Systemic Treatment in Recurrent and Metastatic Unresectable Rectal Cancer

IntroductionMost patients with recurrent and metastatic rectal cancer cannot be cured.Selected patients with local recurrence or liver and/or lung-limited metastatic disease are sometimes curable with radiation therapy (RT) or surgery.However, for the majority of patients, treatment is palliative and systemic therapy remains the mainstay treatment.Over the last ten years, survival of patients with unresectable metastatic or recurrent rectal cancer has considerably improved.The median survival is about two years due to availability of new chemotherapy regimens and targeted therapies.For decades, 5-fluorouracil (5-FU) was the only active and available agent.Since the year 2000, irinotecan and oxaliplatin were approved.Access to all these three active agents strongly correlates with improved survival.More progress was achieved recently with the development of targeted therapies.Bevacizumab is a monoclonal antibody targeting the vascular endothelial growth factor (VEGF).Cetuximab and panitumumab are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR).Combinations of these different drugs are now commonly used.In non-curable patients, goals are improvement of survival and quality of life.The purpose of this chapter is to review data from clinical trials evaluating systemic therapy in unresectable recurrent or metastatic rectal cancer.Commonly used chemotherapy regimens and biologic agents will be described as well as their side effects.General principles of treatment and specific treatment recommendations will also be discussed. Chemotherapy FluoropyrimidinesFluoropyrimidines have been used for the treatment of metastatic colorectal cancer (mCRC) for many years.5-FU is a fluoropyrimidine that causes inhibition of thymidylate synthase and leads to impaired DNA synthesis.Adding folinic acid (leucovorin) intensifies the cytotoxic power of 5-FU stabilizing its bind to the enzyme.Different schedules of administration have shown clinical activity in different trials.Short-term infusional schedules have gained acceptance.A French study, compared a regimen of bolus 5-FU/LV day 1 to 5 every four weeks to bimonthly 5-FU/LV bolus over two hours followed by a 22 hours 5-FU infusion for two consecutive days.The infusional regimen showed better response rate (RR) and progression free survival (PFS).It was also associated with less www.intechopen.comRectal Cancer -A Multidisciplinary Approach to Management 338 hematological and gastrointestinal (GI) toxicity.This "de Gramont regimen" is now a standard (de Gramont et al. 1997).The widely used oral form of fluoropyrimidine is capecitabine.It is a prodrug that needs to be metabolized to 5-FU by multiple sequential enzymatic reactions.In 2001, a phase 3 randomized trial showed that use of oral capecitabine in first-line mCRC patients was more active than 5-FU/LV in the induction of objective tumor responses.Time to disease progression and survival were at least equivalent for capecitabine compared with the 5-FU/LV arm.Capecitabine also demonstrated clinically meaningful benefits over bolus 5-FU/LV in terms of tolerability although hand-foot syndrome was more common (Hoff et al. 2001).Similar results were observed in another identically designed randomized study (Van Cutsem et al. 2001).Dihydropyrimidine dehydrogenase (DPD) is an important enzyme in the metabolism of fluoropyrimidines.It is the rate limiting enzyme in 5-FU catabolism.Patients who are deficient in DPD activity may have severe, even fatal toxicities such as severe diarrhea, mucositis and pancytopenia.For these patients, an alternative to 5-FU is raltitrexed which is a pure thymidylate synthase inhibitor.In a 2002 randomized study, raltitrexed showed similar RR and overall survival (OS) to the de Gramont regimen and was easier to administer, but resulted in greater toxicity (GI and hematological) and inferior quality of life (Maughan et al. 2002).Fluoropyrimidines alone had been the standard first-line treatment of mCRC until the development of combination regimens with irinotecan or oxaliplatin.Fluoropyrimidine monotherapy remains a valid option for patients with contraindications to combined therapies.The infusional regimen (de Gramont) is the preferred fluoropyrimidine monotherapy.Capecitabine is a safe oral alternative to 5-FU. Irinotecan (table 1)Irinotecan is a topoisomerase I inhibitor and has demonstrated efficacy in mCRC as a single agent or in association with a fluoropyrimidine.Irinotecan in monotherapy showed superiority to best supportive care alone after 5-FU failure.A randomized trial showed that the OS was significantly better in the irinotecan group (p=0.0001), with 36.2% 1-year survival in the irinotecan group versus 13.8% in the supportive-care group.Quality of life was also better with less tumor related symptoms.In this trial, irinotecan was given every three weeks (Cunningham et al. 1998).A randomized trial showed an advantage in RR, time to progression (TTP) and median survival for combined treatment with irinotecan/5-FU/LV over 5-FU/LV alone in first-line mCRC.An infusional regimen was used (the Douillard regimen).Treatment was given weekly or every two weeks.There were more toxicities in the irinotecan arm (diarrhea and neutropenia) but they were manageable (Douillard et al. 2000).Results of the BICC-C study suggest that the infusional regimen (FOLFIRI) is associated with better PFS and less toxicities compared to the bolus regimen (IFL).The use of oral capecitabine associated with irinotecan (CapeIRI) was also assessed in the BICC-C study.It was compared to FOLFIRI and IFL.It was associated with more toxicities and less efficacy (Fuchs et al. 2007).Late diarrhea and neutropenia are the main dose-limiting toxicities from irinotecan.UGT1A1 polymorphism predicts irinotecan toxicity.Irinotecan can also cause early-onset symptoms of cholinergic excess including diarrhea, abdominal cramping, lacrimation, rhinitis and salivation.www.intechopen.com

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