Improved Recurrence-Free Survival with ARCON for Anemic Patients with Laryngeal Cancer

Abstract

Purpose: Anemia is associated with poor tumor control. It was previously observed that accelerated radiotherapy combined with carbogen breathing and nicotinamide (ARCON) can correct this adverse outcome in patients with head and neck cancer. The purpose of this study was to validate this observation based on data from a randomized trial.Experimental Design: Of 345 patients with cT2-4 laryngeal cancer, 174 were randomly assigned to accelerated radiotherapy and 171 to ARCON. Hemoglobin levels, measured before treatment, were defined as low when <7.5 mmol/L for women and <8.5 mmol/L for men. The hypoxia marker pimonidazole was used to assess the oxygenation status in tumor biopsies. Data were analyzed 2 years after inclusion of the last patient.Results: Pretreatment hemoglobin levels were available and below normal in 27 of 173 (16%) accelerated radiotherapy and 27 of 167 (16%) ARCON patients. In patients with normal pretreatment, hemoglobin levels treatment with ARCON had no significant effect on 5-year loco-regional control (LRC, 79% versus 75%; P ¼ 0.44) and disease-free survival (DFS, 75% vs. 70%; P ¼ 0.46) compared with accelerated radiotherapy. However, in patients with low pretreatment, hemoglobin levels ARCON significantly improved 5-year LRC (79% vs. 53%; P ¼ 0.03) and DFS (68% vs. 45%; P ¼ 0.04). In multivariate analysis including other prognostic factors, pretreatment hemoglobin remained prognostic for LRC and DFS in the accelerated radiotherapy treatment arm. No correlation between pretreatment hemoglobin levels and pimonidazole uptake was observed.Conclusion: Results from the randomized phase III trial support previous observations that ARCON has the potential to correct the poor outcome of cancer patients with anemia (ClinicalTrials.gov number, NCT00147732). Clin Cancer Res; 20(5); 1345-54. Ó2014 AACR.

Current relevance of hypoxia in head and neck cancer

“…This evidence should encourage us to move away from the common notion of transfusing patients with an Hb < 10 g/dl or a hematocrit (Hct) < 30%. Vaupel et al [31] found that an Hb level between 12 and 14 g/dl was optimal for tumor oxygenation even though no correlation has been found between Hb level and pO 2 [32, 33]. …”

F-18 Fluoromisonidazole for Imaging Tumor Hypoxia: Imaging the Microenvironment for Personalized Cancer Therapy

“…The past decade has seen significant technological advances in investigating hypoxia imaging in radiation treatment planning and in providing us with the ability to individualize radiation delivery and target volume coverage. The presence of widespread hypoxia in the tumor can be effectively targeted with a systemic hypoxic cell cytotoxin or other agents that are more effective with diminished PO 2 , either alone or in combination 45 . Molecular imaging in general and hypoxia imaging in particular will likely become an important in vivo imaging biomarker of the future, complementing the traditional direct tissue sampling methods by providing a snap shot of a primary tumor and metastatic disease and in following treatment response and will serve as adjunct to personalized therapy.…”

“…Carbogen breathing combined with radiotherapy has been successfully used in several clinical trials and has shown benefit in tumors with significant hypoxia 44 . It was the basis for the ARCON (Accelerated Radiotherapy with Carbogen and Nicotinamide) trial that was particularly beneficial in patients with signficant anemia 45 , resulting in better response and survival. Janssens et al found in a chort of 345 laryngeal cancer patients a better five-year disease free survival of 68% vs 45% (p = 0.04).…”

Personalized radiotherapy: concepts, biomarkers and trial design

“…[44][45][46][47] Moreover, in this patient group, hypoxia-targeted interventions (e.g. nimorazole or nicotinamide combined with carbogen breathing) have shown promising results, [48][49][50] although the randomized trial of adding tirapazamine to cisplatin-containing CRT in the experimental arm failed to improve overall survival. 51 In considering the conduct of future combined-modality studies, this will increasingly highlight the dynamic nature of the tumour biology, for example, by including serial biomarker assessments during the course of fractionated radiotherapy to enable biological adaptation to changing tumour vulnerabilities, which will be further discussed below.…”