Carcinoma of the Esophagus Part 2: Adjuvant Therapy

Dr. Minsky’s two-part review of primary and adjuvant treatment of esophageal cancer is current and comprehensive. In it, he details our present understanding of esophageal cancer management by reviewing the most important studies conducted over the past 2 decades. This brief commentary will attempt to highlight some of Dr. Minsky’s findings and also to provide perspective as to how they are reflected in the current management of patients with esophageal cancer.

National Practice Patterns

First, Dr. Minsky points out that the primary treatment of esophageal cancer is broadly defined as either surgical or nonsurgical. He further notes that comparisons of outcomes with the two approaches are problematic for a variety of reasons, which he elucidates.

It is also worthwhile to review the relative frequency of the general management approaches for esophageal cancer. Data from the American College of Surgeons and American Cancer Society, as well as from the Patterns of Care Study of the American College of Radiology, indicate that, nationwide, surgery is used in only 34% of patients. Specifically, 18% of patients undergo surgery alone, 7% are treated with surgery plus adjuvant chemotherapy or radiotherapy, and 9% have surgery combined with both radiotherapy and chemotherapy.[1,2]

In comparison, radiation was a component of treatment in 56% of patients. The major nonsurgical treatments included radiation plus chemotherapy (30%) or radiation alone (13%). Of patients who were treated with chemotherapy and radiation, over 80% received them concurrently. Thus, concurrent chemotherapy and radiation constitute the most frequently used treatment approach for esophageal cancer in the United States.

Staging

One major shortcoming in the evaluation and management of patients with esophageal cancer that bears emphasis is the inadequacy of the present American Joint Committee on Cancer (AJCC) staging system. This system is based primarily on the depth of wall penetration and the extent of nodal involvement, both of which are best determined by esophagectomy or endoscopic ultrasound. Since these procedures are not used in the majority of patients with esophageal cancer, most of these patients cannot be adequately staged.

Studies have shown that other measures of tumor volume, such as tumor length and degree of circumferential involvement, which can be readily obtained in nearly all patients, are important survival prognosticators in patients managed with chemoradiation alone or, in some studies, chemoradiation followed by esophagectomy. To facilitate more accurate staging in patients who are not treated with surgery initially, the staging system needs to be revised to account for these important factors.

Concurrent Chemotherapy and Radiation

The study initially reported in 1992 by Herskovic et al established concurrent chemotherapy and radiation (chemoradiation) as the standard nonsurgical approach for esophageal cancer.[3] That trial represented a significant advance in esophageal cancer treatment in that it demonstrated a 5-year survival improvement from 0% with radiation alone to 27% with chemoradiation. The local failure rate was significantly lower with chemoradiation compared with radiation but was still disappointingly high (45%) as a first site of failure.

Attempts at further improving the outcome of chemoradiation by intensification with neoadjuvant chemotherapy or with brachytherapy have generally been unsuccessful. Studies examining radiation dose intensification and incorporation of newer chemotherapeutic agents, such as paclitaxel (Taxol) are ongoing.

Surgical Approaches

Surgery alone has been a standard therapy for esophageal cancer for decades. Advances in surgery have resulted in a decrease in operative mortality of less than 10%.

Single-modality adjuvant therapies have been largely unsuccessful. A recent meta-analysis showed no survival advantage of preoperative radiation, and limited data suggest that postoperative radiation affords no survival benefit.[4]

Similarly, a recent randomized trial (INT 0133) showed no survival advantage of preoperative chemotherapy followed by surgical resection over surgery alone.[5] That trial also indicated that surgery is associated with a high rate of local failure: Only 59% of patients underwent a complete resection with negative margins, and, of that favorable group, 31% developed a local failure. Although the overall rate of local failure was not stated in the study, Dr. Minsky indicates it may be 61%, which is higher than the 45% local failure rate reported with chemoradiation.

Chemoradiation Followed by Surgical Resection

Recent studies of chemoradiation followed by surgical resection have indicated relatively high survival rates, tolerable morbidity, and an operative mortality of less than 10%. The Patterns of Care Study has demonstrated that chemoradiation followed by surgical resection is used more frequently at academic institutions than at nonacademic settings and is employed more often frequently for patients with adenocarcinoma than for those with squamous cell cancer.[2]

A recent Patterns of Care outcome study suggests that, nationwide, chemoradiation followed by esophagectomy results in survival that is similar to chemoradiation alone.[6] Two of the three randomized trials of chemoradiation followed by surgery vs surgery alone reviewed by Minsky have shown a benefit in survival, while in the third trial, only disease-free survival was improved.[7] (The latter trial used an unconventional regimen of split-course radiation and suboptimal chemotherapy.) These trials should be viewed with some caution, as they are limited by small numbers of patients and short follow-up.

This promising approach of chemoradiation followed by esophagectomy is currently being tested against esophagectomy alone in an important randomized intergroup trial (Cancer and Leukemia Group B [CALGB] 9781).

Another important question that needs to be addressed is whether the benefit of esophagectomy following chemoradiation is limited to certain subgroups of patients. There is evidence that patients who have a clinical complete response to chemoradiation (as determined by endoscopy, computed tomography [CT], and biopsy) or a pathologic complete response (as determined by microscopic examination of the esophagectomy specimen) have a higher rate of survival than do patients who do not have complete responses. Unfortunately, correlation between clinical and pathologic complete response is not strong. As Dr. Minsky points out, in one study, 41% of clinical complete responders to chemoradiation did not have a pathologic complete response.[8] Use of endoscopic ultrasound (EUS) to determine the pretreatment T stage/N stage does not help predict complete response to preoperative chemoradiation, as a recent study showed no dependence of pathologic complete response on EUS-determined T stage or N stage.[9]

A well-designed trial of chemoradiation followed by planned esophagectomy vs chemoradiation followed by “salvage” esophagectomy for patients with clinical evidence of esophageal only persistence or recurrence after chemoradiation may help optimize the use of esophagectomy following chemoradiation.

Summary

Surgery or chemoradiation alone represent the current standards of care for patients with esophageal cancer. The staging system for this cancer is not useful and needs to be revised. Radiation dose intensification, the incorporation of newer chemotherapeutic agents, such as paclitaxel, and optimization of the use of chemoradiation followed by surgical resection are areas of investigation that may improve results over current standard treatments.

Dr. Minsky’s article is both comprehensive and thought-provoking. Clinicians involved in the management of patients with esophageal cancer will benefit from his excellent review.

References:

1. Daly JM, Karnell LH, Ment HR: National cancer database report on esophageal cancer. Cancer 78:1820-1828, 1996.

2. Coia LR, Minsky BD, John MJ, et al: The evaluation of treatment of patients receiving radiation therapy for cancer of the esophagus. Cancer 85:2499-2505, 1999.

3. Herskovic A, Martz LK, Al-Sarraf M, et al: Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N Engl J Med 326:1593-1598, 1992.

4. Arnott SJ, Duncan W, Gignoux M, et al: Preoperative radiotherapy in esophageal carcinoma: A meta-analysis using individual patient data (oesophageal cancer collaborative group). Int J Radiat Oncol Biol Phys 41:579-583, 1998.

5. Kelsen DP, Ginsberg R, Pajak T, et al: Chemotherapy followed by surgery compared with surgery alone for localized esophageal cancer. N Engl J Med 339:1979-1984, 1998.

6. Coia LR, Minsky BD, John MJ, et al: Outcome of patients receiving radiation for cancer of the esophagus (abstract). Proc Am Soc Clin Oncol 17:258a, 1998.

7. Bosset JF, Gignoux M, Triboulet JP, et al: Chemoradiotherapy followed by surgery compared with surgery alone in squamous cell cancer of the esophagus. N Engl J Med 337:161-167, 1997.

8. Bates BA, Detterbeck FC, Bernard SA, et al: Concurrent radiation therapy and chemotherapy followed by esophagectomy for localized esophageal carcinoma. J Clin Oncol 14:156-163, 1996.

9. Mallery S, de Camp M, Bueno R, et al: Pretreatment staging by endoscopic ultrasound does not predict complete response to neoadjuvant chemoradiation in patients with esophageal cancer. Cancer 86:764-769, 1999.