Terje Tollåli

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.

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.

Oligometastatic non-small cell lung cancer: a significant entity outside of specialized cancer centers?

Objective: To report the incidence, patterns of care, and outcomes of oligometastatic non-small cell lung cancer (NSCLC) in a rural practice setting in Norway. Materials and Methods: A retrospective analysis was conducted of all patients with stage IV NSCLC at the initial diagnosis who received active treatment in the central part of Nordland, a rural county in northern Norway, during the period of 2006-2012. We analyzed overall survival and prognostic factors. Results: The initial study population included 113 patients with stage IV disease who received active therapy; of these, 23 (20%) had oligometastatic spread (a maximum of 3 metastases to 1 organ). The median age was 71 years. Of the 23 patients, 16 (70%) did not receive radical or at least moderately aggressive local treatment for their thoracic disease. Of the remaining 7 patients, 4 (17.4%) did not receive systemic therapy. The median actuarial survival was 5.6 months in patients with more advanced metastases and 11.7 months in those with oligometastases (p = 0.03). Significant differences were also seen between the 2 oligometastatic patient groups with and without more intense thoracic treatment (median 19.7 vs. 7.6 months, p = 0.004). Further significant predictors of survival in patients with oligometastases were nodal stage (p = 0.028) and weight loss (p = 0.045). Trends were seen for T stage (p = 0.058) and performance status (p = 0.07). Conclusion: Oligometastatic NSCLC was diagnosed in a relevant proportion of patients; therefore, warranting prospective studies are recommended. Such studies are also needed to confirm the treatment-dependent survival differences observed in our patient population.

External Validation of a Prognostic Score for Patients Receiving Palliative Thoracic Radiotherapy for Lung Cancer

Background Palliative thoracic radiotherapy is a common treatment for patients with incurable lung cancer. A recent study suggested that a prognostic score based on performance status and N and M stage predicts survival and might support decision‐making (eg, when deciding about fractionation). Our aim was to perform a validation study in an independent, larger dataset. Patients and Methods This was a retrospective single‐institution study of 232 patients with small‐ or non–small‐cell lung cancer, with methodology comparable with that of the original study. Three subgroups were created, based on the point sum resulting from assessment of performance status and N and M stage (10‐11, 12‐14, 15‐17 points). Results Performance status and N and M stage were significantly associated with overall survival after palliative radiotherapy in uni‐ and multivariate analyses. An unfavorable prognosis (10‐11 points) was predicted in 56 patients (24%). Their median survival was 1.2 months. The intermediate group consisted of 137 patients (59%) with a median survival of 5.3 months. A favorable prognosis (15‐17 points) was predicted in 39 patients (17%), whose median survival was 8.2 months. The difference between the intermediate and favorable subgroups did not reach statistical significance (P = .1, as compared with P = .0001 for the remaining 2 comparisons). Conclusion In the original study, the median survival of patients in the 3 different prognostic strata was 2, 6, and 38 months. Except for the favorable subgroup, the validation study confirmed these results. Given the large, clinically highly relevant discrepancy (8 vs. 38 months), additional studies are needed in order to inform therapeutic decisions in patients with favorable point sum of 15 to 17. Micro‐Abstract The present study aimed to validate a survival score for patients treated with palliative thoracic irradiation for lung cancer. The impact of all 3 prognostic factors used to assign the 3‐tiered score was confirmed. However, a large discrepancy in median survival of prognostically favorable patients was seen (8 vs. 38 months). Thus, additional studies are needed in order to inform therapeutic decisions in this group.

Scylla or Charybdis: Case Report on Radiation Tolerance of the Spinalcord

A case of rapid cancer progression causing impending spinal cord compression at the margin of a previously irradiated treatment volume close to the thoracic spinal cord in a patient with non-small cell lung cancer is presented. The patient and treating physicians were faced with a difficult decision. Either reirradiate and accept a considerable risk of delayed radiation myelopathy or risk paraplegia as a result of tumour progression. To prevent rapid development of neurological deficits, the patient was reirradiated only 34 days after he had finished his initial course of simultaneous radio- and chemotherapy. The high cumulative spinal cord dose (corresponding to 84 Gy in 2-Gy fractions) and short interval to reirradiation resulted in a high risk of radiation myelopathy according to a previously published risk score. However, no treatment-related toxicity developed and neurological function was preserved for almost 5 months. Eventually, tumour progression resulted in paraplegia. This case illustrates important issues around palliative reirradiation of target volumes close to the spinal cord.

Pembrolizumab as second-line therapy in non-small cell lung cancer in northern Norway: budget impact and expected gain—a model-based analysis

Background Pembrolizumab is a new drug approved in several countries for second-line therapy in non-small cell lung cancer (NSCLC) being programmed cell death ligand (PD-L1) positive. This drug has a high cost, and the cost-effectiveness ratio has been debated. Patients and methods The budget impact to the Northern Norwegian Regional Health Authority trust of implementing pembrolizumab in second-line therapy in patients with PD-L1-positive NSCLC was calculated. A model was developed employing data from the Cancer Registry of Norway, the KEYNOTE-010 study, the price list from The Hospital Pharmacy of North Norway, the cost of analysing PD-L1 expression and the cost of travelling. Todays cost of second-line therapy was compared with the new standard employing pembrolizumab. The sale price of pembrolizumab in Norway was not published due to price confidentiality. Norwegian krone (NKr) was converted into Euros (€) at a rate of 1€=Nkr 8.8138. (Bank of Norway, 21 February 2017). Results 105 new patients were identified available for pembrolizumab per year. The annual cost of pembrolizumab was €5.2 million, hospital pharmacy administration costs €0.1 million, PD-L1 testing €0.3 million, oncologist/pulmonologist/nurses €0.2 million, radiology €0.06 million and transportation €0.4 million. Savings due to avoided present second-line therapy was calculated €0.4 million. Consequently, the cost of implementing pembrolizumab was €5.5 million and the annual budget impact was €5.0 million. A mean gain of at least 9 months per patient treated was necessary to make pembrolizumab cost-effective. Conclusions The net budget impact of pembrolizumab was €5.0 million. The expenditure could not be indicated cost-effective. Price confidentiality is a growing problem in health economics and it has become a ‘menu without prices’ setting.

A Four-Tiered Prognostic Score for Patients Receiving Palliative Thoracic Radiotherapy for Lung Cancer

ABSTRACT Palliative radiotherapy improves lung cancer related symptoms. Prognosis should be taken into account when deciding about fractionation. In this study, prognostic factors derived from multivariate analysis were used to assign a point sum reflecting 6-month survival. Four prognostic groups were compared. Performance status, lactate dehydrogenase, C-reactive protein, liver/adrenal gland metastases, and extrathoracic disease status significantly predicted survival and formed the basis of the score. The four groups had a median survival of 0.8, 1.6, 3.3, and 10.5 months (6-month survival 0, 10, 30, 70%; 12-month survival 0, 0, 12, 40%; p = 0.0001), respectively. In the unfavorable group best supportive care might be preferable.

Palliative Thoracic Radiotherapy for Lung Cancer: What Is the Impact of Total Radiation Dose on Survival?

Background Effective symptom palliation can be achieved with low-dose palliative thoracic radiotherapy. In several studies, median survival was not improved with higher doses of radiation. More controversy exists regarding the impact of higher doses on 1- and 2-year survival rates. Therefore, a comparison of survival outcomes after radiotherapy with different biologically equivalent doses (equivalent dose in 2-Gy fractions, EQD2) was performed. Methods This was a retrospective single-institution study of 232 patients with small or non-small cell lung cancer. Most commonly 2 fractions of 8.5 Gy were prescribed (34%), followed by 10 fractions of 3 Gy or equivalent regimens (30%, EQD2 circa 33 Gy). The highest EQD2 consisted of 45 Gy. Intention-to-treat analyses were performed. Results Survival was significantly shorter with regimens of intended EQD2 < 33 Gy, e.g., 2 fractions of 8.5 Gy (median 2.5 months compared to 5.0 and 7.5 months with EQD2 of circa 33 and 45 Gy, respectively). The 2-year survival rates were 0%, 7% and 11%, respectively. In 128 prognostically favorable patients, median survival was comparable for the three different dose levels (6 - 8.3 months). The 2-year survival rates were 0%, 10%, and 13%, respectively (not statistically significant). Conclusion Although most of the observed survival differences diminished after exclusion of poor prognosis patients with reduced performance status and/or progressive extrathoracic disease, a slight increase in 2-year survival rates with higher EQD2 cannot be excluded. Because of relatively small improvements, a confirmatory randomized trial in this subgroup would have to include a large number of patients.

List of Reviewers Vol. 23, 2014

Abboud, M. Abdel Moneim, A. AbuRuz, S. Abu-Zidan, F. Acar, B. Adams, H. Adler, I. Ager, A. Aggarwal, A. Agrawal, M. Alameddine, A. Albert, M. Alessandro, D. Almas, K. Al-Sarraf, N. Alston, T. Anand, A. Ansari, H. Araj, G. Arboix, A. Armanini, D. Aronoff, D. Arroyo, A. Assimakopoulos, S. Atabai, K. Atanasov, G. Attarian, M. Bailey, D. Bain, B. Balconi, G. Ban, I. Baqain, Z. Baraboutis, I. Basson, M. Bebbington, P. Becker, A. Bednarczuk, T. Ben Dhifallah, I. Bener, A. Bennett, N. Berend, K. Bernard, G. Berney, C. Bernstein, H. Betterle, C. Bhangu, A. Bhat, S. Bhawal, U. Bizzaro, N. Blondeau, J. Boezaart, A. Boffano, P. Bopassa, J.