Trends in Treatment of T1N0 Esophageal Cancer

Tara R. Semenkovich, MD, MPHS; Jessica L. Hudson, MD, MPHS; Melanie Subramanian, MD; Daniel K. Mullady, MD; Bryan F. Meyers, MD, MPH; Varun Puri, MD, MSCI; Benjamin D. Kozower, MD, MPHY

Disclosures

Annals of Surgery. 2019;270(3):434-443. 

In This Article

Discussion

Previous research by Taylor et al[7] has shown increasing use of endoscopic therapy for high-grade dysplasia and early-stage esophageal cancer. In this study, we evaluated nationwide trends in treatment of clinical T1N0 esophageal cancer over a decade, focused on differences by tumor stage. We demonstrated rapidly increasing utilization of endoscopic therapy, with trends of the treatment options and corresponding outcomes differing by subgroup. In the overall T1N0 cohort, endoscopic treatment was used in 33.6% of cancers by 2014 and replaced chemoradiation and esophagectomy. Over time, the percentage of endoscopic local tumor excision versus destruction dramatically increased to 94.0%. This represents an important improvement in the quality of endoscopic care provided, as local excision allows for both accurate pathologic tumor staging and therapeutic management.[1] Esophagectomy, which has historically been the standard of care for early stage resectable esophageal cancer,[6] was associated with better long-term survival on Kaplan-Meier analysis and Cox proportional hazards modeling. This benefit was seen despite a greater upfront risk of mortality, which in this series remained stable at approximately 3.2% and was consistent with previous reports.[8] Although we adjusted for comorbid conditions and other important clinical variables, the observed long-term survival benefit in our study may be because of overall healthier patients being treated with esophagectomy, or may be because of the impact of 13.5% occult nodal disease and improved long-term locoregional cancer control particularly for the T1bN0 patients with deeper invasion. This finding reveals the importance of appropriate risk assessment for operative patients. It also underscores the value of understanding the inaccuracies of esophageal cancer staging—a study by Bartel et al found that up to 11% of patients after pathologic examination were not treated with the optimal modality based on clinical endoscopic ultrasound staging,[9] and demonstrates the significance of our subgroup analysis.

In T1a patients, endoscopic treatment was increasingly used as an alternative to esophagectomy and was utilized in 50.6% of cases by 2014. This represents an appropriate transition to a less morbid but similarly effective form of curative resection for patients with small, low-risk tumors. A previous propensity-matched study of T1a cancers by Marino et al showed that survival was similar after esophagectomy or endoscopic resection, but the endoscopically treated patients experienced less short-term mortality, shorter hospital stays, and fewer readmissions. The esophagectomy patients had greater longevity, but this benefit was tempered by the upfront risk.[10] Another population-based study by Wani et al demonstrated that esophageal cancer-related mortality was similar between patients receiving endoscopic resection and esophagectomy at 2 and 5 years. However, patients receiving endoscopic resection had higher mortality from alternate causes, suggesting the modality is used preferentially in sicker patients.[11] Our study confirms this finding of favorable outcomes with endoscopic resection, but demonstrates stable rates of chemoradiation and no treatment for T1a patients with markedly worse survival. Although some of these patients may not be candidates for endoscopic resection procedures because of comorbidities, functional status, tumor size, or patient preference, a subset may benefit substantially from improved access to endoscopic therapies, which we demonstrate is currently more likely at academic centers. It is also worth noting that although endoscopic ultrasound examination is the most commonly used clinical staging modality, it can be inaccurate, and may affect treatment choice or outcomes. These inaccuracies appear both in the assessed depth of invasion as well as lymph node assessment. Even within the clinical T1a patients, there were 20.2% of patients with deeper invasion seen after esophagectomy and 8.7% of patients that had occult lymph node metastases that were missed on endoscopic ultrasound examination. If these patients are understaged with endoscopic ultrasound and treated with endoscopic mucosal resection, post-procedure surveillance is important to detect recurrent locoregional disease that may be treatable with esophagectomy. Within this dataset, the frequency of recurrent resectable disease is unknown; however, this represents an important area where additional research is needed to inform evidence-based surveillance recommendations.

In T1b disease, endoscopic treatment was used as an alternative to chemoradiation and no treatment, and accounted for 25.1% of cases by 2014. The use of esophagectomy remained stable at approximately 50%, suggesting that patients who were found to have this level of invasion were appropriately referred for surgery if they were deemed acceptable operative candidates. Our study demonstrated a trend toward improved survival with esophagectomy, possibly because of a higher risk of occult positive lymph nodes in T1b disease and improved locoregional control or appropriate adjuvant therapy administration in the surgery group. Previous research has shown the risk of occult lymph nodes can be as high as 7% in T1a tumors and 20% in T1b tumors.[12,13] In the setting of low perioperative mortality and better longevity, referral for esophagectomy in low and moderate risk patients is likely to yield the best outcomes. Additionally, we demonstrated significantly improved survival with endoscopic resection compared to both chemoradiation and no treatment in T1b disease. This suggests patients who are not operative candidates may benefit from the local control provided by endoscopic resection, even without a pathologic examination of lymph nodes. As techniques improve and endoscopic submucosal dissection becomes more widely prevalent, endoscopic treatment may become even more efficacious for these patients. For high-risk operative candidates, a nuanced, patient-focused discussion of risks and benefits of esophagectomy versus endoscopic resection with intensive surveillance may be warranted. Resection with either modality is associated with better survival than chemoradiation alone. With increasing use of endoscopic treatment for T1b disease, there is also a role for investigating the benefit of adjunctive therapies in patients with possible occult regional disease.

Another important finding of this analysis is that there are a substantial number of patients receiving no treatment, and this percentage remained stable at 20% throughout the years of the study. This is despite the apparent increasing availability and utilization of endoscopic resection, which can be quite effective for early-stage esophageal cancer and is comparatively low-risk in patients with substantial comorbidities. In the majority of patients who received no treatment, none was recommended by their providers. Of the patients for whom treatment was recommended, patient refusal was documented as the reason in only roughly half of cases. Certainly, in patients with competing risks to life, no treatment may be appropriate. However, the untreated group encompassed a large number of individuals with a Charlson Deyo Score of 0, and it is unknown why these patients were not deemed candidates for therapy. Perhaps there was a barrier to access of surgery, or there was not adequate consideration of endoscopic resection as a less morbid option. Understanding why a number of potentially curable esophageal cancers go untreated is an important area for further study, and whether improved provider education or wider availability of endoscopic therapy could reduce these numbers merits further investigation.

This study has a few limitations that should be acknowledged. First, because the NCDB is a retrospective database, there is likely treatment selection bias present. Although we can adjust for several important variables when examining treatment outcomes including baseline patient demographics as well as tumor size, grade, and histology, additional relevant information that could affect treatment choice is missing. For example, patient comorbidities are summarized in the Charlson Deyo Score, but detailed data on specific comorbidities and overall functional status are unavailable. Additionally, granular data regarding staging modalities are not available within the NCDB. The available clinical stage is based on what is recorded by a physician or registrar from documents within a patient's record, and does not specify the technique utilized. We therefore cannot assess what percentage of patients was staged with endoscopic ultrasound alone, or had endoscopic resection before esophagectomy. Endoscopic resection is clearly captured when it is the definitive surgical procedure, but not when used diagnostically. Third, endoscopic therapy is provided much more frequently at academic or tertiary centers, and practical availability of skilled endoscopic providers to an individual patient through referrals and travel is unknown. Finally, the recommended treatment for T1N0 cancers differs by depth of invasion—T1a and T1b tumors are different populations with regards to criterion standard treatment options, risks, and benefits. Because AJCC 7 was adopted in 2010, there is a smaller sample size available for this important subgroup analysis.

These limitations are balanced by several major strengths. The NCDB is a large database that captures patients across demographics and practice settings, and tracks the majority of esophageal cancer diagnoses nationally. The broad patient population and years of data captured allow for a useful analysis of trends in national practice patterns. The data and results are generalizable to the real-world care being provided in the United States. In this study, this is especially important because we found that there are a substantial number of patients receiving no treatment. Given the variety of treatment options available for T1N0 disease, this a notable area to improve appropriate provision of care and patient outcomes for potentially curable esophageal cancers.

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