In Esophageal Cancer, Lung Radiation Dose Affects Survival

Roxanne Nelson, RN, BSN

January 22, 2018

SAN FRANCISCO — Among patients undergoing chemoradiation therapy (CRT) for  localized esophageal cancer, the dose of radiation that reaches the lung, but not that reaching the heart, has been shown to be an independent predictor of survival.

Specifically, lung V20, or the volume of the lung receiving a dose of at least 20 Gy, was a significant predictor of overall survival, noted lead author, Patrick Oh, a second-year medical student at Stony Brook University School of Medicine in New York.

Patients with localized esophageal cancer often receive preoperative and definitive chemoradiation therapy, explained Oh. He presented results from a study in 453 patients results here at the Gastrointestinal Cancers Symposium (GICS) 2018.

 "In this large cohort retrospective analysis, lung dose was an independent predictor of survival after CRT," Oh concluded. "This suggests a role for improving CRT outcomes by lowering lung dose."

One way of improving outcomes may be to use more conformal radiation techniques, such as proton therapy, or smaller target volumes, such as reduced margins or elective nodal radiation therapy, he suggested.

"Further dosimetric analysis and validation is needed, ideally in prospective settings," he said.

Radiation Dose in Adjacent Tissue

"Recent studies, in lung cancer in particular, have suggested that the radiation dose received by adjacent tissue may be strongly predictive of survival," he said. "The RTOG 0617 trial, for example, which involved patients with locally advanced non-small cell lung cancer, showed that heart dose such as heart V30 is an independent predictor of overall survival after definitive radiation."

But while studies have shown a relationship in other cancer types, it was yet unclear whether similar dosimetric predictors apply to esophageal chemoradiation.

"Because esophageal radiation involves radiation to the heart, we were interested if similar dosimetric predictors could apply to this patient population," Oh explained. 

Multiple lung metrics have correlated strongly with overall survival, and V20 is the most widely used in practice. "We speculated that higher lung dose may increase risk of fatal cardiopulmonary and postsurgical events," he said.

No Effect From Heart Dose

For the study, the researchers reviewed the records of 453 consecutive patients with stage I to III esophageal cancer who were treated at their institution with definitive or preoperative chemoradiation (median dose, 50.4 Gy in 28 fractions) between 2007 and 2015.

Most patients (n = 442, 98%) received intensity-modulated radiation therapy, and radiation plans were reviewed and multiple dose-volume histogram metrics for heart and lung were extracted for the analysis.

Of this group, about half of the patients had surgery (n = 241) and about half did not (n = 212).

Most of the patients had a smoking history of more than 5 pack-years (n = 310, 68%), and the majority did not have any preexisting cardiac disease (n = 376, 83%).

Adenocarcinoma was the most prevalent histologic type (n = 365, 81%), and about two thirds of patients (n = 304, 67%) had stage III disease. Most patients (83%) had no preexisting cardiac disease.

The median follow-up duration for surviving patients was 28.4 months.

On univariate analysis, older age, lower performance status, stage III disease, lack of surgery, heart V40, lung V5, lung V20, and lung mean dose were all significantly associated with decreased survival.

But on multivariable analysis, only age (hazard ratio [HR], 1.01; P = .034), surgery (HR, 0.60; P < .001), and stage III disease at baseline (HR, 1.98; P < .001) independently predicted survival outcomes. Additionally, lung V20 (HR, 1.03; P = .0389), but not the cardiac radiation dose, was also predictive of survival.

Patients who had less than 20% of the lung exposed to 20 Gy of radiation had a significantly longer survival — nearly double — than did those with exposures of 20% or greater (44 months vs 24 months; P = .01).

Further analysis of disease control and causes of death is ongoing.

Unintended Consequences

Even though chemoradiation is considered standard of care in this population, there may well be unintended consequences of that therapeutic approach, commented Theodore Hong, MD, director of Gastrointestinal Radiation Oncology at Massachusetts General Hospital in Boston, who acted as discussant for the study at the meeting.

Previous data have shown that CRT produces downstaging that may influence the margin-positive resection rate, he said. This may decrease metastatic spread with early therapy, given that positive-margin rates after surgery alone for locally advanced tumors range from 20% to 30%, he noted.

"But when we look across the landscape of multiple neoadjuvant chemoradiotherapy trials, we can see that there has been a mix of positive and negative effects for chemoradiation for the anticancer effect," Dr Hong said.

"So why is the survival benefit so inconsistent? That is the question," he noted, emphasizing that "we are left with a conundrum." If CRT is a highly effective therapy, then it becomes difficult to explain why the survival benefit is so inconsistent, given the seemingly high efficacy of these treatments.

"I would argue that this is a very confusing time," he said. "Much of this can be related to toxicity, and that is the basis for this paper, but I would argue that there may also be unintended adverse consequences on disease progression."

Toxicity is often associated with early mortality in CRT trials, thus confounding the results of neoadjuvant randomized studies.

Dr Hong explained that previous data have shown that the radiation dose to the lungs can lead to complications. The issue with cardiac dose has been less clear, and in lung cancer it has been associated with worse overall survival. However, this trial did not find that.

The results of this study do raise questions, he noted. "Is it just really toxicity or potentially another cause, because cause of death remains under analysis."

"I don't dispute the fact that we lose many of our patients due to toxicity related to neoadjuvant chemoradiation and that is something we need to be very cognizant of," Dr Hong said. "But I don't think it explains the entire conundrum of why we see this decreased overall survival in the face of highly effective therapy and our patients dying of disease progression."

Dr Hong emphasized that hard, mechanistic data are still lacking on why a survival benefit is lost "in light of how much effect we get at the primary tumor. It is very important to tease out if we are losing patients to toxicity or to loss of systemic control."

"I think it is incumbent on our field of radiation oncology to continue investigation into the optimization of radiation techniques and parameters that can help better impact toxicity and systemic control," Dr Hong concluded.

Mr Oh has disclosed no relevant financial relationships; coauthors Dr Goodman and Dr Wu report a consulting or advisory Role with Pfizer and receiving research funding from CivaTech Oncology, respectively. Dr Hong reports a consulting or advisory role with Clinical Genomics and research funding from Novartis and Taiho Pharma.

Gastrointestinal Cancers Symposium (GICS) 2018.  Abstract 3. Presented January 18, 2018.

J Clin Oncol. 2018;36(suppl 4S). Abstract 3.

Follow Medscape Oncology on Twitter: @MedscapeOnc

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