Ignatov, V.

Ivanov, G.

Ivanov, K.

Kolev, N.

Tonev, A.

Zlatarov, A.

English

Varna Medical University Press: Journals

RESECTABILITY OF INITIALLY UNRESECTABLE LIVERMETASTASES FROM COLORECTAL CANCER SHOULD NOT BETHE PRIMARY END POINT OF CLINICAL TRIALSV. Ignatov, N. Kolev, A. Zlatarov, G. Ivanov, A. Tonev, K. IvanovI-st Clinic of Surgery, University Hospital “St. Marina”Sys temic che mo ther apy of ad vanced colorectal can cer(CRC) adds around 9% 5-year sur vival rate with mod ernche mo ther apy. 1 Such an out come is sub stan tially betterwhen sur gi cal re sec tion of liver metastases is per formed onvery well se lected pa tients. The shrink age of tu mor withproper med i cal treat ment has im proved over time, moreand more re sec tions of liver metastases that were ini tiallycon sid ered unresectable are be ing per formed by spe cial -ized sur geons. The par a digm “better re sponses -> more re sec tions ->better ef fi cacy”2 is en cour ag ing, to the point thatresectability is con sid ered a po ten tial pri mary end point ofclin i cal tri als. We could see why such an end point is so at -trac tive to pa tients and phy si cians, but at the same time somis lead ing and bi ased that it should not be used as the pri -mary end point in clin i cal tri als. What drives our ther a peu -tic choices in clin i cal prac tice is not the me dian ef fect, orthe haz ard ra tio for sur vival, or the pro gres sion-freesurvival (PFS) ad van tage with a cer tain treat ment over an -other, rather it is an in di vid ual pa tient could be “an out lier,”ie, he or she might de rive a sig nif i cant ben e fit from ther apy. In this re gard, the abil ity of newer com bi na tions to en ablesur gi cal re sec tion of met a static le sions that were not ini -tially resectable is very at trac tive.3 Fol low ing rad i cal sur -gery, even those pa tients with ini tially unresectable dis easewill have a 30% chance of long-term sur vival,4 which issim i lar to that of pa tients who un dergo pri mary re sec tion.5Of fer ing pa tients with met a static colorectal can cer a chance of cure rep re sents the main driv ing force of our clin i calprac tice. How ever, given the high prob a bil ity that dis easewill re cur within a few months of ma jor liver sur gery, isresectability by it self a rel e vant enough out come to pur sue?“Resectability” in di cates a state of po ten tial re sec tion, itdoes not im ply that the pa tient has had the tu mor com -pletely re moved, is alive, well, and free of dis ease. Thus, itis im por tant to rec og nize that resectability is just the firststage of a se quen tial pro cess con sist ing of the fol low ingsuc ces sive steps: 381Scripta Scientifica Medica, 2011; vol. 43 (5) Copyright © Med i cal Uni ver sity, VarnaTable 1 illustrates the lack of compelling data available from clinical trials on this issue; the reported outcomes, infact, refer only to patients who successfully underwent resection with curative intent, not to all patients consideredeligible for radical surgery after “conversion chemotherapy.” 1. the patient undergoes surgery, 2. the surgeon attempts to resect the tumor (up to 20% ofthese procedures result in an aborted open-closeoperation due to the presence of peritoneal metastases), 3. the tumor is resected by the surgeon, 4. all tumor deposits are resected with adequate margins, 5. the pathologist confirms that an R0 resection wasperformed, 6. the patient fully recovers from the procedure.In gen eral, 10–20 of 100 pa tients with ini tially unresectable dis ease will be con sid ered el i gi ble for liver sur gery fol low -ing neoadjuvant treat ment. Only half of these pa tients,how ever, will be alive, well, and dis ease free af ter sur gery.And when all is said and done, how long might the dis -ease-free state be ex pected to last af ter sur gery? For ex am -ple, in a trial by Alberts et al spe cif i cally de signed to as sessthe ac tiv ity of FOLFOX4 as first-line ther apy for pa tientswith liver-lim ited metastases from colorectal can cer, tu morshrink age oc curred in 60% of the ini tial 42 pa tients, and re -sec tion was at tempted in 40%. Among those pa tients whoun der went sur gery, 33% had an R0 re sec tion, but dis easere curred in 40% of these pa tients within 12 months. Thiscasts doubts on the real value of such an ag gres sive treat -ment plan in clud ing com bi na tion che mo ther apy and ma jorsur gery. Thus, resectability is gain ing more and more pop u lar ityamong in ves ti ga tors, based on very shaky sci en tificground. Let’s con sider the in trin sic pe cu liar i ties of a studythat would com pare two treat ments, pur su ing resectabilityof ini tially unresectable liver metastases as its pri mary endpoint, and let’s con sider the chal lenges that such a studywould pres ent. There are two types of er rors in clin i cal tri -als—ran dom er ror and bias. Ran dom er ror is due to the nat -u ral vari abil ity of bi o log i cal and clin i cal phe nom ena; bias is due to a spe cific se lec tion that clin i cal in ves ti ga tors maymake. The pur pose of a clin i cal pro to col is to min i mizethese two types of er rors. Ac cru ing a large num ber of pa -tients and ran dom iz ing them are the most ef fec tive meansof min i miz ing vari abil ity (ran dom er ror), whereas hav ingstrict el i gi bil ity and ex clu sion cri te ria and an a lyz ing data on an in ten tion-to-treat ba sis are key to min i miz ing bias. In the case of a trial eval u at ing neoadjuvant ther apy of ini tiallyunresectable liver metastases, these ba sic con cepts con sti -tute pro hib i tive chal lenges.Ac cru ing a large num ber of pa tients el i gi ble for such astudy is very dif fi cult due to the in trin sic com plex ity of anymultimodality treat ment trial. Yet, this prob lem can beover come.The key el i gi bil ity cri te rion for a trial like this is that the dis -ease is unresectable at the time of study en try, but may be -come resectable if the le sions shrink suf fi ciently af ter treat -ment ment. There is noth ing more vari able than the eval u a -tion of resectability.7 Ac cess ing dif fi cult an a tomic lo ca tions may be pro hib i tive for a gen eral sur geon but still pos si blefor an ex pe ri enced liver sur geon. The def i ni tion of“resectable” is chang ing over time.8 Ini tially fo cus ing on“what co mes out,” it has pro gres sively shifted to ward“what’s left in,” with “resectable dis ease” con sid ered thatwhich can be re moved while pre serv ing ad e quate hepaticre serve. Thus, what con sti tutes “resectable” still re mainshighly sub jec tive.The temp ta tion not to per form an in ten tion-to-treat anal y sis is very strong in these com pli cated con di tions, as best ex -em pli fied by the EORTC (Eu ro pean Or ga ni za tion for Re -search and Treat ment of Can cer) trial9 that has gen er ated so much de bate re cently.10 We can spec u late that the real hall -mark of ben e fit is nei ther re sponse nor resectability nor theR0 re sec tion rate, but rather how long the pa tient shows noev i dence of dis ease af ter an R0 re sec tion; to wit, re cur -rence-free sur vival (RFS). As a ref er ence point, a 6-monthRFS seems too short an in ter val when we en gage in costlyand risky pro grams of pre op er a tive treat ment fol lowed bysur gery. It is our feel ing that the RFS should be at least 12months in a sig nif i cant pro por tion of pa tients. Any thing be -low 25%–30% of pa tients liv ing re lapse-free for a min i -mum of 12 months would have lit tle clin i cal rel e vance andwould be too costly. This con cept may ap ply both to clin i -cal prac tice (where ex cep tions can ob vi ously be made) andtrial de sign. Our group is con duct ing a trial where clearlyunresectable ad vanced colorectal can cer pa tients are treated with a com bi na tion of three biologics and a che mo ther apydou blet, with the “am bi tious” pri mary end point of12-month RFS in at least 30% of en rolled pa tients. We cer -tainly have set a very high bar for suc cess. But in light of the costs and mor bid i ties of this ap proach we need in no va tiveend points that re al is ti cally merge clin i cal rel e vance withtox ic ity and cost. The cho sen end point should min i mizethe bias con nected with de fin ing resectability and lead to amore care ful se lec tion of pa tients for max i mum ben e fit.REFERENCES1. Sanoff HK, Sargent DJ, Camp bell ME, et al: Five-yeardata and prog nos tic fac tor anal y sis of oxaliplatin andirinotecan com bi na tions for ad vanced colorectal can cer:N9741. J Clin Oncol 26:5721–5727, 2008 2. Folprecht G, Grothey A, Alberts S, et al: Neoadjuvant treat ment of unresectable colorectal liver metastases:cor re la tion be tween tu mour re sponse and re sec tionrates. Ann Oncol 16:1311–1319, 20053. Nordlinger B, Van Cutsem E, Gruenberger T, et al:Com bi na tion of sur gery and che mo ther apy and therole of tar geted agents in the treat ment of pa tientswith colorectal liver metastases: rec om men da tionsfrom an ex pert panel. Ann Oncol Jan 19, 2009 [Epubahead of print]4. Poston GJ: Sur gi cal strat e gies for colorectal livermetastases. J Clin Oncol13:125–136, 20045. Adam R, Delvart V, Pascal G, et al: Res cue sur geryfor unresectable colorectal liver metastasesdownstaged by che mo ther apy: a model to pre dictlongterm sur vival. Ann Surg 240:644–657, 20046. Alberts SR, Horvath WL, Sternfeld WC, et al:Oxaliplatin, fluorouracil, and leucovorin for pa tientswith unresectable liver-only metastases fromcolorectal can cer: a North Cen tral Can cer Treat mentGroup phase II study. J Clin Oncol 23:9243–9249,20053827. Poston GJ, Figueras J, Giuliante F, et al: Ur gent needfor a new stag ing sys tem in ad vanced colorectal can -cer. J Clin Oncol 26:4828–4833, 2008 8. Choti MA: New par a digm in the treat ment of hepaticcolorectal metastases: a sur geon’s per spec tive.Commun Oncol 5:9–14, 2008 9. Nordlinger B, Sorbye H, Glimelius B, et al:Perioperative che mo ther apy with FOLFOX4 and sur -gery ver sus sur gery alone for resectable livermetastases from colorectal can cer (EORTC In ter -group trial 40983): a ran dom ized con trolled trial. Lan -cet 371:1007–1016, 200810. Petrelli NJ: Perioperative or adjuvant ther apy forresectable colorectal hepatic metastases. J Clin Oncol26:4862–4863, 2008383Scripta Scientifica Medica, 2011; vol. 43 (5) Copyright © Med i cal Uni ver sity, Varna

Resectability of initially unrespectable liver metastases from colorectal cancer should not be the primary end point of clinical trials

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Resectability of initially unrespectable liver metastases from colorectal cancer should not be the primary end point of clinical trials

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