Predictive Factors of Severe Toxicities of Pemetrexed-Containing Chemotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer — Oak Academic Publishing
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Predictive Factors of Severe Toxicities of Pemetrexed-Containing Chemotherapy in Patients with Non-Squamous Non-Small Cell Lung Cancer
Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
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Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
,
Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
,
Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
1 Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
2 Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
3 Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
4 Department of Respiratory Medicine, National Center for Global Health and Medicine, Tokyo, Japan
Background: Pemetrexed (PEM) is an efficacious multi-targeted antifolate with acceptable toxicities for non-squamous non-small cell lung cancer (non-Sq NSCLC). However, in the clinical setting, PEM has more severe adverse effects than those reported. The aim of this study was to identify the factors for the toxicities of PEM-containing chemotherapy in non-Sq NSCLC patients in the clinical setting. Patients and Methods: We retrospectively evaluated the factors related to PEM toxicities in chemotherapy-naive patients with non-Sq NSCLC from September 2009 to July 2013 at our hospital. Logistic regression model was used in the univariate and multivariate analyses. Results: In total, 104 patients were analyzed. Grades 3 to 5 hematologic toxicities were frequent and included neutropenia (42%), febrile neutropenia (7%), anemia (18%), thrombocytopenia (17%), and disseminated intravascular coagulation (2%). On multivariate analyses, the predictors were poor performance status (PS) [odds ratio (OR): 4.89, 95% confidence interval (CI): 1.22 - 19.4] and low body mass index (OR: 1.44, 95% CI: 1.05 - 1.98) for febrile neutropenia; concomitant chronic infectious disease (OR: 6.63, 95% CI: 1.59 - 27.5) and bevacizumab use (OR: 3.57, 95% CI: 1.36 - 9.32) for neutropenia; poor PS (OR: 3.02, 95% CI: 1.33 - 6.85) for thrombocytopenia; and low serum albumin level (OR: 0.22 , 95% CI: 0.08 - 0.63 ) for non-hematologic toxicities. Conclusions: In addition to the previously reported predictors of PEM toxicities, the presence of concomitant chronic infectious disease was associated with hematologic toxicities. Patient groups who are not sufficiently evaluated in clinical trials should be carefully monitored for the development of more toxicities than expected.
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Danaei, G., Vander Hoorn, S., Lopez, A.D., Murray, C.J. and Ezzati, M., (Cancers) CRAcg (2005) Causes of Cancer in the World: Comparative Risk Assessment of Nine Behavioural and Environmental Risk Factors. Lancet, 366, 1784-1793. https://doi.org/10.1016/S0140-6736(05)67725-2
Scagliotti, G.V., Parikh, P., von Pawel, J., Biesma, B., Vansteenkiste, J., Manegold, C., Serwatowski, P., Gatzemeier, U., Digumarti, R., Zukin, M., Lee, J.S., Mellemgaard, A., Park, K., Patil, S., Rolski, J., Goksel, T., de Marinis, F., Simms, L., Sugarman, K.P. and Gandara, D. (2008) Phase III Study Comparing Cisplatin plus Gemcitabine with Cisplatin plus Pemetrexed in Chemotherapy-Naive Patients with Advanced-Stage Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 26, 3543-3551. https://doi.org/10.1200/JCO.2007.15.0375
Niyikiza, C., Baker, S.D., Seitz, D.E., Walling, J.M., Nelson, K., Rusthoven, J.J., Stabler, S.P., Paoletti, P., Calvert, A.H. and Allen, R.H. (2002) Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy. Molecular Cancer Therapeutics, 1, 545-552.
Kawazoe, H., Yano, A., Ishida, Y., Takechi, K., Katayama, H., Ito, R., Yakushijin, Y., Moriguchi, T., Tanaka, M., Tanaka, A. and Araki, H. (2017) Non-Steroidal Anti-Inflammatory Drugs Induce Severe Hematologic Toxicities in Lung Cancer Patients Receiving Pemetrexed plus Carboplatin: A Retrospective Cohort Study. PLoS One, 12, e0171066. https://doi.org/10.1371/journal.pone.0171066
Huang, M.S., Tsai, J.R., Shen, M.C., Chou, S.H. and Yang, C.J. (2012) Pemetrexed as a Possible Cause of Severe Rhabdomyolysis in the Treatment of Lung Cancer. Lung Cancer, 76, 491-492. https://doi.org/10.1016/j.lungcan.2012.02.009
Vootukuru, V., Liew, Y.P. and Nally Jr., J.V. (2006) Pemetrexed-Induced Acute Renal Failure, Nephrogenic Diabetes Insipidus, and Renal Tubular Acidosis in a Patient with Non-Small Cell Lung Cancer. Medical Oncology, 23, 419-422. https://doi.org/10.1385/MO:23:3:419
Kulkarni, P.M., Chen, R., Anand, T., Monberg, M.J. and Obasaju, C.K. (2008) Efficacy and Safety of Pemetrexed in Elderly Cancer Patients: Results of an Integrated Analysis. Critical Reviews in Oncology/Hematology, 67, 64-70. https://doi.org/10.1016/j.critrevonc.2008.01.011
Mita, A.C., Sweeney, C.J., Baker, S.D., Goetz, A., Hammond, L.A., Patnaik, A., Tolcher, A.W., Villalona-Calero, M., Sandler, A., Chaudhuri, T., Molpus, K., Latz, J.E., Simms, L., Chaudhary, A.K., Johnson, R.D., Rowinsky, E.K. and Takimoto, C.H. (2006) Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients with Normal and Impaired Renal Function. Journal of Clinical Oncology, 24, 552-562. https://doi.org/10.1200/JCO.2004.00.9720
Takimoto, C.H., Hammond-Thelin, L.A., Latz, J.E., Forero, L., Beeram, M., Forouzesh, B., de Bono, J., Tolcher, A.W., Patnaik, A., Monroe, P., Wood, L., Schneck, K.B., Clark, R. and Rowinsky, E.K. (2007) Phase I and Pharmacokinetic Study of Pemetrexed with High-Dose Folic Acid Supplementation or Multivitamin Supplementation in Patients with Locally Advanced or Metastatic Cancer. Clinical Cancer Research, 13, 2675-2683. https://doi.org/10.1158/1078-0432.CCR-06-2393
Lara, P.N., Higdon, R., Lim, N., Kwan, K., Tanaka, M., Lau, D.H.M., Wun, T., Welborn, J., Meyers, F.J., Christensen, S., O’Donnell, R., Richman, C., Scudder, S.A., Tuscano, J., Gandara, D.R. and Lam, K.S. (2001) Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment. Journal of Clinical Oncology, 19, 1728-1733. https://doi.org/10.1200/JCO.2001.19.6.1728
Soria, J.C., Mauguen, A., Reck, M., Reck, M., Sandler, A.B., Saijo, N., Johnson, D.H., Burcoveanu, D., Fukuoka, M., Besse, B., Pignon, J.P., Meta-Analysis of Bevacizumab in Advanced NSCLC Collaborative Group (2013) Systematic Review and Meta-Analysis of Randomised, Phase II/III Trials Adding Bevacizumab to Platinum-Based Chemotherapy as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer. Annals of Oncology, 24, 20-30. https://doi.org/10.1093/annonc/mds590
Ruckdeschel, J.C., Finkelstein, D.M., Ettinger, D.S., Creech, R.H., Mason, B.A., Joss, R.A. and Vogl, S. (1986) A Randomized Trial of the Four Most Active Regimens for Metastatic Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 4, 14-22. https://doi.org/10.1200/JCO.1986.4.1.14
Antoun, S., Baracos, V.E., Birdsell, L., Escudier, B. and Sawyer, M.B. (2010) Low Body Mass Index and Sarcopenia Associated with Dose-Limiting Toxicity of Sorafenib in Patients with Renal Cell Carcinoma. Annals of Oncology, 21, 1594-1598. https://doi.org/10.1093/annonc/mdp605
Prado, C.M., Baracos, V.E., McCargar, L.J., Reiman, T., Mourtzakis, M., Tonkin, K., Mackey, J.R., Koski, S., Pituskin, E. and Sawyer, M.B. (2009) Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment. Clinical Cancer Research, 15, 2920-2926. https://doi.org/10.1158/1078-0432.CCR-08-2242
Latz, J.E., Karlsson, M.O., Rusthoven, J.J., Ghosh, A. and Johnson, R.D. (2006) A Semimechanistic-Physiologic Population Pharmacokinetic/Pharmacodynamic Model for Neutropenia Following Pemetrexed Therapy. Cancer Chemotherapy and Pharmacology, 57, 412-426. https://doi.org/10.1007/s00280-005-0077-5
van der Watt, J.J., Harrison, T.B., Benatar, M. and Heckmann, J.M. (2011) Polyneuropathy, Anti-Tuberculosis Treatment and the Role of Pyridoxine in the HIV/ AIDS Era: A Systematic Review. International Journal of Tuberculosis and Lung Disease, 15, 722-728.
Ferlay, J., Shin, H.R., Bray, F., Forman, D., Mathers, C. and Parkin, D.M. (2010) Estimates of Worldwide Burden of Cancer in 2008: GLOBOCAN 2008. International Journal of Cancer, 127, 2893-2917. https://doi.org/10.1002/ijc.25516
Danaei, G., Vander Hoorn, S., Lopez, A.D., Murray, C.J. and Ezzati, M., (Cancers) CRAcg (2005) Causes of Cancer in the World: Comparative Risk Assessment of Nine Behavioural and Environmental Risk Factors. Lancet, 366, 1784-1793. https://doi.org/10.1016/S0140-6736(05)67725-2
Scagliotti, G.V., Parikh, P., von Pawel, J., Biesma, B., Vansteenkiste, J., Manegold, C., Serwatowski, P., Gatzemeier, U., Digumarti, R., Zukin, M., Lee, J.S., Mellemgaard, A., Park, K., Patil, S., Rolski, J., Goksel, T., de Marinis, F., Simms, L., Sugarman, K.P. and Gandara, D. (2008) Phase III Study Comparing Cisplatin plus Gemcitabine with Cisplatin plus Pemetrexed in Chemotherapy-Naive Patients with Advanced-Stage Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 26, 3543-3551. https://doi.org/10.1200/JCO.2007.15.0375
Niyikiza, C., Baker, S.D., Seitz, D.E., Walling, J.M., Nelson, K., Rusthoven, J.J., Stabler, S.P., Paoletti, P., Calvert, A.H. and Allen, R.H. (2002) Homocysteine and Methylmalonic Acid: Markers to Predict and Avoid Toxicity from Pemetrexed Therapy. Molecular Cancer Therapeutics, 1, 545-552.
Kawazoe, H., Yano, A., Ishida, Y., Takechi, K., Katayama, H., Ito, R., Yakushijin, Y., Moriguchi, T., Tanaka, M., Tanaka, A. and Araki, H. (2017) Non-Steroidal Anti-Inflammatory Drugs Induce Severe Hematologic Toxicities in Lung Cancer Patients Receiving Pemetrexed plus Carboplatin: A Retrospective Cohort Study. PLoS One, 12, e0171066. https://doi.org/10.1371/journal.pone.0171066
Huang, M.S., Tsai, J.R., Shen, M.C., Chou, S.H. and Yang, C.J. (2012) Pemetrexed as a Possible Cause of Severe Rhabdomyolysis in the Treatment of Lung Cancer. Lung Cancer, 76, 491-492. https://doi.org/10.1016/j.lungcan.2012.02.009
Vootukuru, V., Liew, Y.P. and Nally Jr., J.V. (2006) Pemetrexed-Induced Acute Renal Failure, Nephrogenic Diabetes Insipidus, and Renal Tubular Acidosis in a Patient with Non-Small Cell Lung Cancer. Medical Oncology, 23, 419-422. https://doi.org/10.1385/MO:23:3:419
Kulkarni, P.M., Chen, R., Anand, T., Monberg, M.J. and Obasaju, C.K. (2008) Efficacy and Safety of Pemetrexed in Elderly Cancer Patients: Results of an Integrated Analysis. Critical Reviews in Oncology/Hematology, 67, 64-70. https://doi.org/10.1016/j.critrevonc.2008.01.011
Mita, A.C., Sweeney, C.J., Baker, S.D., Goetz, A., Hammond, L.A., Patnaik, A., Tolcher, A.W., Villalona-Calero, M., Sandler, A., Chaudhuri, T., Molpus, K., Latz, J.E., Simms, L., Chaudhary, A.K., Johnson, R.D., Rowinsky, E.K. and Takimoto, C.H. (2006) Phase I and Pharmacokinetic Study of Pemetrexed Administered Every 3 Weeks to Advanced Cancer Patients with Normal and Impaired Renal Function. Journal of Clinical Oncology, 24, 552-562. https://doi.org/10.1200/JCO.2004.00.9720
Takimoto, C.H., Hammond-Thelin, L.A., Latz, J.E., Forero, L., Beeram, M., Forouzesh, B., de Bono, J., Tolcher, A.W., Patnaik, A., Monroe, P., Wood, L., Schneck, K.B., Clark, R. and Rowinsky, E.K. (2007) Phase I and Pharmacokinetic Study of Pemetrexed with High-Dose Folic Acid Supplementation or Multivitamin Supplementation in Patients with Locally Advanced or Metastatic Cancer. Clinical Cancer Research, 13, 2675-2683. https://doi.org/10.1158/1078-0432.CCR-06-2393
Lara, P.N., Higdon, R., Lim, N., Kwan, K., Tanaka, M., Lau, D.H.M., Wun, T., Welborn, J., Meyers, F.J., Christensen, S., O’Donnell, R., Richman, C., Scudder, S.A., Tuscano, J., Gandara, D.R. and Lam, K.S. (2001) Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment. Journal of Clinical Oncology, 19, 1728-1733. https://doi.org/10.1200/JCO.2001.19.6.1728
Soria, J.C., Mauguen, A., Reck, M., Reck, M., Sandler, A.B., Saijo, N., Johnson, D.H., Burcoveanu, D., Fukuoka, M., Besse, B., Pignon, J.P., Meta-Analysis of Bevacizumab in Advanced NSCLC Collaborative Group (2013) Systematic Review and Meta-Analysis of Randomised, Phase II/III Trials Adding Bevacizumab to Platinum-Based Chemotherapy as First-Line Treatment in Patients with Advanced Non-Small-Cell Lung Cancer. Annals of Oncology, 24, 20-30. https://doi.org/10.1093/annonc/mds590
Ruckdeschel, J.C., Finkelstein, D.M., Ettinger, D.S., Creech, R.H., Mason, B.A., Joss, R.A. and Vogl, S. (1986) A Randomized Trial of the Four Most Active Regimens for Metastatic Non-Small-Cell Lung Cancer. Journal of Clinical Oncology, 4, 14-22. https://doi.org/10.1200/JCO.1986.4.1.14
Antoun, S., Baracos, V.E., Birdsell, L., Escudier, B. and Sawyer, M.B. (2010) Low Body Mass Index and Sarcopenia Associated with Dose-Limiting Toxicity of Sorafenib in Patients with Renal Cell Carcinoma. Annals of Oncology, 21, 1594-1598. https://doi.org/10.1093/annonc/mdp605
Prado, C.M., Baracos, V.E., McCargar, L.J., Reiman, T., Mourtzakis, M., Tonkin, K., Mackey, J.R., Koski, S., Pituskin, E. and Sawyer, M.B. (2009) Sarcopenia as a Determinant of Chemotherapy Toxicity and Time to Tumor Progression in Metastatic Breast Cancer Patients Receiving Capecitabine Treatment. Clinical Cancer Research, 15, 2920-2926. https://doi.org/10.1158/1078-0432.CCR-08-2242
Latz, J.E., Karlsson, M.O., Rusthoven, J.J., Ghosh, A. and Johnson, R.D. (2006) A Semimechanistic-Physiologic Population Pharmacokinetic/Pharmacodynamic Model for Neutropenia Following Pemetrexed Therapy. Cancer Chemotherapy and Pharmacology, 57, 412-426. https://doi.org/10.1007/s00280-005-0077-5
van der Watt, J.J., Harrison, T.B., Benatar, M. and Heckmann, J.M. (2011) Polyneuropathy, Anti-Tuberculosis Treatment and the Role of Pyridoxine in the HIV/ AIDS Era: A Systematic Review. International Journal of Tuberculosis and Lung Disease, 15, 722-728.