Concerns about futility, obsolescence and uncertainties

James Fleck: Anticancerweb 12 (05), 2019

According to the most recent data provided by SEER* Program in US, lung cancer is still the leading cause of death among all types of malignant tumors in both males and females. Comprehensive tobacco control has been responsible for 43% and 17% reduction in lung cancer mortality rate, respectively for male and female. The data emphasizes the importance of preventive interventions. Unfortunately, the same trend has not yet been observed with recent advances in therapeutic interventions. Clinical use of actionable mutations and blockade of immunological checkpoints only improved lung cancer median overall survival in metastatic scenario. Unfortunately, the overall lung cancer curability rate is still low, ranging from 15 to 20%. Most of the patients (85%) have histologic types categorized as non-small cell lung cancer (NSCLC). This terminology has been criticized by the new WHO classification, including immunohistochemical and molecular criteria. Currently, advances in personalized medicine require the routine use of small biopsies for more accurate histologic and molecular classification.

NSCLC is a very aggressive illness. The majority of patients are diagnosed as metastatic or locally advanced disease. At the time of diagnosis, about half of the patients already have metastatic disease (M1) and approximately quarter of the cases are categorized as locally advanced disease (LAD), distributed in stages IIIA (N2 bulky) and IIIB. As a group, NSCLC-LAD has been standard treated using the combination of radiotherapy (60 to 66 Gy) and concurrent chemotherapy doublets (cisplatin + etoposide or carboplatin + paclitaxel), followed by a consolidation platinum-based chemotherapy. Despite curative intent, 50% of NSCLC-LAD treated patients progress to metastatic disease (M1) and about 40% show local recurrence. The high rate of systemic dissemination points out to low efficiency of chemotherapy and the high rate of local recurrence weakens the concept of radio-sensitizing drugs. This concept has been on the road for at least twenty years. Difficulties in identifying new radiosensitizer drugs kept unchanged the induction chemoradiotherapy strategy. The lack of new drugs able to control micro-metastatic disease has also been responsible for its unchanged outcome. Preliminary promising results obtained in a phase II study, using docetaxel consolidation treatment, were not confirmed in further phase III trials and metanalysis. 

There is an urgent need for new well-designed clinical trials seeking to increase the cure rate of NSCLC-LAD.

The new WHO classification showed NSCLC as a very heterogeneous disease.

More recent clinical trials, routinely include histologic, immunohistochemical and molecular subtypes in the eligibility criteria.

Metastatic NSCLC dominant-histology (adenocarcinoma) and large-cell carcinoma have shown better outcome when treated with four cycles of an antifolate (pemetrexede) with cisplatin in comparison with previous standard treatment. In addition, overall survival has increased with pemetrexed used as maintenance treatment. The showed benefits could be, eventually, translated into adenocarcinoma and large cell carcinoma staged as LAD, in a curative intent scenario. A phase III study known as PROCLAIM trial randomly assigned patients with adenocarcinoma or large cell carcinoma for two arms: One test-arm consisting of pemetrexede + cisplatin + concurrent radiotherapy, followed by maintenance with pemetrexed versus a control-arm composed by etoposide + cisplatin + concurrent radiotherapy, followed by consolidation without pemetrexed. Use of pemetrexede + cisplatin as radiosensitizers was already known and well-tolerated. The study was designed to show the superiority of the test arm, supported by the benefit obtained in metastatic disease. In addition, the risk of micro-metastatic disease (clinically hidden M1) was decreased by using PET-CT in more than 80% of eligible patients, which increased median overall survival in both arms of the study. Unfortunately, the study was negative. Subgroup analysis identified a benefit restricted to patients with worse prognosis, characterized by stage IIIB and a high-radiotherapy programed treatment volume (> 700 mL), which showed a better outcome associated to the use of pemetrexede. The study underwent early interruption, based on non-futility, which would prevent the achievement of mature results. Recent incorporation of immunotherapy (durvalumab) in the consolidation treatment of NSCLC-LAD may additionally render PROCLAIM trial results obsolete. Despite preliminary positive results, the use of consolidation immunotherapy in NSCLC-LAD is still based on surrogates. After a defeat and a partial winning, we are still looking forward to having further improvements on the next try.

*SEER = Surveillance, Epidemiology, and End Results

References:

William D. Travis, Elisabeth Brambilla, Andrew G. Nicholson, et al: The 2015 World Health Organization Classification of Lung Tumors Impact of Genetic, Clinical and Radiologic Advances Since the 2004 Classification, J Thorac Oncol, 10: 1243–1260, 2015

Suresh Senan, Anthony Brade, Lu-hua Wang, et al: PROCLAIM: Randomized Phase III Trial of Pemetrexed- Cisplatin or Etoposide-Cisplatin Plus Thoracic Radiation Therapy Followed by Consolidation Chemotherapy in Locally Advanced Nonsquamous Non–Small-Cell Lung Cancer, J Clin Oncol34, Jan 2016

Antonia SJ, Villegas A, Daniel D, et al: Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC, N Engl J Med 379: 2342 – 50, 2018