Neoadjuvant Chemoradiation as Standard in Esophageal Cancer?

Alexander M. Castellino, PhD

August 17, 2015

Long-term results confirm the benefit of neoadjuvant chemoradiotherapy (CRT) for esophageal cancer, and study authors conclude that this treatment should become a standard. But might chemotherapy alone be as good, wonder other experts, noting that a trial comparing CRT with chemotherapy in this setting is underway.

Data from the large randomized CROSS study comparing neoadjuvant CRT plus surgery with surgery alone were reported in 2012. Subsequently, in 2014, data on the clinical benefits of CRT plus surgery were reported.

Now, after a long-term follow-up of 84.1 months, the CROSS investigators have confirmed that for patients with resectable esophageal or esophagogastric junction cancers, the median overall survival benefit of CRT plus surgery is more than double that of surgery alone.

Table. CROSS Study Results at 84-Month Follow-up

Clinical End Point CRT + Surgery (n = 178) Surgery (n = 188) P Value
Overall survival      
   Median, months 48.6 24.0 .003
   Median for squamous cell carcinoma, months 81.6 21.1 .008
   Median for adenocarcinoma, months 43.2 27.1 .038
Progression-free survival      
   Median, months 37.7 16.2 .0002
   Median for squamous cell carcinoma, months 74.7 11.6 .006
   Median for adenocarcinoma, months 29.9 17.7 .010


The CRT regimen used in the trial was carboplatin (area under the curve, 2 mg/mL per minute) plus paclitaxel 50 mg/m², with a concurrent radiation dose of 41 to 44 Gy.

"Neoadjuvant chemoradiotherapy according to CROSS followed by surgical resection should be viewed as a standard of care for patients with resectable locally advanced esophageal or junctional cancer," conclude the CROSS investigators, led by Joel Shapiro, MD, from the Department of Surgery at the Erasmus MC – University Medical Center in Rotterdam, the Netherlands.

The results were published online August 5 in Lancet Oncology.

"The CROSS trial provides robust evidence in support of neoadjuvant chemoradiotherapy treatment strategy, especially for locally advanced squamous cell carcinoma," write Christophe Mariette, MD, from the Department of Digestive and Oncological Surgery at Claude Huriez University Hospital in Lille, France, and colleagues in an accompanying comment.

The latest results "suggest that the CROSS regimen is one of the standard treatment regimens for locally advanced resectable esophageal and junctional cancers," Dr Mariette's team notes. However, they are not ready to endorse neoadjuvant CRT as the gold standard. "Several issues need to be resolved before we can make this conclusion," they explain.

"Alternative treatments might retain their place in the therapeutic algorithm, and before the CROSS regimen can be deemed the gold standard neoadjuvant therapy for this tumor group, further steps to validate these results are needed," they add.

In particular, they suggest that chemotherapy alone, without concurrent radiotherapy, could be another option. The "survival benefit of neoadjuvant chemotherapy for esophagogastric adenocarcinomas has been well demonstrated," they report, citing several studies.

In the FNCLCC and FFCD multicenter phase 3 study, perioperative chemotherapy with 5-fluorouracil and cisplatin provided significantly better overall survival in patients with resectable adenocarcinoma of the lower esophagus, gastroesophageal junction, or stomach (J Clin Oncol. 2011;29:1715-1721). Difficulty in patient recruitment was responsible for the trial being stopped.

Similarly, in the MAGIC study, perioperative chemotherapy with epirubicin, cisplatin, and fluorouracil was associated with significant improvement in overall and progression-free survival (N Engl J Med. 2006;355:11-20). However, a significant limitation cited by the study investigators was that only 42% of patients in the chemotherapy plus surgery group completed all the protocol treatment.

The CROSS investigators raised other concerns about the MAGIC study. "Only a few included patients had distal esophageal cancers (14%) or junctional cancers (12%), which raises questions about their applicability of these results for esophageal or junctional cancers," Dr Shapiro and colleagues write.

"Furthermore, the MAGIC trial, which was published in 2006 after a minimum follow-up of less than 2 years, has not yet reported its long-term results, which makes it unclear whether or not the initially reported survival benefit of perioperative chemotherapy is sustained at longer-term follow-up," they add.

Both the CROSS investigators and Dr Mariette's team indicate that an ongoing study is directly comparing CRT with chemotherapy, and will provide definitive evidence on optimum preoperative treatment (NCT01726452).

Reproducibility in Other Patients?

Dr Mariette and his colleagues question whether results from the CROSS trial are reproducible in patients with poorer performance status (84% of participants had status 0 and 16% had status 1) or in patients with cancers of the middle or upper third esophagus (82% of trial participants had lower third or junctional tumors).

The CROSS investigators agree. "Results from this trial might not be readily extrapolated to patients with poorer performance status, older patients, or those with tumors located in the proximal or middle esophagus, because of the relative scarcity of patients in these categories," Dr Shapiro and colleagues write.

"The value of this treatment regimen will need to be confirmed for these patients in future follow-up studies," they add.

Dr Mariette's team notes that confounding factors might contribute to the favorable toxicity profile of the CROSS regimen — the predominance of adenocarcinomas associated with better patient outcomes and the high proportion of lower third or junctional tumors, which "benefited from both a lower dose of radiation (41 Gy) and greater sparing of lung volumes from the radiation field."

"This point is critical with regard to development of radiation-induced pneumonitis and subsequent postoperative mortality," they write.

The CROSS investigators indicate that personalized treatment strategies should be considered in the management of patients, including watchful waiting protocols after neoadjuvant therapy, with surgery offered to patients when locoregional disease is detected.

They add that "newer, more effective combinations of systemic agents need to undergo further study, such as the addition of targeted therapy to existing chemoradiotherapeutic treatment regimens."

In addition, "one must also remember that not all patients benefit from neoadjuvant chemoradiotherapy, which shows that no single approach to neoadjuvant therapy should be accepted as the sole standard," Dr Mariette's team explains.

"The treatment armory must retain flexibility," and take into account the myriad "patient and tumor characteristics that exist," they conclude.

The CROSS study was funded by the Dutch Cancer Foundation. Dr Shapiro's team and Dr Mariette's team have disclosed no relevant financial relationships.

Lancet Oncol. Published online August 5, 2015. Abstract, Comment


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