New approaches to prevent intestinal toxicity of irinotecan-based regimens

CANCER TREATMENT REVIEWS (2004) 30, 555–562

www.elsevierhealth.com/journals/ctrv

COMPLICATIONS OF TREATMENT

New approaches to prevent intestinal toxicity of irinotecan-based regimens Andrea Alimontia,b,1, Alain Gelibterb,*,1, Ida Pavesea, Francesco Sattaa, Francesco Cognettib, Gianluigi Ferrettib, Debora Rasioc, Aldo Vecchionec, Mario Di Palmaa a b c

Division of Medical Oncology, San Pietro Hospital, FBF International, Rome, Italy Division of Medical Oncology A, Regina Elena Cancer Institute,Via Elio Chianesi 53 00144, Rome, Italy Division of Medical Oncology, La Sapienza II Faculty of Medicine, Rome, Italy

KEYWORDS

Summary Background. Irinotecan is a selective inhibitor of topoisomerase I, an enzyme part of the replication and transcription system of DNA. Irinotecan is employed, with different modalities, in the treatment of metastatic colorectal cancer, and recently it has been officially approved in association with fluorouracil (FU) and leucovorin (LV) as a first-line option in metastatic colorectal cancer. Results. One of the problems linked to the administration of this drug is the high intestinal toxicity, which constitutes its dose limiting toxicity (DLT). In routine practice, loperamide is employed as symptomatic drug for the treatment of CPT-11induced diarrhoea, but is not completely adequate to control the problem. The role of the intestinal bacterial microflora in the pathogenesis of CPT-11-induced intestinal toxicity has been recently discovered. The active metabolite of CPT-11, SN38, is generated from CPT-11 by sieric carboxylesterase, and subsequently conjugated to SN38-G by hepatic UDP–glucuronyltransferase. SN38-G is the inactive metabolite of CPT-11 and is excreted into the small intestine, from which it is eliminated in the faeces. Some studies have shown the ability of intestinal bacterial b-glucoronidases to transform SN38-G into SN38, causing direct damage to the intestinal mucosa. Thus, alternative strategies such as intestinal alkalinization and anti-cyclooxygenase 2 (COX-2) therapy have been explored. Conclusions. In this review, we will illustrate the mechanisms which cause the CPT-11-induced diarrhoea and the potential measures available to prevent it. c 2004 Elsevier Ltd. All rights reserved.

Irinotecan; Diarrhoea; Bacterial b-glucuronidase inhibitors



Introduction Irinotecan (CPT-11) is a semisynthetic analogue of camptothecin, the active agent isolated in the * Corresponding author. Tel.: +39-06-5266-6919; fax: +39-065266-5637. E-mail address: [email protected] (A. Gelibter). 1 These authors contributed equally to this work.



United States in 1966 from Camptotheca Acuminata, a plant native only to China and Tibet. Although camptothecin demonstrated significant anticancer activity in experimental studies, its clinical development was halted due to unacceptable toxicity. In 1985, with the discovery that topoisomerase I was the molecular target of camptothecin, a new wave of research on analogues with a more favorable profile began, leading to the

0305-7372/$ - see front matter c 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.ctrv.2004.05.002

556 discovery, in the 1990s, of a new and less toxic molecule, CPT-11. CPT-11 is a selective inhibitor of topoisomerase I, an enzyme involved in DNA replication and transcription. In 1998, it received full FDA approval for treatment of metastatic colorectal carcinoma that has recurred or progressed after standard chemotherapy.1;2 Recently, CPT-11 has been approved in association with fluorouracil (FU) and leucovorin (LV) as first line treatment of metastatic colorectal cancer.3;4 The role of CPT-11 as single agent or in combined modality regimens has been investigated in a number of other cancers, including small and non-small cell lung cancer, gastric cancer, cervical cancer, malignant brain tumours, ovarian cancer and pancreatic cancer.5–10 Results are promising, especially in small and non-small cell lung cancer. Severe intestinal toxicity remains one of the still unresolved problems linked to irinotecan administration and constitutes its dose limiting toxicity (DLT). Recent clinical trials have shown that CPT11 causes G3–G4 diarrhoea in at least 40% of patients,11 leading to a premature interruption of chemotherapy.12 Leucopenia is another frequent side effect but is more easily managed by administration of granulocyte colony stimulated factor (GCSF).13 In this review, we will illustrate the mechanisms that underlie CPT-11-induced diarrhoea and relevant prevention strategies.

Mechanism of action In 1985, Liu and colleagues14;15 demonstrated that camptothecin creates an unusual type of DNA damage in cancer cells by trapping the enzyme topoisomerase I during its normal action in regulating DNA structure. During DNA replication topoisomerase I produces reversible single-strand breaks in DNA by cutting and reattaching the double chain of DNA. These single-strand breaks relieve the torsional strain generated by advancing replication forks and allow DNA replication to proceed. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I–DNA complex and prevent religation of the DNA strand, resulting in doublestrand DNA breakage and cell death. Irinotecan is cell cycle phase-specific (S-phase) agent. Using high concentrations of irinotecan, killing of cells in other phases of the cell cycle can probably be achieved through transcriptional damage of the DNA.16

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Pharmacokinetics and pharmacodynamics Irinotecan is a pro-drug converted to its active metabolite, SN-38, by the enzyme carboxylesterase (CE). CE is present abundantly in the liver but can also be found in the duodenum, jejunum, ileum, colon, and rectum. Carboxylesterases cleave the piperidine side chain present at the C-10 position of the irinotecan molecule yielding the 100- to 1000-fold more biologically active metabolite, 7ethyl-10-hydroxycamptothecin or SN-38.17 After administration, irinotecan has a terminal half life (t1=2 ) of about 13 h, while the t1=2 of SN-38 is approximately 17–25 h. The distribution volume for a 125 mg/m2 dose is 110  48.5 L/m2 ; for a 340 mg/m2 dose is 234  69.6 L/m2 . Metabolism is primarily hepatic, through P450 CYP3A4, which generates the inactive metabolites APC and NPC.18–20 Although the in vitro activity of APC is inferior to that of SN38, little is known about APC activity in human.21 Some authors have demonstrated that a small part of APC can be metabolized by CE to SN-38.22–23 Recent evidence has shown that NPC constitutes a substrate for CE and is almost completely converted to the metabolically active SN-38.24 After irinotecan conversion into SN-38 by tissue carboxylesterase, detoxification occurs primarily through hepatic glucuronidation by the uridine diphosphate glucuronosyltransferase (UDP-GT) system, with formation of the inactive SN-38G.25 Particular attention must be used in patients with Gilbert’s disease and Crigler–Najjar syndrome. These patients have a reduced or absent UDP-GT activity, which is involved in the elimination of SN38, the active metabolite of irinotecan.26;27 Hence, they are at increasead risk of developing irinotecan-induced toxicity. Irinotecan is eliminated prevalently with the faeces (60–70%); 25% and 10–20% of the drug is eliminated in the bile and urine, respectively.28 When SN-38G is secreted into the bile, it reaches the intestine where part is eliminated with the faeces and part is reabsorbed in the blood. It has been shown that SN-38G, once secreted into the intestinal lumen, can be re-transformed back to SN-38 by the bacterial b-glucuronidase present in the intestinal cells. These data have emerged from studies conducted both in animals and humans.29–31 The plasma concentration of irinotecan and its metabolites decreases in the following order: irinotecan, SN-38G, APC, SN-38, NPC. Irinotecan and SN-38 have a labile hydroxylactone ring that may undergo a pH-dependent reversible hydrolysis in the intestinal lumen,

Irinotecan and intestinal toxicity producing two different isoforms, the carboxylate and lactone form. The carboxylate form is a less potent inhibitor of topoisomerase I and has much weaker antitumour activity than its lactone counterpart.32;33

New strategies to decrease irinotecan-intestinal-toxicity Inhibitors of bacterial b-glucuronidase CPT-11/SN-38-induced diarrhoea may occur in one or both of two different time settings. The first occurs early within 24 h of infusion. Early onset diarrhoea is thought to be part of a cholinergic syndrome mediated by increased anticholinesterase activity of the irinotecan parent compound. It may be accompanied by other cholinergic symptoms such as rhinitis, hypersalivation, miosis, lacrimation, diaphoresis, flushing, and abdominal cramping. It is usually prevented or rapidly suppressed by atropine administration, is generally transient and only occasionally severe.34 Late diarrhoea, has a median onset of 5 and 11 days after the 3-weekly35 and weekly36 dosing schedule of irinotecan, respectively. It can be prolonged, lasting 5–7 days and leading to potentially life-threatening dehydration and electrolyte imbalance. Late onset diarrhoea is thought to be related to abnormal ion transport in the injured intestinal mucosa, leading to increased secretion of water and electrolytes into the intestinal lumen.37 Management of diarrhoea should include prompt treatment with high dose loperamide and fluid and electrolyte replacement. Recent reports have highlighted the significant role of diarrhoea and dehydration in the early death of patients treated with CPT-11.12 CPT-11 weekly monotherapy is associated with a significant incidence of G3–G4 diarrhoea (31%).3 Although several clinical trials in humans have tried to decrease the incidence of diarrhoea by the modification of CPT-11 schedules, the results obtained are still controversial.38 Furthermore, the variability in the severity of intestinal toxicity presents difficulties in management with conventional drugs for diarrhoea. At the moment, there is not a prophylactic therapy capable of reliably preventing irinotecan-induced diarrhoea. High dose loperamide may be effective and in some cases may allow the administration of higher doses of CPT-11.38 Other drugs like acetorphan, butesonide and octreotide have been used to slow intestinal motility and decrease water and electrolyte

557 movement through the bowel.39–42 Recently, the mechanisms of late diarrhoea have been studied in animal and human models.29;31 Many authors have hypothesized the existence of SN-38-induced structural and functional intestinal damage.29;43 Mice treated with irinotecan had intestinal wall thinning with epithelial vacuolation, vascular dilatation, an inflammatory cell infiltrate and evidence of apoptosis in the ileum.43 Guffroy and Hodge44 observed villous atrophy in the small intestine but not caecal lesions in their mouse studies. These studies have led to the discovery of the key role of bacterial b-glucoronidase in the irinotecan-induced intestinal toxicity. At the present time, many authors consider the intestinal bacterial microflora responsible for the damage to the intestinal mucosa because of their capacity of transforming the SN-38G in SN-38 in the intestinal lumen. SN-38, free from the link with glucuronic acid, exerts its toxic action directly on the DNA of the intestinal cells in the same way as cancer cells, causing epithelial disruption. A study by Takasuna et al. has shown a link between the faecal concentration of SN-38 and the anatomic damage to the intestinal mucosa in mice. The authors documented greater anatomical damage in the intestinal segments where the bacterial b-glucuronidase activity was more represented (colon and caecum), and demonstrated that 1 mg of penicillin and 2 mg of streptomycin were able to decrease the incidence of diarrhoea and limit the loss of body weight in rats.30 Only recently has antibiotic therapy been used in humans for the prevention of CPT11-related diarrhoea. Kerher et al.31 used an oral antibiotic, neomycin, to decrease b-gluguronidase activity in the intestinal lumen, and reported good control of CPT-11-induced diarrhoea in seven colorectal cancer patients. As a consequence, many authors have tried to test new inhibitors of intestinal bacterial microflora for the prevention of CPT-11-related diarrhoea. We used an oral association of two common antibiotics (neomycin plus bacitracin) that are able to inhibit the intestinal bacterial microflora, and reported interesting results both in terms of diarrhoea prevention and in patient drug tolerability. Twenty-four metastatic colorectal cancer patients who developed grade P 2 diarrhoea after the first chemotherapy cycle with CPT-11 plus FU/LV were enrolled in the study. After the second cycle they were treated with an association of neomycin 25,000 IU plus bacitracin 2500 IU at a single dose of 1000 mg three times per day from day 2 to 5 and from day 16 to 19 of each course of chemotherapy. In all 24 patients, we observed complete resolution

558 of diarrhoea from the second until the fourth cycle. Only three patients experienced diarrhoea in the fifth cycle (G1 in 2 patients and G2 in 1 patient), and only seven in the last cycle (G1 in 4 patients, G2 in 2 patients, G3 in 1 patient). Our findings indicated that the simultaneous treatment with oral neomycin and bacitracin was able to prevent the incidence and severity of irinotecan-induced diarrhoea. In addition, our study confirmed the important role of the bacterial microflora in the development of this side effect.45;46 A Chinese study has recently shown that the Chinese herb Hange-Shashito (TJ-14), a natural inhibitor of the b-glucuronidase activity of bacterial microflora, can also prevent the delayed diarrhoea caused by CPT-11.47 However, another study has detected up to 30% of irinotecan may be excreted unchanged in the bile partially contesting the role of intestinal bacterial microflora in CPT11-related diarrhoea.48 These observations may be less relevant now that other authors have recently highlighted the existence of direct bowel conversion of irinotecan into SN-38 by a new identified intestinal carboxylesterase.49 Carboxylesterase was detected in human gut biopsies and extracts of these tissues converted CPT-11 to SN-38 in vitro.48 These results suggest that the gut toxicity mediated by CPT-11 may be due in part to direct drug conversion by the enzyme within the small intestine.

Alternative strategies Alternative strategies have been explored to prevent diarrhoea in patient treated with CPT-11. Recently Ikegami et al.32;33;50 showed that irinotecan and SN-38 have a structure with a labile ring a-hydroxy-lactone that undergoes pH-dependent reversible hydrolysis. At physiological pH or higher, equilibrium favors the less toxic carboxylate form, whereas at acid pH the more potent lactone is predominant. In a hamster model, the authors reduced the intestinal SN-38 lactone concentration as well as cellular damage and diarrhoea induced by CPT-11 by increasing the intestinal pH through bicarbonate administration.32 This study is the first to clearly demonstrate that an increased intestinal pH after oral bicarbonate administration is associated with a reduction in the intestinal SN-38 lactone concentration, as well as cellular damage and diarrhoea induced by CPT-11. A daily injection of CPT-11 at a dose of 20–50 mg/kg induced diarrhoea by days 3–5 and was lethal by day 5 at a dose P 100 mg/kg. Under these conditions, oral administration of 5 mg/ml sodium bicarbonate in the

A. Alimonti et al. drinking water significantly reduced both the fecal water content, as well as the intestinal tissue damage induced by 20–50 mg/kg CPT-11. These results are further supported by a Phase II clinical trial suggesting benefit from sodium bicarbonate supplementation against CPT-11-induced severe delayed diarrhoea.33 In rats, lipopeptide JBT 3002 is able to prevent the incidence of CPT-11-induced diarrhoea by the stimulation of IL15, one of the molecules responsible of the integrity of intestinal epithelium.44 The oral administration of this new synthetic bacterial lipopeptide, encapsulated in phospholipid liposomes, was able to prevent damage to the intestinal epithelium and lamina propria, and allow the parenteral administration of high-dose irinotecan to mice with established syngeneic CT-26 colon cancer liver metastases. Histopathological examination of the mice intestines after treatment with four daily i.p. injections of 100 mg/kg irinotecan dose revealed loss of villi, epithelial vacuolation, decrease in the number of cells in the crypts in Sphase, increase in the number of apoptotic cells, and reduction in the number of lymphocytes in the lamina propria. In contrast, treatment of mice with the same irinotecan regimen after oral administration of JBT 3002 produced highly significant inhibition of liver metastases without detectable damage to the intestines. Histological studies revealed that the liver metastases in mice treated with oral JBT 3002 and i.p. irinotecan contained a higher number of macrophages than metastases in mice treated with either drug alone. Tumour cells exposed to both irinotecan and macrophages activated by JBT 3002 were highly susceptible to lysis. These data showed that oral administration of JBT 3002 could prevent irinotecan-induced gastrointestinal toxic effects and maintain the integrity of the lamina propria, allowing for the intensification of irinotecan therapy against liver metastases from colon cancer.51;52 Probenecid, a biliary inhibitor of CPT-11 and SN38 secretion, has been shown to reduce CPT-11 intestinal toxicity in mice. Horikawa et al. reported that the coadministration of probenecid reduced the biliary excretion of CPT-11, an active metabolite (SN-38) and its glucuronide by half with a concomitant increase in their plasma concentration. With this strategy, CPT-11-induced watery diarrhoea, changes in intestinal marker enzymes and body weight reduction were much less frequent in the probenecid-treated group, although the degree of bone marrow suppression was almost the same as that in the control. The authors concluded that the co-administration of probenecid with a reduced dose of CPT-11 potently reduced

Irinotecan and intestinal toxicity both SN-38 exposure and CPT-11-induced late-onset toxicity in gastrointestinal tissues, possibly by inhibiting the biliary excretion of CPT-11 and/or its metabolites.53 No evidence has confirmed this observation in humans. It has been reported that CPT-11 administration is associated with increased colon prostaglandin synthesis in both in vivo and ex vivo models. Both PGE2 and TXA2 , shown to increase after CPT-11 treatment, have been reported to play a key role in water and electrolyte balance in the colon.54;55 Led by these observations, Trifan et al. hypothesized that late diarrhoea could be a consequence of COX-2 induction secondary to colonic mucosal damage after CPT-11 treatment. Thus, addition of a COX-2-specific inhibitor like celecoxib might be useful in decreasing CPT-11-induced diarrhoea. In their study56 animals in the control group (CPT-11 alone) had a high incidence of diarrhoea scores 2 and 3. Cotreatment with celecoxib decreased the severity of late diarrhoea in a dose-dependent manner, with a maximal effect obtained with celecoxib at 30 mg/kg/day. The effect of celecoxib effect on CPT-11-induced diarrhoea may be mediated by a PGE2 -dependent mechanism. CPT11 administration leads to an increase in COX-2 protein and PGE2 levels in the rat colon. COX-2 protein in the colon, as detected by Western blot analysis, increased by day 4 and reached a maximum at day 5. A similar trend could be observed for the PGE2 content of the colon, whereas COX-1 protein levels in the colon showed little change after CPT-11 treatment. The increase in COX-2 was associated with an increase in tissue PGE2 levels. Interestingly, this time course tightly followed the evolution of late diarrhoea in this model, suggesting a causal relationship between COX-2 induction and late diarrhoea, where PGE2 could be the mediator. Govindarajan et al.57 have studied the effect of combined therapy with thalidomide and CPT-11, suggesting a role for thalidomide in the prevention of Irinotecan-related intestinal toxicity. Cotreatments with valproic acid or ceftriaxone have been associated with a reduced frequency of grade 3 irinotecan-induced diarrhoea,58 but this observation needs to be confirmed in studies conducted on humans. Oral cyclosporin (Cs) has been used in association with CPT-11 to prevent intestinal toxicity in a phase I clinical trial. This drug, used in a rationally designed strategy based on the knowledge of irinotecan metabolism, was originally proposed by Ratain et al59;60 to inhibit the biliary clearance of irinotecan metabolites. The hypothesis is that by reducing SN38 and SN38G clearance into the small bowel lumen, late diarrhoea may be

559 avoided or reduced. The lack of severe diarrhoea observed in this study61 is encouraging and supports the study hypothesis. Only one patient out of 37 experienced grade 3 diarrhoea, and grade 4 diarrhoea did not occur. This compares favourably with results from recent phase III trials in which grade 3 or 4 diarrhoea occurred in 22% of patients receiving the standard European schedule of 350 mg/m2 every 3 weeks,1;2 in 31% of patients receiving the standard North American schedule of 125 mg/m2 once per week for 4 weeks,3 and in 18.4% of patients receiving irinotecan once every 2 weeks at 250 mg/m2 .62 Cs itself added some toxicity (abdominal cramps, flushing or sweats, and paresthesia), which was usually brief and low grade, but in one patient was considered intolerable. These findings confirm the success of the pharmacokinetic modulation because they demonstrate that active systemic drug levels were achieved despite the small doses being used. However, further studies are needed to optimize scheduling, to compare the efficacy of the combination with standard schedules, and thereby to establish whether the therapeutic index of irinotecan is improved and intestinal toxicity is reduced by this strategy.

Conclusions During last years CPT-11 has shown huge activity in several cancers and future perspectives could be open for other indications. In the era of dose intensification, many drugs have shown better results when used at higher dose levels or with more dose dense schedules.63;64 Thus, increasing CPT-11 dose could be a useful strategy to improve patient outcome. However, irinotecan-induced intestinal toxicity seems to be the greatest barrier to such an approach. Nowadays, loperamide is employed as symptomatic drug for the treatment of CPT-11induced diarrhoea, even though it is not adequate to control the diarrhoea caused by higher irinotecan dose levels. According to our results, inhibitors of bacterial b-glucuronidase, that modulate CPT-11 intestinal toxicity, could prevent diarrhoea, and thus potentially allow irinotecan dose intensification. Only a few clinical studies focusing on the role of inhibitors of b-glucuronodase have been reported. Our study represents the first clinical experience in which these drugs have been successfully tested in colorectal cancer patients.45;46 However, further prospective randomized investigations are needed to definitively confirm these findings.

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