Joseph Chao, MD

Due to variation in incidence, historical practice and possibly incompletely characterized biologic differences, the standard of care for neoadjuvant approaches in esophageal squamous cell carcinoma has differed between Western and Eastern geographic regions. Namely, preceding esophagectomy neoadjuvant chemoradiation has been the standard of care in Western countries, whereas neoadjuvant chemotherapy alone, without radiation, is the usual approach in Japan.

The phase 3 JCOG1109 trial attempts to reconcile the two approaches, randomly assigning patients to neoadjuvant chemotherapy (two-drug cisplatin with 5-FU) or the same chemotherapy with the addition of concurrent chemoradiation.

The trial also investigated intensification of a chemotherapy-only approach with a third arm by adding docetaxel to cisplatin and 5-FU and extending the duration of neoadjuvant therapy. Despite high pathologic complete response rates in the chemoradiation group, echoing results observed in the Western phase III CROSS trial, this approach did not translate into clear improvement in OS vs. the control arm of two-drug chemotherapy alone. Conversely, even with lower pathologic complete responses, the DCF group exhibited significantly improved survival vs. the control arm, raising questions on the appropriateness of pathologic complete response rate acting as a surrogate of long-term survival, at least in a context of cross-modality comparisons.

The results of JCOG1109 will likely change practice where neoadjuvant chemotherapy alone is the accepted standard of care.

A caveat will be proper selection of patients with good performance status, as per the eligibility requirements of the trial, in which the increased toxicity of DCF does not compromise the improved survival outcomes. Chemoradiation is unlikely to be incorporated into neoadjuvant chemotherapy; however, the trial was not powered to ascertain a survival difference between intensified neoadjuvant chemotherapy and chemoradiation. As such, neoadjuvant chemoradiation will likely remain the usual approach in Western countries, particularly with 1 year of adjuvant nivolumab having received regulatory approval based on the CheckMate 577 trial, which demonstrated patients without a complete pathologic response after trimodality therapy experienced improved DFS with this approach.

Joshua E. Meyer, MD

The JCOG1109 study compares three regimens for esophageal squamous cell carcinoma. This histology is the most common one in Japan, but adenocarcinoma predominates in the United States.

The results clearly demonstrate the improvement of DCF treatment over CF. The comparison of CF vs. CF-RT also showed numerically improved OS and PFS when intensifying therapy with radiation, but this was not statistically significant. There is a hint that there may be more deaths due to other causes among the radiated patients, although this is not definitive and needs further exploration.

How this compares with our standard therapy — carboplatin and paclitaxel plus radiation, followed by surgery — is unknown. All patients without a pathologic complete response are offered nivolumab (Opdivo, Bristol Myers Squibb) in the adjuvant setting, given the benefit shown for this therapy. Therefore, it is not clear that the DCF regimen is superior to our current standard.

Raja Flores, MD

This trial focuses on esophageal squamous cell cancer, which used to be the dominant type until the last several decades, with adenocarcinoma now the most common. It is an important trial because squamous cell carcinoma needs as much attention as adenocarcinoma, which dominates most studies.

It appears clear that DCF is superior to CF in this trial, but the CF-RT regimen seems to still be an acceptable option. The CROSS trial in adenocarcinoma of the esophagus established chemotherapy/radiation as the preferred neoadjuvant treatment. So, it would make sense to try DCF-RT as the next treatment for investigation, especially because docetaxel is known to be a radiation sensitizer.

It is an interesting trial, but I do not think it is the last step in definitive neoadjuvant treatment. I expect radiotherapy to play a key role with chemotherapy in establishing the gold standard for neoadjuvant therapy prior to surgical resection.

Reference:

Shapiro J, et al. Lancet Oncol. 2015;doi:10.1016/S1470-2045(15)00040-6.

Yi-Jen Chen, MD, PhD

Histologically, there are two types of esophageal cancer: adenocarcinoma or squamous cell carcinoma. Squamous cell carcinoma, the most common histology in Eastern Europe and Asia, tends to show earlier lymphatic spread and carries a poorer prognosis.

In Western countries, standard treatment for medically fit stage IB/II/III esophageal squamous cell carcinoma is preoperative chemoradiation followed by esophagectomy. For cases with ypT-positive and/or N-positive disease, nivolumab is added. In contrast, two cycles of neoadjuvant chemotherapy using CF followed by esophagectomy with D2-3 lymphadenectomy has been the standard of care for advanced esophageal squamous cell carcinoma in Japan.

The randomized, three-arm phase 3 JCOG1109 trial by Kato is a long-awaited study. It confirmed the effectiveness of adding docetaxel to CF for cases of esophageal squamous cell carcinoma and that three cycles of upfront chemotherapy are needed for OS benefit. This is consistent with the current belief on the topic and in line with the trend of treating GI malignancies with total neoadjuvant treatment. Cases treated with chemoradiation showed a much higher pathologic complete response rate. Since organ preservation without esophagectomy is an alternative recommendation — especially for nonsurgical candidates — to improve response rate, induction chemotherapy using DCF followed by chemoradiation up to 50.4 Gy should be considered.