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For mesothelioma patients, a number of factors come into play when trying to determine what treatment options will be most effective. For patients who choose to undergo chemotherapy treatments, the commonly used combination of pemetrexed and cisplatin is shown to have potentially harmful effects on a patient's kidneys.
When mesothelioma patients are treated with the anti-folate anti-cancer agent, pemetrexed, and cisplatin, most patients are instructed to supplement with folic acid and vitamin B12 which can reduce some of pemetrexed’s side effects.1,2 About 1 in 3 patients (35%) treated with these two chemotherapy agents improved (their mesothelioma tumors had shrunk).3 In comparison, fewer patients responded as well to the chemotherapeutic mix of cisplatin and gemcitabine, another type of chemotherapy drug (15%).3
After pemedtrexed and cisplatin chemotherapy, patients had a significantly longer duration of no growth of residual mesothelioma (progression-free survival) (median 216 days) than those treated with gemcitabine and cisplatin chemotherapy (median 142 days).3
Stage One of Treatment: Chemotherapy
Pemetrexed is usually given with cisplatin for several cycles (4 cycles are common) as the first stage of trimodal therapy. About 32% of patients respond enough to the chemotherapy to be able to see the reduction on radiographs.4 Afterwards, the patient’s residue tumor is removed by extrapleural pneumonectomy (EPP) surgery as much as possible. In most cases, the patient’s treatment proceeds to radiotherapy to destroy any remaining microscopic mesothelioma cells.
Patients completing the trimodal therapy—chemotherapy, surgery, and radiotherapy—showed longer survival (median survival: 29 months) than 16.8 months for all patients.4
Although clinicians are searching for other agents to improve the response, their search continues.5
Is Pemetrexed Administered to All Patients?
Pemetrexed is not administered to patients with low renal function because pemetrexed treatment can worsen or damage kidney function.
However, most clinicians thought that patients with adequate kidney function could tolerate any damages induced by pemetrexed.2
A recent study suggests that some patients with “adequate renal function” are susceptible to irreversible kidney damage.2
Overview of Renal Function
Kidney function is estimated by at least two methods: Estimated glomerular filtration rate (eGFR) and creatinine clearance rate.
Estimated GFR assesses how well the kidneys are removing wastes from your blood and is the best overall indication of kidney function.6 A normal eGFR reading for healthy individuals is 90 or greater.
Secondly, the creatinine clearance rate (CCR) is used to measure kidney function. In review, normal breakdown of muscle tissue produces waste products, including creatinine. The blood carries creatinine to the kidneys where the glomeruli filter it from blood. Creatinine is excreted in the urine. The creatinine clearance rate is calculated from the differences between the creatinine levels in the blood and the urine over time. Normal daily excretion levels (sum of urine levels) of creatinine are 10-20mg/ kg of patient’s body weight.
Some patients with “adequate renal function” are susceptible to irreversible kidney damage associated with pemetrexed treatment.2
Is Pemetrexel Induced Renal Damage Common?
A recent study examined the potential cause of damage to renal function in 29 patients with non-small cell lung cancer treated with pemetrexed.2 These 29 patients had taken folic acid and vitamin B12 supplements to reduce the incidence of side effects.2 They had adequate renal function (>45mls/min/173m2) according to the pemetrexed’s recommended dosing protocol.
Despite the supplements, six patients (21%) showed acute kidney injury (AKI).2 Five of the six patients with AKI had severe anemia (83%) whereas only 4/23 patients had it (17%).2
Renal function in most patients with AKI (4/6; 68%) recovered within two months after pemetrexed treatment.2
The renal function of the other two patients did not fully recover even by 6 months after treatment.2 One patient was put on dialysis due to the irreversible renal damage.2
Unfortunately, no test yet can predict which patients will develop acute kidney injury from pemetrexed treatment.
Patients with chronic kidney disease (eGFR between 45 and 60) had about a 50% chance of developing AKI from pemetrexed treatment (4/8; 50%). From a different perspective, patients with chronic kidney disease were more common in the group that developed acute kidney injury (4/6; 67.7%) than those who did not display acute kidney injury (4/23; 17.4%).
Thus, choosing a treatment protocol can be challenging because each treatment has its benefits and also its risks. It’s important to ask questions of your oncologist to understand the potential risks and benefits.
Rahman A, White RM. Cytotoxic anticancer agents and renal impairment study: the challenge remains. J Clin Oncol 2006;24(4):533-536.
Rombola G, Vaira F, Trezzi M, Chiappini N, Falqui V, Londrino F. Pemetrexed induced acute kidney injury in patients with non-small cell lung cancer: reversible and chronic renal damage. J Nephrol 2014.
Shukuya T, Takahashi T, Imai H et al. Comparison of cisplatin plus pemetrexed and cisplatin plus gemcitabine for the treatment of malignant pleural mesothelioma in Japanese patients. Respir Investig 2014;52(2):101-106.
Krug LM, Pass HI, Rusch VW et al. Multicenter phase II trial of neoadjuvant pemetrexed plus cisplatin followed by extrapleural pneumonectomy and radiation for malignant pleural mesothelioma. J Clin Oncol 2009;27(18):3007-3013.
Krug LM, Wozniak AJ, Kindler HL et al. Randomized phase II trial of pemetrexed/cisplatin with or without CBP501 in patients with advanced malignant pleural mesothelioma. Lung Cancer 2014.
Natiional Kidney Foundation. Frequently Asked Questions about GFR Estimated. (National Kidney Foundation,, Philadelphia, 2011).