Risk Factors for Septic Shock After Irinotecan-Containing Chemotherapy: An Exploratory Case-Control Study

Irinotecan is used in chemotherapy for gynecological cancers, including cervical cancer and ovarian cancer, sometimes in combination with other cytotoxic agents, such as nedaplatin and cisplatin [1, 2]. Irinotecan is metabolized into SN38, which is an active metabolite of carboxylesterases. SN38 is glucuronidated in the liver by uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) and is inactivated by the formation of SN38 glucuronide (SN38-G). The UGT1A1*6 and UGT1A1*28 polymorphisms affect the pharmacokinetics and toxicity of SN38. Homozygous UGT1A1 variants (*6/*6, *28/*28), double heterozygous (*6/*28), and heterozygous variants (*1/*6 and *1/*28) are associated with reduced UGT1A1 glucuronidation activity, compared with the wild-type allele (*1/*1), resulting in increased risk for severe irinotecan-induced toxicity [3‐5]. It has been reported that some patients may develop lethal septic shock following irinotecan treatment [6‐8]; however, not all patients with homozygous or heterozygous UGT1A1 variants experience such severe adverse effects. Therefore, the risk factors for developing lethal adverse effects following irinotecan therapy remain unclear.

We experienced several clinical cases of septic shock with severe myelosuppression after irinotecan administration (see the representative case in Sect. 1.1). All patients were admitted to the intensive care unit (ICU) and one of them eventually died. Their clinical course was severe and they deteriorated rapidly. We have never experienced this course when using other anticancer agents, therefore we conducted a retrospective case-control study to explore the potential risk factors, other than UGT1A1 polymorphisms, that might induce life-threatening complications in patients receiving irinotecan.

We conducted a retrospective case-control study to explore the risk factors for septic shock following irinotecan administration. All women who received irinotecan-containing chemotherapy for gynecologic malignancies at Shizuoka General Hospital between October 2014 and September 2020 were investigated in this study. Data were retrospectively collected from clinical records.

The clinical background and blood test results before chemotherapy in patients who developed septic shock after irinotecan-containing chemotherapy were compared with those of patients who did not develop septic shock. To explore the risk factors for septic shock due to irinotecan administration, odds ratios (ORs) for developing septic shock after receiving irinotecan were calculated with 95% confidence intervals (CIs) using univariable logistic regression analysis for the following possible risk factors: age, body mass index (BMI), neutrophil count, hemoglobin, platelet count, serum creatinine level, serum total bilirubin level, UGT1A1 polymorphism [3, 5, 11], history of pelvic irradiation [10], administration of hangeshashinto (a Japanese herbal medicine used to treat irinotecan-associated diarrhea) [12], platinum combination therapy, history of chemotherapy [13], and history of abdominal surgery. Abdominal surgery was defined as gastrointestinal surgery and hysterectomy. Less invasive surgeries, including cesarean section, oophorectomy, cystectomy without hysterectomy, or exploratory laparotomy, were excluded. For blood tests and BMI, the data collected within 7 days before irinotecan administration were used. Univariable logistic regression analysis with Firth correction was performed to estimate ORs with 95% CIs using the R package ‘logistf’ version 1.24. Statistical analysis was performed using R version 3.6.0 (The R Foundation for Statistical Computing, Vienna, Austria).

The Institutional Review Board of Shizuoka General Hospital approved this study (reference number: SGHIRB#2021015).

A total of 147 women with cervical, endometrial, ovarian, vaginal, or vulvar cancer received irinotecan-containing chemotherapy in our hospital during the study period. Three women developed septic shock after the first cycle of irinotecan-containing chemotherapy and all three were admitted to the ICU.

The irinotecan dose was 100 mg/m² in irinotecan monotherapy and 60 mg/m² in platinum combined chemotherapy, and for platinum combined chemotherapy, the doses of nedaplatin and cisplatin were 80 mg/m² and 60 mg/m², respectively. The irinotecan dose was reduced by 50% in patients with homozygous UGT1A1 variants (*6/*6, *28/*28) and double heterozygous variants (*6/*28).

UGT1A1 polymorphism affects the risk of irinotecan-related severe toxicity [3, 5, 11]. A dose reduction of irinotecan is recommended for patients with homozygous variants [14], while there is no consensus on the need for dose reduction in patients with heterozygous variants [5]. In our analysis, the point estimate OR of UGT1A1 polymorphism for septic shock was 9.09 but its 95% CI crossed 1 (0.86–1233; p = 0.070) when we excluded 22 cases with missing data for the UGT1A1 polymorphism test. This may be because, before 2015, UGT1A1 polymorphism was evaluated only when severe toxicity was observed. It should be noted that the OR of the UGT1A1 polymorphism might be underestimated since patients with missing data on UGT1A1 were more likely to be wild-type than those without missing data on UGT1A1, resulting in selection bias.

A history of pelvic irradiation can also plausibly increase the risk of septic shock after irinotecan administration. All three cases of septic shock in our study were diagnosed with neutropenic enterocolitis. A similar case has also been reported previously [9]. Neutropenic enterocolitis is a life-threatening complication in immunosuppressed patients and is diagnosed by clinical symptoms and signs, including fever, abdominal pain, and CT or ultrasound findings [10]. Neutropenic enterocolitis is induced by mucosal injury and myelosuppression caused by cytotoxic drugs [10]. We assume that neutropenic enterocolitis was induced in our patients due to the combined effect of intestinal mucosal injury by irinotecan and previous pelvic irradiation.

Irinotecan causes intestinal mucosal injury via the following mechanism: SN38 is converted into the inactive product SN38-G in the liver by UGT1A1, which is then excreted into the bile. In the intestinal compartment, bacterial β-glucuronidase reactivates SN38-G to release SN38 [3, 4]. UGT1A1 variants are associated with reduced UGT1A1 enzyme activity involved in the inactivation of SN38, resulting in increased toxicity to the intestinal mucosa and severe diarrhea in patients with UGT1A1*6 or UGT1A1*28 [3].

Moreover, irradiation is reported to damage the intestinal mucosa [15]. The most common complications in patients with a history of pelvic irradiation are gastrointestinal complications [16]. Considering that damage to the intestine by irradiation has been reported to last for more than 30 years [17], it is plausible that in our patients, irinotecan administration caused further damage to the intestinal mucosa that had already been injured by pelvic irradiation, resulting in loss of the mucosal barrier and ingress of intestinal bacteria. Indeed, blood cultures were positive in two cases: multispecies of intestinal bacteria in Case 1, suggesting bacterial translocation, and Candida albicans in Case 2 (Table 1). Since both bacterial translocation and fungi infection are characteristics of neutropenic enterocolitis, the blood culture results support our hypothesis [10].

Furthermore, a history of pelvic irradiation can also be a risk factor for severe myelosuppression. Irradiation causes bone marrow dysfunction due to direct injury to hematopoietic stem cells and structural functional damage to the stroma or microcirculation [18]. It has been reported that myelosuppression after chemotherapy can be more severe in patients with a history of irradiation [10]. Since the pelvis and vertebrae account for approximately 60% of the functional bone marrow, irradiation of these lesions is more likely to cause severe myelosuppression [19]. Among them, the pelvis is included in the radiation field for cervical cancer [20].

Thus, in our cases, it is possible that pelvic irradiation might have impaired hematopoietic ability and imposed an additive risk for myelosuppression due to chemotherapy [21, 22]. In the representative case, myelosuppression was so severe that the neutrophil count continued to be below 50/μL for 8 days despite daily administration of granulocyte colony-stimulating factor. We assumed that mucosal damage due to irinotecan and previous pelvic irradiation together with severe myelosuppression induced neutropenic enterocolitis and septic shock (Fig. 2).

A history of chemotherapy might also be a risk factor for the development of septic shock (OR 10.7, 95% CI 1.01–1442; p = 0.049). Although the OR of platinum-combined chemotherapy for septic shock was not elevated (0.49, 95% CI 0.04–67.8; p = 0.67), all three patients with septic shock were treated with platinum-combined therapy. Combination chemotherapy including platinum should be administered carefully when patients have homozygous, double heterozygous, or heterozygous UGT1A1 variants and have a history of pelvic irradiation. A history of abdominal surgery was not shown as a risk factor for septic shock (OR 0.81, 95% CI 0.07–6.28) in this study.

Irinotecan is commonly used for various malignancies, including colon cancer, gastric cancer, pancreatic cancer, and gynecologic cancer [4, 6, 7, 14]. In these malignancies, irinotecan is widely used as a platinum combined regimen: FOLFOXIRI for colon cancer, FOLFIRINOX for pancreatic cancer, and irinotecan plus cisplatin for advanced and recurrent small cell lung cancer [4, 23, 24]. Thus, a history of pelvic irradiation, particularly in cases with UGT1A1 variants, should also be considered when administering irinotecan in patients with these cancers, as in patients with gynecologic cancers.

Patients with cervical cancer tend to be relatively young: the median age of diagnosis is reported to be 47 years and almost 50% of cases are diagnosed under the age of 35 years [20]. Concurrent chemoradiotherapy is a standard treatment for cervical cancer and cures a considerable number of these women [25]. It is possible that some of these women with a history of pelvic irradiation may suffer from other malignancies, including colon cancer, gastric cancer, and pancreatic cancer, later in their lives and may then receive irinotecan-containing chemotherapy. Our three cases with septic shock had a history of pelvic irradiation within a year. However, given the long-lasting effects of damage to the intestinal mucosa by irradiation (> 30 years) [17, 18], the effect of pelvic irradiation and the possibility of developing septic shock by irinotecan administration, due to neutropenic enterocolitis, should be kept in mind for a considerably long period after irradiation.

Our study suggests that a history of pelvic irradiation might be a risk factor for lethal complications after irinotecan therapy. In addition to UGT1A1 variants, a history of pelvic irradiation should be acknowledged as a possible risk factor for severe complications following irinotecan-containing chemotherapy. We suggest avoiding the administration of irinotecan, or at least administrating a reduced dose in patients with both UGT1A1 homozygous, double heterozygous, or heterozygous variants and a history of pelvic irradiation. All medical personnel involved in cancer therapy should be aware of the possible risk of developing septic shock due to neutropenic enterocolitis when administering irinotecan in patients with a history of pelvic irradiation. Further studies are required to evaluate this hypothesis.