The handling of metastatic colorectal cancer

Annals of Oncology 16 (Supplement 2): ii141 – ii143, 2005 doi:10.1093/annonc/mdi710

The handling of metastatic colorectal cancer G. Fornarini, A. Guglielmi & A. Sobrero Department of Medical Oncology, S Martino Hospital, Genova, Italy

Introduction

Clearly resectable disease The first approach is for patients with stage IV disease limited to the liver or lung that is clearly resectable. While it is certainly correct to proceed with surgical resection straight away, it must be remembered that 80% of these patients will recur and die of their disease. Therefore, any systemic treatment reducing the chances of recurrence should be considered. Along this line, probably the best approach for these patients is to start chemotherapy for a short time period (i.e. a couple of months) to test for chemosensitivity and then, after response assessment, proceed to surgery. Although no data justifying this approach are available, common sense suggests that whatever chemotherapy worked in the advanced setting (i.e. preoperatively in this case) may still work as adjuvant treatment, affording additional ‘cures’. q 2005 European Society for Medical Oncology

Non-resectable, potentially curable disease The second setting is the patient with disease limited to the liver or lung, but extended enough to be considered not resectable. The treatment goal is tumor shrinkage to the point that the disease becomes resectable. This is not a common event (10– 15% of patients); however, the end point is so highly relevant (resection and potential cure) that the choice of chemotherapy must be made with this in mind, especially considering that this category of patients has a similar prognosis to those patients with primarily resected lesions [1]. Either doublet (FOLFOX or FOLFIRI) may be appropriate in this case, although most of the literature supporting this therapeutic approach has been generated with oxaliplatinbased regimens [1, 2]. Another potential choice in this case could be the triplet regimens, 5-FU + oxaliplatin + irinotecan. These combinations are often associated with more toxicity; therefore, they do not represent standard treatment [3, 4]. The results of a recent paper on 1104 primarily non-resectable patients downstaged by systemic chemotherapy are particularly interesting for predicting the outcome of surgery following neo-adjuvant chemotherapy. In a multivariate analysis conducted on these patients, four preoperative risk factors correlated with worse survival: rectal primary tumor, number of liver metastasis three or more, maximum tumor _ 10 cm and CA 19.9 >100 UI/l. Mean adjusted 5-year sizes > survival according to the presence of none, one, two, three or four factors was 59, 30, 7, 0 and 0%, respectively [5].

Non-resectable, not potentially curable disease The largest proportion of patients with stage IV present with non-resectable disease and more than one metastatic site, so that surgery cannot be radical. In general, systemic chemotherapy is the standard treatment for these patients.

Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 10, 2015

Ten years ago the treatment of metastatic colorectal cancer was based on one drug only, 5-fluorouracil (5-FU); the response rate (RR) was  20%, the progression-free survival (PFS) 4 months and median survival time 12 months. In 10 years, these values have doubled. Now the RR in the first-line treatment is >45%, the PFS  8 months and the median survival time, with the new drug combinations,  20 months. In addition, new concepts have been demonstrated: the clinical relevance of second-line chemotherapy is widely accepted, with RR around 10 –20%, PFS of 4 months and overall survival (OS) of 10 months. Most importantly, in highly selected patients, the radical resection of metastatic disease allows a 30% DFS at 5 years. However, these results may be influenced by two other factors. The higher diagnostic power of present imaging techniques may result in stage migration of patients compared with 10 years ago, accounting for part of these improvements. In addition, it must not be forgotten that all these data and concepts are derived from clinical trials, whereas our daily work entails managing unselected patients, not fit for clinical trials. From a practical viewpoint we can identify three different approaches that encompass the majority of advanced colorectal cancer patients: clearly resectable disease; non-resectable, potentially curable disease; and non-resectable, not potentially curable disease.

The risk of this approach is that a potentially curable patient might be lost because of early progression. However, since the early progression rate with the commonly used doublets is  10%, this risk is well balanced by the potential benefit of using the same chemotherapy as adjuvant in the postoperative period.

ii142 The following are key concepts for the use of chemotherapy in these conditions. (i) Chemotherapy with fluoropyrimidines provides clinical benefit to these patients compared with best supportive care both in terms of quantity (doubling of OS) and quality of life [6]. (ii) Second-line chemotherapy is effective compared with best supportive care [7]. (iii) Doublets are more effective (but more toxic) than single-agent 5-FU as first-line chemotherapy [8 –10]. (iv) Trials that have employed all three active agents (5-FU, oxaliplatin and irinotecan) in >50% of patients show the longest median survival (>20 months), suggesting that irrespective of the sequence, optimal results are obtained when all available agents are used [11]. (v) The initial trials incorporating targeted agents [12, 13] suggest that ‘four agents may be better than three’, meaning that additional survival benefit may be gained by early [13] or late [12] use of these promising compounds. The application of these concepts in clinical practice is not straightforward. In fact, several determinants may indicate that sometimes the ‘best’ (an adjective with no scientific determinant) choice is different from the most effective regimen. A practical approach that can be used in daily practice is to consider: (i) age; (ii) performance status (PS); (iii) tumorrelated symptoms; (iv) tumor bulk; and (v) rate of progression. These factors and their interplay produce the algorithm illustrated in Figure 1. It must be clarified that: (i) the definition of ‘elderly’ in this algorithm refers to anybody ‘looking as if he is 75 years old’,

thus indicating ‘biologically elderly’; (ii) ‘symptoms’ means tumor-related symptoms; and (iii) the proposed algorithm reflects the palliative nature of any medical intervention in this setting (these concepts do not apply to the other two settings discussed earlier in this article). Therefore, this algorithm tends not to be too aggressive. Other European schools may favor more aggressive approaches, including triplet regimens or the indiscriminate use of doublets even in elderly or low PS patients.

Which doublet is to be preferred?

Management strategy for patients with stage IV CRC non resectable and non potentially curable disease

YOUNG

PS 0/1/2

ELDERLY

PS 3

PS 4

PS 0/1

BSC

SX

FP DOUBLET

FP

IMPROVEMENT

SX YES

YES

NO

DOUBLET

BSC

PS 3/4

PS 2

BSC

NO

BULKY

DOUBLET OR FP

NO

YES

WAIT, CT ON PROGRESSION

DOUBLET OR FP

NO

YES

BSC OR FP

FP

FP is meant to indicate: A) oral fluoropyrimidines B) infusional FU SX: tumor-related symptoms (therefore a PS 2 may or not may have tumor related related symptoms) BSC: best supportive care; CT: chemotherapy

Figure 1. Management strategy for patients with stage IV colorectal cancer (CRC) non-resectable and non-potentially curable disease. FP indicates oral fluoropyrimidines and infusional 5-fluorouracil. SX, tumor-related symptoms [therefore a performance status (PS) 2 may or not may have tumor-related symptoms]; BSC, best supportive care; CT, chemotherapy.

Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 10, 2015

There is no clear cut answer to which doublet is to be preferred. In terms of efficacy, the two doublets are equivalent, and this is supported by three randomized studies: a French [2], an Italian [14] and a German [15] trial. The real head-to-head comparison of FOLFOX versus FOLFIRI is the Italian study, since the French is actually a comparison between sequences: FOLFOX! FOLFIRI versus FOLFIRI ! FOLFOX, and the German study uses capecitabine as companion fluoropyrimidine in the doublet (CAPOX versus CAPIRI). All three studies indicate equivalence. The issue that FOLFOX may lead more frequently to secondary hepatic resections in initially unresectable patients is mainly based upon a larger experience with this combination in these particular patients. Even the Tournigand et al. [2] study that has examined this issue reports a higher rate of attempted resections with FOLFOX, although the rate of R0 resections was equivalent.

ii143

How long treatment should be continued? Time to treatment discontinuation in clinical trials is by definition shorter than time to treatment failure, which in turn is shorter than time to progression. Since in most trials in advanced colorectal cancer time to progression is  7 months, most patients in trials receive no more than 6 months of treatment. In addition since the patients in trials are in general those in better clinical conditions, it is likely that outside the clinical trial setting the avarage duration of chemotherapy is  3 months. This is the reason why two important British trials have been conducted and recently reported in first- [16] and second-line [17] treatment, investigating the best strategy between continued treatment until disease progression or discontinuation of treatment after 3 months and re-treatment upon progression. The message from those studies is that, regardless of the setting (first- or second-line), treating patients until progression is no better than giving chemotherapy for a fixed 3-month period and resuming treatment when needed. Of course, this strategy applies only when potential cure is not the goal of treatment.

Acknowledgements The authors acknowledge the support of CNR and AIRC.

References 1. Giacchetti S, Perpoint B, Zidani R et al. Phase III multicenter randomized trial of oxaliplatin added to chronomodulated fluorouracil-leucovorin as first-line treatment of metastatic colorectal cancer. J Clin Oncol 2000; 18: 136 –147.

2. 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. 3. Falcone G, Masi G, Allegrini G et al. Biweekly chemotherapy with oxaliplatin, irinotecan, infusional fluorouracil, and leucovorin: a pilot study in patients with metastatic colorectal cancer. J Clin Oncol 2002; 20: 4006–4014. 4. Roth A, Seium Y, Ruhstaller T et al. Oxaliplatin (Oxa) combined with irinotecan (CPT11) and 5FU/LV (OCFL) in metastatic colorectal cancer (MCRC): a phase I/II study. Proc Am Soc Clin Oncol 2002; 21: 570. 5. 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. 6. Scheithauer W, Rosen H, Kornek G et al. Randomised comparison of combination chemotherapy plus supportive care with supportive care alone in patients with metastatic colorectal cancer. BMJ 1993; 306: 752–755. 7. Cunningham D, Pyrhonen S, James RD et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998; 352: 1413–1418. 8. Douillard JY, Cunningham D, Roth AD et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000; 355: 1041–1047. 9. 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. 10. Grothey A, Deschler B, Kroening H et al. Phase III study of bolus 5fluorouracil (5-FU)/folinic acid (FA) (Mayo) vs weekly high-dose 24h 5-FU infusional/FA + oxaliplatin (OXA) (FUFOX) in advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 2002; 21: 129 Abstr 512. 11. Grothey A, Sargent D, Goldberg RM et al. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil–leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol 2004; 22: 1209–1214. 12. Cunningham D, Humblet Y, Siena S et al. Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 2004; 351: 337 –345. 13. Hurwitz H, Fehrenbacher L, Cartwright T et al. Bevacizumab prolongs survival in first-line colorectal patients: results of a phase III trial of bevacizumab in combination with bolus IFL as first line therapy in subjects with metastatic colorectal cancer. Proc Am Soc Clin Oncol 2003; 22: 253 Abstr 1013. 14. Colucci G, Maiello E, Gebbia V et al. Preliminary results of a randomized multicenter trial of the Gruppo Oncologico Italia Meridionale (GOIM) comparing FOLFIRI vs FOLFOX in advanced colorectal cancer. Proc Am Soc Clin Oncol 2003; 22: 255 Abstr 1021. 15. Grothey A, Jordan K, Kellner O et al. Randomized phase II trial of capecitabine plus irinotecan (Capiri) vs capecitabine plus oxaliplatin (CapOx) as first-line therapy of advanced colorectal cancer (ACRC). Proc Am Soc Clin Oncol 2003; 22: 255 Abstr 1022. 16. Maughan TS, James RD, Kerr DJ et al. Comparison of intermittent and continuous palliative chemotherapy for advanced colorectal cancer: a multicentre randomised trial. Lancet 2003; 361: 457 –464. 17. Lal R, Dickson J, Cunningham D et al. A randomised trial comparing defined-duration with continuous irinitecan until disease progression in fluoropirimidine and thymidylate synthase inhibitorresistant advanced colorectal cancer. J Clin Oncol 2004; 22: 3023–3031.

Downloaded from http://annonc.oxfordjournals.org/ at Kungl Tekniska Hogskolan Biblioteket on July 10, 2015

The issue therefore may become toxicity, but the two regimens appear to have equivalent toxicity rates, although the spectrum of toxicity is different. Neurotoxicity is common with FOLFOX, whereas alopecia and diarrhea are more frequent with FOLFIRI. The neurotoxicity, which can be severe, is a cumulative late event, whereas the toxicity of FOLFIRI can be very early (first cycle). This may be a reason to prefer FOLFOX first (higher chance of having no toxicity problems at the start of the treatment period). However, the incidence of grade 3–4 toxic events with FOLFIRI is lower. Again, since this is due to the higher incidence of granulocytopenia in FOLFOX-treated patients, the actual impact of this toxic events on the patient’s quality of life is almost irrelevant. As a general conclusion, the personal experience with one or the other regimen remains the strongest determinant of choice. Since FOLFOX has recently been approved for adjuvant use in stage III colon cancer, medical oncologists will soon be challenged by patients recurring after FOLFOX. Common sense suggests favoring FOLFIRI in this particular condition, although it may be argued that if the recurrence is late the disease could still be sensitive to FOLFOX.