Optimizing Advanced Technologies to Improve Outcomes in Esophageal Cancer

Sarah E. Hoffe, MD

Esophageal cancer has long been a disease associated with a grim prognosis, largely due to patients presenting with locally advanced stages. Long-term data from one of the earliest trials evaluating patients with squamous cell carcinoma showed a 5-year survival rate of 26% with chemotherapy administered concurrently with radiation versus 0% with radiation alone.¹ Over the last 30 years, the nature of esophageal cancer has changed with adenocarcinoma predominating in the gastroesophageal junction location, with estimates of more than 17,000 cases projected in the United States this year.² Studies have explored integration of chemotherapy, radiation therapy and surgery, with the suggestion that modern technologies may be changing the treatment landscape with better outcomes.

Multidisciplinary management, therefore, centers on how best to treat a patient with a locally advanced tumor. Staging advanced tumors has become more reliable than ever before, given the integration of positron emission tomography (PET) imaging and endoscopic ultrasound. Options ranging from preoperative chemotherapy followed by surgery to preoperative chemoradiation, either concurrently upfront or followed by induction chemotherapy, have been evaluated with multiple trials that have also brought into question the role of surgery itself in this disease.

After much debate over the last 30 years, one recent trial has at least provided some encouraging direction. The randomized controlled CROSS trial reported by van Hagen et al³ has shown a survival advantage with preoperative concurrent chemotherapy and radiation compared with surgery alone, with a median overall survival of 49.4 months versus 24 months. Moreover, this trial showed a complete R0 resection rate of 92% compared with 69% in the surgery-alone arm (P <.001). This trial delivered concurrent chemotherapy with weekly paclitaxel and carboplatin along with 41.4 Gy of radiotherapy, showing no increase in postoperative complications.

At the 2013 American Society of Clinical Oncology Gastrointestinal (GI) Cancers Symposium held in San Francisco, Ravi Shridhar, MD, PhD, presented data on behalf of Moffitt Cancer Center’s Esophageal Research Team that showed that patients with advanced disease who received chemoradiotherapy followed by surgical resection had improved survival compared with chemoradiotherapy alone: 42.3% versus 29%, (P <.0001), respectively.⁴ Median overall survival in those patients who underwent resection was 42.2 months compared with 20.4 months without surgery. Moreover, in the multivariate analysis, 5-year disease-free survival was associated with tumor length of 5 centimeters (P = .0112), surgery (P = 0.007), and radiation technique (P = .0023).

Ken L Meredith, MD, section chief of Esophagogastric Oncology at Moffitt Cancer Center, demonstrates the technique of robotic surgery.

Modern techniques allow the delivery of radiation therapy more accurately to the tumor with less morbidity. With the ability to demarcate the locoregional extent of tumor by endoscopic fiducial marker placement, as well as hypermetabolic volume on PET imaging, radiation oncologists are able to more accurately deliver treatment to the tumor target and limit normal tissue morbidity. By being as accurate as possible with target volume delineation and narrow margins around the moving target, radiation oncologists can integrate these modern techniques to improve outcomes.

For example, Fernandez et al⁵ have shown that by using abdominal compression, respiratoryassociated tumor motion can be decreased by 50%. Moreover, delivery with intensity-modulated radiation therapy has been reported by Lin et al⁶ in a series of 676 patients at MD Anderson Cancer Center and has shown improved overall survival, locoregional control, and non—cancer-related death.

Technological advances are now transforming the surgical landscape, as well. Robotic esophagectomy data are accumulating as more centers adopt this technique. Indeed, Ken L. Meredith, MD, section chief of Esophagogastric Oncology at Moffitt, who has been performing robotic surgeries since 2009 and has one of the highest volume practices in the United States, has reported shorter hospital stays and excellent lymph node harvest rates. His team’s updated data were presented by Moffitt fellow Franz Smith, MBBS, at the ASCO GI Cancers Symposium in a series of 89 patients who underwent robotic-assisted Ivor Lewis RAIL esophagectomy.⁷ In this series, 87% of patients received neoadjuvant therapy and 13% did not. There were no differences in outcomes, showing that RAIL esophagectomy can be safely performed in the neoadjuvant setting.

Over the next 10 years, we hope to continue to optimize these advanced modalities to further improve outcomes in esophageal cancer. Incorporation of biological information about the radiation sensitivity of a patient’s specific tumor would be useful to catapult patient selection to new heights by determining which patient is more likely to have a complete response versus partial response to radiation. Biologically guided radiation may be possible with a molecular assay developed by Javier Torres-Roca, MD, a member of the Radiation Oncology Program at Moffitt, and his colleagues, perhaps opening the door for future organ preservation strategies by optimizing patient selection with integration of personalized medicine techniques.⁸

References

1. Cooper JS, Guo MD, Herskovic A, et al. Chemoradiotherapy of locally advanced esophageal cancer: longterm follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. JAMA. 1999;281(17):1623-1627.
2. Esophagus Cancer. American Cancer Society. http://goo.gl/drpRJ. Updated January 18, 2013. Accessed February 4, 2013.
3. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366(22):2074-2084.
4. Shridhar R, Freilich J, Hoffe S, et al. Survival in patients with esophageal cancer treated with surgery after chemoradiotherapy. J Clin Oncol. 30: 2012 (suppl 34; abstr 98).
5. Fernandez DC, Hoffe SE, Barthel JS, et al. Stability of endoscopic ultrasound-guided fiducial marker placement for esophageal cancer target delineation and imageguided radiation therapy. Practical Radiation Oncology. 2013;3(1):32-39.
6. Lin SH, Wang L, Myles B, et al. Propensity score-based comparison of long-term outcomes with 3-dimensional conformal radiotherapy vs intensity-modulated radiotherapy for esophageal cancer. Int J Radiat Oncol Biol Phys. 2012;84(5):1078-1085.
7. Smith FO, Hoffe S, Almhanna K, et al. Robotic-assisted Ivor Lewis esophagectomy with or without neoadjuvant chemoradiation therapy for esophageal cancer. J Clin Oncol. 30: 2012 (suppl 34; abstr 117).
8. Eschrich SA, Pramana J, Zhang H, et al. A gene expression model of intrinsic tumor radiosensitivity: prediction of response and prognosis after chemoradiation. Int J Radiat Oncol Biol Phys. 2009;75(2):489-496.