Correspondence
Raltitrexed combined with bevacizumab in heavily pretreated metastatic colorectal cancer ABSTRACT No standard chemotherapy regimen has been established for metastatic colorectal cancer (mCRC) after progression on 5-fluorouracil, oxaliplatin, and irinotecan. Here, we report the combination of raltitrexed and bevacizumab as a salvage regimen for the treatment of three heavily pretreated patients with KRAS mutant mCRC. All three patients had stable disease (SD) according to response evaluation criteria in solid tumors (RECIST) criteria, progression free survival (PFS) were 3.0, 3.2 months for the first two patients and have not been reached for over 5 months for the third patient and no severe adverse effect was observed. The combination of raltitrexed plus bevacizumab in mCRC seems worthy of further investigation. KEY WORDS: Bevacizumab, heavily pretreated patients, metastatic colorectal cancer, raltitrexed
INTRODUCTION Colorectal cancer (CRC) ranks as the third most common cancer worldwide.[1] Metastasis is the main reason of death in CRC patients. For metastatic CRC (mCRC) patients, the exposure to all active chemotherapeutic drugs, including 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, can obviously increase the survival. Unfortunately, chemotherapy options are absent after progression on 5-FU, oxaliplatin, and irinotecan. Both raltitrexed and bevacizumab were reported as active agents for mCRC in single[2,3] and combined strategies, respectively. [4,5] Nevertheless, reports on the combination of raltitrexed plus bevacizumab in mCRC are absent in published literatures. Here, we report three heavily pretreated mCRC patients using raltitrexed and bevacizumab as a salvage regimen. CASE REPORTS Case 1 A 57-year-old man with abdominal pain and hematochezia was diagnosed in January 2010 with an adenocarcinoma of the rectum. A total excision of the mesorectum (TME) was performed (stage IIIC, T3N2 bM0, mutant type KRAS) and inoperable metastases of liver was soon detected by postoperative CT 1 month later. Within the following 14-month treatment with successive chemotherapy consisting of FOLFIRI, FOLFOX, and S-1, the patient suffered sequential progression after the chemotherapy regimen respectively. Then, the patient was admitted
again with poor Eastern Cooperation Oncology Group performance status (ECOG PS 3) presenting dyspnea and requiring oxygen. CT scan revealed multiple diffused metastatic lesions in liver, lungs, and celiac lymph nodes [Figure 1]. Blood biochemical parameters indicated that lactate dehydrogenase (LDH) and hydroxy butyl acid dehydrogenase (HBDH) were up to 1986 IU/L (normal range: 110–220 IU/L) and 1278 IU/L (normal range: 72–182 IU/L), respectively. The patient received raltitrexed 2.5 mg/m2 and bevacizumab 7.5 mg/kg on day 1 every 3 weeks, and he felt relief from dyspnea and improvement of PS (ECOG from 3 to 1) and quality of life (QoL). After two cycles of treatment, the response evaluation was stable disease (SD) with a decreased enhancement of liver metastases. Additionally, a decline of serum LDH (634 IU/L) and HBDH (427 IU/L) was found. The patient eventually suffered from a progression of metastases and new lesion after four cycles of treatment, and died 1½ months after the last treatment. No treatment-related side effect was observed in this patient. Case 2 This patient was a 41-year-old woman who was diagnosed with rectal cancer in June 2007. Anterior resection was performed in July 2007 and the lung metastases were found 18 months after the surgery. The KRAS status of the rectal carcinoma showed a codon 13 mutation. Because of disease progression presenting with new pulmonary lesions and metastases of pelvic lymph nodes, the patient successively received several regimens including
Journal of Cancer Research and Therapeutics - October-December 2013 - Volume 9 - Issue 4
Ke Cheng, Ye Chen, Long-Hao Li, Ji-Yan Liu Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Sichuan Province, China For correspondence: Prof. Ji-Yan Liu, Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, Sichuan Province, China. E-mail: liujiyan1972@163. com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.126470 PMID: 24518728 Quick Response Code:
727
Cheng, et al.: Raltitrexed combined with bevacizumab in mCRC
FOLFOX, XELIRI, and GP (gemcitabine plus cisplatin). During the treatment, palliative radiotherapy for pelvic metastatic lesions and video-assisted thoracoscopic surgery (VATS) for the upper right pulmonary nodules were also administered. The patient was re-admitted because of progression of pulmonary lesions once again and received raltitrexed 2.5 mg/m2 plus bevacizumab 7.5 mg/kg on day 1 every 3 weeks as a salvage regimen. After two cycles, pulmonary metastatic lesions were stable as shown by CT; then, two more cycles were given until her next response assessment which displayed suspicious new lung metastases [Figure 2]. During the treatment, only mild hematological and hepatic toxicity and slight gastrointestinal effects were observed. Case 3 A 41-year-old woman with abdominal pain and change of bowel habits was diagnosed with colon cancer in September 2009, and liver metastases was also detected by CT. After the right hemicolectomy was performed, a KRAS codon 12 mutation was detected by tumor sample gene sequencing. In the following 2 years, in spite of administering several chemotherapeutic combinations consisting of 5-FU, irinotecan, oxaliplatin, capecitabine, and gemcitabine, the patient suffered from new metastases in liver, ovaries, and lungs successively. Hysterectomy and bilateral oophorectomy were also done and adnexal mass was confirmed as adenocarcinoma metastases. On this admission, CT scan indicated an increase of small nodules in both lungs over the prior images. Due to PD by Response Evaluation Criteria in Solid Tumors (RECIST), three-weekly raltitrexed 2.5 mg/m2 plus bevacizumab 7.5 mg/kg on day 1 was introduced as a salvage regimen. After two and four cycles, CT revealed SD with a decreased size in pulmonary metastases and unchanged lesion in liver, respectively [Figure 3]. No side effect was observed except for mild nausea and loss of appetite, and the patient was planning to continue the further cycles.
Figure 1: The contrast-enhanced CT images of liver and lung metastases in patient 1: (a and b) before chemotherapy; (c and d) two cycles later, liver nodular blood supply decreased; (e and f) four cycles later, the size of lung metastases increased with new lesions
Figure 2: The contrast-enhanced CT images of lung metastases in patient 2: (a and b) before chemotherapy; (c and d) after two cycles; (e and f) four cycles later, the size of lung metastases increased
DISCUSSION Raltitrexed is a highly polyglutamatable quinazoline antifolate inhibitor of thymidilate synthase (TS), approved for the treatment of colorectal cancer in China in 2010. Its anticancer mechanism as a direct TS inhibitor is different from that of 5-FU. Previous studies have observed that continuous exposure of human colon cancer cells to 5-FU leads to TS gene amplification and overexpression of TS protein with resultant development of fluoropyrimidine resistance[6] and an increase in TS activity was seen in 5-FU–resistant tumors.[7] Therefore, raltitrexed may express antitumor efficacy after failure of 5-FU. In a series of clinical trials, raltitrexed has shown promising efficacy, favorable toxicity profile, and convenient administration schedule in patients with 5-FU–refractory mCRC as second- or third-line regimen.[4,8,9] Bevacizumab has been evaluated in various solid tumors. Several large phase III studies have demonstrated that the addition of bevacizumab to first- or second-line chemotherapy resulted in significant improvement in survival and response 728
Figure 3: The contrast-enhanced CT images of lung metastases in patient 3: (a and b) mutiple lung metastases before chemotherapy; (c and d) slight decrease of lung metastases after two cycles; (e and f) lung metastases further decreased after four cycles
Journal of Cancer Research and Therapeutics - October-December 2013 - Volume 9 - Issue 4
Cheng, et al.: Raltitrexed combined with bevacizumab in mCRC
REFERENCES 1. 2.
3. Figure 4: The changes of tumor marker and sera enzymes. The CEA in patients 2 and 3 decreased to a certain extent, respectively, after their first two cycles. LDH and HBDH of patient 1 decreased obviously after therapy, and rebounded after four cycles of chemotherapy
among patients with mCRC.[5] But there have been little clinical data in the third or more line setting that can provide exact estimates of the activity of bevacizumab in heavily pretreated mCRC. In 2010, raltitrexed and bevacizumab were successively approved by State Food and Drug Administration (SFDA) in China, so we tried to treat the three patients with the combination of the two drugs as a multiline regimen. They presented similarity at the KRAS mutant status, their course of disease development, and sequential failures to standard first- and second-line chemotherapy. The regimen of raltitrexed and bevacizumab showed a favorable safety and tolerability in all three patients. SD was achieved in 3 months in the first two patients (the other female is still under treatment), and patient 1 had recovered a markedly improved QoL, accompanied with decreased serum enzyme levels [Figure 4]. In summary, our report suggests that the combination of raltitrexed plus bevacizumab may be a promising strategy for heavily treated mCRC. Due to the minor sample size in this observation, further studies to evaluate the efficacy and safety are worthy of investigation.
4.
5.
6. 7.
8.
9.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, et al. Final results of a randomised trial comparing ‘Tomudex’ (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. “Tomudex” Colorectal Cancer Study Group. Ann Oncol 1996;7:961-5. Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, van Hazel G, et al. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 1998;16:2943-52. Scheithauer W, Kornek GV, Schuell B, Ulrich-Pur H, Penz M, Raderer M, et al. Second-line treatment with oxaliplatin+raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorinbased chemotherapy. Ann Oncol 2001;12:709-14. Hur witz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. Copur S, Aiba K, Drake JC, Allegra CJ, Chu E. Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil. Biochem Pharmacol 1995;49:1419-26. Fukushima M, Fujioka A, Uchida J, Nakagawa F, Takechi T. Thymidylate synthase (TS) and ribonucleotide reductase (RNR) may be involved in acquired resistance to 5-fluorouracil (5-FU) in human cancer xenografts in vivo. Eur J Cancer 2001;37:1681-7. Comella P, Casaretti R, Crucitta E, De Vita F, Palmeri S, Avallone A, et al. Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients. Br J Cancer 2002;86:1871-5. Laudani A, Gebbia V, Leonardi V, Savio G, Borsellino N, Cusimano MP, et al. Activity and toxicity of oxaliplatin plus raltitrexed in 5-fluorouracil refractory metastatic colorectal adeno-carcinoma. Anticancer Res 2004;24:1139-42.
Cite this article as: Cheng K, Chen Y, Li L, Liu J. Raltitrexed combined with bevacizumab in heavily pretreated metastatic colorectal cancer. J Can Res Ther 2013;9:727-9. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - October-December 2013 - Volume 9 - Issue 4
729
Copyright of Journal of Cancer Research & Therapeutics is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Raltitrexed combined with bevacizumab in heavily pretreated metastatic colorectal cancer ABSTRACT No standard chemotherapy regimen has been established for metastatic colorectal cancer (mCRC) after progression on 5-fluorouracil, oxaliplatin, and irinotecan. Here, we report the combination of raltitrexed and bevacizumab as a salvage regimen for the treatment of three heavily pretreated patients with KRAS mutant mCRC. All three patients had stable disease (SD) according to response evaluation criteria in solid tumors (RECIST) criteria, progression free survival (PFS) were 3.0, 3.2 months for the first two patients and have not been reached for over 5 months for the third patient and no severe adverse effect was observed. The combination of raltitrexed plus bevacizumab in mCRC seems worthy of further investigation. KEY WORDS: Bevacizumab, heavily pretreated patients, metastatic colorectal cancer, raltitrexed
INTRODUCTION Colorectal cancer (CRC) ranks as the third most common cancer worldwide.[1] Metastasis is the main reason of death in CRC patients. For metastatic CRC (mCRC) patients, the exposure to all active chemotherapeutic drugs, including 5-fluorouracil (5-FU), oxaliplatin, and irinotecan, can obviously increase the survival. Unfortunately, chemotherapy options are absent after progression on 5-FU, oxaliplatin, and irinotecan. Both raltitrexed and bevacizumab were reported as active agents for mCRC in single[2,3] and combined strategies, respectively. [4,5] Nevertheless, reports on the combination of raltitrexed plus bevacizumab in mCRC are absent in published literatures. Here, we report three heavily pretreated mCRC patients using raltitrexed and bevacizumab as a salvage regimen. CASE REPORTS Case 1 A 57-year-old man with abdominal pain and hematochezia was diagnosed in January 2010 with an adenocarcinoma of the rectum. A total excision of the mesorectum (TME) was performed (stage IIIC, T3N2 bM0, mutant type KRAS) and inoperable metastases of liver was soon detected by postoperative CT 1 month later. Within the following 14-month treatment with successive chemotherapy consisting of FOLFIRI, FOLFOX, and S-1, the patient suffered sequential progression after the chemotherapy regimen respectively. Then, the patient was admitted
again with poor Eastern Cooperation Oncology Group performance status (ECOG PS 3) presenting dyspnea and requiring oxygen. CT scan revealed multiple diffused metastatic lesions in liver, lungs, and celiac lymph nodes [Figure 1]. Blood biochemical parameters indicated that lactate dehydrogenase (LDH) and hydroxy butyl acid dehydrogenase (HBDH) were up to 1986 IU/L (normal range: 110–220 IU/L) and 1278 IU/L (normal range: 72–182 IU/L), respectively. The patient received raltitrexed 2.5 mg/m2 and bevacizumab 7.5 mg/kg on day 1 every 3 weeks, and he felt relief from dyspnea and improvement of PS (ECOG from 3 to 1) and quality of life (QoL). After two cycles of treatment, the response evaluation was stable disease (SD) with a decreased enhancement of liver metastases. Additionally, a decline of serum LDH (634 IU/L) and HBDH (427 IU/L) was found. The patient eventually suffered from a progression of metastases and new lesion after four cycles of treatment, and died 1½ months after the last treatment. No treatment-related side effect was observed in this patient. Case 2 This patient was a 41-year-old woman who was diagnosed with rectal cancer in June 2007. Anterior resection was performed in July 2007 and the lung metastases were found 18 months after the surgery. The KRAS status of the rectal carcinoma showed a codon 13 mutation. Because of disease progression presenting with new pulmonary lesions and metastases of pelvic lymph nodes, the patient successively received several regimens including
Journal of Cancer Research and Therapeutics - October-December 2013 - Volume 9 - Issue 4
Ke Cheng, Ye Chen, Long-Hao Li, Ji-Yan Liu Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Sichuan Province, China For correspondence: Prof. Ji-Yan Liu, Department of Medical Oncology, Cancer Center, the State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, No. 37, Guo Xue Xiang, Chengdu 610041, Sichuan Province, China. E-mail: liujiyan1972@163. com
Access this article online Website: www.cancerjournal.net DOI: 10.4103/0973-1482.126470 PMID: 24518728 Quick Response Code:
727
Cheng, et al.: Raltitrexed combined with bevacizumab in mCRC
FOLFOX, XELIRI, and GP (gemcitabine plus cisplatin). During the treatment, palliative radiotherapy for pelvic metastatic lesions and video-assisted thoracoscopic surgery (VATS) for the upper right pulmonary nodules were also administered. The patient was re-admitted because of progression of pulmonary lesions once again and received raltitrexed 2.5 mg/m2 plus bevacizumab 7.5 mg/kg on day 1 every 3 weeks as a salvage regimen. After two cycles, pulmonary metastatic lesions were stable as shown by CT; then, two more cycles were given until her next response assessment which displayed suspicious new lung metastases [Figure 2]. During the treatment, only mild hematological and hepatic toxicity and slight gastrointestinal effects were observed. Case 3 A 41-year-old woman with abdominal pain and change of bowel habits was diagnosed with colon cancer in September 2009, and liver metastases was also detected by CT. After the right hemicolectomy was performed, a KRAS codon 12 mutation was detected by tumor sample gene sequencing. In the following 2 years, in spite of administering several chemotherapeutic combinations consisting of 5-FU, irinotecan, oxaliplatin, capecitabine, and gemcitabine, the patient suffered from new metastases in liver, ovaries, and lungs successively. Hysterectomy and bilateral oophorectomy were also done and adnexal mass was confirmed as adenocarcinoma metastases. On this admission, CT scan indicated an increase of small nodules in both lungs over the prior images. Due to PD by Response Evaluation Criteria in Solid Tumors (RECIST), three-weekly raltitrexed 2.5 mg/m2 plus bevacizumab 7.5 mg/kg on day 1 was introduced as a salvage regimen. After two and four cycles, CT revealed SD with a decreased size in pulmonary metastases and unchanged lesion in liver, respectively [Figure 3]. No side effect was observed except for mild nausea and loss of appetite, and the patient was planning to continue the further cycles.
Figure 1: The contrast-enhanced CT images of liver and lung metastases in patient 1: (a and b) before chemotherapy; (c and d) two cycles later, liver nodular blood supply decreased; (e and f) four cycles later, the size of lung metastases increased with new lesions
Figure 2: The contrast-enhanced CT images of lung metastases in patient 2: (a and b) before chemotherapy; (c and d) after two cycles; (e and f) four cycles later, the size of lung metastases increased
DISCUSSION Raltitrexed is a highly polyglutamatable quinazoline antifolate inhibitor of thymidilate synthase (TS), approved for the treatment of colorectal cancer in China in 2010. Its anticancer mechanism as a direct TS inhibitor is different from that of 5-FU. Previous studies have observed that continuous exposure of human colon cancer cells to 5-FU leads to TS gene amplification and overexpression of TS protein with resultant development of fluoropyrimidine resistance[6] and an increase in TS activity was seen in 5-FU–resistant tumors.[7] Therefore, raltitrexed may express antitumor efficacy after failure of 5-FU. In a series of clinical trials, raltitrexed has shown promising efficacy, favorable toxicity profile, and convenient administration schedule in patients with 5-FU–refractory mCRC as second- or third-line regimen.[4,8,9] Bevacizumab has been evaluated in various solid tumors. Several large phase III studies have demonstrated that the addition of bevacizumab to first- or second-line chemotherapy resulted in significant improvement in survival and response 728
Figure 3: The contrast-enhanced CT images of lung metastases in patient 3: (a and b) mutiple lung metastases before chemotherapy; (c and d) slight decrease of lung metastases after two cycles; (e and f) lung metastases further decreased after four cycles
Journal of Cancer Research and Therapeutics - October-December 2013 - Volume 9 - Issue 4
Cheng, et al.: Raltitrexed combined with bevacizumab in mCRC
REFERENCES 1. 2.
3. Figure 4: The changes of tumor marker and sera enzymes. The CEA in patients 2 and 3 decreased to a certain extent, respectively, after their first two cycles. LDH and HBDH of patient 1 decreased obviously after therapy, and rebounded after four cycles of chemotherapy
among patients with mCRC.[5] But there have been little clinical data in the third or more line setting that can provide exact estimates of the activity of bevacizumab in heavily pretreated mCRC. In 2010, raltitrexed and bevacizumab were successively approved by State Food and Drug Administration (SFDA) in China, so we tried to treat the three patients with the combination of the two drugs as a multiline regimen. They presented similarity at the KRAS mutant status, their course of disease development, and sequential failures to standard first- and second-line chemotherapy. The regimen of raltitrexed and bevacizumab showed a favorable safety and tolerability in all three patients. SD was achieved in 3 months in the first two patients (the other female is still under treatment), and patient 1 had recovered a markedly improved QoL, accompanied with decreased serum enzyme levels [Figure 4]. In summary, our report suggests that the combination of raltitrexed plus bevacizumab may be a promising strategy for heavily treated mCRC. Due to the minor sample size in this observation, further studies to evaluate the efficacy and safety are worthy of investigation.
4.
5.
6. 7.
8.
9.
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin 2011;61:69-90. Cunningham D, Zalcberg JR, Rath U, Oliver I, van Cutsem E, Svensson C, et al. Final results of a randomised trial comparing ‘Tomudex’ (raltitrexed) with 5-fluorouracil plus leucovorin in advanced colorectal cancer. “Tomudex” Colorectal Cancer Study Group. Ann Oncol 1996;7:961-5. Cocconi G, Cunningham D, Van Cutsem E, Francois E, Gustavsson B, van Hazel G, et al. Open, randomized, multicenter trial of raltitrexed versus fluorouracil plus high-dose leucovorin in patients with advanced colorectal cancer. Tomudex Colorectal Cancer Study Group. J Clin Oncol 1998;16:2943-52. Scheithauer W, Kornek GV, Schuell B, Ulrich-Pur H, Penz M, Raderer M, et al. Second-line treatment with oxaliplatin+raltitrexed in patients with advanced colorectal cancer failing fluoropyrimidine/leucovorinbased chemotherapy. Ann Oncol 2001;12:709-14. Hur witz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. Copur S, Aiba K, Drake JC, Allegra CJ, Chu E. Thymidylate synthase gene amplification in human colon cancer cell lines resistant to 5-fluorouracil. Biochem Pharmacol 1995;49:1419-26. Fukushima M, Fujioka A, Uchida J, Nakagawa F, Takechi T. Thymidylate synthase (TS) and ribonucleotide reductase (RNR) may be involved in acquired resistance to 5-fluorouracil (5-FU) in human cancer xenografts in vivo. Eur J Cancer 2001;37:1681-7. Comella P, Casaretti R, Crucitta E, De Vita F, Palmeri S, Avallone A, et al. Oxaliplatin plus raltitrexed and leucovorin-modulated 5-fluorouracil i.v. bolus: a salvage regimen for colorectal cancer patients. Br J Cancer 2002;86:1871-5. Laudani A, Gebbia V, Leonardi V, Savio G, Borsellino N, Cusimano MP, et al. Activity and toxicity of oxaliplatin plus raltitrexed in 5-fluorouracil refractory metastatic colorectal adeno-carcinoma. Anticancer Res 2004;24:1139-42.
Cite this article as: Cheng K, Chen Y, Li L, Liu J. Raltitrexed combined with bevacizumab in heavily pretreated metastatic colorectal cancer. J Can Res Ther 2013;9:727-9. Source of Support: Nil, Conflict of Interest: None declared.
Journal of Cancer Research and Therapeutics - October-December 2013 - Volume 9 - Issue 4
729
Copyright of Journal of Cancer Research & Therapeutics is the property of Medknow Publications & Media Pvt. Ltd. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
