Kate Johnson

May 18, 2012

May 18, 2012 (Barcelona, Spain) — Dutch researchers have overcome a major hurdle in the treatment of anemic patients with laryngeal cancer by using accelerated radiotherapy, carbogen, nicotinamide (ARCON) therapy, Hans Kaanders, MD, PhD, announced here at the ESTRO 31: European Society for Radiotherapy and Oncology 2012 Annual Conference.

ARCON is a low-cost enhancement of accelerated radiotherapy (AR) that adds inhaled carbogen and nicotinamide — 2 drugs that reduce hypoxia.

"After decades of research on how to correct for poor outcomes in anemic patients, this is the first treatment modality that demonstrates improved outcome," said Dr. Kaanders, who is professor of translational radiation oncology at Radboud University Nijmegen Medical Centre, in the Netherlands.

The main study, which involved mostly nonanemic laryngeal cancer patients, was recently published (Janssens GO, et al. J Clin Oncol. Published online April 16, 2012). It showed that ARCON therapy resulted in significantly improved 5-year regional control, compared with AR (93% vs 86%; P = .04).

A subanalysis has now shown that the benefit of ARCON is enhanced in patients with preirradiation anemia (27 in the AR group and 27 in the ARCON group).

The entire study involed 345 patients with cT2 to 4 squamous cell laryngeal cancer who were randomly assigned to AR (68 Gy given in 2 Gy fractions in 36 to 38 days) or ARCON, which consisted of nicotinamide 60 mg/kg and inhaled carbogen during radiation therapy (delivered at a reduced dose of 64 Gy).

"We decided on this dose reduction because there are older data suggesting that carbogen might sensitize the laryngeal cartilage," Dr. Kaanders explained.

In the subset of patients with anemia (a hemoglobin concentration below 7.5 mmol/L in women and below 8.5 mmol/L in men), anemic patients who received AR alone had a worse outcome than nonanemic patients. "It's quite a substantial difference — 20% — in terms of locoregional control," said Dr. Kaanders.

Nonanemic patients treated with AR had significantly better locoregional control than anemic patients (76% vs 56%; P < .01), better disease-free survival (72% vs 48%; P < .01), and better metastasis-free survival (90% vs 70%; P < .01).

However, in the ARCON group, "the effect of anemia is entirely compensated for by giving ARCON; this is not only true for locoregional control, it is also true for disease-free survival, which includes distant metastasis," he said.

In the ARCON group, results were similar in anemic and nonanemic patients for locoregional control (81% vs 82%; P = .95), disease-free survival (77% vs 70%; P = .32), and metastasis-free survival (93% vs 89%; P = .33).

"In multivariate analysis, hemoglobin remained a prognostic indicator in the patients treated with accelerated radiotherapy alone, but this was corrected, in the patients treated with ARCON, for locoregional control and disease-free survival," he said.

It is interesting to note that "if the anemic patients recur, they recur very rapidly — within 8 months; in nonanemic patients, you see that it is up to 2.5 years," he added.

Despite the better outcomes with ARCON therapy in patients with anemia, there was no advantage in overall survival, suggesting significant comorbidity in this patient population, he noted.

Anemic patients face disadvantages in tumor control with other forms of cancer as well — namely, cervical cancer, bladder cancer, and breast cancer, said Dr. Kaanders.

"This may not only be important for head and neck cancer patients, but also for other tumor categories."

Asked to comment on the research, Jean Bourhis, MD, PhD, who chaired the session in which it was presented, told Medscape Medical News that it is an important finding.

"This is the first time that we see that manipulation of oxygenation in anemic patients is showing something," said Dr. Bourhis, who specializes in head and neck cancer and is head of radiation oncology at the Institut Gustave Roussy, in Villejuif, France, and is past-president of ESTRO.

"We know that anemic patients, generally speaking, have a prognosis that is worse and they deserve attention. There have been some attempts in the past that didn't show improvement," Dr. Bourhis explained.

Dr. Kaanders said that previous attempts to increase anemic hemoglobin levels using blood transfusions or erythropoietin therapy were probably used in cases that were too chronic, allowing tumors time to adapt. In contrast, ARCON's success might be related to its brevity.

"With carbogen-breathing, which only lasts for 10 minutes at each radiotherapy session, you completely reduce the hypoxia.... Because this is such a short time, there is no adaptive response from the tumor; once you stop the carbogen breathing you get back to the original situation. Every time you give a fraction of radiotherapy, you get this carbogen effect again, without any adaptation mechanism from the tumor.... Of course, we do acknowledge there might well be other potential mechanisms."

Dr. Kaanders and Dr. Bourhis have disclosed no relevant financial relationships.

ESTRO 31: European Society for Radiotherapy and Oncology 2012 Annual Conference: Abstract OC-217. Presented May 12, 2012.

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