Studies Evaluating Chemoradiation in Localized Esophageal Cancer Raise Questions About Possible Unintended Outcomes

Studies Evaluating Chemoradiation in Localized Esophageal Cancer Raise Questions About Possible Unintended Outcomes

There is little doubt that chemoradiation therapy (CRT) is essential to the treatment of localized esophageal cancer. However, two studies that investigated the ways in which neoadjuvant CRT is delivered before surgery and how different parameters influence survival outcomes raise some questions and suggest that CRT may exert unintended consequences.

Evaluation of the Time Between CRT and Surgery

Patients with esophageal cancer who attain pathologic complete response (pCR) after neoadjuvant CRT tend to survive longer than patients who harbor residual disease before surgery. Some studies indicate that patients with esophageal cancer should undergo esophagectomy within 6 to 8 weeks after completing neoadjuvant therapy.1 However, emerging literature for esophageal cancer and other solid tumors suggests that longer time intervals between CRT and surgery may increase the likelihood of pCR, which may then translate into prolonged survival.

Dr. Basem Azab presents Abstract 2 during Oral Abstract Session A.
To better understand how the length of time between neoadjuvant CRT and surgery influences disease and patient outcomes, Basem Azab, MD, of the University of Miami, and colleagues used the National Cancer Database to find answers. The current analysis included 5,181 patients with esophageal adenocarcinoma or squamous cell carcinoma who received neoadjuvant CRT followed 15 to 90 days later by definitive surgery during the period from 2004 to 2014 (Abstract 2).

The average age of the individuals was 62 years, 84% were male, and 94% were white. Overall, 81% had adenocarcinoma, and 73% and 35% had disease staged as cT3 and cN0, respectively, before surgery.

The key endpoints of interest included pCR rates, postoperative mortality, and long-term survival based on the time interval between CRT and surgery. The time intervals were divided into quintiles (Q1, 15 to 37 days; Q2, 38 to 45 days; Q3, 46 to 53 days; Q4, 54 to 64 days; and Q5, 65 to 90 days), and each quintile comprised roughly 1,000 individuals.

The investigators found that pCR rates increased significantly across quintiles as the interval between neoadjuvant CRT and surgery increased (17.9%, 20.7%, 23.9%, 24.7%, 29.1% for Q1 through Q5, respectively; p < 0.001); however, so too did 90-day mortality rates (5.8%, 6.3%, 6.8%, 8.6%, 8.4% for Q1 through Q5, respectively; p = 0.04). This translated into an 11% increase in the pCR rate and a 5% increase in the 90-day mortality rate for each additional week between CRT and surgery. Median overall survival (OS) also decreased significantly across quintiles (36.4, 35.1, 33.9, 33.2, 30.7 months for Q1 through Q5, respectively; p = 0.008) as the interval between neoadjuvant CRT and surgery increased.

Closer inspection of the data revealed that patients without pCR attained superior OS when they underwent surgery within 15 to 64 days after neoadjuvant therapy versus waiting until 65 to 90 days (log-rank p < 0.0001). In contrast, for patients with pCR, the time to surgery after CRT—whether 15 to 64 days or 65 to 90 days thereafter—exerted no influence on survival outcomes (log-rank p = 0.9).

Histologic subtype also mattered. There was no difference in OS outcomes according to the time between CRT and surgery in patients with squamous cell carcinoma (p = 0.8), whereas patients with adenocarcinoma had poorer OS if surgery was delayed until 65 to 90 days after CRT versus occurring earlier (p = 0.001).

Notably, waiting 65 to 90 days between CRT and surgery correlated with worse OS even after patients who died within 90 days after surgery were excluded in order to rule out a confounding effect from short-term deaths. The longer interval was also associated with worse OS when the analysis was restricted to patients with no comorbidities.

Multivariate regression analysis confirmed that attaining pCR was independently associated with a reduced risk of mortality (HR 0.57, 95% CI [0.51, 0.64]; p = 0.001), whereas an interval of 65 to 90 days between CRT and surgery correlated with an increased risk (HR 1.16, 95% CI [1.02, 1.31]; p = 0.027). The analysis also identified an increased risk of mortality with each 1-week increase in the time between CRT and surgery when the interval was assessed as a continuous variable (HR 1.02, 95% CI [1.002, 1.04]; p = 0.029).

Dosimetric Analysis of the Heart and Lung

Patrick Oh, BSc, of Memorial Sloan Kettering Cancer Center, and colleagues studied a different facet of CRT delivery in localized esophageal cancer—the impact of the radiation dose on survival.

Mr. Patrick Oh presents Abstract 3 during Oral Abstract Session A.

Recent data suggest that the radiation dose delivered to the heart is an independent predictor of survival after CRT in patients with locally advanced lung cancer. To determine whether this also applies to esophageal cancer, and whether the lung radiation dose matters as well, the investigators examined a variety of cardiac and pulmonary dose-volume metrics to sift out potential predictors of OS after CRT. These metrics were created with data from 453 consecutive patients with stage I to III esophageal or gastroesophageal junction cancer who received definitive or preoperative CRT at Memorial Sloan Kettering from 2007 to 2015 (Abstract 3).

The average age of the individuals was 64 years; 80% were male, 81% had adenocarcinoma, 67% had stage III disease, and 83% had no preexisting cardiac disease. Nearly all of the patients (98%) received intensity-modulated radiation therapy versus 3D conformal radiation therapy, and all patients received concurrent chemotherapy. The median radiation dose delivered was 50.4 Gy. After CRT, 53% of patients underwent surgery.

Multivariate regression analysis revealed that age (HR 1.01; p = 0.034), surgery (HR 0.60; p < 0.001), and stage III disease at baseline (HR 1.98; p < 0.001) independently predicted for survival outcomes, as expected. In addition, the lung radiation dose, but not the cardiac radiation dose, portended survival outcomes. More specifically, the volume of the lung exposed to 20 Gy of radiation (V20Gy) emerged as an independent predictor of overall survival (HR 1.03; p = 0.039).

Patients were dichotomized according to the median lung V20Gy value, which was 19%, to better understand survival outcomes. Individuals in whom less than 19% of the lung was exposed to 20 Gy of radiation survived significantly longer than individuals with lung volume exposure of 19% or greater (p = 0.01).

“We speculate that the higher lung dose may be contributing to an increased risk for fatal cardiopulmonary and postsurgical events,” Mr. Oh said. As such, the investigators are undertaking additional analyses to explore disease control and causes of death.

Although additional dosimetric analysis and validation of the current findings are needed, ideally in the prospective setting, the data suggest a role for improving CRT outcomes by limiting the amount of radiation exposure to the lungs, according to Mr. Oh. “There are several potential avenues to achieve this,” he said. These might include use of more conformal radiation techniques, such as proton therapy, or a reduced target volume though use of smaller margins and minimized elective nodal radiation.

Possible Unintended Consequences of CRT

Discussant Theodore S. Hong, MD, of Massachusetts General Hospital, tried to make sense of the findings from these two studies. “I would argue that this is a very confusing time,” he said. He acknowledged that toxicity from neoadjuvant CRT often manifests as mortality in esophageal cancer. “But I don’t think that this explains the entire conundrum of why we see an obscuration of the OS benefit in the setting of highly effective therapy. Are patients perhaps dying of increased disease progression?”

“What if radiation has unintended systemic consequences?” Dr. Hong asked. “We have traditionally thought of radiation as only having a locoregional effect. […] But I think there’s greater realization now that radiation can both positively and negatively impact the immune system.”

Results of the ONO-4538-12 trial of nivolumab suggest that esophageal cancer is indeed susceptible to immune surveillance. Data also show that development of grade 4 lymphopenia after CRT for esophageal cancer is associated with poorer OS and disease-free survival outcomes, which suggests that host immunity plays a role in disease control. If circulating immune cells are severely depleted after exposure to radiation, Dr. Hong said, much of the T-cell receptor diversity that proves so effective in metastatic surveillance could be wiped out, leaving behind a limited, oligoclonal T-cell repertoire after lymphocyte recovery. These mechanisms could potentially impact the ongoing CheckMate-577 trial of adjuvant nivolumab in resected esophageal cancer.

“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 said.


–Kara Nyberg, PhD