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Nonoperative Therapy for Squamous-Cell Cancer of the Esophagus
By L. Leichman, A. Herskovic, C.G. Leichman, P.B. Lattin, Z. Steiger, E. Tapazoglou, J.C. Rosenberg,
A. Arbulu, I. Asfaw, and J. Kinzie
Based on the surgical pathology and survival for patients in previous trials using a neoadjuvant program
of chemotherapy (5-fluorouracil [5-FU}-cisplatin) and
radiation (3,000 cGy) before surgery for squamouscell cancer (SCC) of the esophagus, a nonoperative
pilot trial was designed to test if survival and recurrence would differ from our historical controls if routine esophagectomy was eliminated. Twenty patients
were treated. The protocol called for the delivery of 5FU infusion (1,000 mg/m 2/d X 4 d) days 1 to 4 and 29
to 32 with cisplatin (100 mg/m 2 ) day 1 and 29 sandwiched around external beam radiation (3,000 cGy
over 3 weeks). Mitomycin C (10 mg/m2) day 57 was
administered with bleomycin infusion (20 U/d x 4 d)
days 57 to 60 and 78 to 81. A radiation boost of 2,000
cGy was administered 200 cGy/d days 99 to 103 and
106 to 110. Clinical pulmonary toxicity forced withdrawal of bleomycin and mitomycin C in the last four
patients treated; two further courses of 5-FU-cisplatin
were administered instead. The median measurement of the 20 esophageal lesions by barium swallow
was 7 cm. Four patients underwent salvage surgery to
prevent life-threatening aspiration pneumonia. The
median survival for the 20 patients is 22 months, with
a range from 6 to 39 + months. The six patients clinically without cancer are alive 22 + to 39+ months
(median, 35 + months). Three patients died manifesting only local (infield) recurrence; five died manifesting only distant recurrence; and five developed
local and distant recurrence. While the toxicity of the
four drug regimen as administered was prohibitive,
the survival and quality of survival is superior to the
regimen previously used, which routinely used surgery after preoperative chemotherapy and radiation.
J Clin Oncol 5:365-370.© 1987 by American Society
of Clinical Oncology.
R
Esophagectomy followed approximately 3 to 4
ECENTLY,
the
Southwest
Oncology
Group (SWOG) and the Radiation Therapy
weeks after the completion of the second course
Oncology Group (RTOG) completed parallel
of chemotherapy. Morbidity and mortality from
the protocol treatment brought close scrutiny to
the individual components of the protocol. It was
reported that the only long-term survivors from
this treatment were patients who had no cancer in
the surgically resected esophagus (25%). Those
patients with any residual disease (gross or microscopic) found at the time of surgery died of
their cancer.3, 4 In the setting of this protocol
clinical trials testing a multimodality, neoadjuvant surgical approach to localized squamouscell cancer (SCC) of the esophagus.1,2 These
multicentered trials confirmed pilot data obtained at Wayne State University that suggested
that the combination of radiation and chemotherapy before surgery had a major impact on the
primary tumor in the esophagus. The survival of
the patient population treated by this protocol
seemed to be dictated by the effects of therapy
before surgery. The median survival of all patients entered on the single institution protocol
was 18 months, a marked improvement over his-
torical comparisons for similar patients.3
By definition, the neoadjuvant surgical approach assumed that surgery was the mainstay of
treatment; radiation and chemotherapy were designed to enhance the potentially curative effect
of surgery. The initial protocol at Wayne State
University called for chemotherapy with mitomycin C and 5-fluorouracil (5-FU) combined
with radiation before surgery.4 In 1979, mitomycin C was deleted and 5-FU and cisplatin were
used as chemotherapeutic agents with radiation.
treatment, the role of surgery as a curative modality had come into question.'
With this background, a trial that did not include surgery as protocol treatment was designed
for patients with localized SCC of the distal
esophagus. Radiation and chemotherapy were
From the Wayne State University School of Medicine; and
DepartmentsofMedicine, Radiation Therapy, and Surgery, The
Detroit Medical Center.
Submitted July 29, 1986; accepted October 24, 1986.
Address reprint requests to Lawrence Leichman, MD, University of Southern California, Division of Medical Oncology,
Kenneth Norris, Jr Cancer Hospital and Research Institute,
1441 Eastlake Ave, Los Angeles, CA 90033.
© 1987 by American Society of Clinical Oncology.
0732-183X/87/0503-0018$3.00/0
Journal of Clinical Oncology, Vol 5, No 3 (March), 1987: pp 365-370
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Copyright © 2016 American Society of Clinical Oncology. All rights reserved.
365
LEICHMAN ET AL
366
designed as primary, potentially curative treat-
ment modalities. Because the majority of our
previous patients with initially localized SCC of
the esophagus died from distant metastatic disease,3 two non-cross-resistant, modestly active
chemotherapeutic agents, mitomycin C and bleomycin,6 were added to the treatment program. A
follow-up course of radiation for all patients was
designed into the program to add to primary tumor control.
METHODS AND MATERIALS
Between July 1983 and January 1985, 20 patients with localized SCC of the esophagus were entered into a clinical trial in
which the planned course of treatment was chemotherapy and
external beam radiation. To be eligible for this trial, all patients
had to have biopsy-proven SCC of the mid or distal esophagus.
All patients underwent endoscopic examination of the esophagus, trachea, and bronchial tree, as well as careful endoscopy
of the mouth, nose, and throat, including direct laryngoscopy.
Patients with previous malignancy treated for potential cure
were eligible to be placed on study, but those with concomitant
malignancies were ineligible. All patients were given a physical
examination by physicians in the medical, radiation, and surgical teams involved in this trial. A bone scan and a computed
tomography (CT) scan of the abdomen and thorax, as well as
routine blood studies, including screening of renal and liver
function, were performed on all patients. Patients with positive
findings on laboratory or physical examination suggestive of
disseminated malignancy were required to have a negative biopsy of the affected lymph node or organ before qualifying for the
protocol. Patients with tumor in the mediastinum, but contiguous with the primary tumor in the esophagus, were considered
appropriate for this protocol. Only those with normal renal function as measured by BUN - 20 mg/dL and serum creatinine :s
1.4 mg/dL could be placed on study. A WBC count of 4,000/pLt
and a platelet count of 100,000/pL were required before starting
treatment.
Treatment commenced on day 1 with chemotherapy and radi-
Table 1.
Day of
Treatment
1
1-4
1-5
8-12
15-19
29
29-32
57
57-60
78-81
99-103
106-110
Schema: Nonoperative Therapy for SCC
Esophagus
Treatment
Cisplatin 100 mg/m2 IV infusion I mg/min
2
5-FU 1,000 mg/m IV infusion over 24 h
External beam radiation 200 cGy/d
XRT 200 cGy/d
XRT 200 cGy/d
Cisplatin 100 mg/m 2 IV at 1 mg/min
5-FU 100 mg/m2 IV infusion over 24 h
Mitomycin C 10 mg/m2 IV bolus
2
Bleomycin 20 mg/m IV infusion over 24 h
2
Bleomycin 20 mg/m IV infusion over 24 h
200
cGy/d
XRT
XRT 200 cGy/d
ation for both radiation and chemotherapy components (Table
1). Cisplatin at 100 mg/m2 days 1 and 29 was administered at 1
mg/min to try to ameliorate symptoms of nausea and vomiting.
5-FU at 1,000 mg/m 2/d was delivered as a continuous infusion
starting on day 1 and continuing through day 4 for a total of
4,000 mg/m 2 . The 5-FU infusion was repeated on days 29 to 32.
Radiation started on day I and continued daily for 5 days per
week for 3 weeks at 200 cGy per day with a break on days 6, 7,
13, and 14 to a total of 3,000 cGy over the 3-week period. The
radiation portal included the esophagus and adjacent mediastinum, with the superior boundary 5 cm above the upper level of
the lesion as defined by barium swallow. The inferior boundary
was 5 cm below the lower level of the lesion as seen on esophagogram. The width of the portal was 8 cm. The radiation therapy
was administered with parallel opposed anterior and posterior
fields. Both fields were treated on each day of treatment. Radiation was interrupted for leukocyte counts < 1,500/ptL and
platelet counts < 50,000/pL. 5-FU and cisplatin were not administered on day 29 unless total WBC was -3,500/pL and
platelet count was >75,000//pL. A second dose of cisplatin was
administered only if BUN and creatinine values had returned to
normal institutional values.
Treatment continued with bleomycin and mitomycin C on day
57. Patients received mitomycin C at 10 mg/m2 intravenous (IV)
bolus (day 57 only) and started on an infusion of bleomycin at 20
U/d administered as a continuous infusion (10 U over 12 hours)
for four days (57 to 60). Bleomycin alone was reinstituted at the
same dose and schedule on days 78 to 81. Radiation was completed on days 99 to 103 and 106 to 110 to the same volume with
three portals to avoid exceeding 45 Gy to the spinal cord with the
same fractionation scheme (200 cGy/d). The total dose of radiation was 5,000 cGy.
Repeat esophagoscopy or barium swallow was optional and
left to the discretion of the managing physician. Patients were
then followed at 3- to 4-week intervals to assure that body
weight and adequate hydration were maintained.
Surgical treatment included the placement of Hickman catheters or feeding jejunostomy tubes for those patients who could
not maintain an oral caloric intake of 2,000 cal/d after treatment
commenced. Surgical esophagectomy, while not part of the
treatment plan, was allowed if the patient was in danger of lifethreatening aspiration after medical and radiation treatments
were completed.
DemographicData
Fourteen men and six women with localized SCC of the
esophagus were treated in 18 months by the protocol outlined.
The median age of this patient population was 67 years (range,
48 to 87). Four patients treated were over 80 when treatment
started, and one became 80 while on treatment. There were 12
black patients and eight white patients. Except for an 82-yearold women, the other (19 of 20) patients had extensive smoking
histories. Sixteen of 20 (80%) patients presented with dysphagia. Three (15%) presented with odynophagia and one with
dysphagia and symptomatically significant iron deficiency anemia secondary to the tumor of the esophagus. The median
amount of weight lost before discovery of the esophagus tumor
for this group of patients was estimated at 15 pounds (by history). Twelve tumors involved the middle esophagus, while eight
involved the distal esophagus (middle esophagus, 20 to 37 cm;
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367
CANCER OF THE ESOPHAGUS: NONOPERATIVE THERAPY
Table 2.
Pilot Esophagus SCC
No./Age/Sex
Date on Study
Tumor Size
(cm)
1/53/M
2/54/F
3/65/M
4/75/M
5/74/M
6/54/F
7/87/F
8/54/M
9/83/M
10/76/M
11 /73/M
12/48/F
13/51/M
14/85/M
15/72/M
16/80/M
17/79/M
18/67/M
19/49/F
20/62/F
7/83
8/83
8/83
9/83
10/83
11/83
12/83
12/83
1/84
1/84
1/84
1/84
2/84
2/84
3/84
7/84
8/84
9/84
12/84
1/85
5
7
5
7
6
7
8
5
6
4
7
7
5
7
4
8
5
7
10
4
Tumor Status
NED
Local/distant
NED
NED
Distant
Local/NED*
Local
Distant
Distant
Local/distant
NED
NED
Local/distant
Distantt
Distant
Local/distant
Local/distant
Local
NED
Local
Salvage
Surgery
No
Yes
No
No
No
Yes
No
No
No
No
No
No
No
No
No
Yes
No
Yes
No
No
Survival (mo)
39+
25
38+
37+
9
35+
22
14
22
9
33+
6
18
22
8
28+
15
16
22+
11
*NED after surgery and remains NED presently.
tPatient had second primary, squuamous-cell lung cancer.
distal esophagus, 37 to 45 cm.) The median size of the tumors as
measured by barium swallow was 7 cm, with a range from 4.0 to
10 cm. No patient presented without symptoms of obstruction or
pain from the cancer of the esophagus. Table 2 summarizes
important demographic data.
RESULTS
All patients received the first two courses of 5FU and cisplatin. Except for one patient, all received the initial sequence of planned radiation.
The patient who failed to receive the radiation
had biopsy-proven liver cirrhosis with splenomegaly. Her blood counts would not allow for
continuation of radiation. Sixteen of 20 patients
received the planned course of mitomycin C and
bleomycin. The last four patients treated on protocol received two further courses of 5-FU and
cisplatin instead of mitomycin C and bleomycin,
because pulmonary toxicity from the latter two
agents was proving prohibitive from the perspective of a study ongoing for over a year. Nineteen
of 20 patients completed the planned radiation.
All those completing the first course of radiation
(3,000 cGy in 3 weeks) completed the second
course as well (2,000 cGy over 2 weeks). The
overall median survival is 22 months. Those patients clinically free of tumor have a median survival of 35 + months.
TOXICITY
Fourteen of 20 patients (70%) developed mild
to severe stomatitis attributed to either 5-FU or
bleomycin, or both agents. Diarrhea as a gastrointestinal (GI) complication of 5-FU infusion
was reported by seven patients (35%). Five patients who could swallow at least liquids developed complete dysphagia during the first course
of radiation. These patients needed hospitalization for periods of seven to 21 days for IV hydration and/or total parenteral nutrition. No patient
in this trial developed a tracheoesophageal fistula
during therapy. No patient who could swallow at
least liquids at the onset of treatment became
permanently incapable of oral nutrition after
treatment.
The most important and disabling clinical response experienced by patients participating in
this trial was that of the onset of shortness of
breath five to 40 days following the administration of the first course of bleomycin. Six of 16
(38%) developed clinical difficulty with respirations that required a course of corticosteroids.
Five of the six patients had improvement of their
symptoms either during or after corticosteroid
administration. In one patient, symptoms of dyspnea with the slightest exertion continued until
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LEICHMAN ET AL
368
she died of disseminated cancer. Eight of 16 patients (50%) developed radiographic changes of
pneumonitis, which was attributed to bleomycin
toxicity. No patient was hospitalized because of
symptoms of shortness of breath secondary to
presumed bleomycin pulmonary toxicity.
In an effort to ameliorate nausea and vomiting,
a combination of Reglan (A.H. Robins, Richmond, VA) and Decadron (Merck Sharp &
Dohme, West Point, PA) was administered during and immediately after the cisplatin therapy.
Furthermore, cisplatin was administered as an
infusion at 1 mg/min in an effort to further decrease severe nausea and vomiting, and perhaps,
decrease transient renal failure. Nevertheless,
ten of 20 (50%) patients had moderate to severe
nausea and vomiting. Six of 20 (30%) patients
developed transient elevation of renal function as
seen by elevation of creatinine and BUN from
four days to 14 days following treatment. While
no patient developed irreversible elevation of
BUN/creatinine, eight of 20 (40%) manifested
mild azotemia on admission to the hospital to
receive bleomycin. All these patients responded
to fluid administration (3 L of 5% dextrose and
0.45 normal saline [NS]) with normalization of
BUN/creatinine, so that the mitomycin C and
bleomycin could be administered. While this
pre-renal azotemia could be attributed to poor
oral intake, it was seen in the presence of weight
gain for some patients and probably represented
chronic renal tubular damage caused by cisplatin.
Bone marrow toxicity was relatively mild for
this group. Median nadir WBC was 3,200//LL
with a nadir range from 300 to 7,100/lpL. The
median platelet nadir was 137,000, with a nadir
range from 8,000 to 347,000//pL. The median
nadir hemoglobin value was 10.4 g, with a nadir
range from 7.0 to 14.0 g. Eight patients (40%)
received packed red blood cell (RBC) transfusions during the course of therapy. One patient
required random donor platelet transfusion. This
was a 48-year-old woman with biopsy-proven
cirrhosis of the liver from alcohol. While she
started chemotherapy with cisplatin and 5-FU
concomitantly with radiation, the WBC and
platelet count decreased to 1,200/gL and
42,000/IpL within the first seven days of therapy.
She had an excellent clinical response, although
radiation was discontinued after 1,000 cGy had
been administered. A second course of 5-FU-
cisplatin was administered. Six months after her
shortened treatment, she died from an upper GI
hemorrhage (esophageal varices). A postmortem
examination revealed no cancer.
SURGERY
The aim of this clinical trial was to assess the
treatment of a cohort of patients with potentially
curable cancer of the esophagus without surgical
esophagectomy. Nevertheless, four patients
(20%) were operated on with the intent to accomplish an esophagectomy after all treatment was
administered. In each situation, intractable dysphagia and chronic aspiration led to the decision
to operate. An esophagectomy was accomplished for three of the four patients, while one
patient underwent a bypass of the esophagus because the tumor was unresectable. No patient
who had surgery died from a complication of
surgery, and all four left the hospital able to take
feedings by mouth.
SURVIVAL AND RECURRENCE
The first patient entered this trial in July 1983;
the last patient was entered on treatment in January 1985. Seven patients (35%) remain alive, six
(30%) free of disease (NED) 22+ to 39+
months after starting treatment (median 35 +
months). Two surviving patients underwent surgery; one remains free of disease. The median
survival for the 20 patients entered on study is 22
months. Table 1 shows the survival of all patients
and their recurrence pattern. Sixteen patients
(80%) entered on the trial survived at least 1 year
from study entry.
Nine patients (45%) exhibited localized tumor
in the esophagus or mediastinum after treatment.
However, at the time of death, three suffered
from uncontrolled local disease without distant
recurrence. To date, ten patients (50%) have developed distant metastases. Five patients (25%)
had both local and distant metastatic cancer; and
five expired with only distant metastatic cancer.
Obviously, the four patients who underwent surgery failed the medical treatment. One of these
patients remains alive and free of disease. One
remains alive, but has both local and distant metastases.
DISCUSSION
This trial was a logical extension of previous
clinical trials at Wayne State University and the
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CANCER OF THE ESOPHAGUS: NONOPERATIVE THERAPY
Detroit Medical Center for patients with localized SCC of the esophagus.3 ,4 In these trials,
approximately 25% of patients treated had no
cancer in the resected esophagus. Confirmation
of the initial data has now been obtained by the
SWOG and the RTOG.1, 2 Given our previous
experience, the routine surgical resection of the
primary tumor after cisplatin, 5-FU, and radiation was becoming untenable. This is not a new
concept, as others have approached this disease
with radiation only8 or radiation and chemotherapy9 with survival results that have matched the
best surgical results in western medicine.
Our perspective on routine surgical intervention in this disease is further tempered by the fact
that none of the patients who were operated on
for potential cure in our first 5-FU-cisplatin series remains alive.3 All have died of tumor recur-
rence. Of the seven patients in that series who did
not have cancer in the resected esophagus, distant tumor recurrence developed for all 30 to 60
months following resection. Three of these seven
developed recurrence in the mediastinum and residual esophagus, as well as distant cancer. Our
first efforts may have changed the course of the
disease for some patients, but did not lead to a
cure for any of those patients. It is important
to emphasize that treatment beyond the initial chemotherapy (two courses) and radiation
(3,000 cGy) was halted for patients found to
have no evidence of malignancy in the resected
esophagus.
In the present trial, we continued chemotherapy with different and, theoretically, non-crossresistant medications. However, this proved too
toxic, and we continued the cisplatin and 5-FU
for two further cycles. The original rationale for
this change was the necessity to alter toxicity.
Recently, however, data from Carey et al have
demonstrated that 5-FU and cisplatin without radiation caused regression of primary tumor for
over 50% of patients and complete eradication of
all tumor for one patient.7 This was an important
step in understanding the eradication of tumor for
20% to 25% of our patients in the cooperative
group settings using only 3,000 cGy external
beam radiation and 5-FU-cisplatin.1,2 Our final
change in methodology from the neoadjuvant
surgical trials was to give all patients the extra
2,000 cGy of external beam radiation to boost
treatment in the area of known tumor. This increase was designed to give maximum local
369
treatment more comparable to doses in studies
using radiation as a single curative modality.
The clinical presentation of this group of patients was similar to our previous pilot series in
which chemotherapy and radiation were a prologue to surgery.3 In that report, we used survival
as our endpoint, and we have done so again in
this trial. In comparing that group of patients
with our present group, we find that the median
amount of weight lost before treatment and tumor size as measured on barium swallow are
almost identical. We intentionally avoided attempts to preoperatively stage our patients as we
have not found good pathologic correlation between size of our patients' tumors and long-term
survival after undergoing protocol treatment.
While this may be idiosyncratic of our institution, we believe it reflects that the clinical staging of SCC of the esophagus remains difficult
and, all too often, inaccurate.
The median survival of our current group of
patients (22 months) surpasses our neoadjuvant
operative series (18 months). The survival of 15
patients (75%) for at least 1 year from entry into
the study further improves on our surgical study,
when only 12 of 21 patients (57%) survived 1
year. The median survival of those patients clinically free of disease (35 + months) surpasses that
of patients in our neoadjuvant surgical series who
were found pathologically free of disease at the
time of surgery. On the basis of these data, we
believe the subtraction of surgery, a particularly
difficult treatment modality, did not hurt the survival of this group of patients. As a randomized
"surgical v nonsurgical" treatment schema is unlikely, the preliminary results of this trial and
others have served as the basis for the present
two cooperative group trials testing radiation
alone v radiation and chemotherapy (RTOG
8501 and SWOG 8598).
Surgical resection was possible after failure of
chemotherapy and radiation in patients who
could not be medically managed because of the
complications of aspiration. All four patients
survived surgery, but only one remains free of
disease. Thus, as a salvage possibility, surgery
should not be abandoned, as it clearly improved
the quality of life for a selected group.
Whether the changes in the current treatment
will be sufficient to effect a cure for our current
group without clinical evidence of cancer is presently unknown. The prolonged time to tumor
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LEICHMAN ET AL
370
recurrence in our previous population no longer
permits the optimism about cure that we displayed when patients' survival exceeded 30
months from completion of treatment. However,
we are confident that initial control of this cancer
can be obtained without surgery for the majority
of patients presenting with this difficult disease.
The challenge ahead is the definition of new radi-
ation techniques or sources to control local disease and new systemic techniques to control a
disease that disseminates much earlier and manifests itself much later than we previously appreciated. However, we are optimistic that this interesting tumor may well respond to our designs
far better than we believed a decade ago.
ACKNOWLEDGMENT
The authors gratefully acknowledge the secretarial and editorial help given to us by Barbara Foulke.
REFERENCES
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2. Poplin E, Leichman L, Seydel HG, et al: SWOG 8037
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4. Franklin R, Steiger Z, Vaishampayan G, et al: Combined
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Evaluation of the chemotherapy component. J Clin Oncol 4:
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