Commentary

Optimal management of esophageal, gastroesophageal junction cancers remains controversial

The optimal management of esophageal and gastroesophageal junction cancers remains contentious on a number of issues, including the optimal extent of lymph node resection performed at surgery.

Recent surgical series — including some randomized trials — have indicated that a minimum number of lymph nodes needs to be taken at surgery, with potentially inferior survival with inadequate lymphadenectomy.

This dictum is questioned by the report of Lagergren and colleagues, a large single-institution series of more than 600 patients with esophageal cancer (80% with adenocarcinoma) who underwent esophagectomy between 2000 and 2012 at a high-volume hospital in the United Kingdom.

David H. Ilson

The authors report no correlation between extent of lymphadenectomy and OS, even when factoring in pathologic T or N stage. Their results question whether extending lymphadenectomy beyond even zero to 10 nodes achieves any survival impact.

Problematic conclusions

The study and its conclusions, however, are problematic on several levels.

This series does not represent patient outcome with surgery alone, in contrast to earlier series. More than 50% of patients on this study received preoperative chemotherapy.

Because up to 5% to 10% of patients actually progress on preoperative chemotherapy and never make it to surgery, the selection of patients for surgery after preoperative therapy may enrich the population for a better prognosis and weed out patients with a more aggressive biology who progress early on.

In addition, nodal downstaging with preoperative chemotherapy may occur in up to 14% of patients; pathologic nodal stage, therefore, may not reflect the initial nodal stage of such patients, again potentially improving prognosis independent of the surgical management.

Survival estimates in such patients are, at best, an extrapolation of the survival achieved with primary surgery without the addition of adjuvant therapy.

Lagergren and colleagues also misquote the Hulscher trial as not supporting greater lymph node retrieval as impacting on survival. The Hulscher trial compared transhiatal esophagectomy to en bloc transthoracic esophagectomy, and indeed did not indicate a survival benefit with the more aggressive surgical approach. However, lymph node retrieval was respectable with either surgical approach (median, 16 nodes vs. 31 nodes), so an argument about minimal nodal retrieval cannot be made from this series.

The researchers also claim that a single-institution series should be considered superior to multicenter or international studies because surgical quality assurance is likely higher when only a limited number of surgeons operate at one center. One could actually make the counterargument that a single-institution series introduces a greater potential for patient selection bias, and that such a series is less reflective of real-world experience seen across multiple surgeons, centers and countries.

Quite large pooled surgical series of patients undergoing surgery alone without adjuvant therapy — such as the series reported by Peyre and colleagues, who evaluated 2,300 patients, and Rizk and colleagues, who evaluated 4,600 patients — argue that the extent of nodal resection is critical and correlates closely with survival outcome.

The series by Rizk and colleagues indicated that ranges of optimal nodal retrieval varied by T and N stage, and that survival outcome clearly correlated with adequate lymph node retrieval. The Lagergren series, given its methodologic flaws, does not question current therapy guidelines, and I do not suspect that the surgeons who operated on patients from this series will now lessen their lymph node retrieval at surgery.

Continued controversy

Given the poor survival achieved with surgery alone, preoperative therapy with either chemotherapy or combined chemoradiotherapy has been adopted as the standard of care.

The controversy about the benefit of adding radiation to preoperative chemotherapy was further stoked by two recent preoperative chemotherapy trials reported this year from the United Kingdom. They included more than 1,900 patients with esophagogastric adenocarcinoma.

The OEO5 trial — which compared preoperative treatment with two cycles of cisplatin/5-FU vs. four cycles of epirubicin, cisplatin and capecitabine (ECX) in 900 patients with esophageal and gastroesophageal junction adenocarcinoma — failed to indicate a survival benefit for either the addition of epirubicin to two-drug chemotherapy, or for extending preoperative chemotherapy beyond two cycles.

This trial — despite preoperative staging with endoscopic ultrasound, PET scan and laparoscopy — achieved an R0 or curative resection rate of only 60% to 67% with preoperative chemotherapy.

A similar poor rate of R0 resection for preoperative chemotherapy without radiotherapy was reported in more than 1,000 patients with esophagogastric cancer on the U.K. STO3 trial. R0 resection after three cycles of preoperative chemotherapy was achieved in 55% to 59% of patients.

These poor rates of curative resection after preoperative chemotherapy, arguably no better than what is achieved with surgery alone, contrast with results reported from the Dutch CROSS trial in esophageal and gastroesophageal junction adenocarcinoma.

With the combined used of preoperative chemotherapy and radiotherapy, an R0 resection rate of 92% was achieved compared with 69% for surgery alone.

The activity and tolerance of preoperative carboplatin, paclitaxel and radiotherapy reported on the CROSS trial have compelled many investigators to argue that combined chemoradiotherapy should be the preferred care standard for adenocarcinoma of the esophagus and gastroesophageal junction.

References:

Alderson D, et al. Abstract 4002. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Cunningham D, et al. Abstract 2201. Presented at: European Cancer Congress; Sept. 25-29, 2015; Vienna.

Hulscher JB, et al. N Engl J Med. 2002;347:1662-1669.

Peyre CG, et al. Ann Surg. 2008;doi:10.1097/SLA.0b013e318188c474.

Rizk NP, et al. Ann Surg. 2010;doi:10.1097/SLA.0b013e3181b2f633.

Van Hagen P, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1112088.

For more information:

David H. Ilson, MD, PhD, is chief of the gastrointestinal cancer service at Memorial Sloan Kettering Cancer Center and a professor of medicine at Weill Cornell Medicine. He also is HemOnc Today’s gastrointestinal cancer section editor. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: ilsond@mskcc.org.

Disclosure: Ilson reports no relevant financial disclosures.

The optimal management of esophageal and gastroesophageal junction cancers remains contentious on a number of issues, including the optimal extent of lymph node resection performed at surgery.

Recent surgical series — including some randomized trials — have indicated that a minimum number of lymph nodes needs to be taken at surgery, with potentially inferior survival with inadequate lymphadenectomy.

This dictum is questioned by the report of Lagergren and colleagues, a large single-institution series of more than 600 patients with esophageal cancer (80% with adenocarcinoma) who underwent esophagectomy between 2000 and 2012 at a high-volume hospital in the United Kingdom.

David H. Ilson

The authors report no correlation between extent of lymphadenectomy and OS, even when factoring in pathologic T or N stage. Their results question whether extending lymphadenectomy beyond even zero to 10 nodes achieves any survival impact.

Problematic conclusions

The study and its conclusions, however, are problematic on several levels.

This series does not represent patient outcome with surgery alone, in contrast to earlier series. More than 50% of patients on this study received preoperative chemotherapy.

Because up to 5% to 10% of patients actually progress on preoperative chemotherapy and never make it to surgery, the selection of patients for surgery after preoperative therapy may enrich the population for a better prognosis and weed out patients with a more aggressive biology who progress early on.

In addition, nodal downstaging with preoperative chemotherapy may occur in up to 14% of patients; pathologic nodal stage, therefore, may not reflect the initial nodal stage of such patients, again potentially improving prognosis independent of the surgical management.

Survival estimates in such patients are, at best, an extrapolation of the survival achieved with primary surgery without the addition of adjuvant therapy.

Lagergren and colleagues also misquote the Hulscher trial as not supporting greater lymph node retrieval as impacting on survival. The Hulscher trial compared transhiatal esophagectomy to en bloc transthoracic esophagectomy, and indeed did not indicate a survival benefit with the more aggressive surgical approach. However, lymph node retrieval was respectable with either surgical approach (median, 16 nodes vs. 31 nodes), so an argument about minimal nodal retrieval cannot be made from this series.

The researchers also claim that a single-institution series should be considered superior to multicenter or international studies because surgical quality assurance is likely higher when only a limited number of surgeons operate at one center. One could actually make the counterargument that a single-institution series introduces a greater potential for patient selection bias, and that such a series is less reflective of real-world experience seen across multiple surgeons, centers and countries.

Quite large pooled surgical series of patients undergoing surgery alone without adjuvant therapy — such as the series reported by Peyre and colleagues, who evaluated 2,300 patients, and Rizk and colleagues, who evaluated 4,600 patients — argue that the extent of nodal resection is critical and correlates closely with survival outcome.

The series by Rizk and colleagues indicated that ranges of optimal nodal retrieval varied by T and N stage, and that survival outcome clearly correlated with adequate lymph node retrieval. The Lagergren series, given its methodologic flaws, does not question current therapy guidelines, and I do not suspect that the surgeons who operated on patients from this series will now lessen their lymph node retrieval at surgery.

Continued controversy

Given the poor survival achieved with surgery alone, preoperative therapy with either chemotherapy or combined chemoradiotherapy has been adopted as the standard of care.

The controversy about the benefit of adding radiation to preoperative chemotherapy was further stoked by two recent preoperative chemotherapy trials reported this year from the United Kingdom. They included more than 1,900 patients with esophagogastric adenocarcinoma.

The OEO5 trial — which compared preoperative treatment with two cycles of cisplatin/5-FU vs. four cycles of epirubicin, cisplatin and capecitabine (ECX) in 900 patients with esophageal and gastroesophageal junction adenocarcinoma — failed to indicate a survival benefit for either the addition of epirubicin to two-drug chemotherapy, or for extending preoperative chemotherapy beyond two cycles.

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This trial — despite preoperative staging with endoscopic ultrasound, PET scan and laparoscopy — achieved an R0 or curative resection rate of only 60% to 67% with preoperative chemotherapy.

A similar poor rate of R0 resection for preoperative chemotherapy without radiotherapy was reported in more than 1,000 patients with esophagogastric cancer on the U.K. STO3 trial. R0 resection after three cycles of preoperative chemotherapy was achieved in 55% to 59% of patients.

These poor rates of curative resection after preoperative chemotherapy, arguably no better than what is achieved with surgery alone, contrast with results reported from the Dutch CROSS trial in esophageal and gastroesophageal junction adenocarcinoma.

With the combined used of preoperative chemotherapy and radiotherapy, an R0 resection rate of 92% was achieved compared with 69% for surgery alone.

The activity and tolerance of preoperative carboplatin, paclitaxel and radiotherapy reported on the CROSS trial have compelled many investigators to argue that combined chemoradiotherapy should be the preferred care standard for adenocarcinoma of the esophagus and gastroesophageal junction.

References:

Alderson D, et al. Abstract 4002. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.

Cunningham D, et al. Abstract 2201. Presented at: European Cancer Congress; Sept. 25-29, 2015; Vienna.

Hulscher JB, et al. N Engl J Med. 2002;347:1662-1669.

Peyre CG, et al. Ann Surg. 2008;doi:10.1097/SLA.0b013e318188c474.

Rizk NP, et al. Ann Surg. 2010;doi:10.1097/SLA.0b013e3181b2f633.

Van Hagen P, et al. N Engl J Med. 2012;doi:10.1056/NEJMoa1112088.

For more information:

David H. Ilson, MD, PhD, is chief of the gastrointestinal cancer service at Memorial Sloan Kettering Cancer Center and a professor of medicine at Weill Cornell Medicine. He also is HemOnc Today’s gastrointestinal cancer section editor. He can be reached at Memorial Sloan Kettering Cancer Center, 1275 York Ave., New York, NY 10065; email: ilsond@mskcc.org.

Disclosure: Ilson reports no relevant financial disclosures.