In 1995, 12,100 new cases of esophageal cancer were diagnosed
in the United States, and the vast majority, 10,900 patients,
will die of the disease. Esophageal cancer represents 2% of
American cancer deaths and 9% of deaths due to gastrointestinal
cancer. In Western countries, there is a clear association
between the development of squamous cell carcinoma of the esophagus
and the abuse of tobacco and alcohol. Although esophageal squamous
cell cancer remains relatively uncommon in the United States,
it is a leading worldwide cause of cancer, with a particularly
high incidence observed in northern China, the Caspian Littoral,
and the Transkei province of South Africa.
Adenocarcinoma of the esophagus, which in the past represented
only a small proportion of cases of esophageal cancer, is rapidly
overtaking squamous cell carcinoma as the predominant disease
histology in the United States and currently represents half of
newly diagnosed cases. Indeed, esophageal adenocarcinoma poses
a potentially daunting health care problem, with cases increasing
at an annual rate exceeding that of any other malignancy, including
malignant melanoma. Although Barrett's esophagus is one established
premalignant precursor of esophageal adenocarcinoma, the factors
responsible for the rapid rise in the incidence of adenocarcinoma
have yet to be determined. Recent epidemiologic studies have implicated
obesity and tobacco abuse as potential risk factors for
the development of adenocarcinoma of the esophagus. The epidemiologic
factors responsible for the geographic variability in the incidence
of esophageal squamous cell cancer, including potential dietary
and environmental carcinogens, also remain indeterminate.
The prognosis for patients with esophageal cancer treated with
the standard approaches of surgery or radiation therapy is poor.
The poor prognosis for patients with locally advanced esophageal
carcinoma is compounded by poor patient tolerance of therapy,
given the comorbid cardiac, hepatic, and pulmonary diseases that
accompany long-standing alcohol and tobacco abuse. The largest
retrospective series of patients treated with either surgery alone
or radiotherapy alone, reviewed by Earlam and Cunha-Melo, reported
equally poor 5-year survival rates of 4% for surgery alone and
6% for radiotherapy alone.[6,7] In this early surgical review,
the operative mortality for patients treated surgically was a
sobering 29%. This significant operative mortality has fueled
an ongoing debate regarding the relative efficacy of surgery and
radiation therapy for treating local disease, although more recent
surgical series from single institutions have reported an operative
mortality of 5% to 15% for esophagectomy, with Muller et al citing
an overall rate of 12.5% in a review of the surgical literature.
Optimal Surgical Approach
The optimal surgical approach in the local management of esophageal
cancer has been vigorously debated. Of all esophageal surgical
procedures, a laparotomy is performed first, to mobilize the stomach
or colon to reconstitute the upper gastrointestinal tract. One
standard approach, the Ivor Lewis esophagectomy, employs a separate
right thoracotomy for resection of the esophageal tumor, dissection
of regional lymph nodes, and intrathoracic gastroesophageal reanastomosis.
The use of thoracotomy in surgery for esophageal cancer has been
advocated because it allows direct visualization of the mediastinal
contents. Another approach, transhiatal esophagectomy, avoids
thoracotomy and employs an abdominal approach to resect the esophageal
tumor and to dissect mediastinal lymph nodes; it achieves gastroesophageal
reanastomosis via a cervical incision. Proponents of transhiatal
esophagectomy argue that this approach reduces operative morbidity
and mortality. Surgical series, however, have indicated comparable
operative morbidity and mortality whether or not a thoracotomy
is performed, and critics of the transhiatal approach argue that
an adequate mediastinal dissection cannot be performed without
a thoracotomy, particularly for proximal or mid-thoracic esophageal
At the other end of the spectrum, even more radical surgical approaches
have been advocated, involving either en bloc resection of the
mediastinal contents or a three-field lymph node dissection
involving resection of the cervical and abdominal lymph nodes
in addition to the traditional mediastinal lymph node dissection.
Although proponents of more radical surgical approaches contend
that greater local control may lead to an improvement in survival,
this is achieved at the potential cost of higher surgical morbidity
and mortality. The optimal surgical management of a locally
advanced esophageal lesion remains to be established. However,
regardless of the approach taken, ultimately, the majority of
patients treated with surgery are destined to die of recurrent
Causes of Treatment Failure
The failure of standard surgical or radiation-based therapy, even
in patients with disease clinically limited to the locoregional
area prior to treatment, is due to both locoregional failure and
early systemic dissemination of disease. Autopsy series verify
the frequent systemic nature of squamous cell carcinoma, even
at or shortly after the initial presentation. Despite the
brief duration of illness for these patients, the majority were
found to have evidence of distant metastatic disease, often in
association with locally recurrent or persistent disease, at autopsy.
Adenocarcinoma of the distal esophagus or gastroesophageal junction
appears to have a natural history of disease similar to that of
squamous cell esophageal carcinoma, with equally poor survival
after surgical therapy due to a combination of local and systemic
disease recurrence. The clear need to address the early systemic
spread of esophageal carcinoma with systemic treatment has led
to the incorporation of chemotherapy into combined-modality therapy
employing surgery and radiation therapy.
Clinical trials of systemic chemotherapy administered preoperatively
for esophageal cancer, also termed neoadjuvant or primary chemotherapy,
have been undertaken largely because of the poor results achieved
with conventional surgery or radiation therapy and the frequent
systemic pattern of disease recurrence. Such combined-modality
trials employing chemotherapy have taken one of three different
approaches: chemotherapy followed by a planned surgical procedure,
chemotherapy given concurrently with radiation therapy followed
by surgery, and chemotherapy and radiation therapy without subsequent
The rationale, both preclinical and clinical, for neoadjuvant
chemotherapy has been reviewed. For patients with esophageal
cancer, the approach of preoperative chemotherapy offers several
potential clinical benefits, including enhancing resectability
by downstaging the primary tumor. Another potential advantage
is the assessment of the response to preoperative chemotherapy
directly in the primary tumor, making the end point of adjuvant
therapy more precise by identifying patients who respond to chemotherapy
and who might therefore benefit from further chemotherapy postoperatively.
Administering chemotherapy early in the course of disease also
has the advantage of treating subclinical but established micrometastatic
disease, when chemotherapy is likely to have its greatest impact,
given the limited effectiveness of systemic therapy for clinically
apparent metastatic disease. A disadvantage of preoperative chemotherapy
is the delay in achieving local control of disease.
The rationale for concomitant chemotherapy and radiation has also
been reviewed. Concurrent chemoradiotherapy potentially allows
for the achievement of enhanced local tumor control, as well as
the simultaneous treatment of systemic micrometastases.
Although a neoadjuvant, combined-modality approach to esophageal
cancer should be reserved for patients at high risk of death due
to disease recurrence, most US patients present with high-risk
transmural (T3) or lymph node-positive (N1) disease and are therefore
candidates for neoadjuvant therapy. Use of the recently available
technique of endoscopic ultrasonography may provide greater ability
to stage locoregional disease in the esophagus, particularly the
degree of local tumor extension by T-stage and the detection of
regional node involvement. Evaluation by endoscopic ultrasonography
is increasingly being used in clinical trials for staging and
evaluating response, but assessing response by endoscopic ultrasonography
should still be considered investigational.
Preoperative Chemotherapy Followed by Surgery
The use of preoperative chemotherapy for locally advanced esophageal
carcinoma has been the subject of numerous clinical trials. Most
studies have been single-arm, phase II trials evaluating preoperative
chemotherapy in one to up to six cycles followed by a definitive
surgical procedure. In early trials, patients with T3 or node-positive
disease went on to undergo postoperative radiotherapy. However,
in more recent trials, radiotherapy has not been added preoperatively
or postoperatively, because randomized clinical trials have failed
to show a survival benefit resulting from the addition of radiotherapy
to surgery (discussed below). Also, in these more recent trials,
chemotherapy has been performed both preoperatively and postoperatively.
The results of selected phase II trials of preoperative chemotherapy
for esophageal cancer are summarized in Table 1.
Phase II Trials--Virtually all preoperative chemotherapy
trials for esophageal cancer have employed cisplatin (Platinol)-based
combination chemotherapy. Although earlier trials treated squamous
cell carcinoma, with the increased incidence of adenocarcinoma,
both histologies have been treated on preoperative protocols.
Early trials combined bleomycin (Blenoxane) with cisplatin and
other agents, but the pulmonary toxicity associated with bleomycin
and the marginal antitumor activity observed with the combination
of bleomycin and cisplatin in preoperative therapy prompted trials
of other cisplatin-based combinations. In these trials, major
antitumor responses were seen in up to 50% to 60% of patients,
with pathologic complete responses in up to 11% of patients. Most
patients were operable after preoperative chemotherapy, with an
operative mortality ranging from 0% to 24%. Median survival ranged
from only 8 to 28 months.
Kelsen et al reported long-term follow-up of a single trial
of 34 patients with squamous cell carcinoma treated preoperatively
with the combination of cisplatin, vindesine, and bleomycin. In
this study, survival was encouraging, with 18% of patients alive
and free of disease at 5 years and no recurrences occurring after
3.5 years, representing a doubling of survival compared with historic
The combination of cisplatin and 5-fluorouracil (5-FU), given
by continuous infusion for 4 to 5 days, has also been extensively
studied in preoperative chemotherapy trials. Major responses have
been observed in 40% to 60% of patients, with pathologic complete
responses in up to 11% of patients; the majority of patients had
resectable disease after preoperative treatment, with an acceptable
operative mortality. Subsequent trials for both esophageal squamous
cell cancer and adenocarcinoma combining cisplatin with etoposide
(VePesid) and 5-FU, leucovorin and 5-FU, or doxorubicin and etoposide
have noted similar response proportions, rates of resectability,
operative mortality, and survival comparable to those of 5-FU
and cisplatin alone.[19-21] Toxicity in these trials, mainly mucositis,
myelosuppression, and nephrotoxicity, has been substantial but
Overall, preoperative treatment with cisplatin-based combination
chemotherapy achieves a major response in 50% of patients, with
occasional pathologic complete responses. The use of preoperative
chemotherapy appears to be safe, with no demonstrable adverse
effect on surgical outcome. However, the overall survival of patients
treated with preoperative chemotherapy has been disappointing,
with a median survival ranging from 10 to 28 months in larger
series, although a trend toward improved survival has been suggested
in these trials.
The duration of chemotherapy delivered in preoperative chemotherapy
trials has also undergone evolution. Although earlier trials administered
only one to two cycles of chemotherapy preoperatively without
subsequent postoperative therapy, more recent trials have given
up to three or more cycles of preoperative therapy and two or
three cycles of postoperative chemotherapy. The treatment outcome
of earlier and more recent trials may not be directly comparable,
particularly with regard to the impact of additional cycles of
systemic therapy on systemic recurrence.
Phase III Trials--The role of preoperative chemotherapy
in the treatment of locoregional esophageal carcinoma can be clearly
defined only in the context of random-assignment trials with a
surgery-only control arm. Four small, randomized trials comparing
surgery alone with preoperative chemotherapy followed by surgery
have been published, and a fifth trial compared preoperative chemotherapy
with preoperative radiotherapy (Table 1). Roth et al randomized
patients to receive preoperative chemotherapy with cisplatin,
bleomycin, and vindesine vs surgery alone. Reporting in abstract
form only, Schlag randomly assigned patients to undergo surgery
alone or to re- ceive three cycles of preoperative chemotherapy
with 5-FU and cisplatin. Nygaard et al randomized patients
to receive surgery alone, preoperative chemotherapy with cisplatin
and bleomycin, preoperative radiotherapy, or preoperative treatment
with sequential chemotherapy and radiotherapy. LePrise et al compared
surgery alone with sequential preoperative chemotherapy as well
as cisplatin and 5-FU and radiotherapy to a dose of 6,000 cGy,
given in two split courses. None of these small, randomized
trials demonstrated a survival advantage for preoperative chemotherapy.
In the study by Roth et al, the subgroup of patients who responded
to chemotherapy showed a trend toward improved survival, compared
with surgical controls, that nearly reached statistical significance.
A prognostic factor analysis identified percentage of weight loss
prior to diagnosis and objective response to chemotherapy as predictive
of long-term survival. No survival benefit was conveyed by preoperative
chemotherapy in the study by Nygaard et al and the patients
with the poorest survival at 3 years (3%) received preoperative
Kelsen et al randomly assigned 96 patients to receive treatment
with either preoperative high-dose radiotherapy, 5,500 cGy delivered
over 5.5 to 6.0 weeks by a multifield technique, or preoperative
chemotherapy with cisplatin, vindesine, and bleomycin. In this
trial, a survival comparison between the two treatment groups
could not be made because the trial design permitted a postoperative
crossover to the other treatment modality, and most patients received
both chemotherapy and radiation therapy. The actuarial survival
rate observed for all patients was 20% at 5 years, which was superior
to that of historic controls, with the subgroup of responders
to either chemotherapy or radiotherapy showing a trend toward
At present, for patients treated surgically, surgery alone remains
the standard of care, and the use of preoperative chemotherapy
outside an investigational setting cannot be recommended. A conclusive
evaluation of preoperative chemotherapy using the best currently
available combination chemotherapy regimen awaits the completion
of ongoing, random-assignment clinical trials. A national intergroup
trial (Intergroup Trial 113) randomizing patients to receive three
preoperative and two postoperative chemotherapy cycles with cisplatin
and 5-FU vs surgery alone has now been completed, and data analysis
of this trial is under way.
1. Wingo PA, Tong T, Bolden S: Cancer statistics, 1995. CA Cancer
J Clin 45:8-10, 1995.
2. International Agency for Research on Cancer: Alcohol drinking,
IARC Monograph: An evaluation of carcinogenic risks to humans.
Int Agency Res Cancer 44:1988.
3. Blot WJ, Devesa SS, Kneller RW, et al: Rising incidence of
adenocarcinoma of the esophagus and gastric cardia. JAMA 265:1287-1289,
4. Brown MB, Swanson CA, Gridley G, et al: Adenocarcinoma of the
esophagus: Role of obesity and diet. J Natl Cancer Inst 87:104-109,
5. Chow WH, Finkle WD, McLauglin J, et al: The relation of gastroesophageal
reflux disease and its treatment to adenocarcinomas of the esophagus
and gastric cardia. JAMA 274:474-477, 1995.
6. Earlam R, Cunha-Melo JR: Oesophageal squamous cell carcinoma:
I. A critical review of surgery. Br J Surg 67:381-390, 1980.
7. Earlam R, Cunha-Melo JR: Oesophageal squamous cell carcinoma:
II. A critical view of radiotherapy. Br J Surg 67:457-461, 1980.
8. Muller JM, Erasmi H, Stelzner M, et al: Surgical therapy of
oesophageal carcinoma. Br J Surg 77:845-857, 1990.
9. Putnam JB, Suell DA, Natarajan G: A comparison of three techniques
of esophagectomy for carcinoma of the esophagus from one institution
with a residency training program. Ann Thorac Surg 57:319-325,
10. Skinner DB: En bloc resection for neoplasms of the eosphagus
and cardia. J Cardiovasc Thorac Surg 85:59-71, 1983.
11. Tadashi N, Otsuo T, Tsutomu S, et al: Patterns of lymphatic
spread in thoracic esophageal cancer. Cancer 74:4-11, 1994.
12. Roth JA, Putnam JB: Surgery for cancer of the esophagus. Semin
Oncol 21:453-461, 1994.
13. Mandard AM, Chasle J, Marnay J, et al: Autopsy findings in
111 cases of esophageal cancer. Cancer 48:329-335, 1981.
14. Nanus DM, Kelsen DP, Niedzwiecki D, et al: Flow cytometry
as a predictive indicator in patients with operable gastric cancer.
J Clin Oncol 7:1105-1112, 1989.
15. Harris DT, Mastrangelo MJ: Theory and application of early
systemic therapy. Semin Oncol 18:493-503, 1991.
16. Vokes EE, Weichselbaum RR: Concomitant chemoradiotherapy:
Rationale and clinical experience in patients with solid tumors.
J Clin Oncol 8:911-934, 1990.
17. Botet JF, Lightdale C, Zauber AG: Preoperative staging of
esophageal cancer: Comparison of endoscopic US and dynamic CT.
Radiology 181:419-425, 1991.
18. Kelsen DP, Minsky B, Smith M, et al: Preoperative therapy
for esophageal cancer: A randomized comparison of chemotherapy
versus radiation therapy. J Clin Oncol 8:1352-1361, 1990.
19. Bedikian AY, Deniord R, El-Akkak S: Value of preoperative
chemotherapy for esophageal carcinoma. (abstract.) Proc Am Soc
Clin Oncol 6:A375, 1987.
20. Hoffman P, Vokes E, Ferguson M, et al: Induction chemotherapy,
surgery, and concomitant chemoradiotherapy for carcinoma of the
esophagus (abstract). Proc Am Soc Clin Oncol 11:A588, 1992.
21. Ajani J, Roth JA, Ryan B, et al: High-dose chemotherapy with
GM-CSF for resectable adenocarcinoma of the esophagus (ACE)(abstract).
Proc Am Soc Clin Oncol 10:A472, 1991.
22. Roth JA, Pass HI, Flanagan MM, et al: Randomized clinical
trial of preoperative and postoperative adjuvant chemotherapy
with cisplatin, vindesine, and bleomycin for carcinoma of the
esophagus. J Thorac Cardiovasc Surg 96:242-248, 1988.
23. Schlag P: Preoperative chemotherapy in localized squamous
cell carcinoma of the esophagus: Results of a prospective randomized
trial.(abstract.) Eur J Cancer 27:S76, 1991.
24. Nygaard K, Hagen S, Hansen HS, et al: Preoperative radiotherapy
prolongs survival in operable esophageal carcinoma: A randomized,
multicenter study of preoperative radiotherapy and chemotherapy:
The Second Scandinavian Trial in Esophageal Cancer. World J Surg
25. LePrise EA, Meunier BC, Etienne Pierre L, et al: Sequential
chemotherapy and radiotherapy for patients with squamous cell
carcinoma of the esophagus. Cancer 75:430-434, 1995.
26. Gignoux M, Roussel A, Paillot B, et al: The value of preoperative
radiotherapy in esophageal cancer: Results of a study of the EORTC.
World J Surg 11:426-432, 1987.
27. Launois B, Delarue D, Campion JP, et al: Preoperative radiotherapy
for carcinoma of the esophagus. Surg Gynecol Obstet 153:690-692,
28. Wang LJ, Huang GJ: Combined preoperative irradiation and surgery
versus surgery alone for carcinoma of the midthoracic esophagus:
A prospective randomized study in 360 patients (abstract). Presented
at the Fourth World Congress of the International Society for
Diseases of the Esophagus , Rennes, France, 1989.
29. Franklin R, Steiger Z, Vaishampayan G, et al: Combined modality
therapy for esophageal squamous cell carcinoma. Cancer 51:1062-1071,
30. Leichman L, Steiger Z, Seydel HG, et al: Preoperative chemotherapy
and radiation therapy for patients with cancer of the esophagus:
A potentially curative approach. J Clin Oncol 2:75-79, 1984.
31. Leichman L, Herskovic A, Leichman CG, et al: Nonoperative
therapy for squamous-cell cancer of the esophagus. J Clin Oncol
32. Forastiere AA, Orringer MB, Perez-Tamayo C, et al: Concurrent
chemotherapy and radiation therapy followed by transhiatal esophagectomy
for local-regional cancer of the esophagus. J Clin Oncol 8:119-127,
33. Forastiere AA, Orringer MB, Perez-Tamayo C, et al: Preoperative
chemoradiation followed by transhiatal esophagectomy for carcinoma
of the esophagus: Final report. J Clin Oncol 11:1118-1123, 1993.
34. Urba SG, Orringer MB, Perez-Tamayo C, et al: Concurrent preoperative
chemotherapy and radiation therapy in localized esophageal adenocarcinoma.
Cancer 69:285-291, 1992.
35. Forastiere AA, Heitmiller R, Lee DJ, et al: A 4-week intensive
preoperative chemoradiation program for locoregional cancer of
the esophagus (Abstract). Proc Am Soc Clin Oncol 13:195, 1994.
36. Keller SM, Coia LR, Ryan L, et al: Chemoradiation followed
by esophagectomy for adenocarcinoma of the esophagus and gastroesophageal
junction: Results of a phase II study of the Eastern Cooperative
Oncology Group (abstract). Proc Am Soc Clin Oncol 14:196, 1995.
37. Bedenne L, Seitz JF, Milan C, et al: Preoperative radiotherapy
and chemotherapy in epidermoid oesophageal cancers: Results of
a phase II multicenter trial by the French Foundation for Carcinology
of the Digestive Tract. Proc Am Soc Clin Oncol 12:A587, 1993.
38. Urba SG, Orringer MB, Turrisi A, et al: A randomized trial
comparing transhiatal esophagectomy (THE) to preoperative concurrent
chemoradiation (CT/XRT) followed by esophagectomy in locoregional
esophageal carcinoma (CA) (abstract). Proc Am Soc Clin Oncol 14:199,
39. Coia LR, Engstrom PF, Paul AR, et al: Long-term results of
infusional 5-FU, mitomycin-C, and radiation as primary management
of esophageal carcinoma. Int J Radiat Oncol Biol Phys 20:29-36,
40. John MJ, Flam MS, Mowry PA, et al: Radiotherapy alone and
chemoradiation for nonmetastatic esophageal carcinoma: A critical
review of chemoradiation. Cancer 63:2397-2403, 1989.
41. Chan A, Wong A, Arthur K: Concomitant 5-fluorouracil infusion,
mitomycin-C, and radical radiation therapy in esophageal squamous
cell carcinoma. Int J Radiat Oncol Biol Phys 16:59-65, 1989.
42. Keane TJ, Harwood AR, Elhakim T, et al: Radical radiation
therapy with 5-fluorouracil infusion and mitomycin-C for oesophageal
squamous carcinoma. Radiother Oncol 4:205-210, 1985.
43. Richmond J, Seydel HG, Bae Y, et al: Comparison of three treatment
strategies for esophageal cancer within a single institution.
Int J Radiat Oncol Biol Phys 13:1617-1620, 1987.
44. Seitz JF, Giovannini M, Padaut-Cesana J, et al: Inoperable
nonmetastatic squamous cell carcinoma of the esophagus managed
by concomitant chemotherapy (5-fluorouracil and cisplatin) and
radiation therapy. Cancer 66:214-219, 1990.
45. Roussel A, Bleiberg H, Dalesio O, et al: Palliative therapy
of inoperable oesophageal carcinoma with radiotherapy and methotrexate:
Final results of a controlled clinical trial. Int J Radiat Oncol
Biol Phys 16:67-72, 1989.
46. Roussel A, Haegele P, Paillot B, et al: Results of the EORTC-GTCCG
phase III trial of irradiation vs irradiation and CDDP in inoperable
esophageal cancer (abstract). Proc Am Soc Clin Oncol 13:A583,
47. Herskovic A, Martz K, 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.
48. Al-Sarraf M, Pajak T, Herskovic A, et al: Progress report
of combined chemoradiotherapy vs radiotherapy alone in patients
with esophageal cancer. Proc Am Soc Clin Oncol 12:580, 1993.
49. Sischy B, Ryan L, Haller D, et al: Interim report of EST 1282
phase III protocol for the evaluation of combined modalities in
the treatment of patients with carcinoma of the esophagus, stage
I and II. Proc Am Soc Clin Oncol 9:105, 1990.
50. Araujo CM, Souhami L, Gil RA, et al: A randomized trial comparing
radiation therapy versus concomitant radiation therapy and chemotherapy
in carcinoma of the thoracic esophagus. Cancer 67:2258-2261, 1991.
51. Minsky BD, Neuberg D, Kelsen DP, et al: Neoadjuvant chemotherapy
plus concurrent chemotherapy and high-dose radiation for squamous
cell carcinoma of the esophagus: A preliminary analysis of the
phase II intergroup trial 0122. J Clin Oncol 14:149-155, 1996.
52. Wani MC, Taylor HL, Wall ME, et al: Plant antitumor agents:
VI. The isolation and structure of Taxol, a novel antileukemic
and antitumor agent from Taxus brevifolia. J Am Chem Soc 93:2325-2327,
53. Ajani JA, Ilson DH, Daugherty K, et al: Activity of Taxol
in patients with squamous cell carcinoma and adenocarcinoma of
the esophagus. J Natl Cancer Inst 86:1086-1091, 1994.
54. Conroy T, Etienne PL, Adenis A, et al: Vinorelbine: A promising
drug in metastatic epidermoid esophageal carcinoma (abstract).
Proc Am Soc Clin Oncol 12:A553, 1993.
55. Bleiberg H, Jacob JH, Bedenne L, et al: Randomized phase II
trial of 5-fluorouracil (5-FU) and cisplatin (DDP) vs DDP alone
in advanced esophageal cancer (abstract). Proc Am Soc Clin Oncol
56. De Besi P, Sileni VC, Salvagno L, et al: Phase II study of
cisplatin, 5-FU, and allopurinol in advanced esophageal cancer.
Cancer Treat Rep 70:909-910, 1986.
57. Gisselbrecht C, Calvo F, Mignot L, et al: Fluorouracil (F),
Adriamycin (A), and cisplatin (P) (FAP): Combination chemotherapy
of advanced esophageal carcinoma. Cancer 52:974-977, 1983.
58. Ajani JA, Ilson DH, Bhalla K, et al: Taxol, cisplatin, and
5-FU (TCF): A multi-institutional phase II study in patients with
carcinoma of the esophagus (abstract). Proc Am Soc Clin Oncol
59. Javed T, Reed C, Walle T, et al: A regimen of paclitaxel (P),
cisplatin (CP), and 5-fluorouracil (FU) followed by G-CSF is highly
active against epidermoid and adenocarcinoma of the esophagus
(abstract). Proc Am Soc Clin Oncol 14:195, 1995.
60. Knyrim K, Wagner HJ, Bethge N, et al: A controlled trial of
an expansile metal stent for palliation of esophageal obstruction
due to inoperable cancer. N Engl J Med 329:1302-1307, 1993.
61. Hollstein MC, Smits AM, Galiana C, et al: Amplification of
epidermal growth factor receptor gene but no evidence of ras mutations
in primary human esophageal cancers. Cancer Res 48:5119-5123,
62. Lu SH, Hsieh LL, Luo FC, et al: Amplification of the EGF receptor
and c-myc genes in human esophageal cancers. Int J Cancer 42:502-505,
63. Mukaida H, Toi M, Hirai T, et al: Clinical significance of
the expression of epidermal growth factor and its receptor in
esophageal cancer. Cancer 68:142-148, 1991.
64. Iihara K, Shiozaki H, Tahara H, et al: Prognostic significance
of transforming growth factor-alpha in human esophageal carcinoma
(abstract). Cancer 71:2902-2909, 1993.
65. Jankowski J, Coghill G, Hopwood D, et al: Oncogenes and onco-suppressor
gene in adenocarcinoma of the oesophagus. Gut 33:1033-1038, 1992.
66. Casson AG, Mukhopadhyay T, Clear KR, et al: p53 gene mutations
in Barrett's epithelium and esophageal cancer. Cancer Res 51:4495-4499,
67. Hollstein MC, Mewtcalf RA, Welsh JA, et al: Frequent mutation
of the p53 gene in human esophageal cancer. Proc Natl Acad Sci
USA 87:9958-9961, 1990.
68. Boynton RF, Huang Y, Blount PL, et al: Frequent loss of heterozygosity
at the retinoblastoma locus in human esophageal cancers. Cancer
Res 51:5766-5769, 1991.
69. Huang Y, Boynton RF, Blount PL, et al: Loss of heterozygosity
involves multiple tumor suppressor genes in human esophageal cancers.
Cancer Res 52:6525-6530, 1992.
70. Kitagawa Y, Ueda M, Ando N, et al: Significance of int-2/hst-1
coamplification as a prognostic factor in patients with esophageal
squamous carcinoma. Cancer Res 51:1504-1508, 1991.
71. Jiang W, Kahn SM, Tomita N, et al: Amplification and expression
of the human cyclin D gene in esophageal cancer. Cancer Res 52:2980-2983,
72. Blount PL, Galipeau PC, Sanchez CA, et al: 17p Allelic losses
in diploid cells of patients with Barrett's esophagus who develop
aneuploidy. Cancer Res 54:2292-2295, 1994.
73. Coonley CJ, Bains M, Hilaris B, et al: Cisplatin and bleomycin
in the treatment of esophageal carcinoma: A final report. Cancer
74. Kelsen DP, Hilaris B, Coonley CJ, et al: Cisplatin, vindesine,
and bleomycin chemotherapy of local-regional and advanced esophageal
carcinoma. Am J Med 75:645-652, 1983.
75. Forastiere AA, Gennis M, Orringer MB, et al: Cisplatin, vinblastine,
and mitoguazone chemotherapy for epidermoid and adenocarcinoma
of the esophagus. J Clin Oncol 5:1143-1149, 1987.
76. Kies MS, Rosen ST, Tsang TK, et al: Cisplatin and 5-fluorouracil
in the primary management of squamous esophageal cancer. Cancer
77. Ajani JA, Roth JA, Ryan B, et al: Evaluation of pre- and postoperative
chemotherapy for resectable adenocarcinoma of the esophagus or
gastroesophageal junction. J Clin Oncol 8:1231, 1990.
78. Poplin E, Fleming T, Leichman L, et al: Combined therapies
for squamous-cell carcinoma of the esophagus, a Southwest Oncology
Group study (SWOG-8037). J Clin Oncol 5:622-628, 1987.
79. Seydel HG, Leichman L, Byhardt R, et al: Preoperative radiation
and chemotherapy for localized squamous cell carcinoma of the
esophagus: A RTOG study. Int J Radiat Oncol Biol Phys 14:33-35,