Comparison of Myelotoxicity and Nephrotoxicity Between Daily Low-Dose Cisplatin With Concurrent Radiation and Cyclic High-Dose Cisplatin in Non-Small Cell Lung Cancer Patients.

AIM: Antineoplastic effect of cisplatin, the first line treatment in non-small cell lung cancer (NSCLC), is hindered by its nephrotoxicity and myelotoxicity. Both low-dose and high-dose regimens are used in the management of NSCLC. The aim of this study is to assess the risk on myelotoxicity and nephrotoxicity from the daily low-dose cisplatin (DLD) treatment as compared to cyclic high-dose cisplatin (CHD). METHODS: A retrospective cohort study was conducted. NSCLC patients treated with cisplatin between 2011 and 2018 in the Amsterdam UMC or Antoni van Leeuwenhoek cancer hospital were studied. Myelotoxicity and nephrotoxicity were defined based on common terminology criteria (CTCAE v4.03) and categorized as ≥grade 1 and ≥grade 2. Modified Poisson regression and Cox proportional hazards model were used to estimate relative risks and cumulative hazard respectively. RESULTS: Of the 115 NSCLC patients receiving DLD (N=62) and CHD (N=53), 60% had ≥grade 1 anemia, 33.9% leukopenia, 31.3% neutropenia, 27.8% thrombocytopenia, 32.2% acute nephrotoxicity with combined definition (Cr-electrolyte nephrotoxicity), and 58.3% chronic nephrotoxicity. The DLD group was older, had an earlier cancer stage, had more comorbidities, and had higher baseline albumin levels. In the DLD group less ≥grade 2 toxicities were reported compared to the CHD group except for Cr-electrolyte nephrotoxicity. However, there was a stronger association in the DLD group with ≥grade 1 leukopenia, thrombocytopenia, and Cr-electrolyte nephrotoxicity. The DLD group developed significantly more ≥grade 1 leukopenia [adjusted relative risk (adjRR)=1.83, 95% CI 1.02-3.27], thrombocytopenia (adjRR=3.43, 95% CI 1.64-7.15), and ≥grade 2 Cr-electrolyte nephrotoxicity (adjRR=3.02, 95% CI 1.20-7.56). The DLD group had a lower adjusted cumulative hazard for developing ≥grade 2 myelotoxicity and chronic nephrotoxicity but not for Cr-electrolyte nephrotoxicity [adjusted hazard ratio (adjHR)=3.90, 95% CI 1.35-11.23]. In contrast, DLD showed protective effect to ≥grade 2 nephrotoxicity when definition was restricted to the traditional creatinine-based definition (adjRR=0.07, 95% CI 0.01-0.86; adjHR=0.05, 95% CI 0.01-0.56). CONCLUSIONS: Overall, the DLD regimen was safer than the CHD regimen when assessing the risk of ≥grade 2 myelotoxicity and nephrotoxicity. However, this might not be the case in patients with a higher risk of electrolyte abnormalities.

Development of symptomatic brain metastases after chemoradiotherapy for stage III non-small cell lung cancer: Does the type of chemotherapy regimen matter?

OBJECTIVES: Symptomatic brain metastases (BM) occur frequently after chemoradiotherapy (CRT) for stage III NSCLC. Aim of the current study was to determine whether the specific chemotherapy used in a CRT regimen influences BM development. MATERIALS AND METHODS: Retrospective multicenter study including all consecutive stage III NSCLC who completed CRT. Primary endpoints: symptomatic BM development, whether this was the only site of first relapse. Differences between regimens were assessed with a logistic regression model including known BM risk factors and the specific chemotherapy: concurrent versus sequential (cCRT/sCRT), within cCRT: daily low dose cisplatin (LDC)-cyclic dose polychemotherapy; LDC-(non-)taxane cyclic dose; LDC-polychemotherapy subgroups of ≥50 patients. RESULTS: Between January 2006 and June 2014, 838 patients were eligible (737 cCRT, 101 sCRT). 18.2% developed symptomatic BM, 8.0% had BM as only site of first relapse. BM patients were significantly younger, female, had more advanced N-stage and had adenocarcinoma histology. In both cCRT and sCRT BM were found in 18% (p=0.904). In cyclic dose cCRT (N=346) and LDC (N=391) BM were found in 18.8% and 17.9%, respectively (p=0.757). In 7.2% and 8.7%, respectively, BM were the only site of first relapse (p=0.463). The chemotherapy used (cCRT versus sCRT) had no influence on BM development, not for all brain relapses nor as only site of first relapse (OR 0.88 (p=0.669), OR 0.93 (p=0.855), respectively). LDC versus cyclic dose cCRT was not significantly different: neither for all brain relapses nor as only site of first relapse (OR 0.96 (p=0.819), OR 1.21 (p=0.498), respectively). Comparable results were found for LDC versus cyclic dose non-taxane (N=277) and cyclic dose taxane regimens (N=69) and for cCRT regimens with ≥50 patients (LDC versus cisplatin/etoposide (N=188), cisplatin/vinorelbin (N=65), weekly cisplatin/docetaxel (N=60)). CONCLUSION: approximately 18% developed symptomatic BM after stage III diagnosis, not dependent on type of chemotherapy regimen used within a CRT treatment.

Overcoming toxicity-challenges in chemoradiation for non-small cell lung cancer.

Concurrent chemoradiation (CCRT) is the treatment of choice for locally advanced non-small cell lung cancer (NSCLC) with a modest survival benefit over sequential chemoradiation or radiotherapy (SCRT) alone. However, this benefit is at the cost of increasing acute toxicity such as esophagitis. Previous analysis revealed several predictive parameters in dose-volume and patient characteristics which helped us to identify those patients at risk for severe esophagus toxicity. As a result, supportive care interventions including individualized patient information, dietary guidance, adequate medication, hydration and tubefeeding could be initiated. This paper discusses the challenges in overcoming chemoradiation induced acute esophageal toxicity (AET).

Long-term follow-up of patients with locally advanced non-small cell lung cancer receiving concurrent hypofractionated chemoradiotherapy with or without cetuximab.

BACKGROUND AND PURPOSE: Radiation dose escalation using hypofractionation might improve overall survival (OS). We investigated OS in a phase II multicenter study in locally advanced non-small cell lung cancer (LA-NSCLC) patients treated with hypofractionated concurrent chemoradiotherapy. MATERIALS AND METHODS: A 2-armed phase II, multi-center study (NTR2230) was performed with the aim to assess the effect of cetuximab to concurrent chemoradiotherapy in LA-NSCLC patients (stage II/IIIA/B). Arm A received high dose radiotherapy (24 × 2.75 Gy) and concurrent daily low-dose cisplatin (6 mg/m(2)). Arm B received an identical treatment regimen with additional weekly cetuximab. Kaplan-Meier survival curves and 1-, 2- and 5-year OS proportions were calculated. RESULTS: Between February 2009 and May 2011, 102 patients were randomly allocated in two arms. Median OS was 31.5 months (range 12.8-52.3), not significantly different between arms A and B; 33.0 (range 17.0-57.0) and 30.0 (11.0-52.0) months. 1-, 2- and 5-year OS rates were 74.5%, 59.4% and 37.3%, respectively. In multivariate analyses, worse performance score, V35 of the esophagus and the existence of comorbidities were significantly (P-value<0.05) associated with a shorter OS. DISCUSSION: In this phase II trial, the median OS for the entire group was remarkably high; 31.5 months. Furthermore, 5-year OS was still 37.3%. Hypofractionation might contribute to improved OS in LA-NSCLC patients.

Fractures of thoracic vertebrae in patients with locally advanced non-small cell lung carcinoma treated with intensity modulated radiotherapy.

PURPOSE: To report on the incidence of vertebral fractures in patients treated with Intensity Modulated Radiotherapy (IMRT) for locally advanced non-small cell lung carcinoma (NSCLC) and to analyse the association with clinical and dosimetric parameters. PATIENTS AND METHODS: Between 2007 and 2012, 524 patients treated with ⩾51 Gy were retrospectively analysed for the incidence of vertebral fractures (VF). Clinical parameters were assessed. In addition, a case control study in 50 patients was performed to study the association between the radiotherapy dose and fractured vertebrae. RESULTS: Three hundred and thirty-six patients were eligible for analyses. Twenty-eight patients (8%) were observed with VF at a median follow up of 12 months. Age was significantly higher in the group with VF (p<0.01). After balancing age, the mean vertebrae dose was most significantly associated with fractures of the vertebrae (p<0.01). CONCLUSION: VF was observed in 8% of the patients with locally advanced NSCLC. RT dose was associated with the occurrence of thoracic vertebral fractures.

A Validated Prediction Model for Overall Survival From Stage III Non-Small Cell Lung Cancer: Toward Survival Prediction for Individual Patients.

PURPOSE: Although patients with stage III non-small cell lung cancer (NSCLC) are homogeneous according to the TNM staging system, they form a heterogeneous group, which is reflected in the survival outcome. The increasing amount of information for an individual patient and the growing number of treatment options facilitate personalized treatment, but they also complicate treatment decision making. Decision support systems (DSS), which provide individualized prognostic information, can overcome this but are currently lacking. A DSS for stage III NSCLC requires the development and integration of multiple models. The current study takes the first step in this process by developing and validating a model that can provide physicians with a survival probability for an individual NSCLC patient. METHODS AND MATERIALS: Data from 548 patients with stage III NSCLC were available to enable the development of a prediction model, using stratified Cox regression. Variables were selected by using a bootstrap procedure. Performance of the model was expressed as the c statistic, assessed internally and on 2 external data sets (n=174 and n=130). RESULTS: The final multivariate model, stratified for treatment, consisted of age, gender, World Health Organization performance status, overall treatment time, equivalent radiation dose, number of positive lymph node stations, and gross tumor volume. The bootstrapped c statistic was 0.62. The model could identify risk groups in external data sets. Nomograms were constructed to predict an individual patient's survival probability (www.predictcancer.org). The data set can be downloaded at https://www.cancerdata.org/10.1016/j.ijrobp.2015.02.048. CONCLUSIONS: The prediction model for overall survival of patients with stage III NSCLC highlights the importance of combining patient, clinical, and treatment variables. Nomograms were developed and validated. This tool could be used as a first building block for a decision support system.

Supportive care in lung cancer: milestones over the past 40 years.

The evolution of supportive care in lung cancer (LC) is the focus of this article, which aims to present an overall picture of the developments in the field, highlight milestones over the past four decades, and provide directions for future research and practice. Although in the 1970s this study was minimal, from the 1980s onwards, there was an expansion of the range of topics covered in the literature, reflecting the importance of supportive care to clinical practice. These areas include the identification of supportive care needs in LC, symptoms and symptom management, psychosocial aspects and coping with LC (including support of caregivers), quality of life issues and the development and testing of patient-reported outcomes, the option of best supportive care versus treatment, smoking cessation before and after diagnosis of LC, and service delivery models. This article celebrates the evolution of supportive LC care over the past 40 years alongside recognizing that more work needs to be done in the future and new research foci need to be developed to meet the current needs of patients with LC. The role and the continuous efforts of the International Association of the Study of Lung Cancer, including the sixteenth World Conference on Lung Cancer in 2015 to meet this goal, will be crucial and strategic in the future.

Treatment adherence in concurrent chemoradiation in patients with locally advanced non-small cell lung carcinoma: results of daily intravenous prehydration.

PURPOSE: To test the hypothesis that daily intravenous pre-hydration decreases renal toxicity and improves chemotherapy adherence in patients receiving daily cisplatin to concurrent radiotherapy for locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with locally advanced NSCLC were treated between 2008 and August 2012 with daily 6 mg/m(2) cisplatin as a bolus injection in 10 ml; of saline and 66 Gy/24 fr radiotherapy in 32 days. Since January 2011, the administration of cisplatin was routinely preceded by intravenous pre-hydration with 1L of natriumchloride 0.9%. Patients were divided in a pre-hydrated (PH) and non-pre-hydrated (NPH) cohort. Serum-creatinine and glomerular filtration rate (GFR) were assessed twice weekly during treatment. Retrospectively, baseline data, toxicity, treatment adherence and efficacy data were compared. RESULTS: Of the 356 patients 232 NPH patients and 100 PH patients were eligible. Patient-and treatment characteristics compared equally. The median of the maximum decrease in GFR was 24% and 8% for NPH and PH (p<0.01), respectively. Sixty-nine percent of the patients in the NPH group completed the 24 administrations of cisplatin, as compared to 83% of the PH group (p<0.01). Nineteen percent vs. 2% of the patients in the NPH and PH group discontinued cisplatin treatment because of renal toxicity. Surprisingly, the incidence of acute esophageal toxicity grade ⩾ 2 decreased following prehydration: 62% vs. 34% (p<0.001) for the NPH and PH groups, respectively. The one-year survival was comparable between groups (75% for NPH and 71% for PH). CONCLUSION: Daily pre-hydration was associated with a reduced rate of both renal and acute esophageal toxicity and an increased chemotherapy adherence in patients receiving daily dose of cisplatin and concurrent radiotherapy for locally advanced NSCLC.

Additional weekly Cetuximab to concurrent chemoradiotherapy in locally advanced non-small cell lung carcinoma: efficacy and safety outcomes of a randomized, multi-center phase II study investigating.

BACKGROUND: Modest benefits from concurrent chemoradiotherapy in patients with locally advanced NSCLC warrant further clinical investigations to identify more effective treatment regimens. Cetuximab, a monoclonal antibody against the epidermal growth factor receptor has shown activity in NSCLC. We report on the safety and efficacy of the combination of daily dose Cisplatin and concurrent radiotherapy with or without weekly Cetuximab. PATIENTS AND METHODS: Patients received high dose accelerated radiotherapy (66 Gy in 24 fractions) and concurrent daily Cisplatin (6 mg/m(2)) without (Arm A) or with (Arm B) weekly Cetuximab (400 mg/m(2) loading dose one week prior to radiotherapy followed by weekly 250 mg/m(2)). The primary endpoint of the trial was objective local control rate (OLCR) determined at 6-8 weeks after treatment. Toxicity was reported as well. RESULTS: Between February 2009 and May 2011, 102 patients were randomized. Median follow up was 29 months. The OLCR was 84% in Arm A and 92% in Arm B (p=0.36). The one-year local progression free interval (LPFI) and overall survival (OS) were 69% and 82% for Arm A and 73% and 71% for Arm B, respectively (LPFI p=0.39; OS p=0.99). Toxicity compared equally between both groups. CONCLUSION: The addition of Cetuximab to radiotherapy and concurrent Cisplatin did not improve disease control in patients with locally advanced NSCLC but increased treatment related toxicity.

Severe late esophagus toxicity in NSCLC patients treated with IMRT and concurrent chemotherapy.

BACKGROUND AND PURPOSE: We reported the incidence of severe late esophagus toxicity (LET) in locally advanced NSCLC patients treated with intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy. Acute esophagus toxicity (AET) and the dose to the esophagus were analyzed for their associations with severe LET. MATERIAL AND METHODS: Two hundred and thirty-one patients treated from 2008 to 2011 with hypofractionated IMRT (66Gy/24fx) and concurrent daily low dose cisplatin were included. The association between AET and severe LET (grade ≥ 3 RTOG/EORTC) was tested through Cox-proportional-hazards model. Equivalent uniform dose (EUD) to the esophagus and the volume percentage receiving more than x Gy (Vx) were applied by Lyman-Kutcher-Burman (LKB) model. RESULTS: A total of 171 patients were eligible for this study. Severe LET was observed in 6% patients. Both the maximum grade and the recovery rate of AET were significantly associated with severe LET. In the EUDn-LKB model, the fitted values and 95% confidence intervals (CIs) were TD50=76.1 Gy (73.2-78.6), m=0.03 (0.02-0.06) and n=0.03 (0-0.08). In the Vx-LKB model, the fitted values and 95% CIs were Tx50=23.5% (16.4-46.6), m=0.44 (0.32-0.60) and x=76.7 Gy (74.7-77.5). CONCLUSIONS: Severe AET, EUD (n=0.03) and V76.7 to the esophagus were significantly associated with severe LET. An independent validation study is required.

Prediction of acute toxicity grade ≥ 3 in patients with locally advanced non-small-cell lung cancer receiving intensity modulated radiotherapy and concurrent low-dose Cisplatin.

BACKGROUND: Intensity modulated radiotherapy (IMRT) is increasingly used with concurrent chemotherapy but toxicity data are not well investigated. We correlated clinical and dosimetric parameters with acute toxicity grade ≥ 3 in patients with locally advanced NSCLC treated with IMRT and concurrent low-dose cisplatin. PATIENTS AND METHODS: We analyzed age, PS, comorbidities, gross tumor volume, and the volume of the esophagus irradiated with 50 Gy (V50oes) in relation with acute toxicity. The mean lung dose (MLD) and pulmonary toxicity was described. Treatment consisted of 24 × 2, 75 Gy, and daily cisplatin 6 mg/m². Patients with an MLD ≥ 20 Gy or a PS > 2 were excluded from CCRT. Toxicity was prospectively scored using the Common Toxicity Criteria for adverse events version 3.0. The Charlson Comorbidity Index (CCI) was applied for scoring comorbidities. Multivariable logistic regressions for toxicity and survival estimates (Kaplan-Meier) were used for evaluation. RESULTS: From 2008 to 2011, 188 patients received standard CCRT. In 35% of the patients, acute toxicity grade ≥ 3 was reported. Grade 5 toxicity was scored in 1% of the patients. V50oes (odds ratio [OR], 1.33 per 10% increase; P = .01) and PS ≥ 2 (OR, 3.45; P = .07) were significantly correlated with acute toxicity ≥ grade 3. No differences in toxicity were observed between age groups (< 70 and ≥ 70; P = .26), and those with a CCI score < 5 and ≥ 5, and acute severe toxicity (P = .36). Grade ≥ 3 pulmonary toxicity was seen in 7%. The 1- and 2-year overall survival in stage III disease were 78% and 52%, respectively. Patients with a poor PS or a high CCI score had similar survival outcomes. CONCLUSION: Concurrent low-dose cisplatin using IMRT is effective in a large cohort of consecutive patients with NSCLC and life threatening toxicity is rare (1%). PS ≥ 2 and V50oes are correlated with acute toxicity grade ≥ 3.

Prognostic parameters for acute esophagus toxicity in intensity modulated radiotherapy and concurrent chemotherapy for locally advanced non-small cell lung cancer.

BACKGROUND AND PURPOSE: The aim of this study was to correlate clinical and dosimetric variables with acute esophageal toxicity (AET) following Intensity Modulated Radiotherapy (IMRT) with concurrent chemotherapy for locally advanced non-small cell lung cancer (NSCLC). In addition, timeline of AET was reported. MATERIAL AND METHODS: 153 patients with locally advanced NSCLC treated with 66 Gy/2.75 Gy/24 fractions of radiotherapy and concurrent daily low dose cisplatin were selected. Medical records and treatments of these patients were retrospectively reviewed. Maximum AET grade ≥2 and maximum grade 3 were the endpoints of this study. Dates for onset, maximum and recovery (to baseline) of AET were reported. Univariate and multivariate analysis were applied to correlate clinical, tumor, dosimetric and chemotherapy dose variables to AET grade ≥2 and grade 3. RESULTS: AET grade 2 occurred in 37% and grade 3 in 20% of the patients. The median onset of AET was around day 15 for all grades. The median onset of the maximum grade was day 30 for both grades 2 and 3. The median duration was 43 days for grade 1, 50 days for grade 2 and >80 days for grade 3. Of the grade 3 AET patients, 48% recovered within 3 months. Esophagus V50, ethnic background, and the number of cisplatin administrations were significantly correlated with grade 3 AET. CONCLUSIONS: For NSCLC patients treated with concurrent chemotherapy and IMRT A higher number of cisplatin administrations, non-Caucasian background and higher V50oes were associated with grade 3 AET. The median onset of AET grade 3 is 15 days after the start of treatment, maximized at day 30, with a median duration of >80 days.

Relating acute esophagitis to radiotherapy dose using FDG-PET in concurrent chemo-radiotherapy for locally advanced non-small cell lung cancer.

PURPOSE: To correlate radiotherapy (RT) dose to acute esophagitis (AE) by means of FDG-PET scans acquired after concurrent chemo-radiotherapy (cCRT) for locally advanced non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients treated with 24 × 2.75 Gy were selected on presence of a post-RT PET (PET(post)) scan acquired within 3 months after cCRT. The value of PET(post) in relation to AE was evaluated by comparing the mean esophageal SUV of the highest 50% (mathematical left angle bracket SUV(50%) mathematical right angle bracket) between gr < 2 and gr ≥ 2AE. The local dose on the esophagus wall was correlated to the SUV and modeled using a power-law fit. The Lyman-Kutcher-Burman (LKB) model was used to predict gr ≥ 2AE. The local dose-response relation was used in the LKB model to calculate the EUD. Resulting prediction accuracy was compared to D(mean), V(35), V(55) and V(60). RESULTS: Eighty-two patients were included (gr < 2 = 25, gr ≥ 2=57). The mathematical left angle bracket SUV(50%) mathematical right angle bracket ≥ was significantly higher for gr ≥ 2AE (2.2 vs. 2.6, p < 0.01). The LKB parameters (95% CI) were n = 0.130 (0.120-0.141), m = 0.25 (0.13-0.85) and TD(50) = 50.4 Gy (37.5-55.4), which resulted in improved predictability of AE compared to other predictors. CONCLUSION: Esophageal uptake of FDG post-cCRT reflects AE severity. Predictability of grade ≥ 2AE was improved by using the local dose-SUV response model, with narrow confidence intervals for the optimized LKB parameters.

Acute esophagus toxicity in lung cancer patients after intensity modulated radiation therapy and concurrent chemotherapy.

PURPOSE: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m(2)). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, D(mean) and D(max) of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade ≥ 2 and grade ≥ 3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade ≥ 2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment. RESULTS: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade ≥ 3 AET (P=.012). The derived V50 model was shown to predict grade ≥ 2 AET significantly better than the clinical V35 model (P<.001). CONCLUSIONS: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade ≥ 3 AET. There was no difference in the incidence of grade ≥ 2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.