British Journal of Cancer (1996) 74, 1655-1659
`© 1996 Stockton Press All rights reserved 0007-0920/96 $12.00
`
`Survival of patients with advanced urothelial cancer treated with cisplatin(cid:173)
`based chemotherapy
`
`SD Fossa\ C Sternberg2
`E Skovlund'
`
`, HI Scher\ CH Theodore\ B Meads, D Dearnaley6 JT Roberts 7 and
`
`lThe Norwegian Radium Hospital (NRH), Oslo, Norway; 2San Raffaele Scientific Institute (HSR), Rome, Italy; 3Memorial Sloan
`Kettering Cancer Center (MSKCC), New York, USA; 4Institute Gustave Roussy (IGR) , Vil/ejuif, France; 5Royal South Hants
`Hospital (RSHH) , UK; 6Royal Marsden Hospital (RMH) , Sutton, Surrey, UK; 7Northern Centre/or Cancer Treatment (NCCT),
`Newcastle, UK.
`
`Summary The aim of the present retrospective study was to assess long-term survival after cisplatin-based
`chemotherapy in 398 patients with advanced urothelial transitional cell carcinoma (TCC) treated at seven
`international oncological units. Various combinations of cisplatin, methotrexate, vinblastine (or vincristine) and
`doxorubicin were used. The complete response rate according to the WHO criteria was 17%. Partial responses
`were obtained in 42% of the patients. The overall cancer-related 2 year and 5 year survival rates were 21 % and
`II % respectively. Based on multivariate analyses, a good prognosis group could be identified comprising
`patients with a good performance status with disease confined to lymph nodes (14%) or patients with T4b
`disease only. These patients had a 28% 5 year survival rate, which, in part, has to be related to post(cid:173)
`chemotherapy consolidation treatment in patients with pelvis-confined disease (radiotherapy, 26%; total
`cystectomy, II %). Fifteen patients died of chemotherapy-related complications and in 16% of the patients
`toxicity led to discontinuation of treatment. Modern cisplatin-based chemotherapy leads to long-term survival
`and cure of selected patients with advanced urothelial transitional cancer. In routine clinical practice,
`chemotherapy should be offered to good prognosis patients; those presenting with a good performance status
`and a non-metastasising T4b tumour or with metastases confined to lymph nodes. Post-chemotherapy
`consolidation treatment by surgery or radiotherapy should always be considered. Such chemotherapy requires
`oncological expertise in order to avoid unnecessary toxicity.
`
`Keywords: bladder cancer; metastasis; chemotherapy
`
`In the United States bladder cancer is the fifth most common
`cancer in men and the seventh in women, with an annual
`incidence of approximately 18 cases per 100000 or more than
`52 900 new cases per year, leading to II 700 deaths annually
`(American Cancer Society, 1996). The annual age-adjusted
`incidence in the Nordic countries is about 35 cases per
`100000, and the mortality 12 per 100000 (Engeland et al.,
`1993, 1995). Bladder cancer is primarily a disease of the
`elderly, with 80% of cases in the 50-79 year age group, and
`a peak incidence in the seventh decade. About 20 - 30% of all
`patients present with advanced bladder cancer [extension to
`the pelvic wall (T4b); metastatic disease (N +, M +)], while
`about 50% of all patients with muscle-invasive bladder
`cancer develop a pelvic recurrence or metastases during the
`course of their disease, despite curatively intended surgery or
`radiotherapy.
`Systemic chemotherapy has an uncertain role in
`the
`treatment of locally advanced recurrent metastatic urothelial
`transitional cell carcinoma (TCC). Anti-tumour activity has
`been demonstrated with several single agents, but does not
`prolong survival. Cisplatin-based combination chemotherapy
`leads to response rates between 35% and 70% and is more
`effective than cisplatin alone (Sternberg et aI., 1989; Harker et
`al., 1985; Fossa et al., 1982; Loehrer et al., 1992). Typically,
`the response rates from single institution studies are superior
`to those from multicentre trials. Prolonged survival has been
`reported in patients who achieve complete response (CR)
`(Logothetis et al., 1985; Stoter et al., 1987; Sternberg et al.,
`1989). Systemic cisplatin-based combination chemotherapy
`can be toxic, particularly in elderly patients. The potential
`
`Correspondence: SO Fossa, The Norwegian Radium Hospital,
`Montebello, 0310 Oslo, Norway
`Received 9 April 1996; revised 31 May 1996; accepted 12 June 1996
`
`toxIcity must, therefore, be balanced against the expected
`beneficial effects, such as palliation of pain and, in particular,
`increase in life expectancy.
`The aim of the present paper is to analyse the survival in
`patients with advanced urothelial cancer of pure TCC type
`treated with cisplatin-based combination chemotherapy at six
`European centres (NRH, Norwegian Radium Hospital; IGR,
`Institute Gustave Roussy; RMH, Royal Marsden Hospital;
`NCCT, Northern Centre for Cancer Treatment; RSHH,
`Royal South Hants Hospital; HSR, San Raffaele Scientific
`Institute) and at one American hospital (MSKCC, Memorial
`Sloan Kettering Cancer Center). In addition, we examined
`which prognostic factors may assist the clinician in selecting
`those patients in whom long-term survival can be expected.
`
`Patients and methods
`
`The above six European and one American hospitals
`contributed the clinical data from 398 patients to this study
`(Table J). Patients with brain metastases at presentation were
`excluded. All patients had measurable locally advanced or
`metastatic urothelial cancer arising from the bladder, ureter
`or the renal pelvis. All patients had pure TCe. None of the
`patients had
`received chemotherapy before
`the study
`treatment. Fifty-three patients had T4b bladder cancer
`without prior treatment. Sixty-three patients had undergone
`total cystectomy before systemic chemotherapy. A further 79
`patients had been treated with pelvic radiotherapy with or
`without bladder-conserving surgery (TUR B; bladder wall
`resection). Pulmonary metastases were
`the only site of
`metastatic disease in 43 patients. Forty-nine patients had
`disease confined to lymph node sites. About two-thirds of the
`patients had a good performance status [WHO grade 0 or I
`(Miller et al., 1981)] at the start of chemotherapy.
`The European hospitals used a variety of cisplatin-contain(cid:173)
`ing combination chemotherapy regimens with cisplatin doses of
`
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`1656
`
`Survival from advanced urothellal cancer
`SD Foss~ et a/
`
`70-100 mg m- 2 per cycle, administered every third week.
`These included CMV, cisplatin, methotrexate, vinblastine
`(Harker et ai., 1985); CMO, cisplatin, methotrexate, vincris(cid:173)
`tine; CM, cisplatin, methotrexate. Patients received between
`one and seven cycles of chemotherapy (median, three cycles)
`(Table II). At the MSKCC and in Rome, only M-VAC
`[methotrexate, vinblastine, doxorubicin, cisplatin (Sternberg et
`ai., 1988)] was used. In the patients treated at the MSKCC the
`median number of cycles was four (range I - 8).
`In the present report, response was defined according to the
`WHO criteria (Miller et ai., 1981). Complete remission, CR;
`partial remission, PR; no change, NC; progression, PD. In 34
`patients total cystectomy could be performed after cisplatin(cid:173)
`based chemotherapy. Post-chemotherapy radiotherapy was
`used in 88 patients. In particular, of the 245 patients with T4b
`disease or metastases confined to the pelvic lymph nodes, 28
`(11 %) and 64 (26%) underwent post-chemotherapy, total
`cystectomy and radiotherapy respectively. Forty-three patients
`received second-line alternative chemotherapy after failure of
`the initial chemotherapy regimen. A total of 109 patients were
`not given any further anti-cancer treatment after discontinua(cid:173)
`tion of cisplatin-based chemotherapy.
`
`Statistics
`A biostatistician (ES) performed procedures and tests using
`SPSS version 6.1 for Pc. The primary outcome variable was
`the start of
`the cancer-related actuarial survival from
`chemotherapy, evaluated by Kaplan-Meier estimates and
`the log-rank test. Cancer-related death was defined as death
`from or with urothelial cancer, including death during
`chemotherapy owing to complications from chemotherapy.
`A multi variable survival analysis was performed by the Cox
`proportional hazards model. Proportionality assumptions
`were checked and confirmed for the variables included. A
`P-value < 0.05 was regarded as statistically significant.
`
`Results
`
`At the end of the observation period (December 1994) and
`with a median follow-up of 51 months (range, 3-158
`months) 48 patients were alive and 350 were dead. Twelve
`of the surviving patients were alive with disease and 36
`patients were without evidence of urothelial cancer. Seven
`patients have died as a result of intercurrent diseases without
`evidence of urothelial cancer. In 343 patients death was
`cancer-related. In 53 of 340 evaluable patients (16%),
`to discontinuation of
`chemotherapy-induced toxicity
`led
`treatment. Complications of chemotherapy were the cause
`of death in IS (4%) of these patients. Three cancer-related
`deaths occurred more than 5 years after the initiation of
`chemotherapy. The cancer-related 2 year and 5 year survival
`rates were 21 % and II %, respectively, for all patients, with a
`median survival time of 11.3 months (Figure I).
`in 336 patients (Table III).
`Response was assessed
`Complete response was achieved in 17% [95% confidence
`interval (CI) 13-21 %] and partial response in 42% (95% CI
`37 -47%). In patients with lymph node metastases as their
`only site of disease, a 47% CR rate was reported (95% CI
`31-63%). Patients achieving a CR had a 38% 5 year survival
`rate (Figure 2).
`In the univariable analysis (Table IV) the median survival
`of patients with T4b tumours and those with disease confined
`either to lymph nodes or lung metastases was superior to that
`of patients with other or multiple sites of advanced disease.
`The 5 year survival rates were: patients with lymphatic
`metastases only, 18%; patients with T4b tumours, 25%;
`patients with lung metastases only, II %; patients with
`combined or alternative metastatic sites, 7% (Figure 3).
`Patients with a history of prior radiotherapy had a decreased
`survival compared with non-irradiated ones. Patients who
`had received M-VAC chemotherapy had a better outcome
`than those treated with non-M-VAC chemotherapy.
`
`The following pretreatment parameters were included in a
`multivariable analysis: performance status, site of disease (T4
`or lymph node metastases only vs all other alternatives) and
`age. Haemoglobin was excluded from this analysis as this
`factor may vary according to blood transfusion policy. The
`following independent good prognosis factors were con-
`
`Table I Patient characteristics
`
`No. of patients
`Norwegian Radium Hospital, Oslo
`Institute Gustave Roussy, Villejuif
`Northern Centre for Cancer Treatment,
`Newcastle
`Royal Marsden Hospital, London
`Royal South Hants Hospital, Southampton
`San Raffaele Scientific Institute, Rome
`Memorial Sloan Kettering Cancer Center,
`New York
`Males/females
`Mean age at chemotherapy (years)
`Performance status (WHO)
`o
`I
`2
`3
`4
`Unknown
`Disease manifestation
`T4b bladder cancer only
`Lymph node metastases onll
`Lung metastases only
`Biochemistry
`Mean haemoglobin (gdr1r
`
`398
`76
`54
`
`33
`53
`53
`27
`
`\02
`326/72
`62 (23-80)"
`
`93
`176
`86
`27
`3
`13
`
`12.3
`(5.6-18.0)
`
`Previous treatment
`None or bladder-conserving surgeryd
`(without radiotherapy)
`Cystectomy
`Pelvic irradiation (with or without
`79
`bladder-conserving surgeryd)
`39
`Other
`15
`Unknown
`a Range. bpelvic, 27; extrapelvic, 22. cMissing for 41 patients.
`d Includes TUR B and partial cystectomy.
`
`202
`63
`
`Table II Chemotherapy
`
`3
`Cisplatin mono therapy
`83
`CMV
`188
`M~VAC
`30
`CMO
`46
`CM
`48
`Other
`C, cisplatin; M, methotrexate; V, vinblastine; A, doxorubicin
`(adriamycin); 0, vincristine (oncovin).
`
`1.0
`
`0.8
`
`~ 0.6
`(ij
`>
`.~ 0.4
`::I
`III
`
`0.2
`
`0.0
`
`o
`
`12
`
`96 108 120
`84
`72
`60
`48
`36
`24
`Months since chemotherapy start
`
`Figure 1 Cancer-related survival for all 398 patients.
`
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`firmed: performance status 0/1; T4 or lymph node metastases
`only and age ~ 65 years. Combining the first two factors, a
`good prognosis group could be defined consisting of patients
`with a good performance status without visceral metastases.
`These patients represented about 20% of the patients from
`the present series (81 patients) and displayed a 5 year cancer(cid:173)
`related survival of 28% with a median survival rate of 20
`months (compared with 10 months in patients from the poor
`prognosis group) (Figure 4).
`In Table VI the proportion of good prognosis patients
`(performance status 0/1 and no visceral metastases) is given
`for each of the contributing institutions, showing a variability
`from 9-55%.
`
`Discussion
`
`In the last decade clinicians have become increasingly aware
`that TCC of the urothelial tract is responsive to combination
`chemotherapy. As TCC represents the vast majority of
`urothelial cancer seen in routine clinical practice, and for the
`sake of homogeneity, we have performed the present analysis in
`pure TCC only. The most commonly used regimens are the
`CMV (Harker et al., 1985) and the M-VAC combination
`(Sternberg et al., 1988). M -V AC has been shown to be superior
`to single-agent cisplatin (Loehrer et al., 1992) and to CISCA
`(Logothetis et aI., 1990) in randomised trials. No randomised
`trial has been performed comparing M-VAC and CMV.
`
`Table III Sites of disease and response rates
`No of assessed patients
`PIt
`CK'
`Total
`4 (14%)
`28
`14 (50%)
`18 (47%) 1\ (29%)
`38
`
`Site
`Lung metastases only
`Lymph node
`metastases only
`T4b tumour only
`Other metastatic
`sites/combinations
`Total
`57 (17%) 141 (42%)
`336
`a Complete response. b Partial response.
`
`46
`224
`
`16 (35%)
`10 (28%)
`25 (11%) 100 (45%)
`
`No
`response
`
`10
`9
`
`20
`99
`
`138
`
`Table IV Univariable analysis of pretreatment variables
`Median cancer-related
`survival months
`
`P-value
`
`)
`
`Variable
`Sites of disease
`T4 only
`Lymph nodes only
`Lung only
`Other combination
`Haemoglobin (gdl-I
`>12.0
`:;;;12.0
`Chemotherapy
`M-VAC
`Non-M-VAC
`Gender
`Males
`Females
`Age (years)
`:;;;65
`>65 years
`Performance status
`0/1
`2-4
`Previous radiotherapy
`Yes
`No/Unknown
`
`13.4
`15.0
`15.8
`9.8
`
`12.3
`8.3
`
`13.0
`9.0
`
`11.5
`10.8
`
`12.0
`9.8
`
`12.4
`8.1
`
`6.2
`12.0
`
`<0.0001
`
`<0.0001
`
`<0.0001
`
`0.37
`
`om
`
`0.01
`
`<0.0001
`
`1657
`
`Survival from advanced urothellai cancer
`SD FossA et al
`
`Response rates of 35 - 70% are reported in patients
`receiving M-VAC or CMV, with CR rates of 13-20%.
`These figures are confirmed in the present study. In the
`literature the median duration of response is reported to be
`about 9 months. As has been shown by other authors in
`single-institution studies, cisplatin-based chemotherapy
`is
`more effective in patients with nodal disease as compared
`with visceral disease [response rates, 71 % vs 40%; survival,
`33 months vs 12 months (Logothetis et al., 1985; Sternberg et
`al., 1989)]. In patients with visceral metastases, pulmonary
`lesions display the highest response rates, whereas hepatic
`and skeletal deposits are reported to be less responsive.
`Cisplatin-based chemotherapy of urothelial cancer repre(cid:173)
`sents a potentially curative treatment which, however, may be
`severely toxic in these often elderly patients who frequently
`present with concomitant medical problems and chronic
`diseases (Tannock et al., 1989; Fossa et al., 1992). In
`addition, owing to advanced age and the malignancy, renal
`
`1.0
`
`0.8
`
`~ 0.6
`(ij
`>
`.~ 0.4
`:::l
`(/)
`
`CR
`
`o
`
`12
`
`96 108 120
`84
`72
`60
`48
`36
`24
`Months since chemotherapy start
`
`to
`to response
`Figure 2 Cancer-related survival according
`cisplatin-based chemotherapy. CR, complete
`response
`(57
`patients); PR, partial response (141 patients); <CRjPR, no
`response (138 patients).
`
`1.0
`~ 0.8
`(ij 0.6
`>
`.~ 0.4
`:::l
`(/) 0.2
`
`0.0
`
`o
`
`12
`
`96 108 120
`84
`72
`60
`48
`36
`24
`Months since chemotherapy start
`
`Figure 3 Cancer-related survival according to site of disease. I,
`T4 only (53 patients); 2, metastases confined to lymph nodes (49
`patients); 3, lung metastases only (34 patients); 4, other sites or
`> I site (262 patients).
`
`1.0
`
`;;e 0.8
`!a.-
`m 0.6
`>
`.~ 0.4
`:::l
`(/)
`
`0.2
`
`0.0
`
`- - - - - - - - - - - - - - - - - - - - - - - - - -
`
`-L.. _________ _
`
`o
`
`12
`
`96 108 120
`84
`72
`60
`48
`36
`24
`Months since chemotherapy start
`
`Figure 4 Cancer-related survival in the good prognosis group.
`T4 only or disease confined to lymph nodes in patients with
`performance status 0 or I (--), as compared with all other
`patients (- - -).
`
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`1658
`
`Table V Multivariable analysis of pretreatment variables
`
`Survival from advanced urothelial cancer
`SD Foss~ et at
`
`Variable
`
`Performance status
`0/1 vs 2-4
`Site of disease manifestation
`(T4b or lymph nodes
`only vs lung/others)
`Age (years)
`(>65 vs~65)
`
`Estimated hazard ratio
`(95% confidence
`interval)
`
`0.51 (0.40-0.65)
`
`P-value
`
`<0.0001
`
`0.53 (0.40-0.70)
`
`<0.0001
`
`1.32 (1.06-1.65)
`
`0.01
`
`Table VI Proportion of good prognosis patients treated at each
`hospital
`Good risk group
`(no. of patients)
`
`Hospital
`
`Total
`27
`75"
`36%
`NRH
`17%
`54
`IGR
`9
`9%
`5
`53
`RMH
`55%
`18
`NCCT
`33
`5
`53
`RSHH
`9%
`11%
`102
`MSKCC
`II
`HSR
`22%
`6
`27
`Total
`20%
`81
`397
`"Insufficient data for one patient. For abbreviations, see text.
`
`function is often reduced and commonly below the level
`required for cisplatin administration (glomerular filtration
`rate ~ 50 ml min -'). The application of careful hydration,
`modern antiemetics,
`the use of leucovorin (to prevent
`mucositis) and/or haematological growth factors (Grabri(cid:173)
`love et al., 1988) can reduce toxicity. Other cisplatin-based
`combination regimens have been introduced in the last
`decade in an attempt to reduce toxicity. This is also the
`background for the use of vincristine instead of vinblastine,
`or
`the substitution of epirubicin or mitosantrone for
`doxorubicin, or of carboplatin for cisplatin (St6ckle et al.,
`1992; Waxman et aI., 1989; Boccardo et al., 1994). Severe
`toxicity may, however, occur even among these carefully
`selected patients. Four per cent of our 398 patients died as a
`result of chemotherapy-related toxicity. Furthermore, 34 of
`292 evaluable patients (12%) received only one course of
`chemotherapy. Chemotherapy was discontinued owing to
`toxicity in 31 patients,
`to deterioration of the general
`condition in 14 or to patient refusal in 8. These figures are
`in accordance with published information on toxicity, and
`underline the need for careful consideration of the aims of
`therapy when initiating this type of chemotherapy in an
`individual patient.
`there are clearly beneficial effects of
`Nevertheless,
`cisplatin-based chemotherapy
`in patients with advanced
`urothelial cancer. Although the 5 year survival rate was
`only II %, patients with a good performance status and with
`disease confined to lymph nodes only or unresectable T4b
`bladder cancer may achieve long-term survival (> 3 years)
`
`References
`
`AMERICAN CANCER SOCIETY. (1996). Facts and Figures.
`BOCCARDO F, PACE M, GUARNERI D, CANOBBIO L, CUROTTO A
`AND MARTORANA G. (1994). Carboplatin, methotrexate, and
`vinblastine in the treatment of patients with advanced urothelial
`cancer. A phase II trial. Cancer, 73, 1932 - 1936.
`DIMOPOULOS C, FINN LAND LOGOTHETIS CJ. (1995). Pattern of
`failure and survival of patients with metastatic urothelial tumors
`relapsing after cisplatin based chemotherapy. J. Urol., 151, 598-
`601.
`
`with a 28% 5 year survival rate. Inoperable patients may
`become operable following chemotherapy, as occurred in the
`31 patients who were able to undergo post-chemotherapy
`cystectomy. As radiotherapy is usually most effective in small
`tumours, preirradiation chemotherapy leading to tumour size
`reduction may increase the chance of radiocurability of a
`tumour in subgroups of patients. Our series thus supports the
`view that selected patients with technically inoperable pelvis(cid:173)
`confined tumours may benefit from consolidation treatment
`with surgery or radiotherapy after maximum response to
`chemotherapy (Dimopoulos et al., 1994; Miller et al., 1993).
`Other authors have reported the significance of prognostic
`factors during chemotherapy of urothelial cancer (Geller et
`al., 1991; Sengelf1Jv et al., 1994). At the MSKCC, favourable
`prognostic factors for survival in patients treated with M(cid:173)
`V AC included a good performance status, age > 60 years,
`and a normal serum alkaline phosphatase. Sengelf1Jw et al.
`(1994) confirmed the importance of a good performance
`status and of a normal alkaline phosphatase for long-term
`survival, and added normal serum creatinine to the list of
`good prognostic factors. In the Intergroup study, which
`compared M-VAC with cisplatin,
`the most
`important
`prognostic factors for favourable outcome were a good
`performance status, weight loss of < 10%, and lack of
`visceral metastases (Loehrer et al., 1992). Patients who had
`all three favourable factors had a 64% response and a
`median survival of 18 months. The present study confirms the
`favourable effect of good prognosis factors, such as a good
`performance status and lack of visceral metastases, as
`predictive parameters of long-term survival. Contrary to the
`report by Geller et al. (1991), younger patients from the
`present series had a better outcome than older ones. As
`reported by Stoter et al. (1987) and by Logothetis et al.
`(1985), patients with CR had the best survival, whereas PR
`was not related to a beneficial long-term survival. Jeffery and
`Mead (1992) suggested that patients with advanced ureteric
`or renal pelvis TCC represented a good prognostic group.
`Owing to lack of relevant information this factor could not
`be analysed in this study.
`The present study highlights the variability of selection
`factors for patients treated for advanced urothelial cancer at
`different oncological institutions. The heterogeneous distribu(cid:173)
`tion of prognostic factors among patients from different
`institutions may explain the variability of response rates
`recorded in the literature, and the need to stratify results
`according to prognostic factors.
`In conclusion, cisplatin-based chemotherapy
`is both
`feasible and efficacious in carefully selected patients with
`advanced urothelial cancer. The overall response rate is 59%
`(CR, 17%; PR, 42%) and the 5 year cancer-related survival is
`II %. Post-chemotherapy surgery or radiotherapy should
`the need for
`improved
`always be considered. There is
`chemotherapy regimens and, in particular, for the identifica(cid:173)
`tion of new effective drugs and drug combinations, including
`ifosfamide (Witte et al., 1993) and pac1itaxel (Roth, 1995).
`Patients with a good performance status and with disease
`confined to lymph nodes or with a T4b bladder cancer as
`their only disease site have a 28% 5 year survival rate.
`Cisplatin-based chemotherapy in patients with advanced
`urothelial cancer requires oncological expertise in order to
`obtain optimal results and to avoid unnecessary toxicity.
`
`ENGELAND A, HALDORSEN T, TRETLI S, HAKULINEN T, HORTE
`LG, LOUSTARINENT, MAGNUS K, SCHOU G, SIGVALDASON H,
`STORM HH, TULINIUS HAND VAITTINEN P. (1993). Prediction
`of cancer incidence in the Nordic countries up to the years 2000
`and 2010: cancer of the urinary bladder. APMIS, 101,74-77.
`
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`

`ENGELAND A, HALDORSEN T, TRETLI S, HAKULINEN T, HORTE
`LG, LUOSTARINEN T, SCHOU G, SIGVALDASON H, STORM HH,
`TULINIUS HAND VAITTINEN P. (1995). Prediction of cancer
`mortality in the Nordic countries up to the years 2000 and 20 I 0,
`on the basis of relative survival analysis: cancer of the urinary
`bladder. APMIS, 103,96-101.
`FossA SD, HARLAND SJ, KAYE SB, RAGHAVAN D, RUSSELL JM,
`PARMAR MKB, USCINSKA BM AND WOOD R FOR THE MRC
`SUBGROUP IN ADVANCED BLADDER CANCER. (1992). Initial
`combination chemotherapy with cisplatin, methotrexate and
`vinblastine in locally advanced transitional cell carcinoma.
`Response rate and pitfalls. Br. J. Urol., 70, 161-168.
`GABRILOVE JL, JAKUBOWSKI A, SCHER H, STERNBERG C, WONG
`G, GROUS J, YAGODA A, FAIN K, MOORE MAS, CLARKSON B,
`OETTGEN HF, ALTON K, WELTE K AND SOUZA L. (1988). Effect
`of granulocyte colony-stimulating factor on neutropenia and
`associated morbidity due to chemotherapy for transitional-cell
`carcinoma of the urothelium. N. Engl. J. Med., 318, 1414-1422.
`GELLER NL, STERNBERG CN, PENENBERG D, SCHER HAND
`YAGODA A. (1991). Prognostic factors for survival of patients
`with advanced urothelial tumors treated with methotrexate,
`vinblastine, doxorubicin, and cisplatin chemotherapy. Cancer,
`67, 1525 -1531.
`HARKER WG, MEYERS FJ, FREIHA FS, PALMAR JM, SHORTLIFFE
`LD, HANNIGAN JF, MCWHIRTER KM AND TORTI FM. (1985).
`Cisplatin, methotrexate and vinblastine (CMV): an effective
`chemotherapy regimen for metastatic transitional cell carcinoma
`of the urinary tract. J. Clin. Oncol., 3, 1463-1470.
`JEFFERY GM AND MEAD GM. (1992). CMV chemotherapy for
`advanced transitional cell carcinoma. Br. J. Cancer, 66, 542 - 546.
`LOEHRER P, EINHORN LH, ELSON PJM, CRAWFORD D, KUEBLER
`P, TANNOCK L, RAGHAVAN D, STUART-HARRIS R, SAROSDY
`MF, LOWE BA, BLUMENSTEIN B AND TRUMP D. (1992). A
`randomized comparison of cisplatin alone or in combination with
`methotrexate, vinblastine, and doxorubicin in patients with
`metastatic urothelial carcinoma: a Cooperative Group Study. J.
`Clin. Oncol., 10, 1066-1073.
`LOGOTHETIS CJ, SAMUELS ML, OGDEN S, DEXEUS FH, SWANSON
`D, JOHNSON DE AND VON ESCHENBACH A. (1985) Cyclopho(cid:173)
`sphamide, doxorubicin and cisplatin chemotherapy for patients
`with locally advanced urothelial tumors with or without nodal
`metastases. J. Urol., 134,460-464.
`LOGOTHETIS CJ, DEXEUS F, FINN L, SELLA A, AMATO RJ, AYALA
`AG AND KILBOURN RG. (1990). A prospective randomized trial
`comparing CISCA
`to MVAC chemotherapy
`in advanced
`metastatic urothelial tumors. J. Clin. Oncol., 8, 1050 -1055.
`MILLER AB, HOOGSTRATEN B, STAQUET M AND WINKLER A.
`(1981). Reporting results of cancer treatment. Cancer, 47, 207-
`214.
`
`1659
`
`Survival from advanced urothelial cancer
`SD Fossa et a/
`
`MILLER RS, FREIHA FS, REESE JH, OZEN H AND TORTI FM. (1993).
`Cisplatin, methotrexate, and vinblastine plus surgical restaging
`for patients with advanced transitional cell carcinoma of the
`urothelium. J. Urol., 150,65-69.
`ROTH BJ. (1995). Preliminary experience with paclitaxel in advanced
`bladder cancer. Semin. Oncol., 22, 1-5.
`SENGEL0V L, KAMBY C, SCHOU G AND VON DER MAASE H. (1994).
`Prognostic factors and significance of chemotherapy in patients
`with recurrent or metastatic transitional cell cancer of the urinary
`tract. Cancer, 74, 123-133.
`STERNBERG CN, Y AGODA A, SCHER HI, WATSON RC, HERR HW,
`MORSE MJ, SOGANI PC, VAUGHAN ED JR, BANDER N,
`WEISELBERG LR, GELLER N, HOLLANDER PS, LIPPERMAN R,
`FAIR WR AND WHITMORE WF JR. (1988). M-VAC (methotrex(cid:173)
`ate, vinblatine, doxorubicin and cisplatin) for advanced transi(cid:173)
`tional cell carcinoma of the bladder. J. Urol., 139,461-469.
`STERNBERG CN, YAGODA A, SCHER HI, WATSON RC, GELLER N,
`HERR HW, MORSE MJ, SOGANI PC, VAUGHAN ED, BANDER N,
`WEISELBERG L, ROSADO K, SMART T, SHIOUW-YUN L,
`PENENBERG D, FAIR WR AND WHITMORE WF. (1989).
`Methotrexate, vinblastine, doxorubicin, and cisplatin
`for
`advanced transitional cell carcinoma of the urothelium: efficacy
`and patterns of response and relapse. Cancer, 64, 2446 - 2458.
`STOCKLE M, MEYENBURG W, WELLEK S, VOGES G, GERTENBACH
`U, THUROFF JW, HUBER CH AND HOHENFLLNER R. (1992).
`Advanced bladder cancer (stages pT3b, pT4a, pNI and pN2):
`improved survival after radical cystectomy and 3 adjuvant cycles
`of chemotherapy. Results of a controlled prospective study. J.
`Urol., 148, 302 - 307.
`STOTER G, SPLINTER TA, CHILD JA, FossA SD, DENIS L, VAN
`OOSTEROM AT, DE PAUW M AND SYLVESTER R FOR THE
`EUROPEAN ORGANIZATION FOR RESEARCH ON TREATMENT
`OF CANCER GENITO-URINARY GROUP. (1987). Combination
`chemotherapy with cisplatin and methotrexate in advanced
`transitional cell cancer of the bladder. J. Urol., 137,663 - 667.
`TANNOCK I, GOSPODAROWICZ M, CONNOLLY J AND JEWETT M.
`(1989). M-VAC (methotrexate, vinblastine, doxorubicin and
`cisplatin) chemotherapy for transitional cell carcinoma: The
`Princess Margaret Hospital Experience. J. Urol., 142, 289-292.
`WAXMAN J, ABEL P, FARAH IN, O'DONOGHUE EPN, MEE D,
`(1989). New
`CO BECK R, SIKORA K AND WILLIAMS G.
`combination chemotherapy programme for bladder cancer. Br.
`J. Urol., 63, 68 - 71.
`WITTE R, LOEHRER P, DREICER R, WILLIAMS S AND ELSON P.
`(1993). Ifosfamide in advanced urothelial carcinoma: an ECOG
`trial (abstract 707). Proc. Am. Soc. Clin. Oncol., 12, 230.
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