Worse Survival If Severe Lymphopenia Follows Chemoradiation

Pam Harrison

September 24, 2019

CHICAGO ― Patients with esophageal cancer who develop severe lymphopenia after receiving chemoradiotherapy have significantly worse outcomes than those whose lymphocytes are not compromised by treatment, underscoring how important the immune system is in cancer control, say researchers.

"One of the things that has been described across multiple disease sites — lung, brain, pancreas, among others — is that patients who have lower lymphocyte counts tend to do worse in terms of survival," Eddie Zhang, MD, a resident in radiation oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, told Medscape Medical News.

His team presented a study on lymphopenia here at the American Society for Radiation Oncology (ASTRO) 2019 Annual Meeting.

"We found that [radiation] dose to the heart, spine, aorta, and body predict for grade 4 lymphopenia, which is associated with worse recurrence-free and overall survival, and that achieving planning constraints for these parameters may decrease grade 4 lymphopenia and improve outcomes," he reported.

The study involved 189 patients who were followed up for a median of 2.3 years.

Most patients had clinical stage II (34%) or III (60%) disease, distal esophageal/gastroesophageal junction tumors (85%), adenocarcinoma (78%), and poorly differentiated tumors (40%), the team reported.

The median age of the cohort was 65 years; 84% were men, and almost all were white. Interestingly, 20% of the group had never smoked, and 31% of patients reported no history of alcohol use.

All patients received chemoradiotherapy. The median dose of radiotherapy was 50.4 Gy. Slightly more than half of patients were concurrently treated with a carboplatin/paclitaxel regimen; most of the remaining patients received concurrent 5-leucovorin-based regimens.

In addition, 68% of the group underwent surgical resection on completion of chemoradiotherapy.

Almost half of the group (45%) developed grade 4 lymphopenia, the team reported.

Among those whose lymphocyte counts were severely compromised, median recurrence-free survival was only 1.8 years, compared to 4.0 years for patients who did not develop lymphopenia (P = .02).

Median overall survival (OS) was also significantly attenuated in patients with grade 4 lymphopenia, at only 2.4 years, compared to 4.0 years for patients whose lymphocyte counts were not compromised by chemoradiotherapy.

On multivariable analysis, OS was 79% lower for patients with stage III disease compared to those with stage I and II disease, the group pointed out.

For patients with grade 4 lymphopenia, OS was reduced by 55% compared to those who did not have lymphopenia.

On the other hand, surgical resection of the tumor increased OS by 60%.

Treatment Regimens Modified

Zhang explained that there were two parts to this study. The first showed whether and how the development of severe lymphopenia compromises patient outcomes; the second was intended to identify ways in which current treatment regimens might be modified so as to make the development of grade 4 lymphopenia less likely for patients who undergo chemoradiotherapy.

"Most of the patients in our cohort were treated with either 3-D conformal radiation therapy or intensity-modulated radiation (IMRT)," Zhang pointed out. "Our group wanted to look at whether or not there are specific dose criteria when planning IMRT to try and reduce the risk of severe lymphopenia," he added.

Dosimetric data were available for 119 patients, the researchers noted.

On univariable analysis, the group found that if more than 73% of the volume of the heart received 15 Gy of radiation, that there was a strong likelihood of lymphopenia, "so to avoid lymphopenia, we want to keep the percentage of the heart receiving 15 Gy of radiation to below 73%," Zhang emphasized.

Similarly, there was a strong likelihood of grade 4 lymphopenia if more than 72% of the volume of the thoracic spine received 5 Gy, or if more than 50% of the total lung received 5 Gy of radiation, or if more than 50% of the volume of the aorta received 5 Gy.

When the volume of the body receiving 10 Gy exceeded 18%, the risk for grade 4 lymphopenia was increased more than sevenfold. That dose appears to be the strongest predictor of grade 4 lymphopenia.

In multivariable models, in addition to other clinical variables, baseline total lymphocyte counts higher than dose volume histogram cutpoints for heart, thoracic spine, aorta, and body all predicted grade 4 lymphopenia (P < .05), the investigators noted.

"It's an observational cohort, so we have to examine these criteria a bit more closely," Zhang cautioned.

"But it's a good starting point to figure out what dose to which specific organ is actually contributing to lymphopenia, and the ideal plan is one where you can cover the target while at the same time minimize the radiation dose to organs at risk," he observed.

Long-term Impact

Asked by Medscape Medical News to comment on the findings, Daniel Ma, MD, Mayo Clinic School of Medicine, Rochester, Minnesota, felt that Zhang and colleagues should be commended on an excellent study, which has demonstrated that unintentional radiation dose to normal structures not generally associated with toxicity can still have a long-term impact on disease outcome.

"In this case, radiation from esophageal cancer treatment to structures such as the spine and whole body predicted for the likelihood of severe suppression of the immune system (lymphopenia)," he said in an email.

Indeed, nearly half of the patients in the study experienced lymphopenia after chemoradiotherapy, Ma noted, which is very close to the Mayo Clinic's experience ― after standard radiotherapy, 56% of patients with esophageal cancer developed lymphopenia.

The fact that the current study demonstrated an association between severe suppression of the immune system and poor disease outcome highlights the critical importance of minimizing radiation dose to organs at risk, Ma emphasized.

The use of proton beam therapy to avoid unnecessary radiation exposure for esophageal cancer may be a way to reduce this risk, because the rates of severe lymphopenia after proton beam therapy are much lower, he pointed out.

"Additional research into finding ways to reduce unnecessary radiation exposure should be explored," Ma also suggested.

Senior author Joshua E. Meyer, MD, has received honoraria from Varian. Zhang, the other coauthors, and Ma have disclosed no relevant financial relationships.

American Society for Radiation Oncology (ASTRO) 2019 Annual Meeting: Abstract TU_12_2475, presented September 17, 2019.

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