{"product_id":"ugt1a1-genotype-testing-for-irinotecan-a-patient-guide-to-the-new-uk-guideline","title":"UGT1A1 Genotype Testing for Irinotecan: A Patient Guide to the New UK Guideline","description":"\u003cp\u003eNew UK guideline recommends genetic testing before irinotecan treatment. Patients with two reduced-function UGT1A1 gene variants (poor metabolizers) should start with a 30% lower dose to avoid severe side effects like neutropenia and diarrhoea. The guideline, developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx), is based on extensive evidence and aligns with international recommendations.\u003c\/p\u003e\n\n\u003ch1\u003eUGT1A1 Genotype Testing for Irinotecan: A Patient Guide to the New UK Guideline\u003c\/h1\u003e\n\n\u003ch2\u003eTable of Contents\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003e\u003ca href=\"#ddn-key-points\"\u003eKey Points\u003c\/a\u003e\u003c\/li\u003e\n\n  \u003cli\u003e\u003ca href=\"#background\"\u003eBackground: What Is Irinotecan and Why Does Genetics Matter?\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#licensed\"\u003eLicensed Uses of Irinotecan\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#expansion\"\u003eExpanding Uses of Irinotecan\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#howworks\"\u003eHow Irinotecan Works and Causes Side Effects\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ugt1a1\"\u003eThe Role of UGT1A1 Gene Variants\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#frequencies\"\u003ePopulation Frequencies of UGT1A1 Variants\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#evidence\"\u003eEvidence on UGT1A1 and Toxicity\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#guideddosing\"\u003eEvidence for Genotype-Guided Dosing\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#efficacy\"\u003eUGT1A1 Genotyping and Treatment Effectiveness\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#implications\"\u003eClinical Implications and Recommendations\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#limitations\"\u003eLimitations of the Evidence\u003c\/a\u003e\u003c\/li\u003e\n  \u003cli\u003e\u003ca href=\"#ddn-faq\"\u003eFrequently Asked Questions\u003c\/a\u003e\u003c\/li\u003e\n\u003cli\u003e\u003ca href=\"#source\"\u003eSource Information\u003c\/a\u003e\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003c!-- ddn:keypoints:start --\u003e\n\u003ch2 id=\"ddn-key-points\"\u003eKey Points\u003c\/h2\u003e\n\u003cul\u003e\n\u003cli\u003eThe new UK guideline recommends UGT1A1 genetic testing before irinotecan treatment for patients with epithelial malignancies, where testing is available.\u003c\/li\u003e\n\u003cli\u003ePoor metabolizers (two reduced-function UGT1A1 variants) should start irinotecan at a 30% lower dose in Cycle 1 for all indications.\u003c\/li\u003e\n\u003cli\u003eAfter Cycle 1, the dose should be adjusted based on tolerability and neutrophil counts.\u003c\/li\u003e\n\u003cli\u003eUGT1A1 poor metabolizers are at higher risk of severe neutropenia and diarrhoea; genotype-guided dose reduction improves safety without compromising survival in studied populations.\u003c\/li\u003e\n\u003cli\u003eNo recommendation can be made for rare malignancies such as sarcomas due to limited evidence.\u003c\/li\u003e\n\u003c\/ul\u003e\n\u003c!-- ddn:keypoints:end --\u003e\n\n\n\u003ch2 id=\"background\"\u003eBackground: What Is Irinotecan and Why Does Genetics Matter?\u003c\/h2\u003e\n\u003cp\u003eIrinotecan is a chemotherapy drug that belongs to a class called topoisomerase I inhibitors. It works by blocking an enzyme that cancer cells need to divide. The drug comes in two forms: a non-pegylated version and a pegylated liposomal version. The non-pegylated form is approved for advanced colorectal cancer, either alone or with other drugs. But doctors also use it off-label for other gastrointestinal cancers and rare cancers like glioblastoma and sarcomas. The pegylated form is approved for metastatic pancreatic cancer in combination with other agents.\u003c\/p\u003e\n\n\u003cp\u003eIrinotecan is a prodrug. That means the body must convert it into its active form. The liver and intestine use enzymes called carboxylesterases to turn irinotecan into SN-38, which is 100 to 1000 times more toxic to cancer cells than the original drug. SN-38 is then inactivated by another enzyme called uridine diphosphate glucuronosyltransferase (UGT), mainly the UGT1A1 isoform. The inactivated product, SN-38 glucuronide (SN-38G), is excreted in bile and can be recycled back into the gut.\u003c\/p\u003e\n\n\u003cp\u003eThe problem is that the gene that makes UGT1A1, called \u003cem\u003eUGT1A1\u003c\/em\u003e, varies between people. Some people inherit versions (alleles) that reduce how well the enzyme works. These people are called poor metabolizers. They break down SN-38 more slowly, so the active drug builds up in their bodies. This raises the risk of severe side effects, especially diarrhoea and neutropenia (low white blood cell count).\u003c\/p\u003e\n\n\u003cp\u003eSide effects from irinotecan include acute cholinergic syndrome (flushing, sweating, abdominal cramps) and typical chemotherapy effects like diarrhoea, hair loss, mouth sores, and myelosuppression (bone marrow suppression). The dose-limiting toxicities are diarrhoea and neutropenia. Using the Common Terminology Criteria for Adverse Events (CTCAE), these are graded from 1 to 5, with Grade 3 or 4 being severe. With weekly single-agent irinotecan (85–125 mg\/m²), Grade 3 or 4 diarrhoea occurs in 21%–31% of patients, and Grade 3 or 4 neutropenia occurs in 19%–31%.\u003c\/p\u003e\n\n\u003cp\u003eSevere toxicity can happen even without known risk factors like liver or kidney problems. The cause is often loss-of-function genetic variants in \u003cem\u003eUGT1A1\u003c\/em\u003e that increase SN-38 exposure.\u003c\/p\u003e\n\n\u003ch2 id=\"licensed\"\u003eLicensed Uses of Irinotecan\u003c\/h2\u003e\n\u003cp\u003eIn the UK, irinotecan is licensed for intravenous infusion as a conventional non-pegylated formulation (branded as CAMPTO and generics) and as a pegylated liposomal formulation (ONIVYDE). The non-pegylated form is approved for advanced colorectal cancer:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eIn combination with 5-fluorouracil (5-FU) and folinic acid (leucovorin) for patients who have not had prior chemotherapy for advanced disease.\u003c\/li\u003e\n  \u003cli\u003eAs a single agent for patients whose previous 5-FU-based treatment has failed.\u003c\/li\u003e\n  \u003cli\u003eIn combination with cetuximab for patients with EGFR-expressing RAS wild-type metastatic colorectal cancer who have not received prior treatment for metastatic disease or after failure of irinotecan-containing cytotoxic therapy.\u003c\/li\u003e\n  \u003cli\u003eIn combination with 5-FU, folinic acid, and bevacizumab as first-line treatment for metastatic colon or rectal cancer.\u003c\/li\u003e\n  \u003cli\u003eIn combination with capecitabine, with or without bevacizumab, as first-line treatment for metastatic colorectal cancer.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eThe pegylated liposomal form (ONIVYDE) is approved for:\u003c\/p\u003e\n\u003cul\u003e\n  \u003cli\u003eIn combination with oxaliplatin, 5-FU, and leucovorin (LV) as first-line treatment of adults with metastatic pancreatic adenocarcinoma.\u003c\/li\u003e\n  \u003cli\u003eIn combination with 5-FU and LV for metastatic pancreatic adenocarcinoma that has progressed after gemcitabine-based therapy.\u003c\/li\u003e\n\u003c\/ul\u003e\n\n\u003cp\u003eImportant: the two formulations are not interchangeable.\u003c\/p\u003e\n\n\u003ch2 id=\"expansion\"\u003eExpanding Uses of Irinotecan\u003c\/h2\u003e\n\u003cp\u003eFor the rest of this article, \"irinotecan\" refers to the non-pegylated form unless stated otherwise. Irinotecan is used off-label for many other cancers, from neoadjuvant (before surgery) to advanced disease. It can be given daily or every two to four weeks, with different doses depending on the cancer. Higher doses are usually given every three to four weeks.\u003c\/p\u003e\n\n\u003cp\u003eThe table below lists clinical areas where irinotecan may be considered.\u003c\/p\u003e\n\n\u003ctable\u003e\n  \u003cthead\u003e\n    \u003ctr\u003e\n\u003cth\u003eClinical System\u003c\/th\u003e\n\u003cth\u003eCancer\u003c\/th\u003e\n\u003c\/tr\u003e\n  \u003c\/thead\u003e\n  \u003ctbody\u003e\n    \u003ctr\u003e\n\u003ctd\u003eGastrointestinal\u003c\/td\u003e\n\u003ctd\u003eAmpullary, cholangiocarcinoma, colorectal, gastric, oesophageal, pancreatic, small bowel, neuroendocrine\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eBone and soft tissue\u003c\/td\u003e\n\u003ctd\u003eEwing sarcoma, rhabdomyosarcoma\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eOthers\u003c\/td\u003e\n\u003ctd\u003eCancer of unknown primary, glioblastoma, neuroblastoma, embryonal brain tumours (especially medulloblastoma)\u003c\/td\u003e\n\u003c\/tr\u003e\n  \u003c\/tbody\u003e\n\u003c\/table\u003e\n\n\u003ch2 id=\"howworks\"\u003eHow Irinotecan Works and Causes Side Effects\u003c\/h2\u003e\n\u003cp\u003eAs mentioned, irinotecan is converted to SN-38, which kills cancer cells by blocking topoisomerase I. SN-38 is then inactivated by UGT1A1. The gene \u003cem\u003eUGT1A1\u003c\/em\u003e is polymorphic, meaning it has many natural variations. These variations affect how much enzyme a person makes or how well it works.\u003c\/p\u003e\n\n\u003cp\u003eVariants in the promoter region (the part that controls gene activity) include changes in the number of TA repeats. The normal allele, UGT1A1*1, has 6 TA repeats. Fewer repeats, like UGT1A1*36 (5 repeats), increase enzyme function. More repeats, like UGT1A1*28 (7 repeats) and UGT1A1*37 (8 repeats), decrease function.\u003c\/p\u003e\n\n\u003cp\u003eVariants in the coding region (exon 1) include UGT1A1*6 (a G-to-A change at position 211, causing glycine to arginine at position 71). This also reduces enzyme function.\u003c\/p\u003e\n\n\u003cp\u003eThe most clinically important reduced-function variants are UGT1A1*6, *28, and *37. They account for most cases of reduced UGT1A1 activity. Other loss-of-function variants like *7 and *27 exist but are rare.\u003c\/p\u003e\n\n\u003cp\u003eUGT1A1*28 is the most studied. It causes a 35% reduction in gene transcription in heterozygotes (people with one copy) and a 70% decrease in homozygotes (people with two copies). People with the UGT1A1*28\/*28 genotype have an 18%–159% increase in SN-38 exposure and a 61% reduction in metabolic clearance. Both homozygous and heterozygous carriers of UGT1A1*28 have an increased risk of neutropenia, regardless of dose.\u003c\/p\u003e\n\n\u003cp\u003eIn 2005, the US Food and Drug Administration (FDA) first recommended that irinotecan dose reductions be considered for people known to be UGT1A1*28 homozygotes. Over the past two decades, our understanding has grown.\u003c\/p\u003e\n\n\u003ch2 id=\"ugt1a1\"\u003eThe Role of UGT1A1 Gene Variants\u003c\/h2\u003e\n\u003cp\u003eUGT1A1 loss-of-function alleles are linked to Gilbert's syndrome (a mild liver condition causing jaundice) and Crigler-Najjar syndrome (a more severe form of jaundice). The table below lists common variants and their effects.\u003c\/p\u003e\n\n\u003ctable\u003e\n  \u003cthead\u003e\n    \u003ctr\u003e\n\u003cth\u003eVariant\u003c\/th\u003e\n\u003cth\u003eLocation\u003c\/th\u003e\n\u003cth\u003eChange\u003c\/th\u003e\n\u003cth\u003eEffect on Enzyme\u003c\/th\u003e\n\u003cth\u003eClinical Impact\u003c\/th\u003e\n\u003c\/tr\u003e\n  \u003c\/thead\u003e\n  \u003ctbody\u003e\n    \u003ctr\u003e\n\u003ctd\u003eUGT1A1*1\u003c\/td\u003e\n\u003ctd\u003ePromoter\u003c\/td\u003e\n\u003ctd\u003e(TA)\u003csub\u003e6\u003c\/sub\u003eTAA\u003c\/td\u003e\n\u003ctd\u003eNormal function\u003c\/td\u003e\n\u003ctd\u003eNormal\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eUGT1A1*36\u003c\/td\u003e\n\u003ctd\u003ePromoter\u003c\/td\u003e\n\u003ctd\u003e(TA)\u003csub\u003e5\u003c\/sub\u003eTAA\u003c\/td\u003e\n\u003ctd\u003eIncreased function\u003c\/td\u003e\n\u003ctd\u003eNot applicable (non-coding)\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eUGT1A1*28\u003c\/td\u003e\n\u003ctd\u003ePromoter\u003c\/td\u003e\n\u003ctd\u003e(TA)\u003csub\u003e7\u003c\/sub\u003eTAA\u003c\/td\u003e\n\u003ctd\u003eDecreased function\u003c\/td\u003e\n\u003ctd\u003eGilbert's syndrome\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eUGT1A1*37\u003c\/td\u003e\n\u003ctd\u003ePromoter\u003c\/td\u003e\n\u003ctd\u003e(TA)\u003csub\u003e8\u003c\/sub\u003eTAA\u003c\/td\u003e\n\u003ctd\u003eDecreased function\u003c\/td\u003e\n\u003ctd\u003eNeonatal hyperbilirubinemia\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eUGT1A1*6\u003c\/td\u003e\n\u003ctd\u003eExon 1\u003c\/td\u003e\n\u003ctd\u003ec.211G\u0026gt;A (p.Gly71Arg)\u003c\/td\u003e\n\u003ctd\u003eDecreased function\u003c\/td\u003e\n\u003ctd\u003eGilbert's syndrome, neonatal hyperbilirubinemia\u003c\/td\u003e\n\u003c\/tr\u003e\n  \u003c\/tbody\u003e\n\u003c\/table\u003e\n\n\u003cp\u003eGain-of-function variants like UGT1A1*36 exist, but current evidence is not enough to support using them to increase irinotecan doses. The Dutch Pharmacogenetics Working Group (DPWG) recommends dosing as if the person has the normal UGT1A1*1 allele.\u003c\/p\u003e\n\n\u003ch2 id=\"frequencies\"\u003ePopulation Frequencies of UGT1A1 Variants\u003c\/h2\u003e\n\u003cp\u003eThe frequency of these variants differs by population. UGT1A1*28 is common in Europeans (32%–36%), African Americans\/Afro-Caribbean (37%), East Asians (15%), and South Asians (41%). UGT1A1*6 is common in Asian populations (2%–16%) but rare in Caucasians and Africans (0%–4%). UGT1A1*37 is found in 6% of Afro-Caribbean and 4% of African ancestries.\u003c\/p\u003e\n\n\u003ctable\u003e\n  \u003cthead\u003e\n    \u003ctr\u003e\n\u003cth\u003ePopulation\u003c\/th\u003e\n\u003cth\u003e*6 frequency (%)\u003c\/th\u003e\n\u003cth\u003e*28 frequency (%)\u003c\/th\u003e\n\u003cth\u003e*36 frequency (%)\u003c\/th\u003e\n\u003cth\u003e*37 frequency (%)\u003c\/th\u003e\n\u003c\/tr\u003e\n  \u003c\/thead\u003e\n  \u003ctbody\u003e\n    \u003ctr\u003e\n\u003ctd\u003eEuropean (without Finland)\u003c\/td\u003e\n\u003ctd\u003e0.1\u003c\/td\u003e\n\u003ctd\u003e32\u003c\/td\u003e\n\u003ctd\u003e0.1\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eEuropean (Finnish)\u003c\/td\u003e\n\u003ctd\u003e4.4\u003c\/td\u003e\n\u003ctd\u003e36\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eAfrican American\/Afro-Caribbean\u003c\/td\u003e\n\u003ctd\u003e0.4\u003c\/td\u003e\n\u003ctd\u003e37\u003c\/td\u003e\n\u003ctd\u003e8\u003c\/td\u003e\n\u003ctd\u003e6\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eAfrican\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003ctd\u003e40\u003c\/td\u003e\n\u003ctd\u003e7\u003c\/td\u003e\n\u003ctd\u003e4\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eNear\/Middle Eastern\u003c\/td\u003e\n\u003ctd\u003e0.2\u003c\/td\u003e\n\u003ctd\u003e31\u003c\/td\u003e\n\u003ctd\u003e1\u003c\/td\u003e\n\u003ctd\u003e1\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eEast Asian\u003c\/td\u003e\n\u003ctd\u003e16\u003c\/td\u003e\n\u003ctd\u003e15\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eSouth Asian\u003c\/td\u003e\n\u003ctd\u003e2\u003c\/td\u003e\n\u003ctd\u003e41\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003ctd\u003e0\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eAshkenazi Jewish\u003c\/td\u003e\n\u003ctd\u003e0.4\u003c\/td\u003e\n\u003ctd\u003e38\u003c\/td\u003e\n\u003ctd\u003e—\u003c\/td\u003e\n\u003ctd\u003e—\u003c\/td\u003e\n\u003c\/tr\u003e\n  \u003c\/tbody\u003e\n\u003c\/table\u003e\n\n\u003cp\u003eBecause UGT1A1*1\/*28 intermediate metabolizers are so common in Caucasians (46%–55%), conventional dosing has historically been based on this group. All major guidelines recognize a drug–gene interaction for intermediate metabolizers, but they do not recommend dose reduction because of concerns about reducing efficacy. Dose reduction is reserved for poor metabolizers only.\u003c\/p\u003e\n\n\u003ch2 id=\"evidence\"\u003eEvidence on UGT1A1 and Toxicity\u003c\/h2\u003e\n\u003cp\u003eMany studies have looked at the link between UGT1A1 variants and irinotecan side effects. The 2023 DPWG guideline reviewed 48 publications before March 2021, including 12 meta-analyses with thousands of patients, mostly Caucasian and Asian. The results are consistent: people with UGT1A1*28 or *6 alleles have higher rates of serious toxicity than those with the wild-type UGT1A1*1\/*1 genotype. This applies to both heterozygotes (intermediate metabolizers) and homozygotes (poor metabolizers), though to different degrees.\u003c\/p\u003e\n\n\u003cp\u003eUGT1A1*28 and *6 have similar effects on enzyme activity, shown by comparable SN-38G\/SN-38 ratios. Most meta-analyses found that these variants are more strongly linked to CTCAE Grade 3 or 4 neutropenia than to diarrhoea. The risk of diarrhoea increases with higher irinotecan doses. Two meta-analyses found no increased risk of severe diarrhoea at low doses (less than 150 mg\/m² or less than 125 mg\/m²), but two others did report an increased risk of severe neutropenia at these doses.\u003c\/p\u003e\n\n\u003cp\u003ePharmacokinetic studies help guide dose adjustments. Data from six studies including 28 patients with UGT1A1*28\/*28 showed that a 69% dose reduction would be needed to achieve the same SN-38 exposure as the rest of the population, and a 58% reduction compared to wild-type only. This supports the DPWG recommendation to start poor metabolizers at 70% of the standard dose. Studies published after the 2023 guideline confirm these findings in Asian populations.\u003c\/p\u003e\n\n\u003cp\u003eA meta-analysis of 42 Asian cancer studies found that UGT1A1*6 or *28 homozygotes had a 6.23-fold increased risk of neutropenia (p \u0026lt; 0.00001) and a 3.21-fold increased risk of diarrhoea (p \u0026lt; 0.00001) compared with wild-type patients. A more recent meta-analysis of 4,471 colorectal cancer patients across 30 centres found an odds ratio (OR) of 4.10 for neutropenia (p \u0026lt; 0.0001) and 3.24 for diarrhoea (p \u0026lt; 0.0001) in UGT1A1*28 homozygotes. For UGT1A1*6 homozygotes, the risk of diarrhoea was OR = 2.42 (95% confidence interval [CI] 1.14–5.11, p = 0.03) and neutropenia was OR = 1.91 (95% CI 1.17–3.10, p = 0.01).\u003c\/p\u003e\n\n\u003ch2 id=\"guideddosing\"\u003eEvidence for Genotype-Guided Dosing\u003c\/h2\u003e\n\u003cp\u003eRecent research provides real-world evidence on the safety, feasibility, pharmacokinetics, cost-effectiveness, and efficacy of adjusting irinotecan doses based on genotype. Some uncertainty remains about the best dosing.\u003c\/p\u003e\n\n\u003cp\u003eA Dutch prospective multicentre study genotyped 350 adults receiving high-dose irinotecan (at least 180 mg\/m² or 450–600 mg flat dose). People with two copies of UGT1A1*28 and\/or *93 were defined as poor metabolizers. Doses were further optimized based on tolerability and neutrophil counts. UGT1A1*93 is in high linkage disequilibrium with UGT1A1*28 (r² = 0.83) and is linked to higher risk of blood toxicity. The study mostly included Caucasian patients receiving FOLFIRI or FOLFIRINOX for colorectal or pancreatic cancer. Poor metabolizers (n = 31) were compared with historical poor metabolizer controls. Febrile neutropenia dropped from 24% to 7% (p = 0.04) in poor metabolizers who received a reduced dose. This risk was similar to non-poor metabolizers treated at standard doses (7% vs 4%). However, poor metabolizers still had higher overall Grade ≥3 toxicities (58% vs 35%, p = 0.01). Systemic exposure to SN-38 remained 32% higher in this group than in the standard-dose cohort (p = 0.05), explaining the higher toxicity.\u003c\/p\u003e\n\n\u003cp\u003eAn Italian study followed 247 patients with gastrointestinal cancers for 8 years. Poor metabolizers (UGT1A1*28\/*28, n = 28) received a median 40% (range 22%–58%) irinotecan dose reduction. Among them, 39.2% developed CTCAE Grade ≥3 neutropenia, compared with 19.6% of heterozygous or wild-type patients treated at full dose (p = 0.058, n = 219).\u003c\/p\u003e\n\n\u003cp\u003eThe phase III AXEPT trial recruited 620 genotyped patients across 98 hospitals in Japan, China, and South Korea. Poor metabolizers were more likely to develop CTCAE Grade ≥3 neutropenia in early treatment cycles, especially in the FOLFIRI cohort. The trial compared XELIRI (CAPIRI) (irinotecan 200 mg\/m² every 3 weeks) with FOLFIRI (irinotecan 180 mg\/m² every 2 weeks) as second-line therapy for metastatic colorectal cancer. Poor metabolizers (n = 47) received a reduced irinotecan dose of 150 mg\/m² in both arms, equating to a 25% and 16.6% cumulative dose reduction for XELIRI and FOLFIRI, respectively.\u003c\/p\u003e\n\n\u003cp\u003eA Japanese study retrospectively analysed 235 genotyped patients with advanced pancreatic cancer receiving FOLFIRINOX. Poor metabolizers (*6\/*6 and *28\/*28, n = 11) started at a lower irinotecan dose of 80 mg\/m² every 2 weeks instead of 150 mg\/m². Among the 11 poor metabolizers, two developed CTCAE Grade ≥3 neutropenia and one had Grade 3 febrile neutropenia. Overall rates of Grade 3–4 neutropenia\/febrile neutropenia were lower compared with non-poor metabolizers when the lower dose was used.\u003c\/p\u003e\n\n\u003cp\u003eData on genotype-guided dosing for glioblastoma and for lower-dose protracted schedules used in paediatric practice and in adult \"paediatric\" cancers like Ewing sarcoma are limited. In these settings, irinotecan is given at lower doses, often orally. For example, in recurrent\/progressive Ewing sarcoma, irinotecan is given as 10–20 mg\/m² in a 5-day or 10-day schedule (with temozolomide) every 3 weeks. For relapsed rhabdomyosarcoma, 50 mg\/m² on Days 1–5 is common (with temozolomide and vincristine) every 3 weeks, with weekly cumulative doses of 50–250 mg\/m².\u003c\/p\u003e\n\n\u003cp\u003ePaediatric protocols often include an oral cephalosporin (usually starting 2 days before chemotherapy and continuing until 3 days after). This reduces the incidence of CTCAE Grade 3–4 irinotecan-induced diarrhoea by reducing local SN-38 production by bacterial glucuronidases. Paediatric studies report that the main toxicity is diarrhoea, usually managed as an outpatient, with myelosuppression being uncommon. An evaluation of 74 paediatric patients who received irinotecan (15–75 mg\/m²) showed that severe toxicity was not increased in UGT1A1*28 homozygotes, despite higher SN-38 area under the curve. The major limitation here is small sample sizes, confounding from variable (and lower) dosing, oral administration, concomitant cephalosporin, different chemotherapy drugs, and limited assessment of genotype–pharmacokinetics correlation.\u003c\/p\u003e\n\n\u003cp\u003eFor glioblastoma, irinotecan schedules range from 125 mg\/m² every 2 weeks to 350 mg\/m² every 3 weeks. Very few studies have evaluated UGT1A1 genotype in this setting. Interestingly, the effect of UGT1A1 genotype may be modulated by enzyme-inducing anti-seizure medications. One study showed that UGT1A1*28 status was important for toxicity in patients not receiving enzyme-inducing anti-seizure drugs, compared with those receiving an enzyme inducer despite a roughly three-fold lower irinotecan dose. A Phase 1 study of intravenous liposomal irinotecan excluded UGT1A1*28 homozygotes and compared heterozygotes given 60 mg\/m² every 3 weeks (with 30-mg\/m² increases) and wild-type homozygotes given 120 mg\/m² every 3 weeks (with 60-mg\/m² increases). The two groups had equivalent pharmacokinetic profiles and no correlation with toxicity.\u003c\/p\u003e\n\n\u003ch2 id=\"efficacy\"\u003eUGT1A1 Genotyping and Treatment Effectiveness\u003c\/h2\u003e\n\u003cp\u003eEarly studies suggested that higher SN-38 levels due to reduced UGT1A1 activity might improve tumour response. But later studies have not shown better outcomes like survival. A recent meta-analysis including 282\/912 UGT1A1*6 carriers and 281\/1025 UGT1A1*28 carriers from 11 and 12 Chinese studies, respectively, confirmed no benefit in remission rates for intermediate or poor metabolizers compared with wild-type patients. In practice, severe toxicity from reduced UGT1A1 activity may lead to dose reductions, delays, or stopping chemotherapy, which can compromise effective treatment.\u003c\/p\u003e\n\n\u003cp\u003eRandomized controlled trials directly comparing genotype-guided dosing with standard dosing are lacking, because withholding dose reduction in poor metabolizers would be unethical. Three recent studies assessed survival outcomes by genotype.\u003c\/p\u003e\n\n\u003ctable\u003e\n  \u003cthead\u003e\n    \u003ctr\u003e\n\u003cth\u003eStudy\u003c\/th\u003e\n\u003cth\u003eCancer\u003c\/th\u003e\n\u003cth\u003eN\u003c\/th\u003e\n\u003cth\u003eStandard dose\u003c\/th\u003e\n\u003cth\u003eReduced dose for PM\u003c\/th\u003e\n\u003cth\u003eMedian OS WT (months)\u003c\/th\u003e\n\u003cth\u003eMedian OS IM (months)\u003c\/th\u003e\n\u003cth\u003eMedian OS PM (months)\u003c\/th\u003e\n\u003cth\u003ep-value\u003c\/th\u003e\n\u003c\/tr\u003e\n  \u003c\/thead\u003e\n  \u003ctbody\u003e\n    \u003ctr\u003e\n\u003ctd\u003eIwasa et al. (2021)\u003c\/td\u003e\n\u003ctd\u003eColorectal\u003c\/td\u003e\n\u003ctd\u003e650\u003c\/td\u003e\n\u003ctd\u003e200 mg\/m² CAPIRI every 3 weeks OR 180 mg\/m² FOLFIRI every 2 weeks\u003c\/td\u003e\n\u003ctd\u003e150 mg\/m²\u003c\/td\u003e\n\u003ctd\u003e15.9\u003c\/td\u003e\n\u003ctd\u003e17.7\u003c\/td\u003e\n\u003ctd\u003e10.6\u003c\/td\u003e\n\u003ctd\u003e0.008\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eSatake et al. (2022)\u003c\/td\u003e\n\u003ctd\u003ePancreatic\u003c\/td\u003e\n\u003ctd\u003e235\u003c\/td\u003e\n\u003ctd\u003e150 mg\/m² FOLFIRINOX every 2 weeks\u003c\/td\u003e\n\u003ctd\u003e80 mg\/m²\u003c\/td\u003e\n\u003ctd\u003e8.8\u003c\/td\u003e\n\u003ctd\u003e11.5\u003c\/td\u003e\n\u003ctd\u003e—\u003c\/td\u003e\n\u003ctd\u003e0.579\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003eLv et al. (2024)\u003c\/td\u003e\n\u003ctd\u003eGastric\u003c\/td\u003e\n\u003ctd\u003e107\u003c\/td\u003e\n\u003ctd\u003e125 mg\/m²\u003c\/td\u003e\n\u003ctd\u003e100 mg\/m² (IM), 75 mg\/m² (PM)\u003c\/td\u003e\n\u003ctd\u003e9.5\u003c\/td\u003e\n\u003ctd\u003e9.0\u003c\/td\u003e\n\u003ctd\u003e11.2\u003c\/td\u003e\n\u003ctd\u003e0.528\u003c\/td\u003e\n\u003c\/tr\u003e\n    \u003ctr\u003e\n\u003ctd\u003ePeeters et al. (2026)\u003c\/td\u003e\n\u003ctd\u003eColorectal and pancreatic\u003c\/td\u003e\n\u003ctd\u003e779\u003c\/td\u003e\n\u003ctd\u003eVarious (FOLFIRINOX, FOLFIRI, etc.)\u003c\/td\u003e\n\u003ctd\u003e30% dose reduction\u003c\/td\u003e\n\u003ctd\u003e14.9 (colorectal), 14.8 (pancreatic)\u003c\/td\u003e\n\u003ctd\u003e13.4 (colorectal), 11.6 (pancreatic)\u003c\/td\u003e\n\u003ctd\u003e—\u003c\/td\u003e\n\u003ctd\u003e0.42\u003c\/td\u003e\n\u003c\/tr\u003e\n  \u003c\/tbody\u003e\n\u003c\/table\u003e\n\n\u003cp\u003eLv et al. treated 107 Chinese gastric cancer patients with genotype-based dosing. Median overall survival was 9.5 months for wild-type, 9.0 months for intermediate metabolizers, and 11.2 months for poor metabolizers (p = 0.528). Satake et al. found median overall survival of 8.8 months for wild-type and 11.5 months for intermediate metabolizers (p = 0.579). Iwasa et al. found that poor metabolizers had shorter median overall survival (10.6 months) compared with wild-type (15.9 months) and intermediate metabolizers (17.7 months), with a significant p-value of 0.008. Peeters et al. reported median overall survival of 14.9 months for colorectal and 14.8 months for pancreatic cancer in wild-type, and 13.4 months for colorectal and 11.6 months for pancreatic cancer in intermediate metabolizers, with a p-value of 0.42.\u003c\/p\u003e\n\n\u003ch2 id=\"implications\"\u003eClinical Implications and Recommendations\u003c\/h2\u003e\n\u003cp\u003eThe guideline makes clear recommendations for clinical practice.\u003c\/p\u003e\n\u003col\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTest before treatment:\u003c\/strong\u003e Any patient who is about to be prescribed irinotecan for an epithelial malignancy should have pharmacogenetic testing to identify clinically relevant UGT1A1 variants, where testing is available.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eDose reduction for poor metabolizers:\u003c\/strong\u003e For poor metabolizers (two reduced-function variants), reduce the irinotecan dose by 30% at Cycle 1 for all indications.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eTitrate after Cycle 1:\u003c\/strong\u003e After Cycle 1, adjust the dose based on tolerability and neutrophil counts.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eNo recommendation for rare cancers:\u003c\/strong\u003e The lack of evidence means no recommendation can be made for rare malignancies such as sarcomas.\u003c\/li\u003e\n  \u003cli\u003e\n\u003cstrong\u003eConsistency with international guidelines:\u003c\/strong\u003e This guideline is consistent with other international pharmacogenetics prescribing guidelines.\u003c\/li\u003e\n\u003c\/ol\u003e\n\n\u003cp\u003eThe guideline is based on the latest evidence but cannot account for all individual factors relevant to patient care. Therefore, prescribers must conduct a thorough assessment of each patient's risk–benefit profile. The goal is to optimize therapy to maximize benefits while minimizing potential harms.\u003c\/p\u003e\n\n\u003ch2 id=\"limitations\"\u003eLimitations of the Evidence\u003c\/h2\u003e\n\u003cp\u003eSeveral limitations exist. Randomized controlled trials comparing genotype-guided dosing with standard dosing are not available because it would be unethical to withhold dose reductions in poor metabolizers. Some studies have small sample sizes, especially in rare cancers and paediatric settings. Confounding factors include variable and lower dosing regimens, oral administration, concomitant use of cephalosporins, different chemotherapy drugs, and limited assessment of the correlation between genotype and irinotecan pharmacokinetics. There is also uncertainty about the optimal dosing strategy and the role of gain-of-function variants like UGT1A1*36.\u003c\/p\u003e\n\n\u003cp\u003eDespite these limitations, the evidence consistently shows that UGT1A1 poor metabolizers are at higher risk of severe toxicity, and that genotype-guided dose reduction improves safety without compromising survival in the studied populations.\u003c\/p\u003e\n\n\u003c!-- ddn:faq:start --\u003e\n\u003ch2 id=\"ddn-faq\"\u003eFrequently Asked Questions\u003c\/h2\u003e\n\u003ch3\u003eWhat is UGT1A1 genetic testing and why do I need it before starting irinotecan?\u003c\/h3\u003e\n\u003cp\u003eUGT1A1 testing checks for gene variants that affect how your body breaks down SN-38, the active form of irinotecan. People with two reduced-function variants (poor metabolizers) clear SN-38 more slowly, raising the risk of severe diarrhoea and neutropenia. The new UK guideline recommends testing before treatment for epithelial malignancies, where testing is available, so your starting dose can be adjusted.\u003c\/p\u003e\n\u003ch3\u003eIf I am a poor metabolizer, what dose will I start on?\u003c\/h3\u003e\n\u003cp\u003eFor poor metabolizers — people with two reduced-function UGT1A1 variants — the guideline recommends starting irinotecan at a 30% lower dose in Cycle 1 for all indications. After Cycle 1, your dose is adjusted based on how well you tolerate it and your neutrophil counts. This approach aims to lower the risk of severe side effects while keeping treatment effective.\u003c\/p\u003e\n\u003ch3\u003eWhat side effects does irinotecan cause, and how common are the serious ones?\u003c\/h3\u003e\n\u003cp\u003eIrinotecan can cause acute cholinergic syndrome (flushing, sweating, abdominal cramps), diarrhoea, hair loss, mouth sores, and myelosuppression. The dose-limiting toxicities are diarrhoea and neutropenia. With weekly single-agent irinotecan (85–125 mg\/m²), Grade 3 or 4 diarrhoea occurs in 21%–31% of patients and Grade 3 or 4 neutropenia in 19%–31%. Severe toxicity can occur even without known risk factors like liver or kidney problems.\u003c\/p\u003e\n\u003ch3\u003eWhat does it mean if I have one reduced-function UGT1A1 variant (intermediate metabolizer)?\u003c\/h3\u003e\n\u003cp\u003eOne reduced-function variant makes you an intermediate metabolizer. Major guidelines recognize a drug–gene interaction for intermediate metabolizers but do not recommend a dose reduction, because of concerns about reducing efficacy. Dose reduction is reserved for poor metabolizers only. Intermediate metabolizers are common in Caucasians (46%–55%), and conventional dosing has historically been based on this group.\u003c\/p\u003e\n\u003ch3\u003eDoes genotype-guided dose reduction affect how well my cancer treatment works?\u003c\/h3\u003e\n\u003cp\u003eLater studies have not shown better outcomes like survival from higher SN-38 levels due to reduced UGT1A1 activity. In a study of 107 Chinese gastric cancer patients, median overall survival was 9.5 months for wild-type, 9.0 months for intermediate metabolizers, and 11.2 months for poor metabolizers (p = 0.528). Genotype-guided dose reduction improves safety without compromising survival in the studied populations.\u003c\/p\u003e\n\u003ch3\u003eWhat happens after Cycle 1 if I start on a reduced dose?\u003c\/h3\u003e\n\u003cp\u003eAfter Cycle 1, the guideline recommends adjusting the irinotecan dose based on your tolerability and neutrophil counts. This means your healthcare team will monitor how you respond and may increase or further reduce the dose. The goal is to optimize therapy to maximize benefits while minimizing potential harms. Always discuss any side effects with your treatment team promptly.\u003c\/p\u003e\n\u003ch3\u003eAre there situations where this guideline does not apply?\u003c\/h3\u003e\n\u003cp\u003eThe guideline makes no recommendation for rare malignancies such as sarcomas, because evidence is limited. Data on genotype-guided dosing for glioblastoma and for lower-dose protracted schedules used in paediatric practice and in adult 'paediatric' cancers like Ewing sarcoma are also limited. In these settings, irinotecan is often given at lower doses, sometimes orally, and other factors may affect toxicity.\u003c\/p\u003e\n\u003ch3\u003eI'm about to start irinotecan for advanced colorectal cancer and my UGT1A1 test shows I'm a poor metabolizer — should I get a second opinion on the 30% dose reduction?\u003c\/h3\u003e\n\u003cp\u003eA second opinion can help when you carry two reduced-function UGT1A1 variants and are offered a 30% lower irinotecan starting dose. Guidelines recommend testing before treatment for epithelial malignancies and reducing the Cycle 1 dose by 30% for poor metabolizers, then adjusting after Cycle 1 based on tolerability and neutrophil counts. No recommendation exists for rare cancers such as sarcomas, and the optimal dosing strategy remains uncertain. A review can confirm your genotype interpretation and whether the plan fits your situation. Diagnostic Detectives Network provides independent expert second opinions.\u003c\/p\u003e\n\u003c!-- ddn:faq:end --\u003e\n\n\u003ch2 id=\"source\"\u003eSource Information\u003c\/h2\u003e\n\u003cp\u003e\u003cstrong\u003eOriginal article title:\u003c\/strong\u003e UGT1A1 genotype testing for irinotecan: A guideline developed by the UK Centre of Excellence in Regulatory Science and Innovation in Pharmacogenomics (CERSI-PGx).\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors:\u003c\/strong\u003e Chauhan D, Dello Russo C, Thompson J, Hughes DA, Payne K, Tsakiroglou M, Ross P, Chauhan R, Jenkinson S, Keen J, Harding S, Lau E, Braun M, Agarwal R, Adams R, Rolf E, Al-Sheikhli F, Mitchell S, Hammond R, Roberts R, Cairns L, Heggarty S, Graham J, Mencel J, Pirmohamed M.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003ePublication:\u003c\/strong\u003e British Journal of Clinical Pharmacology, 2026; 92: 2986–3001. DOI: 10.1002\/bcp.70659.\u003c\/p\u003e\n\u003cp\u003e\u003cstrong\u003eNote:\u003c\/strong\u003e This patient-friendly article is based on peer-reviewed research. It is not a substitute for professional medical advice. Always consult your healthcare team about your individual treatment plan.\u003c\/p\u003e","brand":"DiagnosticDetectives.Com","offers":[{"title":"Default Title","offer_id":47738981777564,"sku":null,"price":0.0,"currency_code":"USD","in_stock":true}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/0599\/5449\/5644\/files\/ddn-medical-article-ugt1a1-genotype-testing-for-irinotecan-a-patient-guide-to-the-new-uk-guideline-hero.png?v=1791782522","url":"https:\/\/diagnosticdetectives.com\/fi\/products\/ugt1a1-genotype-testing-for-irinotecan-a-patient-guide-to-the-new-uk-guideline","provider":"DiagnosticDetectives.Com","version":"1.0","type":"link"}