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1329
A Phase II Trial of Methotrexate, Cisplatin,
5-Fluorouracil, and Leucovorin in the Treatment of
Invasive and Metastatic Urothelial Carcinoma
William K. Oh, M.D.1
Judith Manola, M.S.2
Jerome P. Richie, M.D.3
Kevin R. Loughlin, M.D.3
Philip W. Kantoff, M.D.1
1
Lank Center for Genitourinary Oncology, Department of Adult Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
2
Department of Biostatistical Sciences, Dana-Farber Cancer Institute, Boston, Massachusetts.
3
Division of Urology, Brigham and Women’s Hospital, Boston, Massachusetts.
BACKGROUND. The current treatment of advanced urothelial carcinoma generates
high response rates but is associated with poor overall survival. The current study
evaluated the efficacy and toxicity of a new combination of active drugs in the
treatment of urothelial carcinoma.
METHODS. Twenty-four patients with muscle invasive or metastatic urothelial
carcinoma were enrolled. Fifteen patients (63%) had metastatic disease whereas 9
patients had T2–T4 disease. Three patients were unevaluable for response because
of significant toxicity. Patients were treated every 28 days with methotrexate, 60
mg/m2, intravenously (i.v.) on Day 1; cisplatin, 25 mg/m2/day, by continuous i.v.
infusion on Days 2– 6; 5-flurouracil (5-FU) 800 mg/m2/day by continuous i.v.
infusion on Days 3– 6; and leucovorin, 500 mg/m2/day, by continuous i.v. infusion
on Days 2– 6. Dosage in subsequent cycles was adjusted according to toxicity.
RESULTS. The median follow-up was 81 months (range, 53–971 months). The
overall response rate (complete response 1 partial response) for all 24 patients was
63% (95% confidence interval, 41– 81%). The median survival was 65 months in the
patients with muscle invasive disease and 17 months in the patients with metastatic disease. The duration of response in patients with metastatic disease was 6
months (range, 4 –19 months). Toxicity was significant, with 82% of patients experiencing Common Toxicity Criteria Grade 3 or 4 neutropenia and 63% experiencing
Grade 3 or 4 thrombocytopenia. However, only three patients developed febrile
neutropenia and gastrointestinal and neurologic toxicity was moderate.
CONCLUSIONS. The combination of methotrexate, cisplatin, 5-fluorouracil, and
leucovorin represents an active regimen in the treatment of urothelial carcinoma
with a moderate toxicity profile. As new drugs are found to treat urothelial carcinoma, further studies will be needed to evaluate the role of traditional agents such
as 5-fluorouracil and methotrexate in new combination chemotherapeutic regimens. Cancer 1999;86:1329 –34. © 1999 American Cancer Society.
KEYWORDS: bladder carcinoma, combination chemotherapy, metastatic, muscle
invasive.
A
Address for reprints: William K. Oh, M.D., Lank
Center for Genitourinary Oncology, Department of
Adult Oncology, Dana-Farber Cancer Institute, 44
Binney Street, Boston, MA 02115.
Received November 30, 1998; revision received
April 12, 1999; accepted April 12, 1999.
© 1999 American Cancer Society
dvanced tumors of the urothelial tract continue to pose a difficult
problem for the clinician. Although combination chemotherapeutic regimens have significant activity against the disease, overall survival rates for patients with advanced urothelial carcinoma remain
poor.1
The current standard treatment of metastatic transitional cell
carcinoma is combination chemotherapy with three- or four-drug
regimens.2 Response rates to combination chemotherapy in metastatic disease are high, ranging from 40 –70%.1,3 The most commonly
used treatment, M-VAC, was developed at the Memorial Sloan-Kettering Cancer Center and is comprised of methotrexate, vinblastine,
1330
CANCER October 1, 1999 / Volume 86 / Number 7
doxorubicin, and cisplatin. In a single institution series, 30% of patients with locoregional disease and
17% of patients with metastatic disease treated with
M-VAC were alive and disease free 6 years after chemotherapy.3 However, an update of a large multicenter trial revealed that only 3.7% of patients treated
with M-VAC were alive and disease free at 6 years.4 In
randomized trials, M-VAC was demonstrated to be
superior to single agent cisplatin5 and a combination
of cisplatin, doxorubicin, and cyclophosphamide
(CISCA).6 The combination of cisplatin, methotrexate,
and vinblastine (CMV) also has shown significant activity in the treatment of transitional cell carcinoma.7,8
Although M-VAC and CMV demonstrate high initial response rates in patients with advanced urothelial carcinoma, the vast majority of patients develop
disease recurrence and die.4,9 Furthermore, the toxicity of these regimens is considerable, with frequent
need for dose reductions or early discontinuation of
therapy.3,10 For this reason, investigators have been
searching for drugs and combinations with comparable or greater activity and fewer side effects.11 The
recent reported activity of paclitaxel plus platinum
analogues12,13 and gemcitabine plus cisplatin14 has
generated hope that treatments may improve.15
Nonetheless, the primary goal of chemotherapy
for patients with advanced urothelial carcinoma
should be the eradication of tumor and ultimate cure.
To this end, the current study was designed to combine drugs with known or predicted activity in urothelial carcinoma to assess for activity and toxicity. Methotrexate16 and cisplatin5 as single agents each have
response rates of approximately 30% in the treatment
of transitional cell carcinoma. 5-fluorouracil (5-FU) as
a single agent has modest activity against urothelial
carcinoma.17 However, to our knowledge the combination of 5-FU with leucovorin potentiation has not
been evaluated in urothelial carcinoma.
Also of note is the embryologic relation between
transitional and squamous epithelium.18 In fact, transitional cell tumors often display areas of squamous
differentiation. Clinically, drugs that are active in
squamous cell carcinoma (e.g., of the head and neck)
also are active in transitional cell carcinoma. For these
reasons, a Phase II study was undertaken to evaluate
the activity and toxicity of M-PFL, a combination of
methotrexate, cisplatin, 5-FU, and leucovorin. The
combination of cisplatin, 5-FU, and leucovorin (PFL)
has been administered safely to patients with carcinoma of the head and neck with high response rates.19
Because of methotrexate’s high single agent activity in
transitional cell carcinoma, this drug was added to the
PFL regimen.
TABLE 1
Baseline Patient Characteristics
No. enrolled
Gender
Age (yrs)
Clinical stage
Sites of metastases among
patients with
metastases
Primary tumor
Histology
Performance status
Creatinine clearance
Evaluable
Unevaluable
Male
Female
Median (range)
Metastatic
Muscle invasive (T2–T4, N0M0)
21
3
15
9
61 (43–74)
15
9
Pelvic lymph nodes only
Distant lymph nodes
Lung
Bone
Liver
Bladder
Renal pelvis
Transitional cell
Squamous cell
0
1
2
Median (range)
1
10
4
3
1
23
1
23
1
14
9
1
84 (52–138)
87.5%
12.5%
63%
37%
63%
37%
7%
67%
27%
20%
7%
96%
4%
96%
4%
58%
38%
4%
MATERIALS AND METHODS
Twenty-four patients were enrolled in the study. Informed consent was obtained from all participants.
Baseline patient characteristics are listed in Table 1.
Patients were eligible if they had transitional, squamous, or mixed carcinoma of the urothelial tract. Patients with invasive tumors (T2–T4b based on the 1997
American Joint Committee on Cancer criteria) were
eligible, as were patients with metastatic disease, including patients with lymph node or visceral involvement. However, measurable disease was necessary.
Entry criteria included no prior chemotherapy for
bladder carcinoma, a Cancer and Leukemia Group B
performance status of 0 –2, age , 80 years, 24-hour
creatinine clearance . 50 mL/minute, bilirubin and
aspartate aminotransferase # 25% above normal, leukocyte count . 4000/mm3, platelet count . 100,000/
mm3, and signed informed consent. Twenty-three of
24 patients (96%) had transitional cell carcinoma,
whereas 1 patient had squamous cell carcinoma. Nine
patients (37%) had invasive bladder carcinoma without evidence of metastases.
Any patient who was seen at the Dana-Farber
Cancer Institute during the study period with a new
diagnosis of muscle invasive or metastatic urothelial
carcinoma and who met the criteria for study entry
was considered for this protocol. The nine patients
with muscle invasive disease clearly were derived from
a selected cohort because they expressed a specific
interest in a bladder-sparing approach after reviewing
M-PFL in Advanced Urothelial Carcinoma/Oh et al.
FIGURE 1.
Schematic of the methotrexate, cisplatin, 5-fluorouracil, and
leucovorin (M-PFL) regimen. MTX: methotrexate; 5-FU: 5-fluorouracil.
1331
cles of chemotherapy were administered, the extent of
disease was assessed by physical examination, computed tomography (CT) scan of the abdomen and
pelvis, bone scan, and chest X-ray. If indicated, cystoscopy was performed. Patients with metastatic disease were treated with up to six cycles of therapy if
they continued to respond, until tumor progression or
if toxicity became limiting. Patients with muscle invasive disease were treated with up to four cycles of
therapy, provided they continued to respond. If any
residual tumor was demonstrated by biopsy after four
cycles, patients proceeded directly to radical cystectomy. If no evidence of tumor was observed, patients
were candidates for pelvic radiotherapy in an attempt
to preserve the bladder.
Response evaluations were based on the site of
initial measurable disease. A complete response (CR)
was defined as absence of all clinically detectable tumor for at least 4 weeks. A partial response (PR) was
defined as a . 50% reduction in the sum of the products of the greatest perpendicular dimensions of all
measurable lesions lasting at least 4 weeks. Progressive disease was defined as a . 25% increase in tumor
volume during the treatment period or the appearance of new lesions. Toxicity was graded according to
the Common Toxicity Criteria. Duration of response
and survival were measured from the start of treatment.
Statistical Methods
FIGURE 2.
Overall survival of patients treated with the methotrexate, cisplatin, 5-fluorouracil, and leucovorin (M-PFL) regimen based on the presence
of muscle invasive or metastatic disease at the time of presentation.
their treatment options with an oncologist or urologist.
Patients were treated every 28 days with a regimen
comprised of methotrexate, 60 mg/m2, intravenously
(i.v.) on Day 1; cisplatin, 25 mg/m2/day, by continuous
i.v. infusion on Days 2– 6; 5-FU, 800 mg/m2/day, by
continuous i.v. infusion on Days 3– 6; and leucovorin,
500 mg/m2/day, by continuous i.v. infusion on Days
2– 6. Figure 1 outlines the treatment in schematic
form. Patients received at least 3 L of saline per day
from the continuous infusion of chemotherapy, with
further i.v. fluid provided only if patients became clinically dehydrated. Dose reductions were not allowed
on subsequent cycles for methotrexate or cisplatin
toxicity, although a treatment delay of up to 7 days
was allowed if patients experienced renal toxicity.
5-FU dose reductions were allowed for myelotoxicity,
diarrhea, stomatitis, or skin rash.
A physician evaluation was performed at the beginning of each cycle of chemotherapy. After two cy-
The primary endpoint of this study was to determine
the objective response rate of advanced urothelial carcinoma to the M-PFL regimen. The study originally
was designed to accrue 40 patients so that the lower
95% confidence limit was higher than the hypothesized “null” response rate of 30%, provided that the
true response rate was $ 52%. This design provided
80% power. After 24 patients, the observed response
rate was 63% and therefore the study was stopped
early. The lower 95% confidence limit for the observed
rate was 41%.
The Kaplan–Meier method was used to provide
graphs of survival and estimates of median survival.20
Confidence intervals were generated for the survival
curve using the Greenwood method to estimate the
variance.21 Exact binomial methods were used to generate confidence intervals for the response rate.
RESULTS
Twenty-four patients were enrolled on this trial. Three
patients were unevaluable for response because of
significant toxicity after the first cycle of therapy. One
of these patients, who presented with a 7-cm muscle
invasive tumor, developed intractable diarrhea and
1332
CANCER October 1, 1999 / Volume 86 / Number 7
TABLE 2
Characteristics of Responding Patients
Patient no.
Age (yrs)/Gender
Extent of
disease
Sites of response
Best
response
Duration of
response (mos)
Overall
survival (mos)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
61/M
66/M
70/M
66/M
58/M
71/M
43/M
57/F
67/M
64/M
58/F
71/F
59/M
74/F
58/M
INV
INV
INV
INV
INV
INV
MET
MET
MET
MET
MET
MET
MET
MET
MET
Bladder
Bladder
Bladder
Bladder
Bladder
Bladder, prostate
Bladder, prostate, bone
Pelvic, distant lymph nodes
Lung, distant lymph nodes
Lung
Lung, pelvic mass
Lung, distant lymph nodes
Distant lymph nodes, bladder
Distant lymph nodes
Bone, pelvic mass
CR
pCR
CR
pCR
CR
PR
PR
CR
PR
CR
PR
PR
CR
CR
PR
43
841
57
421
8
16
5
12
6
8
5
4
6
19
8
861
841
651
421
16
20
20
17
17
13
10
17
14
691
16
M: male; INV: invasive; CR: complete response; pCR: pathologic complete response; PR: partial response; MET: metastatic; F: female.
abdominal pain. An exploratory laparotomy was performed, which was negative. On repeat cystoscopy, he
was noted to have a CR after one cycle. Radiation
therapy and radical cystectomy were both offered; the
patient opted for surgery, at which time he was noted
to have extensive carcinoma in situ but no residual
invasive disease. The other two patients had metastatic disease. Both patients developed febrile neutropenia as well as Grade 4 mucositis and diarrhea, requiring hospitalization for intravenous fluids and
antibiotics.
Of the 21 evaluable patients, 13 had metastatic
carcinoma whereas 8 had locally advanced or muscle
invasive disease. The median follow-up was 81
months (range, 53–97 months). At last follow-up, five
patients were alive: four patients with muscle invasive
disease and one patient who presented with distant
lymphadenopathy. One patient was lost to follow-up
and the remaining patients had died of disease.
A total of 75 cycles of chemotherapy was administered to 24 patients. Patients received a median of
3.5 cycles of M-PFL (range, 1–5 cycles), with 8 of the 24
patients (33%) requiring a dose reduction of chemotherapy. Of the 13 evaluable patients with metastatic
disease, 4 had CRs and 5 had PRs to therapy for a
response rate of 69%. Two patients developed progressive disease whereas two patients had stable disease.
Of the 8 patients with muscle invasive disease, 5 had
CRs and 1 had a PR for a response rate of 75%. Two
patients demonstrated tumor progression. The overall
response rate (CR 1 PR) for all 21 patients was 71%
(95% confidence interval, 48 – 89%). If the three unevaluable patients were included in the analysis as non-
responders, the response rate was 63% (95% confidence interval, 41– 81%).
The median overall survival in the entire group
was 17 months (range, 2– 861 months). Patients with
muscle invasive disease had a median survival of 65
months (range, 5– 861 months), whereas patients with
metastatic disease had a median survival of 17 months
(range, 2– 691 months) (Fig. 2). The median duration
of response in the 15 responding patients was 8
months (range, 4 – 84 months). Among the 9 patients
with metastatic disease responding to treatment, the
median response duration was 6 months (range, 4 –19
months).
Characteristics of responding patients are outlined in Table 2. Among the 6 responding patients
with muscle invasive carcinoma, 3 (50%) received
postchemotherapy bladder irradiation. At last follow-up they had not developed muscle invasive recurrence of disease and maintained intact bladders. Patient 1 initially presented with a clinical T3 transitional
cell carcinoma and developed a disease recurrence .
3 years later with invasive squamous cell carcinoma,
which was treated effectively with radical cystectomy.
Patient 5 developed a recurrent bladder mass 3
months after achieving a CR with chemotherapy and
bladder irradiation. Salvage radical cystectomy was
performed, revealing a pathologic T3b lesion; the patient subsequently developed a disease recurrence
and died 6 months later. Patient 6 only achieved a PR
after three cycles of chemotherapy and underwent a
salvage cystectomy, which also demonstrated pathologic T3b disease. He subsequently developed a systemic recurrence and died 14 months later.
M-PFL in Advanced Urothelial Carcinoma/Oh et al.
TABLE 3
Toxicity of M-PFL
1333
DISCUSSION
No. of patients with maximum grade of toxicity
Toxicity grade
0
1
2
3
4
Neutropenia
Anemia
Thrombocytopenia
Nausea/emesis
Renal
Mucositis
Neurotoxicity
Diarrhea
Fever
Allergy
2
4
6
13
17
14
15
14
19
23
0
6
2
6
4
1
4
1
1
0
3
14
1
2
3
4
3
4
4
1
8
0
8
3
0
2
2
2
0
0
11
0
7
0
0
3
0
3
0
0
M-PFL: methotrexate, cisplatin, 5-fluorouracil, and leucovorin.
Toxicity was formidable (Table 3). Of the 24
patients enrolled, 3 discontinued treatment due to
toxicity after 1 cycle as noted earlier. These patients
have been included in Table 3. Eight of the remaining 21 patients (38%) required a dose reduction in
chemotherapy, primarily by shortening the length of
treatment by half a day. There were no treatmentrelated deaths. Significant myelosuppression was
noted with this regimen. The majority of patients
had Grade 3 or 4 neutropenia, although only three
patients were admitted for four episodes of febrile
neutropenia. All patients eventually recovered with
empiric antibiotic coverage and negative blood cultures. Only mild anemia was noted, and no red
blood cell transfusions were required. Platelet toxicity was more common, with 15 of 24 patients
(63%) demonstrating Grade 3 or 4 thrombocytopenia. Six patients required at least 1 platelet transfusion, with 1 patient receiving a total of 12 infusions
of pheresis platelets. However, no patient experienced an episode of bleeding.
Gastrointestinal toxicity was moderate. Mucositis was mild or absent in the majority of patients,
but three patients experienced severe mucositis requiring intravenous hydration. Diarrhea, nausea,
and emesis generally were moderate and controllable. One patient developed Clostridium difficile diarrhea. Neurotoxicity was not a significant issue
initially, but sensory paresthesias were noted in
nine patients, and were severe enough in two to
interfere with normal activities. Renal toxicity was
mild and generally reversible. The majority of patients experienced mild or moderate fatigue while
participating in the study, but no patients developed
severe or disabling fatigue.
Despite the high response rates to platinum-based
combination chemotherapy for patients with advanced transitional cell carcinoma, overall survival remains poor.22 Efforts to develop regimens that may
improve overall survival thus continue.
M-PFL demonstrates significant activity in the
treatment of invasive and advanced urothelial carcinoma. The overall response rate was 63% (95% confidence interval, 41– 81%), and was similar in both the
muscle invasive and metastatic disease groups. This
response rate is comparable to other platinum-based
combination chemotherapy regimens that have been
used in the treatment of transitional cell carcinoma,
such as M-VAC3– 6 and CMV.7,8 Among those patients
with T2–T4 tumors, three of six responding patients
ultimately were able to avoid cystectomy with long
term follow up. A fourth patient underwent cystectomy after 3 years for an invasive recurrence of a
different histology from his initial tumor. Thus approximately 50% of the patients treated with M-PFL
and subsequent irradiation after CR were likely to be
cured of their initial invasive tumor.
A high response rate was observed among patients with metastatic disease but the duration of response was limited to 6 months. Only 1 patient (6.7%)
from this group was alive and disease free . 6 years
later. The majority of the patients (67%) with metastases in this series had distant lymph node involvement, although visceral or bone involvement was
noted in 8 of 15 patients (53%).
Toxicity was significant but tolerable for the majority of the 24 patients treated. With a median of 3.5
cycles of treatment administered, Grade 3 or 4 neutropenia and thrombocytopenia was observed in 79%
and 63% of patients, respectively. Nevertheless, only
three patients required hospital admission for uncomplicated febrile neutropenia and only six patients required platelet transfusions, none for active bleeding
episodes. Three patients were removed from the study
after developing Grade 4 gastrointestinal toxicity, including mucositis and diarrhea. The major late toxicity
of concern was peripheral neuropathy, which occurred in 37% of the group and was severe enough in
2 patients to be disabling.
New combinations of chemotherapy currently are
being developed that include paclitaxel12,13,23,24 and
gemcitabine14,25,26. These newer drugs appear to have
good activity against urothelial carcinoma and appear
to have favorable side effect profiles. A large randomized trial comparing M-VAC with gemcitabine plus
cisplatin in untreated patients with metastatic transitional cell carcinoma recently completed accrual. If
1334
CANCER October 1, 1999 / Volume 86 / Number 7
equivalent efficacy can be demonstrated from agents
or combinations that have less toxicity, such regimens
clearly will become the new standard of care. Nonetheless, new treatments that improve overall survival
in patients with advanced urothelial carcinoma remain sorely needed.
M-PFL represents an active regimen in the treatment of invasive and metastatic urothelial carcinoma.
Response rates and the median survival of patients are
comparable to those published with other platinumbased regimens. Toxicity was significant but could be
managed effectively in the majority patients. Despite
the availability of newer drugs with encouraging evidence of activity against urothelial carcinoma, older
drugs with known activity should not be excluded
from further study. Future studies will be needed to
evaluate the role of traditional agents such as 5-FU
and methotrexate in combination with newer drugs
such as gemcitabine and paclitaxel.
10.
11.
12.
13.
14.
15.
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