Tumor Hypoxia Identifies Cancer Patients With Worse Prognosis

CHICAGO—The degree of oxygenation of malignancies in the neck may indicate which patients with squamous cell carcinoma should receive adjuvant therapy, according to a study conducted at Duke University Medical Center.

The study revealed a highly significant difference in pretreatment tumor oxygenation status among patients who were pathologically negative and those who had positive tissue evidence of carcinoma at surgery.

Patients with tumor hypoxia had nearly an eightfold increase in the likelihood of residual disease at the time of neck dissection, David M. Brizel, MD, reported at the Second International Chicago Symposium on Malignancies of the Chest and Head & Neck. Hypoxia was an independent predictor of residual disease after the delivery of radiation, which fits with the concept of hypoxia-mediated radioresistance (see also "Hypoxia-Targeting Agent in Phase III Lung Cancer").

"We believe, therefore, that the assessment of tumor pO₂ may represent a biological parameter we can use in the staging of our patients to go along with anatomic staging and allow us to select appropriate patients for either more or less intensive therapy," said Dr. Brizel, associate professor of radiation oncology at Duke.

The study evaluated tumor hypoxia in 49 of 56 patients with measurable nodal disease who underwent modified neck dissection. Tumor oxygenation was assessed before patients received radiotherapy, surgery, or chemotherapy by determining pO₂ values at the primary site or in metastatic neck lymph nodes using polarographic tumor oxygenation.

During the polarographic process, an electrode connected to a computer-controlled servomotor makes several passes through the tumor and captures pO₂ measurements at 100 to 200 discrete and individual points.

All patients in the study received 70 Gy of radiation therapy, at a rate of either 2 Gy per day or 1.25 Gy twice daily, directed to the primary site, with or without concurrent chemotherapy. Four to 8 weeks after radiotherapy, patients who had N2a disease underwent elective neck dissection whether or not they demonstrated a clinical response.

The degree of pretreatment tumor oxygenation, expressed as the median pO2 value for each tumor, was 12.6 mm Hg in 27 patients who had no evidence of residual disease on post-treatment pathologic examination. Pretreatment pO₂ was 3.8 mm Hg in 22 patients with viable residual disease, Dr. Brizel said. The correlation was significant at P = .006.

There was no statistical correlation between pathologic response to treatment and N stage; patients with more advanced disease were not more likely to have residual disease. There also was no relationship between negative pathologic status at neck dissection and chemotherapy. As expected, however, lower doses of radiation therapy, below 7 Gy, were highly correlated with the presence of residual disease at surgery.

Studied Since 1993

This study is the latest in a series of investigations by Duke University Medical Center researchers who have been evaluating tumor hypoxia in the head and neck since 1993.

In a previous multivariate analysis of 59 patients with squamous cell head and neck cancer, the investigators showed that individuals with hypoxic tumors, defined as a median pO₂ less than 10 mm Hg, had an adverse prognosis.

"There was a large spread in the data favoring patients with well-oxygenated tumors, and this prognosis was independent of T stage and conventional anatomic staging factors as well as the treatment that was given," Dr. Brizel said.

The study of neck cancers reported at the Chicago Symposium focused on patients with squamous cell carcinoma because treatment for neck carcinoma varies considerably from institution to institution with regard to neck dissection after radiation therapy and/or chemotherapy, he said.

"These differences in treatment become more pronounced when trying to decide what to do with patients who have a complete response in the neck. In Europe and some institutions in the United States, it is policy to simply follow these patients," Dr. Brizel said. "At our institution, we make a decision at the time of initial presentation whether to perform neck dissection, and we don’t base that decision on response in the neck."

Tumor hypoxia may be a novel way of selecting patients who would benefit from new treatment strategies, Merrill S. Kies, MD, of M.D. Anderson Cancer Center, said at the meeting.

The Duke University researchers "are finding that tumor hypoxia is a very significant predictive factor both for the finding of residual disease in the neck and overall outcome, whether or not there is a mass in the neck."