Drs. Ilson and Kelsen present an excellent review of the current
investigations and treatment recommendations for patients with
esophageal cancer. In a comprehensive and concise fashion, they
detail controversies in surgical and nonsurgical management, neoadjuvant
therapies, and regimens for treating metastatic disease. Their
review provides an opportunity to further highlight several research
Anatomic Considerations and Natural History
When esophageal cancer is initially treated for cure with one
local treatment modality (surgery or radiotherapy), treatment
failure is due to both local and distant disease and both contribute
to mortality. This is important to keep in mind when designing
trials to improve survival. Early distant spread is explained
by the dense network of lymphatics in the mucosa and submucosa
that interconnect with lymphatic vessels in the muscular layers
of the esophagus. These lymphatic channels drain primarily longitudinally
to regional and distant nodal beds. Local recurrence is also to
be expected because circumferential "margins" of resection
are nearly always positive for microscopic tumor, whereas proximal
and distal margins of resection, provided in the surgical pathology
report, are usually negative.
Thus, it does make sense that utilizing all three modalities--radiation
therapy and surgery for local control and chemotherapy for distant
spread--would offer the best chance for cure in a patient presenting
with localized disease. Surgery is the most effective means for
debulking the primary tumor or eradicating residual disease in
the esophagus after preoperative therapy. It makes sense to add
radiotherapy to surgery to improve local control, particularly
for patients with T3 and T4 disease, in whom residual microscopic
disease in the tumor bed is likely. Chemotherapy certainly has
a role in enhancing the effects of radiation and as a systemic
therapy for occult distant spread. The critical question is how
to optimally sequence these three therapies to cure or significantly
increase survival time in the highest percentage of patients who
present with potentially curable localized disease.
Surgery Combined With Radiotherapy
Controlled trials of surgery combined with preoperative or postoperative
radiotherapy do not demonstrate an improvement in survival and
are conflicting with regard to the effects of this combination
on locoregional control. One trial of preoperative radiotherapy
showed a decrease in locoregional failure (46% vs 67%), but others
showed no effect.[1-4] Postoperative radiotherapy has a high rate
of toxicity to normal tissues because of the potentially large
Only two controlled trials of surgery combined with postoperative
radiotherapy are available.[5,6] One trial showed a reduction
in locoregional failure in a subset analysis of pathologically
staged N0 patients, and the other, which involved patients who
had all gross tumor removed and negative resection margins, showed
Surgery Combined With Chemotherapy
Because distant metastasis is a major cause of death and early
failure in patients with esophageal cancer, the addition of preoperative
(neoadjuvant) systemic therapy to surgery makes intuitive sense.
The limitation of this two-modality approach is that only 50%
of tumors are sensitive to current cisplatin (Platinol)-based
chemotherapy regimens and pathologic complete response is infrequent.
This situation is in contrast to squamous cell cancer of the head
and neck (after which these esophageal trials were modeled), in
which 80% to 90% of patients respond and 30% to 50% may achieve
a pathologic complete response. This is a major weakness in this
treatment strategy and diminishes the possibility that adjunctive
chemotherapy will have sufficient impact on locoregional failure
and distant metastasis rates to significantly improve survival
over surgery alone.
The GI Intergroup Trial, which enrolled over 400 patients and
is now undergoing analysis, will provide a definitive answer to
the question of whether the combination of preoperative chemotherapy
and surgery affords a survival benefit. In addition, this trial
was open to patients with adenocarcinoma of the esophagus, as
well as squamous cell carcinoma, so that for the first time comparisons
can be made between the two histologic types with statistical
confidence. This information and that gleaned from various subset
analyses should yield important insights for future trial design.
Until the data analysis of this critically important trial is
mature, surgery remains the standard of care for patients with
Currently, the role of postoperative adjuvant chemotherapy or
chemoradiation is undefined. There are no data to suggest that
administering postoperative adjuvant chemotherapy prolongs either
the disease-free interval or survival, particularly in patients
who have undergone a curative resection and have negative nodes.
Patients who have positive margins of resection, however, should
be considered for postoperative radiation.
Concurrent Chemotherapy and Radiotherapy Without Surgery
Survival benefit has clearly been established for concurrent chemotherapy
and radiotherapy, compared to radiotherapy alone, in patients
with squamous cell cancer, but this has not been adequately addressed
in patients with adenocarcinoma. This conclusion is supported
by the intergroup trial results published by Herskovic, Al-Sarraf,
and colleagues.[7,8] Despite improved survival (median survival,
14 months; 3-year survival rate, 30%) in patients treated with
chemoradiation, the rate of persistent or recurrent disease in
the esophagus at 1 year was unacceptably high.
Results from nonsurgical trials indicate that local failure occurs
in at least 45% to 50% of patients.[7,9,10] This is of particular
concern when treating patients with localized, potentially curable
disease. For most patients, chemoradiation (cisplatin, fluorouracil
[5-FU], or mitomycin [Mutamycin] with 50 to 60 Gy of radiation)
alone will not irradicate bulk disease in the esophagus. Thus,
oncologists should not be satisfied with this therapy as "recommended
treatment" except for patients with disease extending outside
of the esophagus into adjacent structures (T4) or those with medical
risks that preclude resection.
No doubt, there is a subset of patients with squamous cell cancer
who can be cured without surgery. Identifying these patients poses
a challenge since we know that the results of endoscopic biopsy
greatly overestimate the pathologic complete response rate when
compared to resection specimens.[11,12] Esophageal endoscopic
ultrasound is being studied for its accuracy in predicting complete
response but is unlikely to be able to accurately discriminate
tumor given the degree of acute tissue injury and subsequent fibrosis
that occur after chemotherapy and radiotherapy. The best way to
address the question is with very careful staging that includes
endoscopic ultrasound, radiologic imaging, and laparoscopy for
distal lesions before patients enter a controlled trial. It may
then be feasible to identify patient subgroups who are likely
to be cured without surgery.
Concurrent Chemotherapy and Radiotherapy Followed by Surgery
Drs. Ilson and Kelsen discuss several published trials of concurrent
chemoradiation followed by surgery that were conducted in the
1980s. Pilot trials from Wayne State University, the Southwest
Oncology Group (SWOG), and the Radiation Therapy Oncology Group
(RTOG), which entailed the administration of two courses of cisplatin,
with or without 5-FU, combined with 30 Gy of radiation, reported
pathologic complete response rates in 25% to 30% of patients and
suggested a survival advantage for pathologic complete responders.
Most patients died from distant disease without local recurrence.
This finding lends support to the importance of removing the esophagus,
which, in 50% to 70% of patients, harbors residual disease.
The preponderence of distant disease indicates a need for improved
systemic therapy. The data published from the University of Michigan,
Johns Hopkins,[14,15] and, most recently, the University of North
Carolina support this alternative interpretation of the results
of those early trials cited by Dr. Ilson and Dr. Kelsen in their
review. Using protracted low-dose infusional 5-FU and continuous-infusion
cisplatin with concurrent radiotherapy, comparable results from
two sequential pilot trials (total of 93 patients) have been published
by Forastiere and colleagues: median survivals of 29 and 31 months,
respectively; 2-year survival rates of 57% and 58%, respectively;
and long-term survival in approximately 30% of patients with residual
tumor in the resected esophagus and in 60% of pathologic complete
responders.[13-15] Bates, Tepper, and colleagues reported a median
survival of 26 months, 2-year survival rate of 53%, and survival
beyond 3 years in 25% of patients with tumor in the resected esophageal
specimen and in 61% of pathologic complete responders.
These and other recently published trials not included in Table
2 of this review support the need for further evaluation of the
three-modality approach in large randomized trials.[16-19] Local
control was observed in 75% to 90% of patients in these trials
and appears to be optimized. The challenge is to find alternative,
more effective systemic therapies to decrease distant metastases.
Controlled trials that accrue large numbers of patients are needed
so that clinically meaningful survival differences can be demonstrated
with statistical confidence. This has yet to be done. A comparison
of preoperative chemoradiation followed by surgery to surgery
alone and a comparison of a surgical to a nonsurgical multimodality
approach are two randomized trials that need to be conducted.
Until these trials have been carried out, these multimodality
approaches must be considered experimental. Patients will be afforded
the best outcome if treated at centers that have a dedicated multidisciplinary
team and a formal esophageal cancer research program.
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