The THORA trial was conducted in 2014-2017, before immunotherapy was introduced as treatment for small-cell lung cancer.

Randomized phase II trial comparing the efficacy of standard-dose with high-dose twice-daily thoracic radiotherapy in limited disease small-cell lung cancer (THORA)

Lung cancer is one of the most common cancers malignant diseases and the most common cause of cancer-related deaths. Small-cell lung cancer (SCLC) accounts for approx. 15 % of the cases. Untreated, it is usually an aggressive disease with a poor survival prognosis of 2-3 months. Up to 90 % of patients respond to therapy, but most of them relapse, and SCLC accounts for approximately 4 % of all cancer-related deaths. Patients with localized disease can be cured through surgery, but very few are operable. 

Radiotherapy twice daily

Concurrent chemotherapy and thoracic radiotherapy (TRT) is superior to chemotherapy alone when all lesions can be included in a radiotherapy field (limited disease, “LD SCLC”). Chemotherapy alone is the standard treatment for patients with more widespread disease (extended disease, “ED SCLC”). 

The optimal regimen for thoracic radiotherapy (TRT) is debated. Best results have been observed in a study by Turrisi et al. comparing twice-daily hyperfractionated TRT of 45 Gy in 30 fractions (two fractions per day - BID) with 45 Gy in 25 fractions – one fraction per day (OD), but standard therapy in Norway and in other countries has still been 40-42 Gy in 15 fractions (OD). A meta-analysis concluded that shorter TRT treatment time is superior to longer treatment time, and in the Turrisi-study, the treatment time in the hyper-fractionated arm was 3 weeks vs. 5 weeks in the control-arm.

The NLCG has conducted a study comparing 42 Gy in 15 fractions (OD) with 45 Gy in 30 fractions (BID). The study aimed at exploring whether there were indications of a benefit of twice-daily TRT and to compare toxicity from the two TRT-regimens. Preliminary results indicate that the twice-daily regimen is superior (median overall survival: 18.8 vs. 24.7 months; 2-year survival: 41 % vs. 53 %). The patients reported slightly more dysphagia, but the difference was very small. Thus, the NLCG has concluded that based on this and other studies, 45 Gy in 30 fractions (BID) is the standard TRT regimen.

Twice-daily TRT reduces the risk of local failure, but 36 % still experience local recurrence. Improved local control appears to be correlated with better survival. Despite being a chemosensitive disease, dose-intensified chemotherapy has failed to prolong survival. Thus, improved TRT appears to be the best strategy for improving local control and survival rates in LD SCLC. Studies have demonstrated that 70 Gy (OD, 2 Gy per fraction) and 60 Gy (BID, 1.5 Gy per fraction) are tolerable, but none of these regimens have been compared with 45 Gy in 30 fractions (BID) in a prospective, randomized study.

As the first, we compared standard twice daily radiotherapy (three weeks; 45 Gy) to a higher dose of twice daily radiotherapy (four weeks; 60 Gy). All patientes received standard chemotherapy and prophylactic cranial irradiation.

Our aim was to compare two schedules of TRT with respect to local control, progression free survival, overall survival, toxicity and health-related quality of life. Further, to characterize the patients who had the best outcomes and tolerate chemoradiotherapy (e.g. clinical characteristics, blood biomarkers, body composition).

A Randomized Phase III Study Comparing Maintenance Pemetrexed Therapy After Induction Chemotherapy Versus Pemetrexed at Progression in Advanced Non-Small-Cell Lung Cancer (IDA)

Summary

Non-small-cell lung cancer (NSCLC) accounts for a majority (approximately 85%) of lung cancer cases. Patients with localized disease can be cured through surgery, but only 20 % are operable.For the majority of patients with advanced disease, palliative cytotoxic chemotherapy remains the recommended therapy. Chemotherapy prolongs survival and improves quality of life.

The recommended first-line therapy is 4-6 courses of a platinum in combination with a third generation compound (e.g. gemcitabine, vinorelbine, docetaxel, pemetrexed, paclitaxel). After first-line therapy, it has been recommended to observe the patients and offer second-line chemotherapy at disease progression.

Regimens for second-line therapy include docetaxel or pemetrexed monotherapy. Pemetrexed is less toxic and superior to gemcitabine in non-squamous NSCLC, whereas docetaxel is the recommended second-line therapy in squamous cell carcinoma.

The results of the studies of maintenance pemetrexed therapy are encouraging; the observed survival benefit is clinically relevant and relatively large considering the poor survival in patients with advanced NSCLC. Furthermore, pemetrexed appears to be well tolerated. There are, however, several limitations to the studies that have been conducted: Relatively few elderly patients and no PS 2 patients were enrolled - and not all patients on the control-arms received pemetrexed at progression.

In total, 230 patients were enrolled at 20 Norwegian hospitals in the period 2013-2018.

Project aim

The overall aim was to investigate whether immediate maintenance pemetrexed therapy prolongs survival compared to observation and pemetrexed therapy at progression in patients with advanced NSCLC. Furthermore, we will explore whether patients with PS 2 and elderly ≥ 70 years tolerate and benefit from maintenance therapy; and what clinical characteristics and blood biomarkers are associated with sensitivity and tolerability of such therapy.