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  In this article
 »  Abstract
 » Introduction
 »  Search Strategy ...
 »  Pharmacodynamics...
 »  Pharmacokinetics...
 »  Efficacy of Irin...
 »  Efficacy of Ifl ...
 »  Efficacy of Folf...
 »  Efficacy of Xeli...
 »  Insights Into Ir...
 »  Optimal Patient ...
 »  Tumor-Related Fa...
 » Conclusion
 »  References
 »  Article Tables

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  Table of Contents  
REVIEW ARTICLE
Year : 2021  |  Volume : 58  |  Issue : 1  |  Page : 5-16
 

Optimum patient selection for irinotecan-containing regimens in metastatic colorectal cancer: Literature review and lessons from clinical practice


1 Consultant Medical Oncologist, Panchsheel Plaza, Off Hughes Road, Gamdevi, Mumbai, Maharashtra, India
2 Medical Affairs, Pfizer Limited, The Capital 1802/1901, Bandra Kurla Complex, Bandra(E), Mumbai, Maharashtra, India

Date of Submission03-Jun-2019
Date of Decision19-Jun-2020
Date of Acceptance01-Aug-2020
Date of Web Publication24-Nov-2020

Correspondence Address:
Akshata Mane
Medical Affairs, Pfizer Limited, The Capital 1802/1901, Bandra Kurla Complex, Bandra(E), Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_507_19

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 » Abstract 


Metastatic colorectal cancer (mCRC) accounts for over 20% of CRC cases and is associated with a poor prognosis. Irinotecan is an important first- and second-line chemotherapy option for mCRC. In this review, we summarize the clinical efficacy and safety of irinotecan-based regimens for the treatment of mCRC and discuss various tumor- and patient-related factors that affect the clinical response, survival, and toxicity associated with these regimens. Uridine diphosphate glucuronosyltransferase (UGT) gene polymorphisms such as UGT1A1*28/*6, age, performance status, serum lactate dehydrogenase levels, and bilirubin levels could be important considerations for predicting outcomes and tolerability with irinotecan-based regimens. The role of tumor location; chemotherapy backbone; and emerging evidence on the presence of microsatellite instability-high status, consensus molecular subtype 4 tumors, and signet-ring morphology in predicting response to irinotecan-based therapy have also been highlighted. Careful consideration of these factors will help guide clinicians in optimizing the selection of mCRC patients for irinotecan-based treatment.


Keywords: Irinotecan, Irinotecan-based regimens, metastatic colorectal cancer


How to cite this article:
Basade M, Mane A. Optimum patient selection for irinotecan-containing regimens in metastatic colorectal cancer: Literature review and lessons from clinical practice. Indian J Cancer 2021;58:5-16

How to cite this URL:
Basade M, Mane A. Optimum patient selection for irinotecan-containing regimens in metastatic colorectal cancer: Literature review and lessons from clinical practice. Indian J Cancer [serial online] 2021 [cited 2021 Apr 22];58:5-16. Available from: https://www.indianjcancer.com/text.asp?2021/58/1/5/301404





 » Introduction Top


Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second most common cause of cancer-related deaths worldwide.[1] More than 20% of CRC cases are diagnosed with advanced-stage or metastatic CRC (mCRC), which is associated with a poor prognosis. While the 5-year relative survival rate of early/localized CRC is 90%, the corresponding rate for mCRC is only 14%.[2] Research efforts to overcome the increasing burden of mCRC has resulted in a noteworthy evolution of chemotherapy and targeted therapeutic options for the management of mCRC over the last decade, with a considerable improvement in survival rates.[3]

Irinotecan is the backbone chemotherapy in several systemic combination regimens used for both the first- and second-line treatment of mCRC.[4] The survival advantage of irinotecan-based regimens in patients with mCRC are well documented in several clinical studies; a few of the latest studies demonstrate an overall survival (OS) of ≥30 months.[5],[6]

Despite the well-established clinical efficacy of various irinotecan regimens for the treatment of mCRC, irinotecan-induced toxicity can be a potential challenge. Variable incidence of grade 3 or 4 diarrhea and neutropenia has been noted with various irinotecan regimens.[6],[7],[8],[9],[10],[11],[12] Furthermore, irinotecan-induced toxicity and response to irinotecan regimens have been found to depend on several tumor- and patient-related factors.[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] Therefore, it is necessary to identify the mCRC patient population that can experience optimal survival benefits and limited toxicity with irinotecan-containing regimens.

The current review aims to discuss the efficacy and safety of irinotecan regimens and elaborate patient profiles for optimizing outcomes with irinotecan-based regimens in mCRC. While current international guidelines provide an overview of all the treatments for mCRC and their usage, including irinotecan-based regimens, this comprehensive review is an exhaustive compilation of all relevant evidence on irinotecan-based regimens; it will serve as a quick reference guide for clinicians for optimizing patient selection for irinotecan therapy in mCRC.


 » Search Strategy and Selection Criteria Top


We searched PubMed for articles published in English with the terms “metastatic colorectal cancer” AND “irinotecan” AND “UGT1A1 gene polymorphisms” OR “tumor factors” OR “KRAS status” OR “BRAF status” OR “tumor location” OR “microsatellite instability” OR “consensus molecular subtype” OR “signet-ring morphology” OR “patient-related factors” OR “age” OR “performance status” OR “lactate dehydrogenase levels” OR “bilirubin levels” OR “diarrhea” OR “neutropenia” OR “guidelines.” Articles meeting these criteria and available on PubMed before October 30, 2018 were included and reviewed for developing the current manuscript. While summarizing the efficacy of irinotecan, article selection was restricted to phase-III randomized clinical trials and recent mCRC guidelines. Additionally, retrospective studies and chart reviews were also considered for elaborating tumor- and patient-related factors influencing outcomes with irinotecan-based therapy in mCRC.


 » Pharmacodynamics of Irinotecan Top


Irinotecan is an antineoplastic chemotherapy drug classified as plant alkaloid and topoisomerase I inhibitor. It is a camptothecin derivative, specifically binds with topoisomerase I and relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent relegation of these single-strand breaks. Mammalian cells cannot efficiently repair these double-strand breaks. The exact role of SN-38 in the activity of irinotecan in humans is not known. Irinotecan is cell cycle phase specific (S-phase).[23]


 » Pharmacokinetics of Irinotecan Top


The half-life of irinotecan is about 6–12 hours, the terminal elimination half-life of the active metabolite, SN-38, is 10–20 hours. Irinotecan exhibits moderate plasma protein binding (30–68% bound). SN-38 is highly bound to human plasma protein, especially albumin (approximately 95% bound). Irinotecan is subject to extensive metabolic conversion by various enzymes primarily in the liver. The metabolic conversion of irinotecan to the active metabolite SN-38 is facilitated by carboxylesterase enzymes. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. The disposition of irinotecan has not been fully studied in humans. The clearance is primarily biliary (66%) and independent of dose estimated at 12–21 L/h/m2. The urinary excretion of irinotecan is 11–20%; SN-38, <1%; and SN-38 glucuronide, 3%.[23]


 » Efficacy of Irinotecan Regimens in Extending Survival in Patients With Mcrc Top


An overview of the various irinotecan regimens (FOLFIRI, FOLFOXIRI, and XELIRI) recommended by the latest pan-Asian consensus guidelines for Asian patients, and the IFL (irinotecan, leucovorin, and fluorouracil regimens) tested in clinical studies—along with their survival outcomes in mCRC clinical trials—is provided in [Table 1].
Table 1: Overview of irinotecan regimens recommended in mCRC


Click here to view



 » Efficacy of Ifl and Folfiri Regimens With or Without Targeted Therapy Top


In two separate phase-III studies, the IFL and FOLFIRI regimens were associated with significantly better survival rates than the conventional 5-FU (fluorouracil) plus leucovorin regimen.[7],[8] The addition of targeted therapy to IFL/FOLFIRI regimens further improved progression-free survival (PFS) and OS compared to treatment with IFL/FOLFIRI alone.[10],[24],[25],[28] The combination of FOLFIRI with targeted therapy has also been compared with FOLFOX (5-FU, leucovorin, and oxaliplatin regimen) plus targeted therapy in patients with mCRC. No significant differences were noted in survival rates between these two regimens. However, the PFS with FOLFIRI plus targeted therapy achieved significance for noninferiority vs. mFOLFOX6 plus targeted therapy [Table 1].[6],[30]

The survival rate with FOLFIRI plus targeted therapy is influenced by several factors, including the Kristen rat sarcoma (KRAS) status, the targeted agent used, and the location of the tumor.[9],[14],[26],[27],[31],[32],[33],[34] Combining FOLFIRI with anti-EGFR targeted therapy has been found to yield better survival rates than FOLFIRI plus bevacizumab in patients with wild-type KRAS mCRC.[9],[31],[32] This patient cohort has also been noted to have better survival benefits with FOLFIRI plus panitumumab regimen.[26],[27] Furthermore, the benefits of FOLFIRI plus anti-EGFR therapy in KRAS wild-type mCRC are more pronounced in patients with left-sided tumors than in those with right-sided tumors.[14],[33],[34]


 » Efficacy of Folfoxiri Regimen With or Without Targeted Therapy Top


Clinical studies have also compared the FOLFIRI with the FOLFOXIRI regimen in mCRC. While the Hellenic Oncology Research Group (HORG) study was not associated with a significant improvement in time to treatment progression and OS with FOLFOXIRI vs. FOLFIRI,[20] the Gruppo Oncologico Nord Ovest (GONO) study revealed a significant improvement in both PFS and OS with the triplet combination vs. FOLFIRI.[11] The difference in the survival rates in these two studies may be due to the patient selection criteria: The GONO study included more patients with performance status (PS) 0–1 and younger patients compared to the HORG study.[11],[20]

The addition of targeted therapy to FOLFOXIRI demonstrated a clear survival benefit vs. FOLFIRI plus targeted therapy in the Triplet plus Bevacizumab study: Both PFS and OS were found to be significantly better with FOLFOXIRI plus targeted therapy.[5]


 » Efficacy of Xeliri Regimen With or Without Targeted Therapy Top


Several clinical studies, observational registries, and meta-analyses have compared the efficacy and safety of XELIRI regimen vs. FOLFIRI regimens with or without bevacizumab for the first-line treatment of mCRC.[35],[36],[37],[38] In all these studies, the efficacy of the XELIRI regimen was found to be comparable to the FOLFIRI regimen, in terms of objective response rate,[36],[38] median PFS, and median OS.[35],[36],[37],[38] Furthermore, the toxicity with the two regimens was comparable and manageable in all the cited studies,[35],[36],[37],[38] with the XELIRI regimen being associated with a higher incidence of diarrhea compared to the FOLFIRI regimen.[35],[36],[38]

The Asian XELIRI ProjecT (AXEPT), a phase 3 trial conducted among Asian patients (Japan, China, and South Korea), compared the efficacy and safety of the XELIRI regimen (n = 326) vs. the FOLFIRI regimen (n = 324)—both regimens with or without bevacizumab—for the second-line treatment of mCRC. After a median follow-up of 15.8 months, the median OS in the XELIRI and FOLFIRI groups was noted to be 16.8 and 15.4 months, respectively (Pnon-inferiority<0.0001). While the incidence of grades 3–4 neutropenia was higher in the FOLFIRI group, the incidence of grades 3–4 diarrhea was higher in the XELIRI group.[29]


 » Insights Into Irinotecan-Induced Toxicity Top


The active metabolite of irinotecan, SN-38, undergoes metabolism through the glucuronic acid conjugation pathway to form a water-soluble glucuronide.[16],[39] This glucuronidation of SN-38 is carried out by the uridine diphosphate glucuronosyltransferase (UGT) enzyme, which is encoded by the gene UGT1A1. The wild-type allele associated with normal enzyme activity is the UGT1A1*1.[16] Interindividual and interracial differences may occur with glucuronidation because of genetic polymorphisms in UGT1A1,[16],[39],[40] resulting in a reduction in UGT enzyme activity and leading to the accumulation of SN-38 and subsequent irinotecan-induced toxicity—including diarrhea and neutropenia.[16],[30] The UGT1A1*28, *6, and combined *6/*28 genetic polymorphisms have been associated with an increased risk of irinotecan-induced toxicity in several clinical studies.[41],[42],[43],[44],[45],[46],[47],[48],[49],[50] The frequency of UGT1A1*6 polymorphisms is higher in Asians than in Caucasians.[4],[51],[52]

As per the recent European Society for Medical Oncology (ESMO) and pan-Asian guidelines, UGT1A1 phenotyping is recommended in patients with a suspicion of UGT1A1 deficiency or in patients in whom the administration of an irinotecan dose of >180 mg/m2 is planned. This could be a useful indicator for recommending the UGT1A1 polymorphisms test [Table 2].[4],[17]
Table 2: Guideline recommendations on testing for UGT1A1 polymorphisms in mCRC patients


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 » Optimal Patient Selection for Irinotecan-Based Regimens in Mcrc Top


Irinotecan-induced adverse effects and response to irinotecan regimens can be influenced by several tumor- and patient-related factors. Therefore, it is important to understand these factors to select the patient population that can derive maximal survival benefits with limited toxicity.


 » Tumor-Related Factors Top


Genetic abnormalities in tumor (KRAS/RAS/BRAF status) and location of tumor

KRAS/BRAF status

FOLFIRI plus anti-EGFR therapy is associated with significantly better survival and response rates in mCRC patients with wild-type KRAS compared to mCRC patients with KRAS mutations.[13] In a systematic review and metaanalysis, the chemotherapy backbone used in combination with cetuximab for treating patients with wild-type KRAS mCRC had a significant impact on survival outcomes. Irinotecan-based chemotherapy backbone was associated with a significantly better PFS and OS compared to an oxaliplatin-based chemotherapy backbone.[54] This significant PFS benefit was also noted when studies included combination therapy with cetuximab or panitumumab in wild-type KRAS patients.[55],[56]

The pan-Asian consensus guidelines recommend FOLFOXIRI plus bevacizumab as the first-line choice in patients with wild-type RAS and right-sided tumors and as the second-line choice in patients with mutated RAS mCRC.[4] According to these guidelines, FOLFOXIRI alone may be one of the preferred first-line choices for disease control in mCRC patients with BRAF-mutated disease and right- or left-sided tumors.[4]

Location of tumor

The location of the primary tumor also has prognostic value among patients with wild-type KRAS mCRC. Treatment with FOLFIRI plus anti-EGFR therapy has a markedly better prognosis in wild-type KRAS mCRC patients with left-sided tumors than in those with right-sided tumors.[14] Therefore, these factors must be considered when choosing a chemotherapy regimen for mCRC.

Biological characteristics of tumor

Microsatellite instability-high status

Microsatellite instability (MSI) occurs due to a dysfunction of the mismatch repair (MMR) system. Microsatellites or short tandem repeats are repetitive DNA sequences with a unit length ranging from one to six bases. Their repetitive nature makes them sensitive to mismatch errors. The MMR system helps correct the mismatches of microsatellites occurring during replication. Dysfunction of the MMR system results in the accumulation of mutations of repeat length alterations (MSI), which characterizes a hypermutable state of cells.[57],[58],[59]

Germline and sporadic mutations of the MMR genes account for about 5 and 15%, respectively, of all CRC cases.[15] Literature has mixed views on the prognostic value of the MSI phenotype in predicting response rate to irinotecan regimens in mCRC patients. A few experimental and retrospective studies have revealed higher sensitivity of the MSI CRC phenotype to irinotecan therapy.[15],[58],[60]

A study by Jacob et al. on the role of MMR system in the cytotoxicity of the topoisomerase inhibitors, camptothecin, and etoposide to human CRC cells has shown that CRC cell lines defective in DNA MMR exhibit increased sensitivity to both drugs.[61]

In a retrospective study of 72 patients with mCRC, the relationship between CRC tumor responsiveness to irinotecan and MSI was found to be statistically significant (P = 0.009). All patients received irinotecan as second- or third-line treatment after disease progression on 5-FU-based chemotherapy. The tumor samples were assessed for MSI status. While four out of seven tumors that displayed an MSI-H phenotype responded to irinotecan, only seven of the 65 MSI-L/microsatellite stable tumors did respond to irinotecan treatment (P = 0.009).[15] The mechanisms underlying the response of MSI-H tumors to irinotecan chemotherapy are not clear. A hypothesis is that the MSI phenotype in most tumors results from the inactivation of either MSH2 or MSH1 genes, both of which are known to participate in recombination. Defect in MMR may result in a decrease in the recombinational repair efficiency of these genes, thereby enhancing the sensitivity of tumors to irinotecan therapy, which acts by generating double-strand breaks in the DNA.[15]

However, a few other retrospective studies and a metaanalysis suggest that MSI status may not be a useful predictor of response to irinotecan-based chemotherapy in mCRC patients.[57],[62],[63] In this context, it may be noted that the ESMO guidelines have not considered MSI as a predictive marker for chemotherapy. This remains an active area in clinical and molecular research.[64]

Consensus molecular subtype of CRC

Consensus molecular subtyping (CMS) of CRC is a robust, new classification system that divides CRC into four subtypes from CMS1 to CMS4: Each subtype bearing specific biological characteristics and a related prognosis.[65] The CMS1 (MSI immune) subtype is hypermutated and displays a widespread hypermethylation status and a low prevalence of somatic copy number alterations (SCNAs). This subtype also encompasses most MSI tumors. The CMS2 (canonical) subtype displays strong upregulation of WNT and MYC downstream targets. The CMS3 (metabolic) subtype is a metabolic cancer phenotype, with fewer SCNAs, 30% hypermutated status, high prevalence of CpG Island Methylator Phenotype, and intermediate levels of gene hypermethylation. The CMS4 (mesenchymal) subtype expresses a strong stromal gene signature, with significant overexpression of proteins involved in stromal invasion, mesenchymal activation, and complement pathways. Of all the four subtypes, while CMS2 tumors are associated with the highest OS, CMS4 tumors are associated with worse OS and relapse-free survival, after adjusting for clinicopathological features, MSI status, and BRAF and KRAS mutation status.[65]

Several studies have been conducted to evaluate the association between the CMS classes and efficacy of chemotherapeutic agents, including irinotecan, for the treatment of mCRC.[66],[67] Rio et al. evaluated the association between molecular subtypes of mCRC and response to first-line therapy for mCRC and noted that the CMS4 subtype—compared to other CMS subtypes—was more prevalent in responders to irinotecan-based therapy.[66] In another recent retrospective study, comprehensive gene expression data were used to classify 193 mCRC cases into the four CMS classes, and associations between the subtypes and treatment outcomes were analyzed. The study findings revealed that first-line irinotecan-based chemotherapy was significantly superior to first-line oxaliplatin-based chemotherapy for the treatment of mCRC, in terms of PFS (Hazard ratio (HR) = 0.31, 95% confidence interval (CI) 0.13–0.64) and OS (HR = 0.45, 95% CI 0.19–0.99) in patients with CMS4 tumors. The response rate and disease control rate were also noted to be better for the irinotecan-based group when compared with the oxaliplatin-based group; however, the differences were not significant. Gene expression in CMS4 tumors revealed that the expression of the DNA topoisomerase I (TOP1) and carboxylesterase 2 (CES2) genes was significantly higher in CMS4 tumors compared to other CMS tumor subtypes.[68] In this context, it may be noted that the expression of TOP1 and CES2 genes has been associated with a better clinical response to irinotecan-based therapy in previous studies.[69],[70] Therefore, this could be one of the plausible mechanisms for better outcomes with irinotecan-based therapy in mCRC patients with CMS4 tumors.

Morphological characteristics of tumor (Signet-ring morphology)

CRC with signet-ring morphology is a rare form of CRC that is diagnosed at an advanced stage; it affects mostly men and is associated with poor outcomes.[71],[72] In a case report of a 70-year-old man with metastasis of signet-ring cell adenocarcinoma of the colon, the irinotecan-based regimen was successfully used as second-line treatment.[72] In a retrospective chart review of 142 patients with poorly differentiated and signet-ring cell appendiceal adenocarcinomas, 78 patients received chemotherapy for metastatic disease. There was a nonsignificant increase in PFS in patients who received first-line irinotecan-based chemotherapy for metastatic disease (1.0 vs. 0.5 years in patients who did not receive irinotecan-based first-line chemotherapy; P = 0.07).[19] Prospective studies may be needed in the future to further establish the clinical significance of the findings of these reports.

Patient-related factors

Age

In the HORG study, younger patients were associated with a significantly lower rate of first-line FOLFOXIRI-induced grade 3/4 diarrhea than patients older than 65 years.[20] Furthermore, to derive the potential benefits of intensive irinotecan regimens such as FOLFOXIRI with or without bevacizumab, it has been suggested that the optimal patient population should be aged <75 years with PS ≤1[12],[73] or 70–75 years with PS0.[12] Fit and motivated patients for whom cytoreduction (tumor shrinkage) is the goal also form an optimal patient group for treatment with these intensive regimens.[4]

Performance status

Performance status is an important factor for predicting both survival and the incidence of adverse effects with first- and second-line irinotecan therapy. In the HORG study, patients with a PS of 0–1 treated with a first-line FOLFOXIRI regimen were associated with a significantly lower rate of grade 3/4 diarrhea and neutropenia than patients with a PS of 2 treated with the same regimen.[20] A PS of 2 has also been found to be an important prognostic factor predicting worse survival and higher rates of grades 3–4 delayed diarrhea in patients treated with second-line irinotecan therapy.[22],[74]

Serum lactate dehydrogenase (LDH) levels

In the study by Chibaudel et al., in addition to PS, baseline serum level was found to be an important and significant prognostic factor for predicting OS in patients treated with first-line irinotecan-based chemotherapy (P < 0.001); a normal baseline serum LDH level (<1 × ULN) was associated with a better survival rate.[21] Furthermore, higher LDL levels (≥400 IU/L) have also been found to be associated with worse survival rates in patients treated with second-line irinotecan therapy.[22]

Bilirubin levels

While low total bilirubin level (≤13.0 μmol/L) and unconjugated bilirubin (≤4.1 μmol/L) at baseline were associated with a better response rate in patients treated with first-line irinotecan therapy in a study by Yu et al.,[18] a high baseline bilirubin level (≥68 [% UNL]) was found to be an important predictor of a higher rate of grades 3–4 neutropenia with second-line irinotecan regimens in an analysis by Freyer et al.[74]

A summary of the various prognostic factors influencing the outcomes and tolerability of first- and second-line irinotecan regimens is shown in [Table 3] and [Table 4].
Table 3: Prognostic factors influencing survival, response rate, and/or toxicity with first-line irinotecan-based therapy in mCRC


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Table 4: Prognostic factors influencing the outcomes and tolerability of second - line irinotecan - based therapy in mCRC


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Management of irinotecan-induced toxicity

In addition to optimal patient selection, appropriate assessment and timely management of irinotecan-induced toxicity may also help in improving treatment outcomes in patients with mCRC treated with irinotecan-based regimens.

Management of irinotecan-induced diarrhea

Irinotecan-induced diarrhea may be early (occurring during or shortly after the treatment) or late (occurring more than 24 hours after the treatment). Early diarrhea usually manifests as rhinitis, increased salivation, miosis, lacrimation, diaphoresis, flushing, and intestinal hyperperistalsis that may result in abdominal cramping. Late diarrhea may be life threatening and result in dehydration, electrolyte imbalance, or sepsis.[75]

Guidelines for the treatment of cancer treatment-induced diarrhea recommend rigorous evaluation based on (1) duration of symptoms; (2) severity of symptoms; (3) number and composition of stools; (4) presence of nocturnal diarrhea; (5) patient's hydration status; and (6) presence of additional risk factors such as fever, orthostatic symptoms, abdominal pain/cramping, or weakness.[76] Appropriate management is dependent on whether the diarrhea is uncomplicated (grade 1 or 2 diarrhea with no other complicating signs or symptoms) or complicated (grade 3 or 4 diarrhea; or grade 1 or 2 diarrhea with added risk factors such as fever, decreased PS, sepsis, neutropenia, frank bleeding, moderate-to-severe cramping, dehydration or ≥ grade 2 nausea/vomiting). While uncomplicated diarrhea may be managed conservatively, complicated diarrhea may require aggressive management.

Currently, the drugs approved for the treatment of irinotecan-induced uncomplicated diarrhea include first-line loperamide and second-line agents such as subcutaneous (SC) octreotide, oral budesonide, and tincture of opium.[76] Complicated cases should be managed aggressively with intravenous (IV) fluids and antibiotics such as fluoroquinolones; in cases with severe dehydration, IV or SC octreotide should be administered with dose escalations, as needed.[76] Irinotecan therapy should be delayed or stopped until patients return to pretreatment bowel function for at least 24 hours without the antidiarrhea medication. The dose of irinotecan should be decreased in case of recurrence of grades 2–4 diarrhea.[75]

Interventions for the prevention of irinotecan-induced diarrhea have also been an important area of research. A recent systematic review and metaanalysis has suggested a beneficial effect of probiotics in the prevention of chemotherapy-induced grade ≥2 diarrhea.[77]

Management of irinotecan-induced neutropenia

Irinotecan-induced neutropenia can be managed with antibiotics. Treatment with irinotecan should be stopped in case of neutropenic fever or when the absolute neutrophilic count is <1000/mm3.[75] Subsequent doses of irinotecan may be reduced after the recovery of neutrophil count to ≥1000/mm3.[75] Clinical studies have reported the use of granulocyte colony-stimulating factor for the prevention and treatment of neutropenia from the use of irinotecan-based regimens in patients with colorectal cancer.[78],[79]

Guideline recommendations on use of irinotecan-based therapies

Several CRC guidelines, including the National Comprehensive Cancer Network 2018, the ESMO 2016, the pan-Asian-adapted ESMO 2017, the Japanese Society for Cancer of the Colon and Rectum 2016, and the 2014 consensus guidelines from the Indian Council of Medical Research, recommend the use of irinotecan-based combination regimens with or without targeted therapies for the first-line, maintenance, and second-line treatment of mCRC.[4],[17],[53],[54],[80] The significance and impact of the clinical condition of the patient, goal of treatment, primary tumor location, and KRAS and BRAF mutations in optimizing the first-line and subsequent lines of treatment in patients with mCRC have been emphasized in most treatment guidelines.[4],[17],[53] The association between UGT1A1*6 and/or *28 polymorphisms and an increased risk of diarrhea and neutropenia with irinotecan-based therapy in mCRC have also been outlined in these guidelines.[4],[17],[53]


 » Conclusion Top


Irinotecan is an important backbone chemotherapy of several systemic combination regimens used for both first-line and second-line treatment of mCRC. Irinotecan-based regimens are associated with significantly better survival outcomes than the conventional (5-FU and leucovorin) chemotherapy in mCRC. The need of the hour is to carefully consider various patient- and tumor-related factors and achieve the right balance between improved survival and tolerability outcomes with irinotecan regimens in mCRC. A comprehensive description of the various factors, along with guidance on the management of irinotecan-induced toxicity, has been provided in this review, which can help clinicians in optimizing patient selection for irinotecan-based treatment in mCRC.

Financial support and sponsorship

Medical writing support was provided by Ms. Sirisha Madhu from BioQuest Solutions Pvt. Ltd and funded by Pfizer India Ltd. The authors would also like to thank Ms. Tanaya Bharatan, Pfizer, for her editorial support for this manuscript.

Conflicts of interest

Dr Akshata Mane is an employee of Pfizer. Dr. Maheboob Basade received honorarium from Pfizer Limited.



 
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