Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations

Yoshino, Takayuki; Yamada, Yasuhide; Yamazaki, Kentaro; Tsuji, Akihito; Umemura, Takashi; Grothey, Axel; Cutsem, Éric Van; Wagner, Andrea; Cihon, Frank; Hamada, Yoshimasa; Ohtsu, Atsushi

doi:10.1007/s10637-014-0154-x

Cited by 103 publications

(115 citation statements)

References 14 publications

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“…The dose intensity of Reg was lower in Japanese compared with that in non-Japanese patients, as dose modifications due to AEs were more frequent in the Japanese group. The rate of treatment discontinuation due to Reg-associated AEs was also higher in the Japanese group (15). When Reg was launched in May, 2013, treatment was initiated at the dose of 160 mg.…”

Section: Discussionmentioning

confidence: 97%

“…However, AEs such as HFSR, hypertension, thrombocytopenia and proteinuria occurred at a higher incidence among Japanese patients, and it was also reported that 1 Japanese patient succumbed to liver dysfunction due to Reg. In addition, dose modifications due to AEs were more frequent and the dose intensity of Reg was lower in Japanese compared with that in non-Japanese patients (15). Therefore, although Reg achieved clinical benefits with tolerable AEs according to previous studies (14,16), its efficacy and safety in Japanese patients should be verified in the clinical setting.…”

Section: Introductionmentioning

confidence: 95%

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Response to regorafenib at an initial dose of 120 mg as salvage therapy for metastatic colorectal cancer

Osawa

2017

Molecular and Clinical Oncology

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Abstract. Regorafenib (Reg) is an oral multikinase inhibitor that has achieved improved overall survival in patients with metastatic colorectal cancer (mCRC) in the salvage therapy setting. However, Reg is difficult to manage and determine the optimal dose due to adverse events (AEs). The objective of this study was to retrospectively evaluate the clinical benefit and determine the optimal dose of Reg in mCRC patients. A total of 20 mCRC patients were enrolled in this retrospective study. Initially, 8 patients who received a starting dose of 160 mg Reg (160 mg group) once a day were evaluated; however, they were unable to continue with the initial dose of 160 mg due to grade 3 adverse events (AEs), such as hand-foot skin reaction (HFSR) and small intestinal hemorrhage. Furthermore, 2 of the 8 patients refused subsequent treatment due to HFSR and the remaining 6 patients received a dose reduction from 160 to 120 mg Reg. A reduced dose of 120 mg Reg was also assessed with our dose modification method in 12 patients (120 mg group). The optimal response of the 160 and 120 mg group patients was 0.0 and 8.3% (1/12), respectively. In the 160 mg group, 3 patients exhibited stable disease (SD). Surprisingly, among the the 120 mg group patients 1 exhibited partial response (PR) and 6 had SD. The PR case displayed shrinkage of the local recurrence and morphological changes. One of the SD cases exhibited formation of a cavity in the lung metastasis, with intralesional morphological changes of the liver metastasis. The duration of the treatment in the PR case and the SD case with the cavitation was 6.5 months (9 cycles) and 5 months (6 cycles), respectively. The median progression--free survival (PFS) was 77 days (range, 30-230+ days) and the median overall survival (OS) was 204 days (range, 53-511+ days). The final date of the follow-up period was July 31, 2016. The 160 mg group was associated with a 25% (3/8) incidence of HFSR, 12.5% (1/8) of small intestinal hemorrhage and 12.5% (1/8) of anemia and thrombocytopenia; the AEs were grade >3. The 120 mg group was associated with an incidence of only 8.3% (1/12) of grade >3 hypertension. Thus, the 120 mg group experienced lower treatment-related toxicity compared with the 160 mg group. Despite a reduced initial dose of Reg, a significant effect was observed, with 1 PR and 6 favorable SD cases, with good tolerability. Therefore, an initial dose modification of 120 mg Reg is recommended as an alternative strategy for the treatment of mCRC in the salvage setting. IntroductionThe pattern of cause of death and the annual odds of death in metastatic colorectal cancer (mCRC) are similar between Japan and the global standards (1,2). Approximately 20-25% of patients with CRC have metastatic disease at diagnosis and the majority of mCRC patients require intensive or palliative chemotherapy (3,4). Patients with mCRC generally receive a combination of 5-fluorouracil (5-FU)/leucovorin and either oxaliplatin (L-OHP) (FOLFOX) or irinotecan (CPT-11) (FOLFIRI) with molecular-targeted therapy a...

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 95%

Response to regorafenib at an initial dose of 120 mg as salvage therapy for metastatic colorectal cancer

Osawa

2017

Molecular and Clinical Oncology

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“…The most frequent regorafenib-related AEs of grade ≥3 in the CORRECT trial were hand-foot skin reaction, fatigue, diarrhea, hypertension and rash or desquamation (2). Regarding the incidence of regorafenib-related hepatotoxicity, including hyperbilirubinaemia and elevation of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, it was relatively low in a non-Japanese population, while it was high in a Japanese population (5). These results were supported with the CONCUR trial (3), which was performed by institutions in Asia.…”

Section: Introductionmentioning

confidence: 85%

Pseudocirrhosis caused by regorafenib in an advanced rectal cancer patient with multiple liver metastases

Kumamoto

Endo

Isohata

et al. 2016

Molecular and Clinical Oncology

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Abstract.A 70-year-old man who was diagnosed with unresectable advanced rectal cancer with multiple liver metastases, received oxaliplatin-based treatment with bevacizumab as first-line chemotherapy and irinotecan-based treatment with bevacizumab as second-line chemotherapy for a total of 17 months. The patient was treated with regorafenib (160 mg/day for 3 weeks) as third-line chemotherapy. Following completion of one course of regorafenib treatment, the patient complained of abdominal distension. Computed tomography (CT) examination identified liver atrophy and massive ascites, while no such symptoms were observed prior to the regorafenib treatment. Blood testing revealed increases in the aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) levels. The patient was admitted to the Aizu Medical Center (Aizuwakamatsu, Japan). Approximately 2,000 ml of ascitic fluid were aspirated daily for 1 week by abdominal puncture. The patient was administered oral diuretics, including 20 mg/day of furosemide and 25 mg/day of spironolactone. Albumin was administered to correct the albumin deficit. The levels of AST, ALT and ALP were decreased from the peak value reported on admission and the patient was discharged from our hospital 16 days following treatment initiation. The CT examination after 1 month revealed that the volume of the liver had been restored and the ascites had disappeared. Furthermore, almost all the liver metastases were reduced in size. The carcinoembryonic antigen level, which was elevated prior to regorafenib treatment, also decreased to normal.

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“…One of the most common adverse events associated with Regorafenib is Hand-foot Skin Reaction (HFSR). In the CORRECT study, HFSR occurred at a rate of 44.6% overall and 16.6% at grade 3 [2], and showed higher proportions (80 and 27.7%, respectively) in the Japanese subpopulation [3]. HFSR is not life-threatening adverse event, but may cause considerable deterioration of patients' Quality of Life (QOL), resulting in discontinuation of treatment.…”

Section: Introductionmentioning

confidence: 99%

“…HFSR associated with TKIs occurs earlier compared with cytotoxic anticancer agents (fluoropyrimidines or taxanes). Patients with TKIs-associated HFSR often present with erythema, swelling, bullae, and hyperkeratosis, especially in pressure-bearing skin surface such as plams or soles [3][4][5][6][7][8][9][10][11]. Although there are no established therapeutic options available for TKIs-associated HFSR, it has recommended that pressure bearing should be avoided in daily life [4].…”

Section: Introductionmentioning

confidence: 99%

Effectiveness of Topical Steroid Therapy for Prevention of Regorafenib associated Hand-foot Skin Reaction

Ishikawa¹,

Hamauchi²,

Tanaka³

et al. 2017

J Appl Pharm

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Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations

Cited by 103 publications

References 14 publications

Response to regorafenib at an initial dose of 120 mg as salvage therapy for metastatic colorectal cancer

Response to regorafenib at an initial dose of 120 mg as salvage therapy for metastatic colorectal cancer

Pseudocirrhosis caused by regorafenib in an advanced rectal cancer patient with multiple liver metastases

Effectiveness of Topical Steroid Therapy for Prevention of Regorafenib associated Hand-foot Skin Reaction

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