Øystein Fløtten

Phase III Study by the Norwegian Lung Cancer Study Group: Pemetrexed Plus Carboplatin Compared With Gemcitabine Plus Carboplatin As First-Line Chemotherapy in Advanced Non–Small-Cell Lung Cancer

PURPOSE To compare pemetrexed/carboplatin with a standard regimen as first-line therapy in advanced non-small-cell lung cancer NSCLC. PATIENTS AND METHODS Patients with stage IIIB or IV NSCLC and performance status of 0 to 2 were randomly assigned to receive pemetrexed 500 mg/m(2) plus carboplatin area under the curve (AUC) = 5 (Calverts formula) on day 1 or gemcitabine 1,000 mg/m(2) on days 1 and 8 plus carboplatin AUC = 5 on day 1 every 3 weeks for up to four cycles. The primary end point was health-related quality of life (HRQoL) defined as global quality of life, nausea/vomiting, dyspnea, and fatigue reported on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 and the lung cancer-specific module LC13 during the first 20 weeks. Secondary end points were overall survival and toxicity. Results Four hundred thirty-six eligible patients were enrolled from April 2005 to July 2006. Patients who completed the baseline questionnaire were analyzed for HRQoL (n = 427), and those who received > or = one cycle of chemotherapy were analyzed for toxicity (n = 423). Compliance of HRQoL questionnaires was 87%. There were no significant differences for the primary HRQoL end points or in overall survival between the two treatment arms (pemetrexed/carboplatin, 7.3 months; gemcitabine/carboplatin, 7.0 months; P = .63). The patients who received gemcitabine/carboplatin had more grade 3 to 4 hematologic toxicity than patients who received pemetrexed/carboplatin, including leukopenia (46% v 23%, respectively; P < .001), neutropenia (51% v 40%, respectively; P = .024), and thrombocytopenia (56% v 24%, respectively; P < .001). More patients on the gemcitabine/carboplatin arm received transfusions of RBCs and platelets, whereas the frequencies of neutropenic infections and thrombocytopenic bleedings were similar on both arms. CONCLUSION Pemetrexed/carboplatin provides similar HRQoL and survival when compared with gemcitabine/carboplatin with less hematologic toxicity and less need for supportive care.

Influence of comorbidity on survival, toxicity and health-related quality of life in patients with advanced non-small-cell lung cancer receiving platinum-doublet chemotherapy.

AIM OF THE STUDY To investigate whether patients with severe comorbidity receiving platinum-based chemotherapy for advanced non-small-cell lung cancer (NSCLC) have a shorter overall survival, experience more toxicity or more deterioration of health-related quality of life (HRQoL) than other patients during treatment. PATIENTS AND METHODS Patients enrolled onto a phase III trial comparing pemetrexed/carboplatin with gemcitabine/carboplatin as first-line therapy of stage IIIB/IV NSCLC were analysed. Eligible patients had performance status 0-2 and adequate kidney/liver/bone-marrow function. Comorbidity was assessed from hospital medical records using the Cumulative Illness Rating Scale for Geriatrics (CIRS-G). Toxicity was graded using the CTCAE v3.0 and the patients reported HRQoL on the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30/LC13. RESULTS Data from 402 of the 436 of the patients enrolled onto the phase III trial were analysed. The patients with severe comorbidity had similar survival as other patients (6.9 versus 8.1months; p=.34), similar frequency of neutropenia (48% versus 42%; p=.16), but experienced more neutropenic fevers (12% versus 5%; p=.012) and deaths from neutropenic infections (3% versus 0%; p=.027). They had more thrombocytopenia (46% versus 36%; p=.03), but not more thrombocytopenic bleedings (3% versus 4%; p=.65). In general, the patients with severe comorbidity reported poorer HRQoL, but not significantly more deterioration of HRQoL. CONCLUSIONS The results from our study suggest that patients with advanced NSCLC who have severe co-existing disorders benefit from and tolerate platinum-doublet chemotherapy as well as other patients. They do, however, appear to have a higher risk of acquiring infections when neutropenic.

Strategies for clinical implementation of TNM-Immunoscore in resected nonsmall-cell lung cancer.

Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates and appears highly promising as a supplement to the tumor-node-metastasis (TNM) classification of various tumors. In colorectal cancer, an international task force has initiated prospective multicenter studies aiming to implement TNM-Immunoscore (TNM-I) in a routine clinical setting. In breast cancer, recommendations for the evaluation of tumor-infiltrating lymphocytes (TILs) have been proposed by an international working group. Regardless of promising results, there are potential obstacles related to implementing TNM-I into the clinic. Diverse methods may be needed for different malignancies and even within each cancer entity. Nevertheless, a uniform approach across malignancies would be advantageous. In nonsmall-cell lung cancer (NSCLC), there are several previous reports indicating an apparent prognostic importance of TILs, but studies on TILs in a TNM-I setting are sparse and no general recommendations are made. However, recently published data is promising, evoking a realistic hope of a clinical useful NSCLC TNM-I. This review will focus on the TNM-I potential in NSCLC and propose strategies for clinical implementation of a TNM-I in resected NSCLC.

Vinorelbine and gemcitabine vs vinorelbine and carboplatin as first-line treatment of advanced NSCLC. A phase III randomised controlled trial by the Norwegian Lung Cancer Study Group.

Background:Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination.Methods:Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0–2. Patients received up to three cycles of vinorelbine 60 mg m−2 p.o.+gemcitabine 1000 mg m−2 i.v. day 1 and 8 (VG) or vinorelbine 60 mg m−2 p.o. day 1 and 8+carboplatin area under the curve=5 (Calverts formula) i.v. day 1 (VC). Patients ⩾75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy.Results:We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P=0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P=0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P<0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups.Conclusion:The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile.

Low muscle mass is associated with chemotherapy-induced haematological toxicity in advanced non-small cell lung cancer.

BACKGROUND Recent research suggests a significant relationship between lean body mass (LBM) and toxicity from chemotherapeutic agents. We investigated if higher drug doses per kg LBM were associated with increased toxicity in stage IIIB/IV non-small cell lung cancer (NSCLC) patients receiving a first-line chemotherapy regimen dosed according to body surface area (BSA). METHODS Data from patients randomised to receive intravenous gemcitabine 1000 mg/m(2) plus orally vinorelbine 60 mg/m(2) days 1 and 8 in a phase III trial comparing two chemotherapy regimens were analysed. LBM was estimated from assessment of the cross-sectional muscle area at the third lumbar level (L3) on computed tomography images obtained before chemotherapy commenced. Common terminology criteria for adverse events (CTCAE) grade 3-4 haematological toxicity and dose reduction and/or stop of treatment after the first course of chemotherapy were defined as primary and secondary toxicity outcomes. RESULTS The study sample included 153 patients, mean age was 66 years, 55% were men, 87% had disease stage IV and 75% had performance status (PS) 0-1. Gemcitabine doses per kg LBM varied from 23.2 to 53.1 mg/kg LBM, and vinorelbine doses from 1.5 to 3.3 mg/kg LBM. Higher doses of gemcitabine per kg LBM were significantly associated with grade 3-4 haematological toxicity in bivariate (OR=1.12, 95% CI 1.03-1.23, p=0.008) and multivariate analyses (OR=1.15, 95% CI 1.01-1.29, p=0.018), as were also higher doses of vinorelbine per kg LBM. No significant association was found between drug doses per kg LBM and dose reduction and/or stop of treatment. CONCLUSION The study showed that dose estimates according to BSA lead to a substantial variation in drug dose per kg LBM, and higher doses per kg LBM are a significant predictor for chemotherapy-induced haematological toxicity. The results indicate that taking LBM into account may lead to a better dose individualisation of chemotherapy.

Concurrent palliative chemoradiation leads to survival and quality of life benefits in poor prognosis stage III non-small-cell lung cancer: a randomised trial by the Norwegian Lung Cancer Study Group

Background:The palliative role of chemoradiation in the treatment of patients with locally advanced, inoperable non-small-cell lung cancer stage III and negative prognostic factors remains unresolved.Methods:Patients not eligible for curative radiotherapy were randomised to receive either chemoradiation or chemotherapy alone. Four courses of intravenous carboplatin on day 1 and oral vinorelbin on days 1 and 8 were given with 3-week intervals. Patients in the chemoradiation arm also received radiotherapy with fractionation 42 Gy/15, starting at the second chemotherapy course. The primary end point was overall survival; secondary end points were health-related quality of life (HRQOL) and toxicity.Results:Enrolment was terminated due to slow accrual after 191 patients from 25 Norwegian hospitals were randomised. Median age was 67 years and 21% had PS 2. In the chemotherapy versus the chemoradiation arm, the median overall survival was 9.7 and 12.6 months, respectively (P<0.01). One-year survival was 34.0% and 53.2% (P<0.01). Following a minor decline during treatment, HRQOL remained unchanged in the chemoradiation arm. The patients in the chemotherapy arm reported gradual deterioration during the subsequent months. In the chemoradiation arm, there were more hospital admissions related to side effects (P<0.05).Conclusion:Chemoradiation was superior to chemotherapy alone with respect to survival and HRQoL at the expense of more hospital admissions due to toxicity.

A placebo-controlled, randomized phase II study of maintenance enzastaurin following whole brain radiation therapy in the treatment of brain metastases from lung cancer

INTRODUCTION Enzastaurin is a protein kinase C inhibitor with anti-tumor activity. This study was designed to determine if maintenance enzastaurin improved the outcome of whole brain radiotherapy (WBRT) in lung cancer (LC) patients with brain metastases (BMs). METHODS Patients with LC (any histology) who had received WBRT for BMs were randomized to receive oral maintenance enzastaurin (1125 mg on Day 1 followed by 500 mg daily) or placebo. The primary endpoint was time to progression (TTP) of BMs. RESULTS Fifty-four patients received enzastaurin and 53 patients received placebo. The median TTP of BMs was (months) enzastaurin: 6.9 (95% confidence interval [CI]: 3.4-11.9); placebo: 4.9 (95% CI: 3.6-not assessable); p=0.82. Median overall survival (OS) was (months) enzastaurin: 3.8 (95% CI: 2.6-5.6); placebo: 5.1 (95% CI: 3.7-5.7); p=0.47. Median progression-free survival (PFS) was (months) enzastaurin: 2.2 (95% CI: 1.1-2.3); placebo: 2.0 (95% CI: 1.3-2.3); p=0.75. The overall response rate (ORR) for extracranial disease was enzastaurin: 0%; placebo: 4.5% (p=0.49) and for intracranial disease was enzastaurin: 9.3%; placebo 6.8% (p=0.71). Grade 4 hematologic treatment-emergent adverse events were (enzastaurin vs. placebo) thrombocytopenia (5.6% vs. 1.9%) and neutropenia (5.6% vs. 0%). There was 1 treatment-related death in each arm (enzastaurin: unknown cause; placebo: pulmonary embolism). No significant differences in health-related quality of life (HRQoL) were observed. CONCLUSIONS Enzastaurin was well tolerated but did not improve TTP of BMs, ORR, OS, PFS, or HRQoL after WBRT in LC patients with BMs.

Randomized phase II trial comparing twice daily hyperfractionated with once daily hypofractionated thoracic radiotherapy in limited disease small cell lung cancer

Abstract Background: Concurrent chemotherapy and thoracic radiotherapy (TRT) is recommended for limited disease small cell lung cancer (LD SCLC). Twice daily TRT is well documented, but not universally implemented – probably mainly due to inconvenience and concerns about toxicity. A schedule of three-week hypofractionated TRT is a commonly used alternative. This is the first randomized trial comparing twice daily and hypofractionated TRT in LD SCLC. Material and methods: Patients received four courses of cisplatin/etoposide (PE) and were randomized to TRT of 42 Gy in 15 fractions (once daily, OD) or 45 Gy in 30 fractions (twice daily, BID) between the second and third PE course. Good responders received prophylactic cranial irradiation of 30 Gy in 15 fractions. Results: 157 patients were enrolled between May 2005 and January 2011 (OD: n = 84, BID: n = 73). Median age was 63 years, 52% were men, 84% had performance status 0–1, 72% had stage III disease and 11% non-malignant pleural effusion. The treatment arms were well balanced. The response rates were similar (OD: 92%, BID: 88%; p = 0.41), but more BID patients achieved a complete response (OD: 13%, BID: 33%; p = 0.003). There was no difference in one-year progression-free survival (PFS) (OD: 45%, BID: 49%; p = 0.61) or median PFS (OD: 10.2 months, BID: 11.4 months; p = 0.93). The median overall survival in the BID arm was 6.3 months longer (OD: 18.8 months, BID: 25.1 months; p = 0.61). There were no differences in grade 3–4 esophagitis (OD: 31%, BID: 33%, p = 0.80) or pneumonitis (OD: 2%, BID: 3%, p = 1.0). Patients on the BID arm reported slightly more dysphagia at the end of the TRT. Conclusion: There was no difference in severe toxicity between the two TRT schedules. The twice daily schedule resulted in significantly more complete responses and a numerically longer median overall survival, but no firm conclusions about efficacy could be drawn from this phase II trial.

Muscle mass and association to quality of life in non-small cell lung cancer patients

Cancer wasting is characterized by muscle loss and may contribute to fatigue and poor quality of life (QoL). Our aim was to investigate associations between skeletal muscle index (SMI) and skeletal muscle radiodensity (SMD) and selected QoL outcomes in advanced non‐small cell lung cancer (NSCLC) at diagnosis.

Drug Dose Per Kilogram Lean Body Mass Predicts Hematologic Toxicity From Carboplatin-Doublet Chemotherapy in Advanced Non–Small-Cell Lung Cancer

Background Variations in lean body mass (LBM) have been suggested to explain variations in toxicity from systemic cancer treatment. We investigated if drug doses per kilogram of LBM were associated with severe hematologic toxicity (HT) in patients with stage IIIB/IV non–small‐cell lung cancer (NSCLC) enrolled onto randomized trials comparing first‐line carboplatin‐doublets. Patients and Methods Patients received carboplatin (AUC [area under the plasma concentration vs. time curve] = 5) plus either pemetrexed 500 mg/m2, gemcitabine 1000 mg/m2, or vinorelbine 60 mg/m2. LBM was estimated from the cross‐sectional muscle area at the third lumbar vertebra on computed tomographic scans. Administered doses on day 1, first cycle, were recalculated as milligram of drug per kilogram of LBM. Primary outcome was Common Terminology Criteria for Adverse Events version 3.0 grade 3/4 HT after cycle 1. Results Data from 424 patients were analyzed. Mean age was 65 years, 57% were men, and 78% had stage IV disease. Despite dose individualization by body surface area for the nonplatinum drugs, mean (range) doses expressed as mg/kg LBM showed ˜3‐fold range: gemcitabine 38.0 (22.5‐61.7) mg/kg LBM, pemetrexed 19.1 (8.1‐27.9) mg/kg LBM, and vinorelbine 2.4 (1.4‐3.6) mg/kg LBM. For these drugs, dose per kilogram of LBM was associated with HT in adjusted multivariate models (P = .004). Taking mean dose per kilogram LBM for each drug as reference, a 1% increase (odds ratio [OR] = 1.03; 95% confidence interval [CI], 1.01‐1.06) or 1% decrease (OR = 0.97; 95% CI, 0.95‐0.99) was associated with altered risk of grade 3/4 HT. For doses > 20% above and below mean (14% and 15% of patients, respectively) the risk of grade 3/4 HT was almost doubled (OR = 1.93, 95% CI, 1.21‐3.10) and halved (OR = 0.52; 95% CI, 0.32‐0.83), respectively. Conclusion Dose per kilogram of LBM varied considerably and was an independent predictor of HT. Computed tomography–defined LBM may provide a future basis for better dose individualization. Micro‐Abstract Variations in lean body mass (LBM) are proposed to contribute to interindividual differences in toxicity from cancer drugs. In advanced non–small‐cell lung cancer patients receiving carboplatin‐doublets, dose per kilogram of LBM of the nonplatinum drug dosed by body surface area was a significant independent predictor of grade 3/4 hematologic toxicity. Taking body composition into account may improve dose individualization of chemotherapeutic agents.