Pharmacokinetic and dose-finding study of osimertinib in patients with impaired renal function and low body weight

The safety of osimertinib is limited in patients with severe or moderate renal impairment, or low body weight. This study aimed to investigate the safety, pharmacokinetics (PK) and recommended dose (RD) of osimertinib in patients with epidermal growth factor receptor (EGFR)-mutated non–small cell lung cancer (NSCLC) with impaired renal function and low body weight. Thirty-one eligible patients were enrolled and allocated into four cohorts: A, normal renal function (estimated glomerular filtration rate [eGFR] ≥ 50 mL/min/1.73 m²) and normal body weight (≥45 kg); B, moderate renal impairment (eGFR = 30-50 mL/min/1.73 m²); C, low body weight (<45 kg); and D, severe renal impairment (eGFR <30 mL/min/1.73 m² or undergoing dialysis). PK parameters and safety were evaluated with a starting dose of 80 mg osimertinib administered orally once daily in cohorts A, B, and C and 40 mg once daily in cohort D. The PK parameters in cohorts A, B, and C were found to be similar. No dose-limiting toxicity was observed, and the RD was determined to be 80 mg once daily in patients with moderate renal function and low body weight. Four serious adverse events, acneiform rash, diarrhea, QTc prolongation, and interstitial lung disease, were noted. Although the PK parameters of osimertinib were similar across all cohorts, toxicity occurred more frequently in patients with impaired renal function and low body weight. Clinicians should prescribe osimertinib with caution in NSCLC patients with impaired renal function and low body weight.     

Effects of Bosutinib Treatment on Renal Function in Patients With Philadelphia Chromosome-Positive Leukemias

BackgroundThe purpose of the study was to assess renal function in patients with Philadelphia chromosome-positive leukemias receiving bosutinib or imatinib.Patients and MethodsPatients received first-line bosutinib (n = 248) or imatinib (n = 251; phase III trial), or second-line or later bosutinib (phase I/II trial; n = 570). Adverse events (AEs) and changes from baseline in estimated glomerular filtration rate (eGFR) and serum creatinine were assessed.ResultsTime from the last patient's first dose to data cutoff was ≥ 48 months. Renal AEs were reported in 73/570 patients (13%) receiving second-line or later bosutinib, and in 22/248 (9%) and 16/251 (6%) receiving first-line bosutinib and imatinib, respectively. eGFR in patients receiving bosutinib declined over time with more patients developing Grade ≥ 3b eGFR (< 45 mL/min/1.73 m² according to the Modification of Diet in Renal Disease method) with second-line or later bosutinib (139/570, 24%) compared with first-line bosutinib (26/248, 10%) and imatinib (25/251, 10%); time to Grade ≥ 3b eGFR was shortest with second-line or later bosutinib. Similar proportions of patients receiving second-line or later bosutinib (74/139, 53%), first-line bosutinib (15/26, 58%), and first-line imatinib (15/25, 60%) improved to ≥ 45 mL/min/1.73 m² eGFR as of the last follow-up. In a regression analysis, first-line treatment with bosutinib versus imatinib was not a significant predictor of Grade ≥ 3b eGFR.ConclusionLong-term bosutinib treatment is associated with an apparently reversible decline in renal function with frequency and characteristics similar to renal decline observed with long-term imatinib treatment. Patients with risk factors for Grade ≥ 3b eGFR should be monitored closely.     

Association of cancer with moderately impaired renal function at baseline in a large,representative, population‐based cohort followed for up to 30 years

Patients with chronic renal failure show a greater incidence of malignancies. We evaluated whether moderately impaired renal function at baseline influenced risk of all cancers during long‐term follow in young persons. Our cohort included 33,346 subjects, aged 26–61 years at baseline, in a representative, population‐based study enrolling subjects from 1974 to 1992. Median follow‐up time was 28 years. Plasma creatinine was analyzed as a single measure at baseline. Incident cases of cancer were identified from the Swedish Cancer Registry. We studied 24,552 subjects from the cohort. To account for the unique sampling design, participants were divided by sex and age at baseline into 1,132 older men (age 60), 14,254 younger men (age 40–52), 7,498 older women (age 47–57) and 1,688 younger women (age 35–43). Glomerular filtration rate (GFR) was estimated using the CKD‐EPI formula. Patients were classified as having either normal to mildly impaired kidney function (eGFR ≥ 60 mL/min/1.73 m²), or moderate kidney dysfunction (eGFR<60 mL/min/1.73 m²). We calculated the risk of all cancers using competing risks regression. Overall, 6,595 participants were diagnosed with cancer, and 854 subjects (3.5%) had moderately impaired renal dysfunction at baseline. There was a significant association between moderately decreased GFR and subsequent risk of kidney cancer in younger men (hazard ratio, 3.38; 95% CI, 1.48 to 7.71; p = 0.004). However, we found no association with overall long‐term cancer risk. Our confirmation of an association between moderately impaired renal function and risk of kidney cancer in younger men requires further exploration of high‐risk groups and biological mechanisms.     

Monitoring the estimated glomerular filtration rate (eGFR) in patients with small-cell lung cancer during chemotherapy: equations based on serum creatinine or cystatin C?

Background

This study compared the differences between the estimated glomerular filtration rate (eGFR) calculated by several equations based on serum creatinine (Scr) and cystatin C (CysC) concentrations for monitoring renal function in patients with small-cell lung cancer (SCLC) during chemotherapy.

Methods

Seventy-one patients with SCLC were retrospectively analyzed. The eGFR before and after each chemotherapy cycle was calculated by the following equations: the chronic kidney disease epidemiology collaboration (CKD-EPI) equation, the modification of diet in renal disease (MDRD) equation, the Cockcroft–Gault (CG) equation, and five CysC-based equations. The patients were compared among the different eGFR groups.

Results

The mean decreases in eGFR_CKD-EPI (?2.25 ± 9.89 ml/min/1.73 m²) between each treatment cycle were more significant than the decreases in eGFR_CG (?0.46 ± 10.17 ml/min/1.73 m²), eGFR_MDRD (?0.48 ± 9.79 ml/min/1.73 m²), and five calculated eGFR_CysC (p < 0.05). Single-/multiparameter analyses showed that patients with a higher body mass index (BMI >23) and receiving more treatment cycles (>3) were at increased risk for developing renal impairment with an eGFR less than 60 ml/min/1.73 m² during chemotherapy.

Conclusions

The eGFR calculated by the CKD-EPI equation changed more significantly between each chemotherapy cycle than did the eGFR from the other equations based on Scr or CysC in patients with SCLC. Oncologists should pay more attention to the renal function of specific patient groups during treatment.

     

Impact of short warm ischemic time on longitudinal kidney function and survival rate after partial nephrectomy for renal cell carcinoma in patients with pre-existing chronic kidney disease stage III: A multi-institutional propensity score-matched study

PurposeIt remains unclear whether a short warm ischemic time (WIT) improves long-term renal function after partial nephrectomy (PN) for patients with pre-existing chronic kidney disease (CKD). We evaluated renal function after PN according to WIT duration in patients with stage III CKD.Materials and methodsWe identified 277 patients with stage III CKD who underwent PN during 2004–2017. Propensity score matching was used to created two matched groups of patients: Group A (WIT of <25 min) and Group B (WIT of ≥25 min). The outcomes of interest were longitudinal kidney function change, new-onset stage IV CKD (eGFR <30 mL/min/1.73 m²) and overall survival.ResultsThe two matched groups contained 85 patients each. The median follow-up durations were 49 months in Group A and 42 months in Group B. The median pre-treatment eGFRs were 52.4 mL/min/1.73 m² in Group A and 52.6 mL/min/1.73 m² in Group B. There were no differences in kidney function between the two groups throughout the follow-up period (P > 0.05). The 5-year rates of new-onset stage IV CKD were not significantly different between Group A and Group B (8.2% vs. 7.1%), with no significant difference in the risk of developing stage IV CKD in Group A (vs. group B, hazard ratio: 0.527, 95% confidence interval: 0.183–1.521; P = 0.236). The 5-year overall survival rates were 90.3% for Group A and 96.2% for Group B (P = 0.549).ConclusionsA short WIT was not associated with better postoperative kidney function or survival after PN in patients with stage III CKD.     

Combining Stereotactic Body Radiotherapy and Microwave Ablation Appears Safe and Feasible for Renal Cell Carcinoma in an Early Series

Microwave (MW) ablation and stereotactic body radiation therapy (SBRT) are both used in treating inoperable renal cell carcinoma (RCC). MW ablation and SBRT have potentially complementary advantages and limitations. Combining SBRT and MW ablation may optimize tumor control and toxicity for patients with larger (> 5 cm) RCCs or those with vascular involvement.Seven patients with RCC were treated at our institution with combination of SBRT and MW ablation, median tumor size of 6.4 cm. Local control was 100% with a median follow-up of 15 months. Four patients experienced grade 2 nausea during SBRT. Three patients experienced toxicities after MW ablation, 2 with grade 1 hematuria and 1 with grade 3 retroperitoneal bleed/collecting system injury. Median eGFR (estimated glomerular filtration rate) preceding and following SBRT and MW ablation was 69 mL/min/1.73 m² and 68 mL/min/1.73 m² (P = .19), respectively.In patients who are not surgical candidates, larger RCCs or those with vascular invasion are challenging to treat. Combination treatment with SBRT and MW ablation may balance the risks and benefits of both therapies and demonstrates high local control in our series. MW ablation and SBRT have potentially complementary advantages and limitations.     

Renal Effects of Crizotinib in Patients With ALK-Positive Advanced NSCLC

IntroductionWe retrospectively analyzed the effects of crizotinib on serum creatinine and creatinine-based estimated glomerular filtration rate (eGFR) in patients with anaplastic lymphoma kinase–positive advanced NSCLC across four trials (NCT00585195, NCT00932451, NCT00932893, and NCT01154140).MethodsChanges from baseline data in serum creatinine and eGFR, calculated using the Chronic Kidney Disease Epidemiology Collaboration creatinine-based equation, were assessed over time. eGFR was graded using standard chronic kidney disease criteria.ResultsMedian serum creatinine increased from 0.79 mg/dL at baseline to 0.93 mg/dL after 2 weeks of treatment (median percentage increase from baseline, 21.2%), was stable from week 12 (0.96 mg/dL) to week 104 (1.00 mg/dL), and decreased to 0.90 mg/dL at 28 days after last dose (median percentage increase from baseline, 13.1%). Median eGFR decreased over time (96.42, 80.23, 78.06 and 75.45 mL/min/1.73 m² at baseline, week 2, week 12, and week 104, respectively) and increased to 83.02 mL/min/1.73 m² at 28 days after the last dose. Median percentage decrease from baseline was 14.9%, 17.0%, and 10.4% at week 2, week 12, and 28 days after last dose of crizotinib, respectively. Overall, 12.6% of patients had a shift from eGFR grade less than or equal to 3a (≥45 mL/min/1.73 m²) at baseline to greater than or equal to 3b (<45 mL/min/1.73 m²) post-baseline.ConclusionsCrizotinib resulted in a decline in creatinine-based estimates of renal function mostly over the first 2 weeks of treatment. However, there was minimal evidence of cumulative effects with prolonged treatment and these changes were largely reversible following treatment discontinuation, consistent with previous reports suggesting this may be predominantly an effect on creatinine secretion as opposed to true nephrotoxicity.     

Estimated glomerular filtration rate independently predicts outcome of azacitidine therapy in higher-risk Myelodysplastic syndromes. Results from 536 patients of the Hellenic National Registry of Myelodysplastic and Hypoplastic syndromes

Higher-risk Myelodysplastic syndromes (MDS) patients undergoing treatment with 5-azacytidine (AZA) are typically elderly with several comorbidities. However, the effect of comorbidities on the effectiveness and safety of AZA in real-world settings remains unclear. We analyzed data from 536 AZA-treated patients with higher-risk MDS, Myelodysplastic/Myeloproliferative neoplasms and low blast count Acute Myeloid Leukemia enrolled to the Hellenic National Registry of Myelodysplastic and Hypoplastic Syndromes. Multivariate analysis adjusted also for the International Prognostic Scoring System (IPSS), its revised version (IPSS-R) and the French Prognostic Scoring System (FPSS), demonstrated independent associations of overall and leukemia-free survival with estimated glomerular filtration rate (eGFR) <45 mL min⁻¹/1.73 m² (P = .039, P = .023, respectively), ECOG performance status <2 (P = .015, P = .006), and presence of peripheral blood blasts (P = .008, P = .034), while secondary MDS also correlated with significantly shorter leukemia-free survival (P = .039). Addition of eGFR <45 mL min⁻¹/1.73 m², in IPSS-R and FPSS increased the predictive power of both models. Only FPSS ≤2 and eGFR <45 mL min⁻¹/1.73 m² predicted worse response to AZA in multivariate analysis, whereas eGFR <45 mL min⁻¹/1.73 m² correlated significantly with death from hemorrhage (P = .003) and cardiovascular complications (P = .006). In conclusion, in the second largest real-world series of AZA-treated MDS patients, we show that an eGFR <45 mL min⁻¹/1.73 m² is an independent predictor of worse response and survival. This higher cut-off, instead of the commonly used serum creatinine >2 mg/dL, can be utilized as a more precise indicator of renal comorbidity during AZA therapy. Incorporation of eGFR in the prognostic assessment of AZA-treated MDS patients may prove useful not only in routine practice, but also for the appropriate patient stratification in clinical trials with AZA combinations.     

Dose-escalating and pharmacological study of bortezomib in adult cancer patients with impaired renal function: a National Cancer Institute Organ Dysfunction Working Group Study

Purpose

To determine the toxicities, pharmacokinetics, pharmacodynamics, and maximum tolerated dose of bortezomib in patients with renal impairment and to develop dosing guidelines for such a patient population.

Patients and Methods

Sixty-two adult cancer patients received intravenous bortezomib at 0.7?C1.5?mg/m² on days 1, 4, 8, and 11 every 3?weeks. Patients were stratified by 24-h creatinine clearance (CrCl) normalized to body surface area (BSA) 1.73?m² into five cohorts: normal renal function (??60?ml/min/1.73?m²); mild dysfunction (40?C59?ml/min/1.73?m²); moderate dysfunction (20?C39?ml/min/1.73?m²); severe dysfunction (<20?ml/min/1.73?m²); and dialysis. Dose escalation was planned for the four cohorts with renal dysfunction. Plasma bortezomib concentrations and blood 20S proteasome inhibition were assayed.

Results

Bortezomib escalation to the standard 1.3?mg/m² dose was well tolerated in all patients with CrCl ??20?ml/min/1.73?m²; 0.7?mg/m² was tolerated in three patients with severe renal dysfunction (<20?ml/min/1.73?m²). Bortezomib dose escalation was well tolerated in nine dialysis patients, including to 1.3?mg/m² in four patients. Decreased CrCl did not affect bortezomib pharmacokinetics or pharmacodynamics. Bortezomib-related side-effects were neither more common nor severe in patients with renal dysfunction versus those with normal renal function.

Conclusion

Bortezomib 1.3?mg/m² is well tolerated, and dose reductions are not necessary in patients with renal dysfunction. Extrapolation from clinical and pharmacologic data suggests patients with severe renal dysfunction, including dialysis patients, can receive bortezomib at the full dose established to be clinically effective in the general patient population.     

Phase I/II trial of 2‐weekly docetaxel combined with cisplatin plus fluorouracil in metastatic esophageal cancer (JCOG0807)

We carried out a phase I/II trial of adding 2‐weekly docetaxel to cisplatin plus fluorouracil (CF) therapy (2‐weekly DCF regimen) in esophageal cancer patients to investigate its safety and antimetastatic activity. Patients received 2‐weekly docetaxel (30 mg/m² [dose level (DL)1] or 40 mg/m² [DL2] with a 3 + 3 design in phase I, on days 1 and 15) in combination with fixed‐dose CF (80 mg/m² cisplatin, day 1; 800 mg/m² fluorouracil, days 1–5) repeated every 4 weeks. The primary endpoint was dose‐limiting toxicity (DLT) in phase I and central peer review‐based response rate in phase II. At least 22 responders among 50 patients were required to satisfy the primary endpoint with a threshold of 35%. Sixty‐two patients were enrolled in phase I and II. In phase I, 10 patients were enrolled with DLT of 0/3 at DL1 and 2/7 in DL2. Considering DLT and treatment compliance, the recommended phase II dose was determined as DL1. In phase II, the response rate was 62% (P < 0.0001; 95% confidence interval, 48–75%); median overall survival and progression‐free survival were 11.1 and 5.8 months, respectively. Common grade 3/4 adverse events were neutropenia (25%), anemia (36%), hyponatremia (29%), anorexia (24%), and nausea (11%). No febrile neutropenia was observed. Pneumonitis caused treatment‐related death in one patient. The 2‐weekly DCF regimen showed promising antimetastatic activity and tolerability. A phase III study comparing this regimen with CF therapy is planned by the Japan Clinical Oncology Group. This study was registered at the UMIN Clinical Trials Registry as UMIN 000001737.     

Chronic kidney disease after nephroureterectomy for upper tract urothelial carcinoma and implications for the administration of perioperative chemotherapy

BACKGROUND:

The prevalence of chronic kidney disease (CKD) in patients with upper tract urothelial carcinoma (UTUC) is poorly defined, both before and after nephrouretectomy. Although multimodal treatment paradigms for UTUC are under‐developed, this has important implications on patients' ability to receive cisplatin‐based combination chemotherapy (CBCC).

METHODS:

Estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease formula in 336 patients with UTUC, who were treated at the Cleveland Clinic by nephroureterectomy since 1992. An eGFR cutoff of 60 mL/min/1.73 m² was used to determine the presence of CKD and eligibility for CBCC.

RESULTS:

Median age was 72 years and median preoperative eGFR was 59 mL/min/1.73m². Before nephroureterectomy, only 48% of patients were eligible to receive CBCC and this decreased to 22% postoperatively (P < .001). In the 144 patients with pT2‐pT4 and/or pN1‐pN3 disease who are suitable to receive CBCC, these proportions were 40% and 24%, respectively (P = .009). Although 50 patients overall received some form of perioperative chemotherapy, only 3 and 11 patients received neoadjuvant and adjuvant CBCC, respectively.

CONCLUSIONS:

CKD is prevalent in the UTUC population and a minority of patients has an optimal eGFR to receive neoadjuvant CBCC. Nephrouretectomy may eliminate CBCC as a therapeutic option in 49% of high‐risk patients if it is deferred to the adjuvant setting. Multimodal treatment strategies for UTUC should focus on neoadjuvant chemotherapy, as few patients are eligible for adjuvant CBCC because of the substantial decline in eGFR caused by nephroureterectomy. Cancer 2010. © 2010 American Cancer Society.     

Technetium-99m DTPA renography and angiography in renal artery stenoses of varying severity

Thirty-five hypertensive patients, consecutively studied between 1986 and 1991, were retrospectively reviewed, to compare Technetium-99m (^99mTc) DTPA renal scanning for renal artery stenosis with angiography. Ten patients were on chronic angiotensin converting enzyme (ACE) inhibitor medication and 20 underwent angioplasty of their stenoses. In patients not on ACE inhibitors the renal scan specificity was 83%, sensitivity 82%, negative predictive value 89% and positive predictive value 74%. In the 10 patients on ACE inhibitors the specificity was 67% (relatively more stenoses of < 50% were reported in this group), sensitivity 100%, negative predictive value 100% and positive predictive value 60%. Low levels of function (<10mL/min/1.73m²) in 9 kidneys did not militate against diagnoses that correlated well with angiography. Hence, renal scanning, particularly with ACE inhibition, is efficacious in the evaluation of possible renal artery stenosis. With a mean follow-up period of 29 months after percutaneous transluminal angioplasty (PTA), four patients had clinical improvement of hypertension control. Each had pre-PTA total glomerular filtration rates (GFR) of approximately 75mL/min/1.73m². No improvement was detected in cases with pre-PTA total GFR of <50mL/min/1.73m². This may be the level of renal function below which PTA therapy or surgery will not provide benefit.     

Extreme Prostate‐Specific Antigen Response to Infusional 5‐Flourouracil in Castrate‐Resistant Prostate Cancer

Prostate cancer that has progressed after androgen deprivation, abiraterone, and taxane therapy is challenging to treat successfully. Herein we report a dramatic response to continuous‐infusion 5‐fluorouracil (5‐FU) at a dose of 200 mg/m² in a patient with rapidly progressive, heavily pretreated, metastatic castrate‐resistant prostate cancer. Baseline prostate‐specific antigen values declined from 1,890 ng/mL to <1 ng/mL after 5‐FU therapy. We hypothesized that prostate‐specific membrane antigen overexpression may result in cancer cells uniquely susceptible to antifolate therapies.     

Phase I study of weekly nab‐paclitaxel combined with S‐1 in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer

We conducted a phase I study of a weekly nab‐paclitaxel and S‐1 combination therapy in patients with human epidermal growth factor receptor type 2‐negative metastatic breast cancer. The primary objective was to estimate the maximum tolerated and recommended doses. Each treatment was repeated every 21 days. Levels 1, 2a, 2b, and 3 were set depending on the S‐1 dose (65 or 80 mg/m²) and nab‐paclitaxel infusion schedule (days 1 and 8 or days 1, 8, and 15). Fifteen patients were enrolled. Dose‐limiting toxicity was observed in one patient at Level 3 (100 mg/m² nab‐paclitaxel on days 1, 8, and 15 with 80 mg/m² S‐1 daily for 14 days, followed by 7 days of rest). Although the maximum tolerated dose was not reached, the recommended dose was determined to be Level 3. Neutropenia was the most frequent grade 3–4 treatment‐related adverse event. For patients with measurable lesions, the response rate was 50.0% and the median time to treatment failure and median progression‐free survival was 13.2 and 21.0 months, respectively. The present results show the feasibility and potential for long‐term administration of this combination therapy.     

Dose-escalation study of fixed-dose rate gemcitabine combined with capecitabine in advanced solid malignancies

Purpose  To define dose limiting toxicities (DLTs) and the maximum tolerated dose (MTD) of capecitabine with fixed-dose rate (FDR) gemcitabine. Methods  Eligible adults (advanced solid tumor; performance status ≤2) received capecitabine 500 mg/m² PO BID days 1–14 and FDR gemcitabine (400–1,000 mg/m² escalated by 200 mg/m² increments) at 10 mg/m²/min days 1 and 8 on a 21-day cycle. A traditional 3 + 3 cohort design was used to determine the MTD. Results  Thirty patients (median age 59 years) were enrolled. The predominant grade ≥3 toxicity was myelosuppression, particularly neutropenia. At dose level 4 (1,000 mg/m² gemcitabine), two out of five evaluable patients had a DLT (grade 4 neutropenia ≥7 days). At dose level 3 (800 mg/m² gemcitabine), one patient had a DLT (grade 3 neutropenia ≥7 days) among six evaluable patients. Therefore, the MTD and recommended phase II dose was designated as capecitabine 500 mg/m² PO BID days 1–14 with 800 mg/m² FDR gemcitabine days 1 and 8 infused at 10 mg/m² per min on a 21-day cycle. Partial responses occurred in pretreated patients with esophageal, renal cell and bladder carcinomas. Conclusions  This regimen was well tolerated and may deserve evaluation in advanced gastrointestinal and genitourinary carcinomas. The results of this research appeared as abstract ID 13509 at the 2008 American Association of Clinical Oncology meeting in Chicago, IL, USA.     

Association of kidney function with cancer incidence and its influence on cancer risk of smoking: The Japan Multi-Institutional Collaborative Cohort Study

The association between kidney function and cancer incidence is inconsistent among previous reports, and data on the Japanese population are lacking. It is unknown whether kidney function modifies the cancer risk of other factors. We aimed to evaluate the association of estimated glomerular filtration rate (eGFR) with cancer incidence and mortality in 55 242 participants (median age, 57 years; 55% women) from the Japan Multi-Institutional Collaborative Cohort Study. We also investigated differences in cancer risk factors between individuals with and without kidney dysfunction. During a median 9.3-year follow-up period, 4278 (7.7%) subjects developed cancer. Moderately low and high eGFRs were associated with higher cancer incidence; compared with eGFR of 60-74 ml/min/1.73 m², the adjusted hazard ratios (HRs) (95% confidence intervals [CIs]) for eGFRs of ≥90, 75-89, 45-59, 30-44 and 10-29 ml/min/1.73 m² were 1.18 (1.07-1.29), 1.09 (1.01-1.17), 0.93 (0.83-1.04), 1.36 (1.00-1.84) and 1.12 (0.55-2.26), respectively. High eGFR was associated with higher cancer mortality, while low eGFR was not; the adjusted subdistribution HRs (95% CIs) for eGFRs of ≥90 and 75-89 ml/min/1.73 m² were 1.58 (1.29-1.94) and 1.27 (1.08-1.50), respectively. Subgroup analyses of participants with eGFRs ≥60 and <60 ml/min/1.73 m² revealed elevated cancer risks of smoking and family history of cancer in those with eGFR <60 ml/min/1.73 m², with significant interactions. Our findings suggest that the relationship between eGFR and cancer incidence was U-shaped. Only high eGFR was associated with cancer mortality. Kidney dysfunction enhanced cancer risk from smoking.     

Chronic kidney disease in patients with the Philadelphia-negative chronic myeloproliferative neoplasms

Background

The progression of kidney function and frequency of chronic kidney disease (CKD) in patients with the Philadelphia-negative myeloproliferative neoplasms (MPN) is unknown, although CKD is linked to increased mortality.

Methods

This longitudinal retrospective study evaluates the estimated glomerular filtration rate (eGFR) in 143 MPN patients over a period of 9 years.

Results

29% of patients had CKD stage 3 or 4 at time of diagnosis. 20% of patients had a rapid annual loss of eGFR (>3 mL/min/1.73 m²) and eGFR was negatively correlated to monocyte and neutrophil counts.

Conclusion

Kidney impairment might contribute to the increased mortality observed in MPN patients.     

Impact of the CKD-EPI equation for estimating renal function on eligibility for cisplatin-based chemotherapy in patients with urothelial cancer

Background

Although a creatinine clearance (CrCl) of <60 mL/min, as calculated by the Cockroft-Gault (CG) equation, is a commonly used threshold for “cisplatin-ineligibility,” the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation has recently emerged as a more accurate method of estimating renal function. We sought to determine the impact of using the CKD-EPI equation for estimating renal function on cisplatin eligibility.

Methods

All patients pathologically diagnosed with muscle invasive and/or metastatic bladder urothelial carcinoma (T2-4, N or M positive) at Mount Sinai Medical Center between January 1, 2000, and January 27, 2011, were identified. For each patient, CrCl was estimated by using the CG equation and glomerular filtration rate (GFR) was estimated by using the CKD-EPI equation. The patients were considered cisplatin-ineligible if CrCl <60 mL/min or if GFR was <60 mL/min per 1.73 m².

Results

A total of 116 patients were included. The median CrCl estimated by CG was 58.93 mL/min, whereas the median GFR estimated by CKD-EPI was 64.67 mL/min per 1.73 m². When using the CG formula, 53% of our cohort was cisplatin ineligible, whereas 46% of the cohort was ineligible when using the CKD-EPI formula. The probability of deeming a patient ineligible when using the CG formula was 17% higher than the probability of deeming a patient ineligible when using the CKD-EPI formula: PR 1.17 (95% CI, 1.03-1.34); P = .0203.

Conclusion

In our retrospective study, the CKD-EPI formula was less likely to deem a patient ineligible for cisplatin-based therapy compared with the CG formula. This finding was hypothesis generating, and prospective evaluation is necessary to determine the clinical relevance of using this more accurate method of renal function assessment in chemotherapy decision making.     

Phase I study of daily S-1 combined with weekly irinotecan in patients with advanced non-small cell lung cancer

Background  S-1 is a novel oral fluorouracil prodrug active against non-small cell lung cancer (NSCLC). To determine the feasibility of S-1 combined with weekly irinotecan for patients with advanced NSCLC, we performed a phase I study to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of irinotecan. Methods  Patients with advanced NSCLC received S-1 (80 mg/m²) on days 1–14 and irinotecan (50–80 mg/m²) on days 1, 8, and 15 of each 28-day cycle. Three to six patients were treated with each dose of irinotecan, with the MTD defined as the dose at which dose-limiting toxicity (DLT) appeared in 33% of patients. Results  At doses of 50–70 mg/m², no patients experienced any DLT, whereas, at a dose of 80 mg/m², two of four patients experienced DLTs. Two patients experienced grade 3 toxicities — neutropenia and diarrhea. Conclusion  The MTD of weekly irinotecan was 80 mg/m², making its RD for phase II trials 70 mg/m².     

Moderate renal dysfunction may not require a cisplatin dose reduction: a retrospective study of cancer patients with renal impairment

Objective

The aim of this study was to assess the tolerability of cisplatin (CDDP) in patients with moderate renal dysfunction.

Methods

To investigate the relationship between CDDP dose and nephrotoxicity, a retrospective chart review was conducted of patients with a creatinine clearance (Ccr) of 30–60 mL/min. Subjects were classified into three groups according to the CDDP dose, as determined by the physician, and the nephrotoxicity among these groups was compared. Additionally, we investigated the correlation coefficients between maximum serum creatinine (Scr) level or minimum estimated glomerular filtration rate (eGFR) and baseline Ccr.

Results

Fifty-six patients were included in this study. Among these patients, 13 patients received 30–40 mg/m² CDDP (group I), 18 patients received 40–70 mg/m² (group II), and 25 patients received 70–80 mg/m² (group III). No significant difference in nephrotoxicity was observed (median Scr 1.53, 1.61, and 1.53 mg/dL, respectively), and no correlation was observed between baseline Ccr and maximum Scr (r = 0.004, p = 0.979) or minimum eGFR (r = 0.21, p = 0.119). Only two patients (3.5 %) experienced grade 3 or 4 Scr elevation—one patient with a Ccr of 52.6 mL/min received 60 mg/m² CDDP, and the other patient with a Ccr of 52.1 mL/min received 70 mg/m² of CDDP. Hemodialysis was not observed.

Conclusion

CDDP was tolerated at doses of 35–80 mg/m² among patients with moderate renal impairment. Empiric dose reduction might create a risk of under-treatment.