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918
Rapidly Alternating Chemotherapy and Radiotherapy
Instead of Cystectomy for the Treatment of MuscleInvasive Carcinoma of the Urinary Bladder
Long Term Results of a Pilot Study
Bhadrasain Vikram, M.D.1
Manjeet Chadha, M.D.1
Stephen C. Malamud, M.D.2
Hubert Hecht, M.D.3
Harry Grabstald, M.D.3
BACKGROUND. The authors studied rapidly alternating chemotherapy and radiotherapy as the initial treatment for patients with muscle-invasive transitional cell
carcinomas of the urinary bladder whose advanced age and lack of strength precluded cystectomy.
METHODS. Twenty-one patients with T2 (28%) or T3 (72%) NXM0 carcinomas were
1
Department of Radiation Oncology, Albert Einstein College of Medicine/Beth Israel Medical
Center, New York, New York.
2
Department of Medicine, Albert Einstein College of Medicine/Beth Israel Medical Center,
New York, New York.
3
Department of Urology, Albert Einstein College
of Medicine/Beth Israel Medical Center, New
York, New York.
treated by transurethral resection followed by chemoradiotherapy. Their median
age was 73 years. The chemotherapy (consisting of methotrexate, vinblastine, doxorubicin, and cisplatin) was given during Weeks 1, 4 and 7. Radiotherapy (1.8–2
Gray [Gy] twice a day, to a total dose of 18–20 Gy per week) was given during
Weeks 2, 5 and 8, for a final dose of 40 Gy to the pelvis plus 14–20 Gy boost to
the affected bladder.
RESULTS. There was 1 treatment-related death (5% of patients), but otherwise the
acute toxicity was relatively mild. Cystoscopy 1 month after chemoradiotherapy
did not reveal invasive cancer in any patient. Subsequent cystoscopies detected
recurrent invasive cancer in 3 patients after 30, 44, and 82 months, respectively.
The observed survival rate after 5 years was 37%, the cause specific survival rate
was 63%, the metastasis free rate was 71%, and the local control rate was 80%.
Eighty-four percent of patients had normal bladder function.
CONCLUSIONS. Transurethral resection plus chemoradiotherapy was successful in
preserving bladder function in the majority of the patients. The survival and progression free rates compared favorably with what has been reported recently after
radical cystectomy and chemotherapy, and they add to the growing body of evidence that chemoradiotherapy might be a safe, effective alternative to cystectomy
for many patients with muscle-invasive carcinoma of the urinary bladder. Cancer
1998;82:918–22. q 1998 American Cancer Society.
KEYWORDS: bladder carcinoma, organ preservation, combined modality therapy,
chemoradiotherapy.
I
Address for reprints: Bhadrasain Vikram, M.D.,
Department of Radiation Oncology, Albert Einstein College of Medicine, Montefiore Medical
Center, 111 East 210 Street, Bronx, NY 10467.
Received May 23, 1997; revision received September 18, 1997; accepted September 18, 1997.
n the past, standard treatments for muscle-infiltrating bladder carcinomas included cystectomy or radiotherapy. The former can result
in poor quality of life, whereas the latter has a high failure rate.1 – 3 In
recent years, transitional cell carcinoma of the urinary bladder has
been shown to be responsive to chemotherapy.4,5 In an effort to improve the results of radiotherapy and decrease the need for cystectomy, some investigators have administered chemotherapy prior to
radiotherapy, with encouraging results.6,7 We reasoned, on the basis of
laboratory and clinical studies,8,9 that concomitant, rapidly alternating
administration of chemotherapy and radiotherapy might be more
q 1998 American Cancer Society
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W: Cancer
Chemoradiotherapy for Bladder Carcinoma/Vikram et al.
effective, and our early results (published when the
median follow-up was 2 years) were encouraging.10
We now present our updated results, with a median
follow-up of 4 years. Such combined, alternating therapy has also been found to yield encouraging tumor
control in cancers of the head and neck11,12 and the
esophagus.13
PATIENTS AND METHODS
We treated 21 patients with muscle-invasive transitional cell carcinoma of the urinary bladder by concomitant, rapidly alternating chemoradiotherapy,
rather than cystectomy, between June 1987 and January 1992. Most of these patients were referred by urologists who felt that the patients’ advanced ages and lack
of strength precluded such major surgery. The study
was approved by the Human Investigations Committee at Beth Israel Medical Center, New York, New York,
and informed consent was obtained from each subject. There were 18 men and 3 women, with ages ranging from 58 to 92 years (median, 73 years). Their pretreatment evaluation consisted of history and physical
examination, chest radiograph, complete blood count,
and biochemistry. All the patients underwent cystoscopy, evaluation under anesthesia, and as complete a
transurethral resection as feasible, although complete
resection was not explicitly required. The prognostic
importance of a palpable mass, the size of the lesion(s), and complete transurethral resection has been
suggested by publications in recent years,3,7 but such
was not the case at the outset of our study, and this
information was not consistently or uniformly recorded. However, histologic verification of muscle-invasive carcinoma was mandatory. The primary tumor
was classified as T2 in 6 (28%), T3a in 10 (48%), and
T3b in 5 (24%) of the patients (according to criteria
in the Manual for Staging of Cancer, Third Edition,
American Joint Committee on Cancer, 1987). No patient had hydronephrosis. One patient also underwent
pelvic lymph node dissection, which revealed metastases in the lymph nodes. The exclusion criteria included
the presence of distant metastases; an absolute granulocyte count of less than 3500/mm3; a platelet count of
less than 100,000/mm3; serum creatinine, blood urea
nitrogen, alanine aminotransferase, or aspartate aminotransferase elevated more than 50% above the upper limit of normal; or the inability to give informed
consent.
The treatment scheme called for the administration of chemotherapy during Weeks 1, 4, and 7, with
radiotherapy given during Weeks 2, 5, and 8 (Table 1).
The total treatment consisted of 3 cycles of chemotherapy plus 54 – 60 Gray (Gy) radiotherapy over an 8week period. Posttreatment evaluation was by cystos-
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919
copy, with biopsy of the original disease site performed 1 month posttreatment. Cystoscopy was repeated every 3 – 4 months thereafter, but further biopsies were not obtained unless suspicious lesions were
observed. The only investigations routinely obtained
during follow-up visits included hematologic and biochemical profiles and an annual chest X-ray. Other
investigations, such as computed tomography (CT)
scans, magnetic resonance imaging (MRI) scans, or
bone scans, were only obtained if symptoms suspicious for metastases appeared. The follow-up of the
surviving patients ranged from 2 to 7 years (median,
4 years).
RESULTS
Acute Toxicity
One patient (5%) died during treatment due to nadir
sepsis. Another patient (5%) developed Grade 3 hematologic toxicity after the first cycle and chose to discontinue chemotherapy. There were no other serious toxicities, although Grade 1 – 2 hematologic and gastrointestinal toxicity was experienced by virtually all
patients. One other patient declined any further treatment after only one cycle. Details of acute toxicity have
been published previously.10
Tumor Response and Survival
Cystoscopy 1 month after treatment revealed no residual invasive carcinoma in the bladder of any patient,
although in 2 patients it revealed residual carcinoma
in situ, and both were rendered disease free by transurethral resection. Subsequent cystoscopies detected
recurrence of invasive carcinoma in the bladder in 3
patients, after 30, 44, and 82 months, respectively, for
a local control rate of 80% at 5 years (Fig. 1). Three
other patients developed recurrent carcinoma in situ
in the bladder after 27, 33, and 42 months, respectively, and all have been managed cystoscopically; 2
of them also received intravesical bacillus Calmette –
Guérin. Four patients developed distant metastases
11 – 44 months after treatment. The actuarial incidence
of development of distant metastases was 29% (Fig.
1). The observed survival rate, including death from
any cause, was 37% after 5 years, whereas the cause
specific survival rate, including only deaths related to
the cancer, was 63% (Fig. 2).
Chronic Toxicity and Bladder Function
Two patients (10%) had chronic frequency and 1 (5%)
incontinence that necessitated the use of pads. One
patient (5%), the only one who had undergone bilateral pelvic lymphadenectomy, developed chronic scrotal edema. The remaining patients suffered no chronic
side effects. The actuarial incidence of normal bladder
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920
CANCER March 1, 1998 / Volume 82 / Number 5
TABLE 1
Schema of Alternating Chemoradiotherapya
Chemotherapy (modified MVAC regimen)
Day of
treatment
1
2
Agent and dose
Methotrexate 30 mg/m2
Vinblastine 6 mg/m2
Doxorubicin 25 mg/m2
Cisplatin 80 mg/m2
Ratiotherapy
Days of
treatment
8–12
Dose
10 MV photons used with custom blocks
4-field technique
1.8–2.0 Gy per fraction
2 fractions per day, 6 hrs apart
10 fractions (total 18–20 Gy) per course
Total dose: 40 Gy to whole pelvis, plus boost dose of 14–20 Gy.
a
Chemotherapy was delivered during Weeks 1, 4, and 7, and radiotherapy during Weeks 2, 5, and 8.
FIGURE 1. The proportions of the patients who, after chemoradiotherapy, remained free of invasive cancer in the pelvis or free of distant
metastases are shown.
function among the patients with local control was
84% at 5 years.
DISCUSSION
One of the principal obstacles to the simultaneous
use of chemotherapy and radiotherapy is the fear of
excessive toxicity. It was suggested by Looney,8 based
on his laboratory studies, that delivering these two
modalities in a rapidly alternating fashion might improve tumor control without prohibitive toxicity. A pilot study of an accelerated, interrupted, twice-a-day
radiotherapy regimen by Vikram9 revealed markedly
decreased acute mucosal toxicity without prolonging
the overall time compared with conventional, oncea-day irradiation. The current study was undertaken
because this radiotherapy regimen appeared almost
ideally suited for alternating with chemotherapy, and
our results did reveal a high response rate as well as
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FIGURE 2. The observed survival rate (including deaths due to any
cause) and the cause specific survival rate (including only deaths related
to bladder carcinoma or its treatment) are shown, after treatment with
transurethral resection and rapidly alternating chemoradiotherapy for muscle-invading bladder carcinoma (Kaplan–Meier method). The numbers in
parentheses indicate the numbers of patients alive.
gratifying local control and bladder preservation rates,
without prohibitive toxicity, in these elderly patients
with muscle-invasive bladder carcinoma.
Our patients were probably understaged because
they were staged clinically, in contrast to patients
treated by cystectomy, who are pathologically staged;
but their survival rate (Fig. 2) and the patterns of failure (Fig. 1) do compare favorably to those reported in
recent years after cystectomy plus chemotherapy.14 – 16
For instance, Freiha et al. at Stanford University School
of Medicine recently reported results for 25 patients
with muscle-invasive bladder carcinoma treated with
radical cystectomy plus chemotherapy that included
cisplatin, vinblastine, and methotrexate.16 Their patients were considerably younger than ours (median
W: Cancer
Chemoradiotherapy for Bladder Carcinoma/Vikram et al.
age, 59 years vs. 73 years), but the 5-year survival rates
were similar (40% vs. 37%, respectively). Forty-five
percent of the patients in the Stanford series were progression free at 5 years, versus 65% in ours; and in
both series, most of the cancer deaths were due to
distant metastases rather than local failure. Our local
failure rate of 20% (Fig. 1) is considerably lower than
the reported results with external beam radiotherapy
alone in muscle-invasive bladder carcinomas, wherein
approximately one-half to two-thirds of the patients
relapsed with invasive cancer in the pelvis.3 Recently
published results of a Canadian prospective, randomized trial also showed that, in patients with invasive
bladder carcinomas, radiotherapy plus concurrent cisplatin resulted in significantly fewer pelvic recurrences
than did radiotherapy without chemotherapy.22
It is likely that many patients with locally advanced bladder carcinoma harbor occult distant metastases at the time of diagnosis, and present-day chemotherapy is unable to eradicate these consistently.
Newer chemotherapeutic, immunotherapeutic, or
gene therapy approaches will be necessary to decrease
the rate of failure due to distant metastases. The cause
specific survival rate of our patients was 63% at 5 years,
whereas the overall survival rate was 37%. This was
not surprising, given that many of our patients were
elderly or had been deemed unsuitable for radical surgery due to comorbid conditions, and no definitive
conclusions can be reached about survival as compared with initial cystectomy without conducting a
prospective, randomized trial involving comparable
groups of patients. The principal goal of our study was
to preserve good bladder function without compromising survival, and it appears that bladder function
was indeed well preserved, although the number of
truly long term survivors was small due to adverse
selection factors, such as advanced age. Our results,
however, are quite consistent with those in other recent studies in which modern radiation techniques
were employed,17,23 the results of which suggested that
excellent bladder function was not only possible but
very likely in patients with local control after chemoradiotherapy.
It has been suggested recently that cystoscopic
reevaluation, after one-half to two-thirds of the
planned total dose of irradiation has been delivered
together with chemotherapy, might help identify those
patients who have achieved early complete response
and who might be quite successfully treated without
cystectomy, versus those whose response is unsatisfactory and who therefore might benefit from early
cystectomy.3,17 We did not perform cystoscopic reevaluations before the end of planned chemoradiotherapy,
and we cannot offer direct evidence in support of or
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921
against this strategy in the treatment of bladder carcinoma. It is noteworthy, however, that in our analogous
study of alternating chemotherapy and radiotherapy
for cancers of the hypopharynx, where such an intermediate evaluation of the response was performed,
complete response after 40 Gy was indeed found by
us to be a powerful predictor of long term tumor control and survival.12 Also worth evaluating in future
studies might be the role of novel predictive assays,24
that help identify which patients might be cured with
radiotherapy alone, which patients require chemoradiotherapy, and which patients might benefit from
cystectomy at the outset.
In conclusion, the results of this pilot study suggest that alternating chemoradiotherapy, after as complete a transurethral resection as possible, could control locally advanced bladder carcinoma with good
bladder function in many patients. Our study adds to
the growing body of evidence17 – 24 that initial treatment
by chemoradiotherapy rather than by cystectomy
might be a safe, effective alternative for many patients
with muscle-invasive bladder carcinoma. Which of the
many chemoradiotherapy combinations under investigation is the best remains to be determined by randomized studies.
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