The changing face of esophageal cancer: How to avoid the knife?

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oncologynew.com.au rebecca wongProfessor Rebecca K.S. Wong for oncologynews.com.au.

For patients presenting with localized esophageal cancer, conventionally the first treatment decision is often whether the patient is a surgical candidate, or not.

For patients with heightened operative risks, combination chemoradiotherapy alone (without surgery) has been the treatment of choice, having been shown to be superior to radiotherapy alone[1]. For patients without significant comorbidities, trimodality has been clearly established as part of the standard treatment option, providing a survival benefit compared with surgery alone[2]. For those who are fortunate enough to achieve a complete response following chemoradiotherapy, the question is frequently asked “Can surgery be omitted?”

Two randomized trials has been completed addressing the question: “does the inclusion of surgery improve patient outcomes following chemoradiotherapy” for patients with squamous cell carcinomas. They also share the common equivalence designs. Stahl et al[3] compared  CRT ( induction chemotherapy, CRT 40Gy in 20fr) followed by surgery, or further CRT (to a total of 65Gy). Accepting a delta of 15% as being equivalent, there were no survival difference. Local control and relapse free survival are superior in the patients receiving surgery, but this is achieved at the expense of increased morbidity. A more critical observation is perhaps the prognostic importance of response to induction therapy – the single most important prognostic factor for overall survival.  Bedenne et al[4] incorporated the importance of response in their study design, randomizing only responders to moderate doses of chemoradiotherapy.  patients were assigned to either surgery, or further chemoradiotherapy (to a total dose of >65Gy). The overall survival at 2 y were 39.6±4.5% CRT vs 33.6±4.5% CRTS; favoring CRT (no surgery), providing convincing evidence that the omission of upfront surgery for responders to CRT is unlikely to compromise survival.

oncologynews.com.au COSA ASM 2013

Professor Rebecca Wong. Source: www.radonc.utoronto.ca

What if recurrence is observed following initial CRT? What is the role of surgery?
While this is not well mapped out within the two randomized studies, Ariga et al[5] employed an interesting prospective, non-randomized design providing us with some insights. Patients with localized squamous cell carcinoma were recruited into this study. Following explanation by the attending surgeon of the pros and cons of the two treatment strategies, surgery or chemoradiotherapy reserving S as salvage, patients were asked to choose their treatment strategy. Of the 99 patients recruited, 51 choose surgery, and 48 chemoradiotherapy. Survival was 75% (CRTS) versus 51% (S); (p=0.0169). With the plan to provide salvage surgery upon local recurrence, thirteen (26%) patients were suitable and underwent salvage esophagectomy. This study would support the use of surgery as salvage following chemoradiotherapy as feasible and unlikely to compromise survival.

The case for adenocarcinomas is less sound however.
Pathological complete response following trimodality, has long been recognized as a strong prognostic factor for favorable long term survival. Arguably, this is the first step towards potential for cure in the absence of surgery and an important intermediate outcome in the absence of randomized data examing the potential impact of deferring surgery. When examining data limited to adenocarcinomas, pCR rates is generally lower and can only be expected in approximately 13-25% [2, 6, 7, 8], an event rate that needs to be significantly augmented if CRT deferring surgery is likely to be a successful strategy for the majority of patients to achieve a disease free state. Novel diagnostic strategies that has the potential of identifying, or therapeutics capable of increasing the pathological or clinical complete response rates in adenocarcinomas are needed.

Taken together, for patients with squamous cell carcinoma of the esophagus, who are responders  to chemoradiotherapy, there is now level I evidence to support chemoradiotherapy alone (avoiding surgery upfront) as an initial treatment strategy. Omission of surgery in these patients is not expected to compromise survival and limit the need for esophagectomy to approximately 30% of patients. In patients with adenocarcinomas however, the evidence is less persuasive. A lower pathological response rate expected from adenocarcinomas would suggest the omission of surgery to be is less successful as a treatment strategy. Novel diagnostic and therapeutic strategies that would improve the pathologic complete or near complete responses is needed to develop this area further.

Presented at the 40th Annual Scientific Meeting of the Clinical Oncology Society of Australia, Adelaide, 12-14 Nov 2013.

Oncologynews.com.au, part of the Oncology Network Australia, thanks Rebecca for sharing her work with us. We hope to share more of her thoughts with our readers in the new year!

References:
[1] Cooper et al Chemoradiotherapy of locally advanced Esophageal Cancer. Long-term Follow-up of a prospective randomized trial (RTOG 85-01). JAMA 281, 17, 1623, 1999.
[2] Van Hagen et al Preoperative chemoradiotherapy for esophageal or junctional cancer NEJM 366: 2074-84, 2012
[3] Stahl et al Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. JCO 23, 2310-2317, 2005
[4] Bedenne et al Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102 JCO 25: 1160-1168, 2007
[5] Ariga et al Propsective comparison of surgery alone and chemoradiotherapy with selective surgery in resectale squamous cell carcinoma of the esophagus. IJROBP 75, 2, 348-356, 2009
[6] Walsh et al A comparison of multimodal therapy and surgery for esophageal adenocarcinoma NEJM 335: 462-7, 1996
[7] Bermeister et al Is concurrent radiation therapy required in pateints receiving preoperative chemotherapy for adenocarcinoma of the oesophagus? A randomized phase II trial European J Cancer 47 , 354-360,2011
[8] Stahl et al Phase III comparison of preoperative chemotherapy compared with chemoradiotherapy in patients with locally advanced adenocarcinoma of the esopahgogastric junction JCO 27:851-856, 2009

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