRC with tases from CRC. Beva plus FOLFIRI is feasible, but further studies are needed to define its clinical relevance. Retrospective analyses and data from phase III Pre-operative chemotherapy studies on metastatic disease showed that some patients initially treated with a palliative intent be - The importance of a possible preoperative therapy came susceptible to radical resection of their derives from the observation that, unfortunate, the LM 17,18 . Tournigand et al 16 evidenced a 54% OR majority of patients undergoing liver resection re - rate for the combination of 5-FU/FA and OXA lapse after surgery. For this reason, new approach - (FOLFOX) and of 56% for the combination of 5- es have been investigated in recent years. A FU/FA and IRI (FOLFIRI). Liver metastases EORTC randomized controlled trial demonstrated treated with FOLFOX resulted resectable in 13% a significant advantage in terms of progression- of cases, while those treated with FOLFIRI were free survival (PFS) in patients treated with peri- resectable in 7% of cases. Goldberg et al 17 com - operative chemotherapy 14 . pared FOLFOX with a combination regimen of Pre-operative chemotherapy could make re - IRI and bolus 5-FU/FA (IFL) and with the associ - sectable LM in patients with initially unresectable ation of OXA and IRI (IROX), evidencing an OR disease and could increase the percentage of radi - rate significantly higher for the FOLFOX regimen cal resections. This approach allow limited hepa - (45% vs 31% vs 35%, respectively). In this study tectomies in patients with initially resectable LM, the percentage of patients who subsequently un - with the aim of reducing surgery-related morbidi - derwent surgery with radical intent after FOL - ty and improving post-operative recovery. Pre-op - FOX (4.1%) was also higher than after IFL

2 PRE-OPERATIVE CHEMOTHERAPY FOR COLORECTAL CANCER

(0.75%) 18 . A phase III study published by the during surgery in 15 patients who had initially re - Gruppo Oncologico Nord Ovest (GONO) com - sectable disease. Anyway, pathologic examination pared fluorouracil, leucovorin, oxaliplatin, and of the cRR resected areas showed the presence of irinotecan (FOLFOXIRI) with FOLFIRI as first- viable tumour cells in 12 patients (80%). Recur - line chemotherapy in unresectable metastatic col - rence was observed 1 year after liver resection in orectal cancer. Response rates as assessed by an 10 patients (66.6%). After 1 year, 14 of 15 patients external panel was 34% (FOLFIRI) versus 60% were alive. In initially unresectable metastases (FOLFOXIRI) ( p < .0001). Interestingly, the R0 liver examination and intraoperative US upholded resection rate of metastases in liver-limited dis - that there were no remaining visible tumour at the ease was greater in the FOLFOXIRI arm (12% v site of 31 LM that had a cRR; these lesions were 36%; p = .017). Progression-free survival and OS not resected. At 1 year, 23 patients (73%) devel - were both significantly improved in the FOL - oped recurrences at the site of the unresected le - FOXIRI arm (median PFS, 6.9 v 9.8 months; haz - sions 24 . Benoist et al showed that although ard ratio [HR], 0.63; p = .0006; median OS, 16.7 v radiological complete response may be a useful 22.6 months; HR, 0.70; p = .032) 19 . criterion for evaluating the efficacy of chemother - Adam et al reported an update of the aforesaid apy, it does not mean a potential cure. Therefore, a data with an analysis of 701 patients; radical re - systemic chemotherapy with neoadjuvant intent in section was possible in 14% of patients with a 5- patients with initially unresectable LM from CRC year survival of 35% 19 . Giacchetti et al analyzed looks a potential therapeutic weapon. Anyway, 151 patients initially considered unresectable for which is the optimal neoadjuvant regimen and the presence of large LM (> 5 cm), multiple how many cycles are more appropriate before sur - metastases (> 4 nodules) or metastasis localized in gery it is still debated. Several issues remain open: the hepatic hilus. All patients were treated with an the planned curative resection should be deter - oxaliplatin-containing chemotherapy regimen. mined by radiogralogical response? Does the re - Objective response rate was 59%. After sponse to neoadjuvant chemotherapy condition chemotherapy, 51% of patients were considered the continuation of the same therapy after sur - resectable but only 38% of patients underwent gery? Therefore, all patients with initially unre - radical resection. The median survival was 48 sectable LM from CRC should always be aimed months for the resected patients and 15.5 months by a multidisciplinary team to define the best for the unresected ones 20 . treatment program. Alberts et al analyzed 42 patients treated with Also, for the high perioperative morbidity FOLFOX4 reporting a 62% OR rate, a 33% of he - rates, all patients with resectable LM eligible for patic resections and a median survival of 31.4 neoadjuvant chemotherapy require accurate months in resected patients 21 . Quenet et al evalu - risk/benefit evaluation. Gruenberger et al 25 stud - ated 34 patients treated with a chemotherapy regi - ied 50 patients with resectable LM (1 metastasis men containing oxaliplatin, irinotecan and 5-FU, 30%; 2-3 metastasis 22%; > 4 metastases 48%) obtaining resection of hepatic disease in 37,5% of treated with a neoadjuvant regimen containing ox - patients 22 . Pozzo et al treated 40 patients with aliplatin (30 patients with XELOX, 20 patients FOLFIRI, obtaining an objective response in with FOLFOX4). All patients underwent surgery 47,5% of patients and resection of LM in 27.5% and obtained hepatic resection R0, with no sur - of patients. The median survival of resected pa - gery-related deaths and a morbidity of 12%. At a tients had not yet been achieved after a median preliminary follow-up, 58% of patients were dis - follow-up of 30.4 months 23 . Also, Benoist et al an - ease-free, 20% had relapsed and 22% had died. alyzed 38 patients derived from a prospective Besides, do not forget that there are two main mono-institutional series of 586 consecutive pa - types of liver damage have been reported: vascu - tients treated for LM from CRC. The authors’ ob - lar changes and chemotherapy-associated steato- jective was to perform liver resection, including hepatitis 26-29 . the sites of the disappeared LM in patients with In conclusion, these data suggest the use of bi - resectable metastases. In initially unresectable pa - ologic agents in the neoadjuvant setting and open tients, resection or local ablation of all visible LM a real opportunity for pursuing curative resection was performed, leaving the disappeared liver also in patients with initially unresectable LM. metastases in the remnant liver. Of the 38 patients, Both cetuximab and and bevacizumab appear 22 had unresectable LM (multiple bilobar de - equally effective in combination with chemother - posits in 20 patients and invasion of major liver apy. The addition of cetuximab should be pre - vessels in 2 patients) while 16 patients had re - ferred in patients with wild-type KRAS tumors. sectable disease. Complete radiological remission Data from CRYSTAL and OPUS are pooled from (cRR) was upholded by liver examination and US subgroup analysis within large phase III studies in

3 the metastatic setting and thus, they suffer of sta - adding Cetux to FOLFIRI or FOLFOX6 in the tistical pitfalls. Prospective, ad hoc trials are war - neoadjuvant treatment of patients with unre- ranted in the near future in order to assess the sectable CRC LM (technically unresectable ac- effective role of biologic agents in the neoadju - cording to the evaluation of the radiologist and the vant setting and establish which targeted agent is surgeon, or number of metastases >5). Main ob- the preferred combination partner for specific jective of this trial was to evaluate the response chemotherapy. rates and, among the secondary, the evaluation of patients brought to resection. Patients were considered eligible in the pres- Neoadjuvant chemotherapy and ence of a massive hepatic involvement, assuming the introduction of biologic agents the possibility of surgery in case of good response to chemotherapy. At the present, the best choice in the management of One-hundred-eleven patients were enrolled patients with unresectable LM consists of pharmaco - and randomized to receive FOLFOX6 plus Cetux logical treatments characterized by high response (56 patients) or Cetux plus FOLFIRI (55 patients). rate for a limited number of cycles, and then instru - The analysis of the status of EGFR, KRAS and mental re-evaluation of the disease to define again BRAF was conducted retrospectively. Patients the susceptibility to curative surgery (the so-called were evaluated for resectability by the local surgi- “conversion chemotherapy”) and, in the alternative, cal team after the first 16 weeks of therapy and then a systemic treatment to palliative purposes only. every 8 weeks to 2 years. A group of 7 between ra- The Conversion Therapy is given to patients in diologists and surgeons has reviewed all the images good overall clinical condition, with limited independently, without knowing the details about metastatic disease, mainly liver, for which a sys - the medical history of each patient (Figure 1). temic drug treatment plays a decisive role. It could, The response rate was 68% in patients treated in patients in quick response, allowing a potentially with Cetux plus FOLFOX 6 and 57% in those in curative surgery on secondary injuries. Therefore, the FOLFIRI arm, difference is not statistically in this subpopulation of patients regimes character - significant. A retrospective analysis showed a ized by high response rate are preferred, regardless higher rate of response in both arms in patients of their ability to impact on survival. wild type, both as regards the only KRAS (70% The systemic treatment consist in a combina - versus 41% in the mutant, p = 0.008) that both tion of two drugs (5-fluorouracil, and oxaliplatin genes KRAS and BRAF (72% versus 40%, p = or irinotecan) with a response rate that does not 0.003). The percentage of subjects radically re- exceed 40%. sected (RO) was 38% with Cetux and FOLFOX6 The randomized Phase II called “CELIM” 30 and 30% with Cetux plus FOLFIRI, with a signif- was designed to evaluate the effectiveness of icant increase in surgery patients compared to

Figure 1. CELIM: re - sectability based on blinded assessment of seven surgeons.

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