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Aoki, Masahiko, Hirokazu Shoji, Hiroshi Imazeki, Takahiro Miyamoto, Hidekazu Hirano, Yoshitaka Honma, Satoru Iwasa, et al. "The hyperprogressive disease during nivolumab treatment or irinotecan treatment in patients with advanced gastric cancer." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 124. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.124.
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124 Background: Nivolumab has demonstrated a survival benefit as a single agent in patients with advanced gastric cancer (AGC) refractory to, or intolerant of, two or more previous regimens in phase III study (ATTRACTION-2). However, an acceleration of tumor growth during immunotherapy, (hyperprogressive disease: HPD), was reported in advanced cancers treated with immunotherapy. The frequency and outcome of HPD in AGC comparing between immunotherapy and cytotoxic agents are little known. The aim of this study was to clarify the prevalence and background of HPD in patients treated with nivolumab or irinotecan. Methods: The subjects of this retrospective study were AGC patients with measurable disease defined by RECIST version 1.1 who were treated with nivolumab or irinotecan at our institution between June 2009 and September 2018, and whose tumors were assessed at least 3 times (during prior therapy, immediately before and after initiating nivolumab or irinotecan). The tumor growth rates (TGR) both before and after nivolumab or irinotecan were calculated as reported (Stéphane Champiat, Clin Cancer Res 2017). HPD was defined as an increase in the TGR exceeding 50% after nivolumab or irinotecan compared with prior therapy. Results: 32 and 66 patients received nivolumab and irinotecan (20 patients received both irinotecan and nivolumab). There were more prior chemotherapy before nivolumab than irinotecan (median: 3 vs 2). The median overall survival (MST) was 4.1 months (95%CI; 4.6-9.3 months) after nivolumab, and 7.0 months (95%CI; 6.3-9.3 months) after irinotecan. There were 9 patients showing HPD (28.1%) after initiating nivolumab and 9 patients (13.5%) after irinotecan (p = 0.0824). There were no differences in background between patients with and without HPD either after nivolumab or irinotecan. 9 patients with HPD showed shorter survival than those without HPD after nivolumab (median: 1.9 vs 6.4 months, p = 0.0007) while there was no such difference after irinotecan (median: 7.3 vs 7.0 months, p = 0.3345). Conclusions: HPD was observed more frequently after initiating nivolumab compared with irinotecan, and was associated with a poor prognosis after nivolumab but not after irinotecan.
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Falcone, Alfredo, Antonello Di Paolo, Gianluca Masi, Giacomo Allegrini, Romano Danesi, Monica Lencioni, Elisabetta Pfanner, Silvia Comis, Mario Del Tacca, and Pierfranco Conte. "Sequence Effect of Irinotecan and Fluorouracil Treatment on Pharmacokinetics and Toxicity in Chemotherapy-Naive Metastatic Colorectal Cancer Patients." Journal of Clinical Oncology 19, no. 15 (August 1, 2001): 3456–62. http://dx.doi.org/10.1200/jco.2001.19.15.3456.
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PURPOSE: To investigate the sequence effect of irinotecan and a 48-hour infusion of fluorouracil (5-FU) modulated by leucovorin (LV) on the plasma pharmacokinetics of irinotecan and its metabolites, the toxicity profile of this combination, and irinotecan’s maximum-tolerated dose (MTD). PATIENTS AND METHODS: Thirty-three metastatic colorectal cancer patients were randomized to receive a 60-minute infusion of irinotecan before or after a 48-hour infusion of 5-FU modulated by LV. The reverse sequence was used after 21 days for the second cycle. 5-FU 3,500 mg/m2 was preceded by l-LV 250 mg/m2. Irinotecan 150 mg/m2 (starting dose) was administered to the first three patients. The dose was escalated by 50 mg/m2 in subsequent groups of three to six patients to determine the MTD for both sequences. Pharmacokinetic analysis of irinotecan and its metabolites was performed after each cycle. RESULTS: Toxicities were affected by the sequence of administration of irinotecan and 5-FU, with an improved tolerability for irinotecan followed by 5-FU. The irinotecan MTD was reached at 300 mg/m2 when irinotecan followed 5-FU and at 450 mg/m2 when it preceded 5-FU. In seven of 23 patients who received both sequences at identical irinotecan doses, the dose-limiting toxicity was observed only when irinotecan followed 5-FU. Pharmacokinetic analysis revealed that the administration sequence significantly affected the SN-38 area under the concentration-versus-time curve (AUC), which was 40.1% lower (P < .05) when irinotecan preceded 5-FU. CONCLUSION: The sequence of treatment with irinotecan and infusional 5-FU affects the tolerability of this combination. This can be explained in part by a reduced SN-38 AUC when irinotecan preceded infusional 5-FU. Well-defined 5-FU/irinotecan regimens are needed because the administration sequence or the interval between the agents might affect treatment tolerance and perhaps also activity.
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Vanhoefer, Udo, Andreas Harstrick, Wolf Achterrath, Shousong Cao, Siegfried Seeber, and Youcef M. Rustum. "Irinotecan in the Treatment of Colorectal Cancer: Clinical Overview." Journal of Clinical Oncology 19, no. 5 (March 1, 2001): 1501–18. http://dx.doi.org/10.1200/jco.2001.19.5.1501.
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PURPOSE AND METHODS: For more than three decades, the therapeutic options for patients with advanced colorectal cancer have almost exclusively been based on fluoropyrimidines. With the recognition that topoisomerase-I (TOP-I) is an important therapeutic target in cancer therapy, irinotecan, a semisynthetic TOP-I–interactive camptothecin derivative, has been clinically established in the treatment of colorectal cancer. RESULTS: Irinotecan was investigated as second-line chemotherapy after prior treatment with fluorouracil (FU)-based regimens in two large randomized phase III trials comparing irinotecan with either best supportive care or an infusional FU/leucovorin (LV) regimen. The outcomes of these trials established irinotecan as the standard therapy in the second-line treatment of colorectal cancer. The therapeutic value of irinotecan in the first-line treatment of metastatic colorectal cancer was investigated in two large randomized phase III trials comparing the combination of irinotecan and FU/LV with FU/LV alone. Both trials demonstrated significant superior efficacy for the combination of irinotecan and FU/LV in terms of response rate, median time to disease progression, and median survival time. Consequently, the combination of irinotecan and FU/LV has been approved as first-line chemotherapy for patients with metastatic colorectal cancer and constitutes the reference therapy against which other treatment options must be tested in the future. CONCLUSION: In this review, the clinical rationale and update of the present clinical status of irinotecan in the treatment of colorectal cancer and future prospects of irinotecan-based combinations are discussed.
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Bailly, Christian. "Irinotecan: 25 years of cancer treatment." Pharmacological Research 148 (October 2019): 104398. http://dx.doi.org/10.1016/j.phrs.2019.104398.
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Kockaya, Guvenc, Mine Polat, Albert Wertheimer, Ahmet Ozet, Simten Malhan, İsmail Mert Vural, Akif Akbulat, Guven Artıran, Hakkı Gursoz, and Saim Kerman. "Treatment cost of metastatic colon cancer in Turkey." Farmeconomia. Health economics and therapeutic pathways 14, no. 1 (January 30, 2013): 19–25. http://dx.doi.org/10.7175/fe.v14i1.472.
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OBJECTIVES: Colon cancer is the third most common in the top cancer incidence list in Europe. In Europe 212,000 patients die every year due to colon cancer. In Turkey 120,000-130,000 new cancer patients are diagnosed every year, 7.1% of whom are diagnosed to have developed colon cancer. Metastases will occur in up to 50% of the patients who are newly diagnosed. Survival appears to be further prolonged to more than 20 months with new pharmaceuticals; however, these new pharmaceuticals increase the total cost of care. The aim of this study is to estimate the cost implications of new colon cancer treatment options for Turkey.METHODS: Gazi University Hospital treatment protocols for colon cancer treatment were used. Cost of FUFA (5 FU/LV), FOLFIRI, FOLFOX, bevacizumab/FUFA, bevacizumab/FOLFIRI, bevacizumab/FOLFOX, irinotecan and irinotecan/cetixumab protocols were calculated. The cost of combination of protocols were calculated depending on a Markov analysis. The exchange rate was US$ 1 for TL 1.5.RESULTS: Depending on the life expectancy the lowest total cost was established by FUVA (US$ 5,359). It was followed by FOLFIRI then FOLFOX and FOLFOX, US$ 14,144 and US$ 16,553, respectively. The lowest cost for each week of life expectancy was established by FUVA with US$ 98.CONCLUSIONS: Only FUFA, FOLFIRI followed by FOLFIX, FOLFIRI/bevacizumab then FOLFOX then cetuximab, FOLFOX/bevacizumab then irinotecan then cetuximab/irinotecan and FOLFIRI/bevacizumab then FOLFOX then cetuximab/irinotecan were under the cost effectiveness curve. In addition no treatments ICER was under the WHO`s threshold for Turkey, except FOLFIRI then FOLFOX compared with FUVA.
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Radajewska, Anna, Helena Moreira, Dorota Bęben, Oliwia Siwiela, Anna Szyjka, Katarzyna Gębczak, Paulina Nowak, et al. "Combination of Irinotecan and Melatonin with the Natural Compounds Wogonin and Celastrol for Colon Cancer Treatment." International Journal of Molecular Sciences 24, no. 11 (May 31, 2023): 9544. http://dx.doi.org/10.3390/ijms24119544.
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Colorectal cancers are one of the leading cancers worldwide and are known for their high potential for metastasis and resistance to therapy. The aim of this study was to investigate the effect of various combination therapies of irinotecan with melatonin, wogonin, and celastrol on drug-sensitive colon cancer cells (LOVO cell line) and doxorubicin-resistant colon cancer stem-like cells (LOVO/DX cell subline). Melatonin is a hormone synthesized in the pineal gland and is responsible for circadian rhythm. Wogonin and celastrol are natural compounds previously used in traditional Chinese medicine. Selected substances have immunomodulatory properties and anti-cancer potential. First, MTT and flow cytometric annexin-V apoptosis assays were performed to determine the cytotoxic effect and the induction of apoptosis. Then, the potential to inhibit cell migration was evaluated using a scratch test, and spheroid growth was measured. The results showed important cytotoxic effects of the drug combinations on both LOVO and LOVO/DX cells. All tested substances caused an increase in the percentage of apoptotic cells in the LOVO cell line and necrotic cells in the LOVO/DX cell subline. The strongest effect on the induction of cancer cell death was observed for the combination of irinotecan with celastrol (1.25 µM) or wogonin (50 µM) and for the combination of melatonin (2000 µM) with celastrol (1.25 µM) or wogonin (50 µM). Statistically significant improvements in the effect of combined therapy were found for the irinotecan (20 µM) and celastrol (1.25 µM) combination and irinotecan (20 µM) with wogonin (25 µM) in LOVO/DX cells. Minor additive effects of combined therapy were observed in LOVO cells. Inhibition of cell migration was seen in LOVO cells for all tested compounds, while only irinotecan (20 µM) and celastrol (1.25 µM) were able to inhibit LOVO/DX cell migration. Compared with single-drug therapy, a statistically significant inhibitory effect on cell migration was found for combinations of melatonin (2000 µM) with wogonin (25 µM) in LOVO/DX cells and irinotecan (5 µM) or melatonin (2000 µM) with wogonin (25 µM) in LOVO cells. Our research shows that adding melatonin, wogonin, or celastrol to standard irinotecan therapy may potentiate the anti-cancer effects of irinotecan alone in colon cancer treatment. Celastrol seems to have the greatest supporting therapy effect, especially for the treatment of aggressive types of colon cancer, by targeting cancer stem-like cells.
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Aoki, Masahiko, Hirokazu Shoji, Kengo Nagashima, Hiroshi Imazeki, Takahiro Miyamoto, Hidekazu Hirano, Yoshitaka Honma, et al. "Hyperprogressive disease during nivolumab or irinotecan treatment in patients with advanced gastric cancer." ESMO Open 4, no. 3 (May 2019): e000488. http://dx.doi.org/10.1136/esmoopen-2019-000488.
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BackgroundNivolumab showed a survival benefit for advanced gastric cancer (AGC). However, an acceleration of tumour growth during immunotherapy, (hyperprogressive disease, HPD) has been reported in various cancers. This study reviewed the HPD in patients with AGC treated with nivolumab or irinotecan.MethodsThe subjects of this retrospective study were patients with AGC with measurable lesions, and their tumour growth rates (TGR) during nivolumab or irinotecan were compared with those during prior therapy. HPD was defined as an increase in TGR more than twofold.Results34 and 66 patients received nivolumab and irinotecan in third or later line between June 2009 and September 2018 at our hospital; 22 patients receiving nivolumab had prior treatment with irinotecan, and one patient received irinotecan after nivolumab. Nivolumab and irinotecan showed no differences in disease control rates (38.2% and 34.8%) and in progression-free survival (PFS) (HR 1.1, 95% CI 0.7 to 1.6, p=0.802). The incidence of HPD was slightly higher after nivolumab (29.4%) than after irinotecan (13.5%) (p=0.0656), showing no differences in background between the patients with and without HPD. Compared between HPD and PD other than HPD after nivolumab, the HRs for PFS and overall survival (OS) were 1.1 (95% CI 0.5 to 2.7; p=0.756), and 2.1 (95% CI 0.7 to 5.8; p=0.168), but such clear difference in OS was not observed after irinotecan.ConclusionsHPD was observed more frequently after nivolumab compared with irinotecan, which was associated with a poor prognosis after nivolumab but not so clearly after irinotecan.
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Kciuk, Mateusz, Beata Marciniak, and Renata Kontek. "Irinotecan—Still an Important Player in Cancer Chemotherapy: A Comprehensive Overview." International Journal of Molecular Sciences 21, no. 14 (July 12, 2020): 4919. http://dx.doi.org/10.3390/ijms21144919.
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Irinotecan has been used in the treatment of various malignancies for many years. Still, the knowledge regarding this drug is expanding. The pharmacogenetics of the drug is the crucial component of response to irinotecan. Furthermore, new formulations of the drug are introduced in order to better deliver the drug and avoid potentially life-threatening side effects. Here, we give a comprehensive overview on irinotecan’s molecular mode of action, metabolism, pharmacogenetics, and toxicity. Moreover, this article features clinically used combinations of the drug with other anticancer agents and introduces novel formulations of drugs (e.g., liposomal formulations, dendrimers, and nanoparticles). It also outlines crucial mechanisms of tumor cells’ resistance to the active metabolite, ethyl-10-hydroxy-camptothecin (SN-38). We are sure that the article will constitute an important source of information for both new researchers in the field of irinotecan chemotherapy and professionals or clinicians who are interested in the topic.
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Sagawa, Tamotsu, Hironaga Satake, Koshi Fujikawa, Yukimasa Hatachi, Hisateru Yasui, Masahito Kotaka, Takeshi Kato, and Akihito Tsuji. "Phase Ib study of ramucirumab and irinotecan for metastatic gastric cancer previously treated with fluoropyrimidine with/without platina and taxane." Journal of Clinical Oncology 36, no. 4_suppl (February 1, 2018): 155. http://dx.doi.org/10.1200/jco.2018.36.4_suppl.155.
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155 Background: Optimal salvage line chemotherapy for previously heavily treated advanced/ metastatic gastric cancer (AGC) is unknown, but treated with irinotecan in Japan. Ramucirumab, a human IgG-1 monoclonal antibody that targets the extracellular domain of VEGF receptor 2, is the first molecularly targeted agent proven to be effective in second-line therapy for AGC in combination with chemotherapy. Furthermore, combination chemotherapy with ramucirumab and irinotecan based regimen (FOLFIRI) is recognized as one of the promising regimens for metastatic colorectal cancer. To date, however, use of the ramucirumab plus irinotean regimen for AGC patients has not been investigated, and recommended doses (RD) of ramucirumab plus irinotecan for patients with AGC therefore remain unknown. The aim of this study was to determine the maximum tolerated dose (MTD) and RD for systemic chemotherapy with rumucirumab plus irinotecan for AGC previously treated with fluoropyrimidine with/without platina and taxane. Methods: Patients received systemic chemotherapy with ramucirumab (8mg/kg) and irinotecan on day 1, repeated every 2 weeks. A decrease in irinotecan dose was planned from start level 1 (irinotecan 150mg/m2). This trial was registered with the University Hospital Medical Network (UMIN no. 000018606). Results: Six patients were enrolled from August 2015 to September 2017. MTD was not reached at level 1. Irinotecan 150 mg/m2 in combination with ramucirumab 8mg/kg could be administered with acceptable toxicity, and all patients were treated at these doses. No DLT was observed at Level 1. No treatment-related death was observed. Adverse events of grade 3/4 were neutropenia (17%), anemia (17%), hyponatremia (17%), hypertension (17%). Five of the six patients were evaluable for efficacy based on the RECIST criteria, and response rate and disease control rate were 20% and 100%, respectively. Conclusions: Salvage chemotherapy with a ramucirumab plus irinotecan regimen was well tolerable for patients with previously heavily treated AGC. RD was defined as ramucirumab 8 mg/kg in combination with irinotecan 150 mg/m2/day. Clinical trial information: 000018606.
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Shun, Yu-Ting, Hsien-Yung Lai, Yi-Ting Chuang, and Hsuen-Fu Lin. "Successful Treatment of Irinotecan-Induced Muscle Twitching: A Case Report." Clinical Medicine Insights: Case Reports 16 (January 2023): 117954762211503. http://dx.doi.org/10.1177/11795476221150354.
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Irinotecan, a topoisomerase I inhibitor, is commonly used in the treatment of advanced colorectal cancer. Its adverse effects include delay diarrhea, severe myelosuppression, and cholinergic-like symptoms. Though 2 cases of irinotecan-induced muscle twitching were reported but the successful treatment of this adverse event still not shown. We present a 24-year-old female patient with advanced colorectal cancer received bevacizumab and FOLFIRI (irinotecan + calcium leucovorin + 5-fluorouracil) treatment. Her right pectoralis major muscle presented with involuntary muscle twitching during the infusion of irinotecan at the sixth cycle of chemotherapy. The muscle twitching was slowly dissipated about 4 hours after the halted of irinotecan infusion. Then lorazepam 2 mg iv was injected before administration of irinotecan in an attempt to prevent the muscle twitching in the seventh cycle of chemotherapy. The patient did not report further muscle twitching. After that, lorazepam was routine administered before each cycle of FOLFIRI regiment. No any muscle twitching was observed after the use of lorazepam. This case provides valuable insight that muscle twitching can occur as rare irinotecan-related adverse effect. Benzodiazepine agonists, such as lorazepam, is the potential treatment of choice.
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Hulshof, Emma C., Mirjam de With, Femke M. de Man, Geert-Jan Creemers, Birgit ALM Deiman, Jesse J. Swen, Saskia Houterman, et al. "Safety and pharmacokinetic analysis of UGT1A1 genotype-guided dosing of irinotecan." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): 3574. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.3574.
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3574 Background: Irinotecan is commonly used in the treatment of advanced colorectal and pancreatic cancer. The polymorphisms UGT1A1*28 (7 TA repeats) and UGT1A1*93 (SNP -3156G > A) are significantly associated with increased systemic exposure of irinotecan’s active metabolite SN-38 and subsequently severe irinotecan-associated adverse-events (AEs) including (febrile) neutropenia and diarrhea. Severe AEs may lead to hospitalization, loss of quality of life, treatment delay and/or treatment discontinuation. Nonetheless, prospective genetic screening is not yet routinely performed. The aim of this study was to determine the safety and pharmacokinetics of UGT1A1 genotype-guided dosing of irinotecan in UGT1A1 poor metabolizers (PMs), i.e. UGT1A1 *28/*28 and/or UGT1A1*93/*93 individuals, in order to reduce the incidence of severe irinotecan-associated AEs. Methods: A prospective, multi-center, non-randomized study was conducted in patients intended to be treated with irinotecan at a dose of ≥ 180 mg/m2 or 450-600 mg flat dose. All patients were pre-therapeutically genotyped for UGT1A1*28 and UGT1A1*93. In UGT1A1 PMs, an initial 30% dose reduction in the first cycle was applied followed by further individual dose titration based on neutrophil count and clinical tolerability. The primary endpoint was the incidence of febrile neutropenia in the first 2 cycles of irinotecan treatment. UGT1A1 PMs were compared to 1] historical control patients, i.e. homozygous polymorphic patients treated with full dose therapy identified from systematic literature review and to 2] UGT1A1 non-PMs treated with standard dose therapy. In addition, systemic SN-38 exposure (AUC0-500h) of reduced dosing in the UGT1A1 PM cohort was compared to a standard dosed irinotecan patient cohort [doi: 10.1200/JCO.2000.18.1.195] by an independent T-test. Results: A total of 349 patients were pre-therapeutically genotyped and included for analysis. Thirty-one (8.9%) patients were UGT1A1 PM, in whom an initial median 30% dose reduction was applied. The incidence of febrile neutropenia in this group was 6.5% compared to 24% in historical controls (n = 50) (p = 0.042) and comparable with the incidence (4.1%; p = 0.632) in UGT1A1 non-PMs treated with full dose therapy. The systemic exposure of SN-38 of reduced dosing in UGT1A1 PMs (n = 17) was comparable to the systemic exposure of the standard dosed irinotecan patient cohort (n = 46) with a relative difference of +24% (p = 0.054) with a geometric mean (CV) of SN-38 AUC0-500h of 391 (43.7%) versus 298 (75.3%) ng*h/mL, respectively. Conclusions: UGT1A1 genotype-guided dosing significantly reduces the incidence of febrile neutropenia in UGT1A1 PM patients treated with irinotecan. In addition, systemic drug exposure remained adequate, despite the 30% dose reduction. Therefore, UGT1A1 genotype-guided dosing of irinotecan should be considered standard of care in order to improve the individual patient safety. Clinical trial information: Trial NL6270 (NTR6612).
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Jahan, Zeenat, Fahad A. Benthani, Nicola Currey, Hannah W. Parker, Jane E. Dahlstrom, C. Elizabeth Caldon, and Maija R. J. Kohonen-Corish. "MCC Gene Silencing Is a CpG Island Methylator Phenotype-Associated Factor That Predisposes Colon Cancer Cells to Irinotecan and Olaparib." Cancers 14, no. 12 (June 9, 2022): 2859. http://dx.doi.org/10.3390/cancers14122859.
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Chemotherapy is a mainstay of colorectal cancer treatment, and often involves a combination drug regime. CpG island methylator phenotype (CIMP)-positive tumors are potentially more responsive to the topoisomerase-inhibitor irinotecan. The mechanistic basis of the increased sensitivity of CIMP cancers to irinotecan is poorly understood. Mutated in Colorectal Cancer (MCC) is emerging as a multifunctional tumor suppressor gene in colorectal and liver cancers, and has been implicated in drug responsiveness. Here, we found that CIMP tumors undergo MCC loss almost exclusively via promoter hypermethylation rather than copy number variation or mutations. A subset of cancers display hypomethylation which is also associated with low MCC expression, particularly in rectal cancer, where CIMP is rare. MCC knockdown or deletion was found to sensitize cells to SN38 (the active metabolite of irinotecan) or the PARP-inhibitor Olaparib. A synergistic effect on cell death was evident when these drugs were used concurrently. The improved SN38/irinotecan efficacy was accompanied by the down-regulation of DNA repair genes. Thus, differential methylation of MCC is potentially a valuable biomarker to identify colorectal cancers suitable for irinotecan therapy, possibly in combination with PARP inhibitors.
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Bugat, R. "Irinotecan in the treatment of gastric cancer." Annals of Oncology 14 (June 2003): ii37—ii40. http://dx.doi.org/10.1093/annonc/mdg727.
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Wilke, H., O. Bouché, P. Rougier, and C. H. Köhne. "Irinotecan for the treatment of gastric cancer." European Journal of Cancer Supplements 2, no. 7 (June 2004): 48–51. http://dx.doi.org/10.1016/j.ejcsup.2004.04.015.
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Fuchs, Charles, Edith P. Mitchell, and Paulo M. Hoff. "Irinotecan in the treatment of colorectal cancer." Cancer Treatment Reviews 32, no. 7 (November 2006): 491–503. http://dx.doi.org/10.1016/j.ctrv.2006.07.001.
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Sobrero, Alberto F., Joan Maurel, Louis Fehrenbacher, Werner Scheithauer, Yousif A. Abubakr, Manfred P. Lutz, M. Eugenia Vega-Villegas, et al. "EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer." Journal of Clinical Oncology 26, no. 14 (May 10, 2008): 2311–19. http://dx.doi.org/10.1200/jco.2007.13.1193.
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PurposeTo determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.Patients and MethodsThis multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor–expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m2day 1 followed by 250 mg/m2weekly) plus irinotecan (350 mg/m2every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).ResultsMedian OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P ≤ .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms.ConclusionCetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.
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Wang, Wenjie, Monica Rodriguez-Silva, Arlet M. Acanda de la Rocha, Aizik L. Wolf, Yanhao Lai, Yuan Liu, William C. Reinhold, Yves Pommier, Jeremy W. Chambers, and Yuk-Ching Tse-Dinh. "Tyrosyl-DNA Phosphodiesterase 1 and Topoisomerase I Activities as Predictive Indicators for Glioblastoma Susceptibility to Genotoxic Agents." Cancers 11, no. 10 (September 23, 2019): 1416. http://dx.doi.org/10.3390/cancers11101416.
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Glioblastoma (GBM) patients have an estimated survival of ~15 months with treatment, and the standard of care only modestly enhances patient survival. Identifying biomarkers representing vulnerabilities may allow for the selection of efficacious chemotherapy options to address personalized variations in GBM tumors. Irinotecan targets topoisomerase I (TOP1) by forming a ternary DNA–TOP1 cleavage complex (TOP1cc), inducing apoptosis. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is a crucial repair enzyme that may reduce the effectiveness of irinotecan. We treated GBM cell lines with increasing concentrations of irinotecan and compared the IC50 values. We found that the TDP1/TOP1 activity ratio had the strongest correlation (Pearson correlation coefficient R = 0.972, based on the average from three sets of experiments) with IC50 values following irinotecan treatment. Increasing the TDP1/TOP1 activity ratio by the ectopic expression of wild-type TDP1 increased in irinotecan IC50, while the expression of the TDP1 catalytic-null mutant did not alter the susceptibility to irinotecan. The TDP1/TOP1 activity ratio may be a new predictive indicator for GBM vulnerability to irinotecan, allowing for the selection of individual patients for irinotecan treatment based on risk–benefit. Moreover, TDP1 inhibitors may be a novel combination treatment with irinotecan to improve GBM patient responsiveness to genotoxic chemotherapies.
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Giuliani, F., and G. Colucci. "Cetuximab in Colon Cancer." International Journal of Biological Markers 22, no. 1_suppl4 (January 2007): 62–70. http://dx.doi.org/10.1177/17246008070221s408.
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In the last decade remarkable progress has been made in the treatment of metastatic colorectal cancer due to the introduction of oxaliplatin and irinotecan in clinical practice. The addition of biological agents seems to offer a chance to further enhance the activity of conventional chemotherapy. Cetuximab, a chimeric mouse-human monoclonal antibody targeting the extracellular domain of the epidermal growth factor receptor (EGFR), has shown low but detectable activity when employed in pretreated patients either as a single agent or in combination with irinotecan. Cetuximab in combination with irinotecan has been registered in the USA and Europe for the treatment of patients with metastatic colorectal cancer expressing the EGFR after failure of prior irinotecan-based cytotoxic therapy. The role of cetuximab in first-line therapy is still investigational. Some phase II trials assessing cetuximab plus chemotherapy demonstrated a high objective response rate and promising results in terms of time to progression and overall survival; data from phase III trials are pending. Further studies are needed to investigate the efficacy of cetuximab in combination with conventional chemotherapy in the adjuvant/neoadjuvant setting and to define criteria for a better selection of patients for this type of treatment.
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Hironaka, Shuichi, Shinya Ueda, Hirofumi Yasui, Tomohiro Nishina, Masahiro Tsuda, Takehiko Tsumura, Naotoshi Sugimoto, et al. "Randomized, Open-Label, Phase III Study Comparing Irinotecan With Paclitaxel in Patients With Advanced Gastric Cancer Without Severe Peritoneal Metastasis After Failure of Prior Combination Chemotherapy Using Fluoropyrimidine Plus Platinum: WJOG 4007 Trial." Journal of Clinical Oncology 31, no. 35 (December 10, 2013): 4438–44. http://dx.doi.org/10.1200/jco.2012.48.5805.
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Purpose This phase III study compared treatment with weekly paclitaxel and biweekly irinotecan in patients with advanced gastric cancer refractory to treatment with fluoropyrimidine plus platinum. Patients and Methods Patients were randomly assigned to receive either paclitaxel (80 mg/m2 on days 1, 8, and 15, every 4 weeks) or irinotecan (150 mg/m2 on days 1 and 15, every 4 weeks). Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, adverse events, and proportion of patients who received third-line chemotherapy. Results Of 223 patients, 219 were eligible for analysis. Median OS was 9.5 months in 108 patients allocated to the paclitaxel group and 8.4 months in 111 patients allocated to the irinotecan group (hazard ratio [HR], 1.13; 95% CI, 0.86 to 1.49; P = .38). Median PFS was 3.6 months in the paclitaxel group and 2.3 months in the irinotecan group (HR, 1.14; 95% CI, 0.88 to 1.49; P = .33). Response rate was 20.9% in the paclitaxel group and 13.6% in the irinotecan group (P = .24). Common grade 3 to 4 adverse events were neutropenia (paclitaxel group, 28.7%; irinotecan group, 39.1%), anemia (21.3%; 30.0%), and anorexia (7.4%; 17.3%). Treatment-related deaths occurred in two patients (1.8%) in the irinotecan group. Third-line chemotherapy was administered in 97 patients (89.8%) after paclitaxel treatment and in 80 patients (72.1%) after irinotecan treatment (P = .001). Conclusion No statistically significant difference was observed between paclitaxel and irinotecan for OS. Both are reasonable second-line treatment options for advanced gastric cancer.
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Strock, Christopher J., Jong-In Park, D. Marc Rosen, Bruce Ruggeri, Samuel R. Denmeade, Douglas W. Ball, and Barry D. Nelkin. "Activity of Irinotecan and the Tyrosine Kinase Inhibitor CEP-751 in Medullary Thyroid Cancer." Journal of Clinical Endocrinology & Metabolism 91, no. 1 (January 1, 2006): 79–84. http://dx.doi.org/10.1210/jc.2005-1882.
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Abstract Context: Medullary thyroid cancer (MTC) is a cancer of the parafollicular C cells that commonly presents with an inherited or acquired RET gene mutation. There is currently no effective systemic treatment for MTC. Objective: The objective of this study was to investigate a systemic therapeutic approach to treat MTC. We studied the sensitivity of an MTC cell line and xenograft to irinotecan, alone and in combination with the tyrosine kinase inhibitor, CEP-751. Results: In TT cell culture and xenografts, irinotecan treatment was highly effective. This effect was augmented by treatment with CEP-751. Treatment of TT cell xenografts resulted in durable complete remission in 100% of the mice, with median time to recurrence of 70 d for irinotecan alone and more than 130 d for irinotecan plus CEP-751. Although irinotecan induced an S phase checkpoint arrest in TT cells, CEP-751 in combination with irinotecan resulted in a loss of this arrest. CEP-751 induced a loss in the induction of the DNA repair program marked by phospho-H2AX and the checkpoint pathway marked by the activated Chk1 pathway. Conclusions: Irinotecan treatment was highly effective in a preclinical model of human MTC, resulting in complete remission in 100% of the xenografts treated. The duration of remission was further enhanced by combination with the kinase inhibitor, CEP-751. These results suggest that irinotecan, alone or in combination, may be useful for the treatment of MTC.
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O'Reilly, Eileen Mary, Andy Surinach, Allison Dillon, Paul Cockrum, and Kenneth H. Yu. "Impact of prior irinotecan exposure on outcomes of metastatic pancreatic cancer (mPC) patients." Journal of Clinical Oncology 38, no. 4_suppl (February 1, 2020): 667. http://dx.doi.org/10.1200/jco.2020.38.4_suppl.667.
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667 Background: Published data suggests prior exposure to irinotecan infers a lower likelihood of benefit to liposomal irinotecan. This analysis seeks to expand this hypothesis by evaluating U.S. patterns of care to understand how prior irinotecan therapy impacts outcomes in mPC. Methods: Using the Flatiron Health database, data were extracted and analyzed for treated mPC patients (pts) in the 2L+ setting between Jan 1, 2014 and Jun 30,2019. Therapies of interest included: gemcitabine/ nab-paclitaxel (GnP), FOLFOX, FOLFIRI, FOLFIRINOX (FFX), and liposomal irinotecan/5-FU/LV (nal-IRI). The reference date for each treatment group was the date of treatment initiation. Prior irinotecan was defined as any irinotecan given in a prior regimen in mPC diagnosis. Cox proportional hazard (PH) methods were used to calculate mortality hazard ratios (HRs). HRs were adjusted to account for demographics and relevant covariates. Pts with prior exposure to irinotecan were used as the reference population for the Cox PH model (an HR < 1 represents worse survival for exposed pts relative to the unexposed). Results: N = 1,978 were included in this analysis. The median age at treatment initiation, and the proportion of pts previously treated with irinotecan are reported in table. Crude mortality was: GnP pts, HR 0.93 [95% CI: 0.77 – 1.11, adjusted HR, 0.94, 0.76 – 1.15]; nal-IRI pts, HR 0.81 [0.64 – 1.02, adjusted HR: 0.89, 0.67 – 1.19]; HR for FOLFOX was 0.55 [0.38 – 0.78, adjusted HR: 0.51, 0.33 – 0.79]. HRs are not reported for FFX and FOLFIRI due to the small numbers with prior irinotecan exposure. Conclusions: In mPC, prior irinotecan treatment may not preclude benefit from later treatment with nal-IRI or GnP as can be seen from the adjusted and unadjusted HRs. These findings are hypothesis-generating and need to be considered in the context of wide CI’s, retrospective nature and the limitations of such data. Further study is required to understand the less-favorable signal observed with FOLFOX and prior irinotecan.[Table: see text]
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Cunningham, Julia Marie, Petra Prins, Brian Conkright, Simina Boca, Shruti Rao, Andrew Gabrielson, Andrew Oseran, et al. "Molecular profiling of TOPO1: A way to evaluate irinotecan treatment in colorectal cancer?" Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 546. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.546.
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546 Background: Front-line chemotherapy for metastatic colorectal cancer (mCRC) consists of a fluoropyrimidine backbone plus either oxaliplatin (FOLFOX or XELOX) or irinotecan (FOLFIRI or XELIRI). Large, prospective trials enrolling chemotherapy-naïve patients (pts) show FOLFOX and FOLFIRI treatment to be equivalent with similar response rates. Methods: Irinotecan inhibits TOPO1, which is now a candidate marker for irinotecan treatment benefit. Thus, we retrospectively analyzed TOPO1 expression level in 49 pts with mCRC who were treated with irinotecan-containing regimens at the Lombardi Comprehensive Cancer Center between 2009 and 2014. Patient characteristics and outcomes were compiled through chart review and the effect of TOPO1 expression on clinical outcomes was assessed. TOPO1 expression in tumor tissue from each pt was analyzed using a commercially available molecular profiling (MP) service (Caris Life Sciences). Results: The median overall survival (OS) for all pts was 33.9 months (mo), defined as the time from metastasis to death or censorship. When grouped by “high” or “low” TOPO1 expression, as defined by Caris at the time of the testing, 29 pts were high-expressers and 20 were low-expressers. High TOPO1 expressers receiving irinotecan (n = 22) had a median OS of 27.2 mo, compared with median 41.5 mo for low-expressers (n = 14) (p = 0.27). Irinotecan is conventionally given as second-line therapy. The median OS of pts receiving second-line irinotecan was 38.2 mo for high-expressers [n = 11] vs. 68.5 mo for low-expressers [n = 5]) (p = 0.32). Conclusions: Our limited data do not support the use of TOPO1 expression levels as a predictive marker for irinotecan therapy in mCRC. However, our conclusions are limited by small sample size, lack of a control group to distinguish prognostic from predictive markers, and timing of TOPO1 measurement, which in many cases was after irinotecan therapy. Physicians currently lack an evidence-based way to choose between potentially efficacious regimens for mCRC. More rigorous studies are needed to assess the benefit of MP in mCRC care. We are currently planning a prospective study with the hope of validating the use of TOPO1 expression as a predictive marker for treatment of this disease.
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Amonkar, Mayur, David Gomez-Ulloa, Smita Kothari, Winson Y. Cheung, Ian Chau, John Raymond Zalcberg, Nuria Lara, and Alfredo Falcone. "Real-world treatment patterns and clinical outcomes in patients receiving second-line (2L) treatment for advanced or metastatic gastric cancer (GC)." Journal of Clinical Oncology 37, no. 4_suppl (February 1, 2019): 102. http://dx.doi.org/10.1200/jco.2019.37.4_suppl.102.
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102 Background: Despite increased survival demonstrated for patients with advanced / metastatic GC due to 2L chemotherapy, different standard of care options exist. This study aims to describe RW treatment patterns and clinical outcomes in patients with advanced / metastatic GC receiving 2L treatment. Methods: Retrospective chart review study conducted in Australia, Canada, Italy and UK. Patients diagnosed with metastatic / unresectable GC receiving 2L treatment between January 2013 and July 2015 were enrolled. Patient characteristics, treatment patterns and clinical outcomes were captured for 12 months from the start of 2L treatment or until death. Results: 280 patients were included (mean age 60.9 years, 68.9% male). Half of the patients (51.8%) received monotherapy in 2L. Among these, taxanes were most prescribed (69.0%) followed by irinotecan (22.1%). Doublet chemotherapy was the most common combination therapy in 2L (75.6%) with fluoropyrimidine + irinotecan (33.3%) being the most used, followed by fluoropyrimidine + platinum (17.8%). Less than a third of patients (29.3%) received subsequent third-line (3L) treatment; 62.7% received monotherapy [mainly taxanes (69.2%) or irinotecan (19.2%)]. Most 3L patients who had combination therapy received a doublet (86.7%), most frequently fluoropyrimidine combined with irinotecan (53.3%) or platinum (20.0%). The majority of 2L patients (93.6%) had received combination therapy as first-line treatment, of whom 67.9% had received triplet chemotherapy, most commonly anthracycline + fluoropyrimidine + platinum (51.1%). Estimated median real-world progression free survival (PFS) and overall survival (OS) after 2L treatment initiation was 3.09 (95% CI: 2.76-3.68) and 6.54 (5.29-7.76) months, respectively, and estimated probability of PFS and OS at 12 months was 8% and 26%, respectively. Conclusions: The clinical management of advanced / metastatic GC patients in 2L treatment commonly involves taxanes or irinotecan as monotherapy, or irinotecan or platinum-based combinations with fluoropyrimidines. RW clinical outcomes for 2L treatment are similar to randomised controlled trials but remain poor.
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Mir, Tanveer Ahmad, Ahmed S. Yassin, Eric Joseph Denha, Raad Al Shaikhli, Ali Rahim, Sabah Ambreen, and Prateek Lohia. "Irinotecan inducing sinus pause bradycardia in a patient with small round cell cancer." BMJ Case Reports 13, no. 5 (May 2020): e232053. http://dx.doi.org/10.1136/bcr-2019-232053.
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Irinotecan is a novel anticancer drug that has worked wonders in combination with other anticancer drugs. It can be used as a single chemotherapy agent in colonic cancer treatment or in combination with 5-fluorouracil. Irinotecan has been found a better salvage therapy in patients who are resistant to 5-fluorouracil. It is also used in combination with cisplatin and other drugs for cancers such as pleural mesothelioma, Ewing’s sarcoma, lung cancer and others, and has helped reduce tumour burden. Irinotecan is generally associated with gastrointestinal side effects including nausea, vomiting and diarrhoea, while cardiovascular toxicity (5%) has been reported mainly as vasodilatation and possible bradycardia with no known incidence. A case was reported in 1998 by Miya et al of a 65-year-old man with bradycardia which was managed with atropine without modifications in the dosage of irinotecan or in the rate of infusion. We report a case of a patient with small round cell cancer who presented with sinus pause bradycardia after infusion with irinotecan. The patient was managed with atropine during chemotherapy.
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Kim, Seong-Ryong, Hyun Jung Lee, and Dalyong Kim. "Consistent Response on Challenge and Rechallenge of Liposomal Irinotecan in a Patient with Metastatic Pancreatic Adenocarcinoma Previously Treated with Gemcitabine plus Nab-Paclitaxel: A Case Report." Case Reports in Oncology 14, no. 3 (December 30, 2021): 1882–88. http://dx.doi.org/10.1159/000521315.
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Approximately 80% of pancreatic cancer is diagnosed at an advanced stage, due to lack of or vague symptoms when the cancer is still localized, leading to a high mortality rate. Known risk factors for developing pancreatic cancer are family history, obesity, type 2 diabetes, and alcohol and tobacco use. There has been a remarkable development in diagnosis modalities and molecular testing, but early detection is still infrequent. The majority of clinical trials have not shown significant efficacy in pancreatic cancer, and treatment strategy remains limited. Additional prognostic factors should be highlighted to obtain appropriate treatment options, including precision medicine, and improve survival outcomes. After the PRODIGE study in 2011 and the MPAC trial in 2013, a new drug (liposomal irinotecan; Onivyde ®) appeared in the strategy, especially after failure of gemcitabine-based treatment. In 2016, the NAPOLI-1 trial showed evidence of the efficacy of the liposomal irinotecan combination (liposomal irinotecan +5-fluorouracile + folinic acid); now, it is considered the standard treatment for relapsing patients. Since NAPOLI-1, real-world data have provided similar results. Herein, we report the story of a 61-year-old woman who was treated with liposomal irinotecan combination (nal-IRI/5-FU/LV) for 8 months with good surgical response, but treatment was discontinued due to economic burden. After the start of treatment (or 1? cycle of liposomal irinotecan treatment), the patient was in a better condition. The liver metastases had disappeared. The combination with liposomal irinotecan was re-administered with patient’s approval. Upon rechallenge with the liposomal irinotecan combination, she showed a partial response, and the treatment was given for 7 months. In this report, we tried to identify the prognostic factors leading to the efficacy of the liposomal irinotecan combination.
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Jang, Hyun Joo, Eun Mi Hong, Juah Jang, Jung Eun Choi, Se Woo Park, Hyun Woo Byun, Dong Hee Koh, Min Ho Choi, Sea Hyub Kae, and Jin Lee. "Synergistic Effects of Simvastatin and Irinotecan against Colon Cancer Cells with or without Irinotecan Resistance." Gastroenterology Research and Practice 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/7891374.
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Aims. We here investigated whether the combination of simvastatin and irinotecan could induce the synergistic effect on colon cancer cells with or without resistance to irinotecan.Methods. We investigated cell proliferation assay and assessed cell death detection ELISA and caspase-3 activity assay of various concentrations of simvastatin and irinotecan to evaluate the efficacy of drug combination on colon cancer cells with or without irinotecan resistance.Results. The IC50values of simvastatin alone and irinotecan alone were115.4±0.14 μM (r=0.98) and62.5±0.18 μM (r=0.98) in HT-29 cells without resistance to irinotecan. The IC50values of these two drugs were221.9±0.22 μM (r=0.98) and195.9±0.16 μM (r=0.99), respectively, in HT-29 cell with resistance to irinotecan. The results of combinations of the various concentrations of two drugs showed that combined treatment with irinotecan and simvastatin more efficiently suppressed cell proliferation of HT-29 cells even with resistance to irinotecan as well as without resistance. Furthermore, the combination of simvastatin and irinotecan at2:1molar ratio showed the best synergistic interaction.Conclusion. Simvastatin could act synergistically with irinotecan to overcome irinotecan resistance of colon cancer.
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Gonzalez-Baron, M., M. Blanco, J. Feliu, C. Gómez, E. Casado, J. Castro, C. Belda-Iniesta, M. Garrido, C. Aguayo, and M. A. Campos. "Cetuximab and irinotecan in patients with colorectal cancer refractory to oxaliplatin and irinotecan." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 14600. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.14600.
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14600 Background: Patients with chemotherapy-resistant metastasic colorectal cancer have a poor prognosis with few therapeutic options. The purpose of this work is to evaluate the results of treatment with cetuximab and irinotecan in this group of patients. Methods: Between January 01 and July 06, 24 patients were treated in our centre with cetuximab. 19 patients received irinotecan 180 mg/m2 every two weeks with cetuximab at standard doses: 400 mg/m2 loading dose over 2 hours, then 250 mg/m2 over 1 hour weekly, and 5 patients received FOLFIRI schedule and cetuximab at the same doses as previously. Results: Characteristics of the 24 patients were: male/female 15/9; median age 63 years old (range 48–75); performance status 0–1 (10 patients), and 2–3 (14 patients). The median number of chemotherapy regimens preceding first cetuximab administration was 2 (range 1 to 4).12% had received one chemotherapy line, 64% two chemotherapy lines, 16% three chemotherapy lines and 8% received four chemotherapy lines. EGFR status was positive in all patients. The median of administrated cycles was 7.5 (range 2–26). There were 4 objective responses (16%; 95% CI: 5–38.5%) and 7 patients with stable disease (29%). The median progression free survival was 3.2 months and median overall survival was 7.8 months (95% CI: 3–14). The treatment was well tolerated. 6% of the patients had not cutaneous toxicity with the cetuximab treatment, 14 (25%) had a cutaneous toxicity grade 1 or 2 while 25% had a grade 3 or 4 toxicity, that lead to dose reduction in three cases and treatment drop out in one case. Other adverse effects with the treatment included four cases (17%) with diarrhoea grade 3, all of them in treatments with irinotecan, two patients (8%) suffered vomits grade 3, and one patient with grade 3 trombopenia. Conclusions: This therapeutic survey in an unselected population is in accordance with the results of the BOND survey for OS, tumour responses and toxicity. No significant financial relationships to disclose.
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Lim, Sung Hee, Jae-Joon Kim, Hyeon-Su Im, Hye Sook Han, In-Ho Kim, Dong-Hoe Koo, Jang Ho Cho, et al. "Comparison of efficacy between immune checkpoint inhibitors and irinotecan-based chemotherapy as third-line treatment for patients with advanced gastric cancer: A Korean real-world multicenter study (KCSG ST22-06)." Journal of Clinical Oncology 41, no. 16_suppl (June 1, 2023): e16047-e16047. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e16047.
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e16047 Background: Immune checkpoint inhibitor (ICI) or irinotecan-based chemotherapy are frequently used after paclitaxel plus ramucirumab as second-line treatment for patients with recurrent and/or metastatic gastric cancer (RMGC). This study aimed to compare the efficacy between ICI and irinotecan-based chemotherapy as third-line treatment in patients with RMGC. Methods: We retrospectively reviewed patients with RMGC, whose third-line treatment started between July 2019 and June 2021 at 17 centers in South Korea. The ICI group included patients who received nivolumab or pembrolizumab and the irinotecan-based chemotherapy group included those patients who received irinotecan or FOLFIRI. Results: A total of 363 patients (129 in the ICI group and 234 in the irinotecan-based chemotherapy group) were analyzed. The median progression-free survival (PFS) was 2.2 and 2.9 months in the ICI and irinotecan-based chemotherapy groups, respectively. The median overall survival (OS) was 5.5 months (95% CI, 3.6-7.4) in the ICI group and 6.0 months (95% CI, 4.8-7.0) in the irinotecan-based chemotherapy group [HR 0.97 (95% CI, 0.75-1.25); P=0.786]. Multivariable Cox-regression analysis showed that weight loss, peritoneal metastasis, low serum sodium, low serum albumin and short duration of second-line treatment were associated with inferior OS ( P<0.05), meanwhile microsatellite instability-high (MSI-H)/mismatch repair-deficient (MMR-D) tumor was an independent prognostic factor for superior OS. The ICI group showed significantly longer OS than the irinotecan-based chemotherapy group in patients without peritoneal metastasis [HR 0.54 (95% CI 0.30-0.99); P=0.047)]. Whereas the irinotecan-based chemotherapy group showed significantly longer OS in patients without PD-L1 expression [HR 1.62 (95% CI 1.03-2.55); P=0.037] than the ICI group. Conclusions: No significant difference in survival outcome was observed between ICI and irinotecan-based chemotherapy as third-line treatment for patients with RMGC. ICI might be preferred for patients without peritoneal metastasis and irinotecan-based chemotherapy for patients with tumors without PD-L1 expression.
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Guo, Weijian, Xiaowei Zhang, Yusheng Wang, Wen Zhang, Xin Liu, Wei Shen, Yifu He, et al. "FOLFIRI versus irinotecan monodrug as second-line treatment in metastatic colorectal cancer patients: An open, multicenter, prospective, randomized controlled phase III clinical study." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 4038. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.4038.
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4038 Background: The most commonly used treatment methods for metastatic colorectal cancer (mCRC)are systemic chemotherapy, molecular targeted therapy and local treatment. The main chemotherapy drugs for mCRC include Irinotecan, Oxaliplatin and 5-Fu. V308 Research shows that FOLFOX and FOLFIRI can be standard first or second-line of each other in the treatment of metastatic colorectal cancer. However if the first-line treatment regimen containing 5-FU fails, whether it is necessary to re-challenge 5-FU when Irinotecan is applied in the second line is unknown. There is no head-to-head comparative study to answer whether the FOLFIRI regimen is better than the Irinotecan monodrug. Therefore, it is necessary to carry out a comparative study of FOLFIRI Versus Irinotecan monodrug to observe whether adding 5-Fu on the basis of Irinotecan can improve the therapeutic effect. Methods: This was a randomized phase III trial. Patients from 5 centers in China with metastatic colorectal adenocarcinoma, for whom first-line of chemotherapy including oxaliplatin combined with fluorouracil drugs (combined or not combined with targeted therapy) had failed, were enrolled. 172 patients with mCRC were randomly treated with FOLFIRI or Irinotecan monodrug were included in this study. FOLFIRI group: Irinotecan 180mg/m2; Lecovorin 400mg/m2; 5-Fu 400mg/m2; 5-Fu 2400mg/m2 CIV 46h. Irinotecan monodrug group 180mg/m2, The regimen was repeated every 2 weeks. The primary endpoint is PFS, and this clinical trail is a superiority trial. Results: ITT (Intention-To-Treat) analysis: Among 172 patients, 10 had PR, 93 had SD, and 63 had PD, 6 patients have not received efficacy evaluation yet. The ORR was 5.68% VS. 5.95%, and the DCR was 61.36% and 54.76% in FOLFIRI group and Irinotecan monodrug group, respectively. Adverse reactions included neutropenia, stomatitis, diarrhea, fatigue, abnormal liver enzymes, pyrexia, arrhythmia, nausea and most of these were grade 1-2. The dose reduction rate induced by drug tocixity of was 13.64% and 7.14% in FOLFIRI group and Irinotecan monodrug group, respectively. Conclusions: These data show that Irinotecan monodrug has the similar ORR and DCR with FOLFIRI regimen in second-line treatment of mCRC. Irinotecan monodrug has lower adverse effect. Clinical trial information: NCT02935764 .
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Yu, Qianqian, Zhihuan Li, Xiaoqi Nie, Lu Wang, Chen Gong, Bo Liu, Xin Liao, et al. "Predictive Value of UGT1A1 Polymorphisms in Irinotecan-Induced Toxicity and Therapeutic Efficacy in Colorectal Cancer Patients." Journal of Cancer Treatment and Diagnosis 4, no. 2 (September 1, 2020): 39–46. http://dx.doi.org/10.29245/2578-2967/2020/2.1182.
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Irinotecan-based chemotherapy is a fundamental cytotoxic regimen for advanced colorectal cancer. The disposition of irinotecan is known to vary in a fashion partially depending on genetic variations in the drug metabolic pathways. UDP-glucuronosyltransferase (UGT)1A1 is a predominant enzyme that converts the active metabolite of irinotecan to the inactive form via a glucuronidation process. Several UGT1A1 polymorphisms are linked to SN-38 glucuronidation and irinotecan-related adverse events, while the predictive role of UGT1A1 polymorphisms regarding therapeutic outcome is controversial. In this review, we will evaluate the impact of UGT1A1 genotypes on irinotecan-induced toxicity and therapeutic efficacy in colorectal cancer patients receiving irinotecan-based treatment.
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Paulík, Adam, Jiří Grim, and Stanislav Filip. "Predictors of Irinotecan Toxicity and Efficacy in Treatment of Metastatic Colorectal Cancer." Acta Medica (Hradec Kralove, Czech Republic) 55, no. 4 (2012): 153–59. http://dx.doi.org/10.14712/18059694.2015.39.
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The colorectal cancer ranks high among the malignant tumours in incidence and mortality and irinotecan is standardly used in palliative treatment of metastatic disease in every therapeutic line. Unfortunately, the treatment with irinotecan is often associated with severe toxicities, especially neutropenia and diarrhea. The majority of the toxic manifestation is caused by the insufficient deactivation (glucuronidation) of irinotecan active metabolite SN-38 by UGT1A enzyme. The elevated SN-38 plasma concentration is responsible for the hematological and gastrointestinal toxicity that can become life-threatening. The patients carrying the mutation of the gene encoding UGT1A enzyme lack the ability of bilirubin glucuronidation, and suffer from the inherited un-conjugated hyperbilirubinemia (Gilbert syndrome, Crigler- Najjar type 1 and 2 syndrome). The mutations in other enzyme systems also play role in the etiopathogenesis of the irinotecan toxicity: CYP3A (cytochrome P-450), ABC family of transmembrane transporters (adenosine-triphosphate binding cassette). The goal of the contemporary research is to determine the predictive factors that will enable the individual adjustment of the individual drug dosage while minimising the adverse effects and maintaining the treatment benefit.
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Janjigian, Yelena Yuriy, Laura H. Tang, Stephen Shibata, David Paul Kelsen, Michal Segal, Catherine Cheng, Gary K. Schwartz, L. Austin Doyle, and Manish A. Shah. "A multicenter random assignment phase II study of irinotecan and flavopiridol versus irinotecan alone for patients with p53 wild-type gastric adenocarcinoma (NCI 8060)." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14586-e14586. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14586.
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e14586 Background: Preclinical studies demonstrate that tumors wild-type for p53 (p53wt) are refractory to irinotecan relative to non-functional or mutant p53, and that sequential therapy with flavopiridol, a cyclin dependent kinase inhibitor that inhibits homologous recombination and DNA repair, and irinotecan overcomes p53 mediated drug resistance in vivo. This phase II study is designed to assess cell cycle mediated drug resistance in p53wt gastric cancer, and test the hypothesis that administration of flavopiridol following irinotecan can overcome resistance to irinotecan. Methods: Pts with advanced p53wt (≤ 20% nuclear IHC staining using D07 antibody) gastric adenocarcinoma and disease progression on non-irinotecan chemotherapy regimen were randomized in 2:1 fashion to irinotecan 100 mg/m2 followed 7 h later by flavopiridol 60 mg/m2 administered over 1h or irinotecan 100 mg/m2 administered weekly on a 2 week on/1 week off schedule. Response assessment is performed every 2 cycles and the primary endpoint is 3-month progression free survival (PFS). Pre- and post-treatment biopsies were obtained for molecular assessments of p53 mediated drug resistance. Results: To date 30 of 55 patients screened were p53wt (54%), 19 pts were randomized to receive irinotecan + flavopiridol (n=13) and irinotecan (n=6). Median characteristics of 19 evaluable patients: age 61 (44 to 76), KPS 80% (70 to100), 13 male, 1 prior regimen (1 to 2). The common treatment emergent toxicities were anemia (Grade 2/3 21%), neutropenia (grade 2/3 31%, grade 4 .05%), nausea (grade 2/3 21%) and fatigue (grade 2/3 37%). With irinotecan + flavopiridol 1/13 (8%) confirmed partial response was seen and 5 month disease stabilization in 3/13 (23%) patients. No responses were seen with single agent irinotecan. The median PFS was similar, 1.6 mos irinotecan + flavopiridol vs 1.3 mos in irinotecan group (p=0.21). Conclusions: 54% of gastric cancers are p53wt. Correlative tissue analysis including p53 sequencing, p21, Rad51 is ongoing. Due to lack of activity with irinotecan alone, an amendment to a single arm irinotecan + flavopiridol study is planned.
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Lal, Rohit, James Dickson, David Cunningham, Ian Chau, Andrew R. Norman, Paul J. Ross, Clare Topham, Gary Middleton, Mark Hill, and Jacqui Oates. "A Randomized Trial Comparing Defined-Duration With Continuous Irinotecan Until Disease Progression in Fluoropyrimidine and Thymidylate Synthase Inhibitor—Resistant Advanced Colorectal Cancer." Journal of Clinical Oncology 22, no. 15 (August 1, 2004): 3023–31. http://dx.doi.org/10.1200/jco.2004.01.005.
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Purpose Irinotecan given until disease progression is an accepted standard treatment for advanced colorectal cancer (CRC) resistant to fluoropyrimidines. It is not known whether a predefined period of irinotecan treatment would result in similar duration of disease control. We performed a multicenter phase III trial to compare the two policies of defined-duration versus continuous irinotecan treatment. Patients and Methods Three hundred thirty-three eligible patients with advanced CRC progressing on or within 24 weeks of completing fluoropyrimidine-based chemotherapy were prospectively registered. After receiving eight cycles of irinotecan given at 350 mg/m2 once every 3 weeks, 55 patients with responding or stable disease were randomly assigned to stop irinotecan (n = 30) or continue until disease progression (n = 25). Registered patients were not randomly assigned predominantly due to disease progression (n = 236) and intolerable toxicity (n = 38). Results From the time of random assignment, there were no differences in failure-free survival (P = .999) or overall survival (P = .11) between the two arms. No difference was seen in mean global health status quality-of-life score between the two arms at 12 weeks after random assignment. No grade 3 diarrhea and febrile neutropenia was seen in the continue-irinotecan arm after random assignment. Conclusion For most patients, the decision to continue on irinotecan beyond 24 weeks is influenced by disease progression or treatment-related toxicity. However, for 17% of patients in whom this decision is clinically relevant, there seems to be little benefit from continuing irinotecan, though the drug was well tolerated without any deterioration in quality of life.
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Almasmoum, Hussain. "Characterization of mucin 2 expression in colorectal cancer with and without chemotherapies, in vivo and in vitro study." Journal of Umm Al-Qura University for Medical Sciences 7, no. 1 (June 1, 2021): 18–22. http://dx.doi.org/10.54940/ms28179947.
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Background: Colorectal cancer (CRC) is the third and second most prevalent cancer affecting males and females, respectively. 5-fluorouracil (5-FU) and irinotecan are the main chemotherapies for CRC. Down regulation of mucin 2 (MUC2) expression is associated with poor prognosis. Aim: This study examines the expression levels of MUC2 in response to treatment with 5-FU and/or irinotecan in vivo and in vitro. Method: HT29 CRC cells were treated with 5- FU and/or irinotecan, and the expression of MUC2 at mRNA and protein levels was examined by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC), respectively. CRC was induced in rats by injecting azoxymethane (AOM) prior to 5-FU treatment. Results: HT29 cells treated with 5-FU and/or irinotecan displayed a significant increase in the expression of MUC2. MUC2 mRNA expression was similar in response to monotherapy with irinotecan or 5 FU, and combinatorial treatment with irinotecan and 5-FU significantly increased MUC2 mRNA expression. Treatment of colon malignancy in rats with 5-FU resulted in increased expression of MUC2 compared with that in the positive control (rats treated with AOM only). The levels of MUC2 protein were restored and were similar to those in untreated rats. Conclusion: To our knowledge, this is the first in vitro study to report the effects of irinotecan treatment on MUC2 expression in CRC. MUC2 expression was increased by 5-FU and irinotecan. Therefore, further study could be undertaken to explore the potential use as a predictive marker in CRC.
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Gatzemeier, U. "Options for Treatment of Lung Cancer with Irinotecan." Oncology Research and Treatment 23, no. 4 (2000): 34–36. http://dx.doi.org/10.1159/000055055.
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Douillard, J.-Y. "Irinotecan: a new treatment in metastatic colorectal cancer." Journal of Oncology Pharmacy Practice 6, no. 3 (March 1, 2000): 3–9. http://dx.doi.org/10.1191/107815500117842.
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Takano, Masashi, and Toru Sugiyama. "UGT1A1 polymorphisms in cancer: impact on irinotecan treatment." Pharmacogenomics and Personalized Medicine Volume10 (February 2017): 61–68. http://dx.doi.org/10.2147/pgpm.s108656.
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Douillard, Jean-Yves. "Irinotecan: a new treatment in metastatic colorectal cancer." Journal of Oncology Pharmacy Practice 6, no. 3_suppl (September 2000): S3—S9. http://dx.doi.org/10.1177/107815520000600i301.
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Haller, Daniel G., Mace L. Rothenberg, Alfred O. Wong, Piotr M. Koralewski, Wilson H. Miller, Gyorgy Bodoky, Nassir Habboubi, Carlos Garay, and Luis O. Olivatto. "Oxaliplatin Plus Irinotecan Compared With Irinotecan Alone as Second-Line Treatment After Single-Agent Fluoropyrimidine Therapy for Metastatic Colorectal Carcinoma." Journal of Clinical Oncology 26, no. 28 (October 1, 2008): 4544–50. http://dx.doi.org/10.1200/jco.2008.17.1249.
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Purpose To determine whether irinotecan plus oxaliplatin (IROX) is superior to irinotecan alone in patients with metastatic colorectal cancer (CRC) previously treated with single-agent fluoropyrimidines. Patients and Methods A phase III, randomized, open-label, multicenter study of patients with metastatic or recurrent CRC that had progressed or recurred during or after adjuvant or first-line fluoropyrimidines (fluorouracil/leucovorin or capecitabine, the latter only for metastatic CRC). Patients received IROX (irinotecan 200 mg/m2 plus oxaliplatin 85 mg/m2) or irinotecan alone (350 mg/m2) every 3 weeks. Results At the data cutoff (when 447 of 628 randomly assigned patients had died), median overall survival was 13.4 months (95% CI, 12.4 to 14.7 months) and 11.1 month (95% CI, 10.0 to 12.7 months) in the IROX and irinotecan groups, respectively (hazard ratio = 0.78; 95% CI, 0.65 to 0.94; P = .0072). Overall response rate (22% v 7%, respectively; P < .0001), median time to progression (5.3 v 2.8 months, respectively; P < .0001), and improvement in tumor-related symptoms (32% v 19%, respectively; P = .0072) were also improved with IROX as compared with irinotecan. With the exception of granulocytopenia (25% v 13%), diarrhea (28% v 23%), and sensory disturbances (5% v 0%), grade 3 to 4 toxicities were comparable between the IROX and irinotecan groups, respectively. Conclusion IROX is an effective treatment for metastatic CRC that has progressed after first-line fluoropyrimidine therapy. IROX improves efficacy compared with irinotecan alone, providing an additional option in the postadjuvant or second-line treatment setting for patients who experience treatment failure with single-agent fluoropyrimidine therapy.
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Kawakami, Takeshi, Nozomu Machida, Masahiro Kawahira, Sadayuki Kawai, Yosuke Kito, Yukio Yoshida, Satoshi Hamauchi, et al. "Efficacy and safety of irinotecan monotherapy as third line treatment for advanced gastric cancer." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 113. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.113.
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113 Background: Several randomized trials demonstrated the survival benefit in advanced gastric cancer patients (AGC pts) receiving irinotecan or taxanes as second-line chemotherapy (SLC). Taxanes are used for SLC in daily clinical practice in Japan because of its less toxicity, especially in AGC pts with peritoneal dissemination, compared with irinotecan. Although irinotecan is often administered after refractory or intolerant to taxanes as SLC, the efficacy and safety of irinotecan as third-line chemotherapy (TLC) is still unclear. Methods: We retrospectively investigated the data of AGC pts administered irinotecan 150mg/m2 as TLC every two weeks until disease progression, unacceptable toxicity, or pts’ refusal between December 2002 and June 2015. Inclusion criteria were (1) age 75 years or less (2) refractory or intolerant to fluoropyrimidine with or without platinum as first-line chemotherapy (3) refractory or intolerant to taxanes as SLC. Results: A total of 52 pts were analyzed. Pts’ characteristics were as follows: median age, 66 (range, 33-75) years; male/female, 35/17 pts; ECOG PS 0-1/2, 42/10 pts; peritoneal dissemination +/-, 32/20 pts; ascites +/-, 22/30 pts, number of metastatic sites 1-2/3-4, 44/8 pts. Median follow-up period was 548 (141-1931) days. Median progression-free survival was 70 days (95%CI 49-137) and median overall survival was 144 days (95%CI 120-231) from the initiation of irinotecan administration. Response rate and disease control rate was 10.8% and 50.4%, respectively. Relative dose intensity was 74.7% (56 mg/m2/week); 14 pts needed dose reduction in the first course, and 22 pts after the second course. Grade 3 or 4 neutropenia, anemia, diarrhea, nausea, and febrile neutropenia were observed in 13 (25%), 21 (40.4%), 5 (9.6%), 3 (5.8%) and 3 (5.8%) pts, respectively. No treatment-related death was observed. Conclusions: This study suggests that irinotecan monotherapy as TLC has acceptable anti-tumor effect and has manageable toxicity in appropriately selected AGC pts.
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Hutchcraft, Megan L., Nan Lin, Shulin Zhang, Catherine Sears, Kyle Zacholski, Elizabeth A. Belcher, Eric B. Durbin, et al. "Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes." Cancers 13, no. 18 (September 8, 2021): 4524. http://dx.doi.org/10.3390/cancers13184524.
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The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-relevant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with toxicity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabolizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercaptopurine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was feasible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be performed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine.
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Ishii, Takahiro, Akihito Kawazoe, Akinori Sasaki, Saori Mishima, Sawada Kentaro, Yoshiaki Nakamura, Daisuke Kotani, et al. "Clinical and molecular factors for selection of nivolumab or irinotecan as third-line treatment for advanced gastric cancer." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592094237. http://dx.doi.org/10.1177/1758835920942377.
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Background: The use of nivolumab or irinotecan as the third-line treatment for patients with advanced gastric cancer (AGC) remains controversial. Methods: This study analyzed patients with AGC treated with nivolumab or irinotecan (nivolumab group or irinotecan group, respectively) from May 2016 to April 2019 following two or more previous lines of chemotherapy. Univariate survival analysis was conducted to identify the clinical and molecular factors associated with progression-free survival (PFS). Results: A total of 156 patients (74 treated with nivolumab and 82 treated with irinotecan) were analyzed. The median PFS was 1.9 months in both treatment groups. The median overall survival (OS) was 7.2 and 6.2 months in the nivolumab and irinotecan groups, respectively. Eastern Cooperative Oncology Group performance status of 1 or more, liver metastasis, a large tumor size at baseline, and HER2-positive status were associated with a worse PFS in the nivolumab group compared with the irinotecan group. The nivolumab group showed a significantly longer PFS (median 3.1 versus 2.0 months) and OS (median 12.9 versus 7.8 months) than the irinotecan group in patients with 0 or 1 of these factors, whereas the irinotecan group showed a significantly longer PFS (median 1.0 versus 1.8 months) and a trend of longer OS (median 3.9 versus 6.1 months) in patients with ⩾2 of these factors. Conclusions: Some clinical and molecular factors were associated with outcomes following nivolumab or irinotecan as the third- or later-line treatment in patients with AGC. These factors must be considered while selecting an optimal treatment option.
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Scheithauer, Werner, Gabriela V. Kornek, Markus Raderer, Herbert Ulrich-Pur, Wolfgang Fiebiger, Claudia Gedlicka, Birgit Schüll, et al. "Randomized Multicenter Phase II Trial of Oxaliplatin Plus Irinotecan Versus Raltitrexed as First-Line Treatment in Advanced Colorectal Cancer." Journal of Clinical Oncology 20, no. 1 (January 1, 2002): 165–72. http://dx.doi.org/10.1200/jco.2002.20.1.165.
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PURPOSE: Irinotecan and oxaliplatin are two new agents with promising activity in advanced colorectal cancer. Based on preclinical and clinical evidence that both drugs act synergistically, a randomized phase II study was initiated to investigate the therapeutic potential and tolerance of this combination in the front-line setting. PATIENTS AND METHODS: Ninety-two patients with previously untreated, measurable disease were randomized to receive biweekly oxaliplatin 85 mg/m2 plus irinotecan 175 mg/m2 or raltitrexed 3 mg/m2 given on day 1 every 3 weeks. Upon development of progressive disease, second-line treatment with the opposite arm was effected. RESULTS: Patients allocated to oxaliplatin/irinotecan had a significantly better radiologically confirmed response rate (43.5% v 19.6%; P = .0025) and longer progression-free survival (median, 7.1 v 5.0 months; P = .0033). Improvement in overall survival, however, did not reach the level of significance (median, 16.0 v 16.5 months; P = .3943). The response rate after cross-over was 33.3% (eight of 24) for assessable patients treated with oxaliplatin/irinotecan compared with 14.2% (three of 21) for those treated with second-line raltitrexed. Oxaliplatin/irinotecan caused more hematologic and gastrointestinal toxicities, necessitating dose reductions in 10 of the first 20 patients. After adjustment of the irinotecan starting dose from 175 to 150 mg/m2, tolerance of treatment was acceptable; the most commonly encountered events (all grades) were neutropenia (81%), alopecia (65%), nausea/emesis (62%), peripheral sensory neuropathy (62%), and diarrhea (46%). CONCLUSION: Oxaliplatin/irinotecan seems beneficial as first-line therapy in advanced colorectal cancer, with an acceptable toxicity profile at the reduced irinotecan dose level. Its promising therapeutic potential is supported by the high response activity noted in the raltitrexed control arm after cross-over, which may also explain the lack of a difference in overall survival.
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Yu, Kenneth H., Andrew Eugene Hendifar, Olatunji B. Alese, Amber Draper, Maen Abdelrahim, Ethan Burns, Gazala Naaz Khan, et al. "A multicenter chart review study of patients with metastatic pancreatic ductal adenocarcinoma receiving liposomal irinotecan after gemcitabine-based therapy." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16733-e16733. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16733.
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e16733 Background: Real-world data allows healthcare decision-makers to assess and manage therapeutic and economic options for patients, including those who would and would not have met eligibility criteria for randomized control trials (RCT) and are instead managed under usual care. This retrospective multi-academic center chart review study describes real-world characteristics and outcomes of US patients receiving liposomal irinotecan for the management of metastatic pancreatic ductal adenocarcinoma (mPDAC). Methods: Patients with mPDAC treated with liposomal irinotecan were eligible. Initiation of liposomal irinotecan defined index date; covariates assessed included clinical characteristics and treatment patterns; real-world overall survival (rwOS) was assessed via Kaplan-Meier methodology. The target enrollment is 300 patients. The study centers included were Memorial Sloan Kettering Cancer Center, Cedars-Sinai Medical Center, Emory Winship Cancer Institute, Houston Methodist Cancer Center, Henry Ford Cancer Institute, and University of Pittsburgh Medical Center. Results: Data on 26 patients were available for initial analyses. Mean age was 68 years; 58% were female and 65% Caucasian. 54% of patients had stage IV disease at first diagnosis, and 17%, 65%, and 17% had index ECOG score of 0, 1, and 2, respectively. Common genetic mutations include KRAS (40%) and TP53 (40%). Prior to liposomal irinotecan, treatments received for metastatic disease include gemcitabine+nab-paclitaxel (77%) and fluorouracil (5-FU)/leucovorin (LV)+irinotecan+oxaliplatin (19%). Patients had received 0 (12%), 1 (23%), and ≥2 (65%) lines of therapy in the metastatic setting prior to liposomal irinotecan. Mean duration of liposomal irinotecan use was 3.0 months; liposomal irinotecan was mostly received with 5-FU (23%) or 5-FU/LV (69%). Median rwOS was 4.9 months (95% CI: 3.0, 6.3). Conclusions: Real-world data of the first 26 patients in this study show patients treated with liposomal irinotecan are older, sicker, and have had more lines of therapy than previously reported in RCT data.
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Smith, Caleb J., Tanios S. Bekaii-Saab, Kathryn Cook, Rachel Eiring, Thorvardur Ragnar Halfdanarson, Mina Samir Erian Hanna, Zhaohui Jin, et al. "Nanoliposomal irinotecan-based chemotherapy after regular irinotecan-based chemotherapy in patients with pancreas cancer." Journal of Clinical Oncology 39, no. 3_suppl (January 20, 2021): 402. http://dx.doi.org/10.1200/jco.2021.39.3_suppl.402.
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402 Background: Pancreas cancer is an aggressive malignancy with limited therapeutic options. Nanoliposomal irinotecan (Nal-IRI) is a preferred second-line treatment, and current guidelines recommend its use in the absence of prior irinotecan. This study aimed to assess whether patients who had received regular irinotecan derive benefit from Nal-IRI. Methods: Medical records of metastatic pancreas cancer patients who had received regular irinotecan and then Nal-IRI were reviewed. The following information was extracted from each medical record: patient demographics, confirmation of a diagnosis of exocrine pancreas cancer, initial cancer stage, dates of administration of the drugs of interest, adverse events that occurred with Nal-IRI treatment, reasons for stopping regular irinotecan, and reasons for starting and stopping Nal-IRI. The primary endpoint was overall survival after the initiation of Nal-IRI (an a priori threshold of > 4 months defined success). Survival data were censored based on date of last follow up. Direct quotes from the medical record were documented to provide insight on prescribing Nal-IRI when guidelines advised the contrary. Results: Sixty four patients met eligibility criteria with a median age of 65 years (range: 36, 80 years). Prior to Nal-IRI, 61 patients had received FOLFIRINOX, and 3 FOLFIRI. Of these, 32 patients manifested progressive disease on regular irinotecan-based therapy. Nal-IRI was prescribed with a fluoropyrimidine; only one patient received monotherapy. At time of analysis, 54 patients had died. Median overall survival from initiation of Nal-IRI was 5.1 months (95% confidence interval (CI): 5.6, 4.3, months). An exploratory comparison, based on no cancer progression with regular irinotecan versus progression, showed improved survival with Nal-IRI in the former group: 6.1 months (95% CI: 9.3, 5.1 months) versus 4.3 months (95% CI: 4.8, 2.3 months); p=0.0006. Nal-IRI adverse events occurred as expected. Qualitative data illustrated several themes, including “limited treatment options,” which appeared to drive the decision to prescribe Nal-IRI. Conclusions: Nal-IRI might be considered in pancreas cancer patients who had received regular irinotecan, particularly in the absence of disease progression with the latter.
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Kehrer, Diederik F. S., Ron H. J. Mathijssen, Jaap Verweij, Peter de Bruijn, and Alex Sparreboom. "Modulation of Irinotecan Metabolism by Ketoconazole." Journal of Clinical Oncology 20, no. 14 (July 15, 2002): 3122–29. http://dx.doi.org/10.1200/jco.2002.08.177.
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PURPOSE: Irinotecan (CPT-11) is a prodrug of SN-38 and has been registered for the treatment of advanced colorectal cancer. It is converted by the cytochrome P450 3A4 isozyme (CYP3A4) into several inactive metabolites, including 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin (APC). To investigate the role of CYP3A4 in irinotecan pharmacology, we evaluated the consequences of simultaneous treatment of irinotecan with a potent enzyme inhibitor, ketoconazole, in a group of cancer patients. PATIENTS AND METHODS: A total of seven assessable patients was treated in a randomized, cross-over design with irinotecan (350 mg/m2 intravenously for 90 minutes) given alone and followed 3 weeks later by irinotecan (100 mg/m2) in combination with ketoconazole (200 mg orally for 2 days) or vice versa. Serial plasma, urine, and feces samples were obtained up to 500 hours after dosing and analyzed for irinotecan, metabolites (7-ethyl-10-hydroxycamptothecin [SN-38], SN-38 glucuronide [SN-38G], and APC), and ketoconazole by high-performance liquid chromatography. RESULTS: With ketoconazole coadministration, the relative formation of APC was reduced by 87% (P = .002), whereas the relative exposure to the carboxylesterase-mediated SN-38 as expected on the basis of dose (area under the plasma concentration-time curve normalized to dose) was increased by 109% (P = .004). These metabolic alterations occurred without substantial changes in irinotecan clearance (P = .90) and formation of SN-38G (P = .93). CONCLUSION: Inhibition of CYP3A4 in cancer patients treated with irinotecan leads to significantly increased formation of SN-38. Simultaneous administration of various commonly prescribed inhibitors of CYP3A4 can potentially result in fatal outcomes, and up to four-fold reductions in irinotecan dose are indicated.
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Ebrahimpour, Mahnaz, Mahshid Mohammadian, Bagher Pourheydar, Zhino Moradi, and Zhaleh Behrouzkia. "Effects of Radiotherapy in Combination With Irinotecan and 17-AAG on Bcl-2 and Caspase 3 Gene Expression in Colorectal Cancer Cells." Journal of Lasers in Medical Sciences 13, no. 1 (February 28, 2022): e9-e9. http://dx.doi.org/10.34172/jlms.2022.09.
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Introduction: In this study, the cytotoxic and anti-cancer effects of Irinotecan as a conventional chemotherapeutic agent compared to 17-(allyl amino)-17-demethoxygeldanamycin (17-AAG) as possible radiosensitizers in the HCT-116 cell line were investigated. Methods: HCT-116 cells were treated with various concentrations of irinotecan and 17-AAG and also irradiated with a 2-Gy of X-ray radiation. Then, the cell viability was examined by a water-soluble tetrazolium-1 assay after 24 hours. For single therapies and double and triple combination cases, IC50, 0.5×IC50 and 0.25×IC50 concentrations of each drug were selected respectively for a terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay and other tests. In treated and untreated cells, the caspase 3 and Bcl-2 gene expression ratios were evaluated by the real-time PCR method. Likewise, caspase 3 activity was detected with a colorimetric assay. Results: In all combined treatments, including 17-AAG- radiation, irinotecan - radiation, irinotecan -17-AAG, and irinotecan-17-AAG-radiation, decreased cellular viability and increased TUNEL positive cells were presented versus the control group (P<0.05). There were increased TUNEL positive cells in the triple combination, in concentrations of 0.25×IC50 of each drug, in comparison with single and double agent treatments. Moreover, in triple combination, the caspase 3 mRNA level and caspase 3 activity increased versus related single treatments. Likewise, in the irinotecan-17-AAG-radiation combined treatment and the 17-AAG-radiation double treatment, the Bcl-2 gene expression level decreased in comparison with single therapies. Conclusion: It can be indicated that the combination of chemo-radiotherapy versus single treatments has significant anti-cancer effects.
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Kim, George P., Daniel J. Sargent, Michelle R. Mahoney, Kendrith M. Rowland, Philip A. Philip, Edith Mitchell, Abraham P. Mathews, et al. "Phase III Noninferiority Trial Comparing Irinotecan With Oxaliplatin, Fluorouracil, and Leucovorin in Patients With Advanced Colorectal Carcinoma Previously Treated With Fluorouracil: N9841." Journal of Clinical Oncology 27, no. 17 (June 10, 2009): 2848–54. http://dx.doi.org/10.1200/jco.2008.20.4552.
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Purpose The primary goal of this multicenter phase III trial was to determine whether overall survival (OS) of fluorouracil (FU) -refractory patients was noninferior when treated with second-line infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4; arm B) versus irinotecan (arm A). Cross-over to the other treatment on disease progression was mandated. Patients and Methods Patients who experienced treatment failure with one prior FU-based therapy and had not received prior irinotecan or oxaliplatin, either for metastatic disease or within 6 months of adjuvant FU therapy, were randomly assigned to arm A (irinotecan 350 or 300 mg/m2 every 3 weeks) or arm B (FOLFOX4). Results A total of 491 patients were randomly assigned (arm A, n = 245; arm B, n = 246); 288 (59%) had experienced treatment failure with FU for metastatic colorectal cancer. Two hundred twenty-seven patients (46%) received protocol-mandated third-line therapy (arm A, 43%; arm B, 57%). Median survival was 13.8 months (95% CI, 12.2 to 15.0 months) for initial treatment with FOLFOX4 and 14.3 months (95% CI, 12.0 to 15.9 months) for irinotecan (P = .38; hazard ratio = 0.92; 95% CI, 0.8 to 1.1). Response rates (RR; 28% v 15.5%; P = .0009) and time to progression (TTP; 6.2 v 4.4 months; P = .0009) were significantly superior with FOLFOX4. In the nonrandom subset of patients who crossed over, RR and TTP improvements with FOLFOX4 continued into third-line treatment. Irinotecan therapy was associated with more grade 3 nausea, vomiting, diarrhea, and febrile neutropenia; FOLFOX4 was associated with more neutropenia and paresthesias. Conclusion In patients who experienced treatment failure with front-line FU therapy, OS does not significantly differ whether second-line therapy begins with irinotecan or FOLFOX4. FOLFOX4 produces higher RR and longer TTP. Both arms had notable OS in patients who experienced treatment failure with first-line FU therapy.
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Cockrum, Paul, Andy Surinach, Stella Arndorfer, Jim M. Koeller, and George P. Kim. "National Comprehensive Cancer Network (NCCN) category I/FDA-approved metastatic pancreatic adenocarcinoma (mPDAC) treatments in commercially insured patients: An analysis of inpatient (IP) and emergency room (ER) admissions." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e16739-e16739. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e16739.
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e16739 Background: There are currently four NCCN category 1 systemic regimens approved in the United States for the treatment of mPDAC: FOLFIRINOX (FFX), gemcitabine+nab-paclitaxel (gem+nab-P), gemcitabine monotherapy (gem), and liposomal irinotecan + 5-fluorouracil/leucovorin (5-FU/LV) following progression with gem-based therapy. There is limited real-world research on the IP admissions and ER visit healthcare resource utilization (HRU) of patients receiving these treatments. Methods: Using the IQVIA PharMetrics Plus administrative claims database, data were analyzed for adult patients with mPDAC treated with NCCN category 1 regimens in first through fourth line of therapy between January 1, 2014 and May 31, 2019. For each line of therapy, continuous treatment was defined as the time from first administration of a therapy until the last administration. Mean all-cause and mPDAC-related IP admissions, ER visits, inpatient length of stay (LOS) during treatment were assessed. Results: Of the 2,731 patients with mPDAC included in the study, 101 (3.7%) were treated with a liposomal irinotecan based regimen, 1,316 (48.2%) were treated with gem+nab-P, 612 (22.4%) with FFX, and 624 (22.8%) with gem in any treatment line. The mean number of IP admissions was 1.2 for liposomal irinotecan treated patients, 1.5 for gem+nab-P, 1.5 for FFX, and 1.2 for gem. Among patients with at least one IP admission the mean LOS was 4.5 days for liposomal irinotecan, 5.4 days for gem+nab-P, 3.8 for FFX, and 5.1 for gem treated patients. Patients treated with liposomal irinotecan had a mean of 1.3 ER visits during treatment. Gem+nab-P, FFX, and gem-treated patients experienced 1.7, 1.4, and 1.8 mean ER visits, respectively. Mean mPDAC-related IP admissions ranged from 1.1 – 1.5, ER visits ranged from 1.1 – 1.7, and mean LOS ranged from 3.8 – 5.5 days. Conclusions: In this descriptive retrospective study patients receiving liposomal irinotecan, across all treatment episodes, generally experienced numerically lower mean IP admissions and ER visits. LOS was similar across all regimens. Further studies are necessary to characterize the IP and ER HRU burden among mPDAC patients treated with approved regimens.
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Kipps, Emma, Kate Young, and Naureen Starling. "Liposomal irinotecan in gemcitabine-refractory metastatic pancreatic cancer: efficacy, safety and place in therapy." Therapeutic Advances in Medical Oncology 9, no. 3 (March 2017): 159–70. http://dx.doi.org/10.1177/1758834016688816.
Full textAbstract:
Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. The majority of patients are diagnosed with locally advanced or metastatic disease with a prognosis of short months. Therapeutic options are limited and until recently, there was no standard second-line chemotherapy option. Liposomal constructs have been engineered to encapsulate chemotherapy thereby preventing premature metabolism, improving distribution and minimizing toxicity. Favourable preclinical data on liposomal irinotecan and early phase trials, led to a recently published phase III trial of liposomal irinotecan in combination with fluorouracil and folinic acid in patients with metastatic PDAC, who progressed after gemcitabine-based chemotherapy. As a direct result, the United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have approved the use of liposomal irinotecan in this setting. However, first-line treatment options for this disease now include the combination regimen, FOLFIRINOX, in patients with good performance status, and the role of second-line combination treatment with liposomal irinotecan in this setting is unclear. Recent advances have changed the therapeutic landscape, as clinicians are now able to choose a sequential approach to treatment tailored to the individual patient characteristics. This article reviews current treatment options for metastatic PDAC and focuses on the efficacy, safety and place in therapy of liposomal irinotecan.