Atreya Dash was supported by a gift from the Tina and Richard V. Carolan Foundation.
A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder†‡
A retrospective experience
Article first published online: 29 SEP 2008
Copyright © 2008 American Cancer Society
Volume 113, Issue 9, pages 2471–2477, 1 November 2008
How to Cite
Dash, A., Pettus, J. A., Herr, H. W., Bochner, B. H., Dalbagni, G., Donat, S. M., Russo, P., Boyle, M. G., Milowsky, M. I. and Bajorin, D. F. (2008), A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder. Cancer, 113: 2471–2477. doi: 10.1002/cncr.23848
See editorial on pages 2379–81, this issue.
Presented in part at the American Society of Clinical Oncology Annual Meeting, Chicago, Illinois, May 30-June 3, 2008.
- Issue published online: 17 OCT 2008
- Article first published online: 29 SEP 2008
- Manuscript Accepted: 8 APR 2008
- Manuscript Revised: 21 MAR 2008
- Manuscript Received: 7 FEB 2008
- urothelial carcinoma;
- radical cystectomy
Neoadjuvant cisplatin-based chemotherapy improves survival in muscle-invasive urothelial cancer, with MVAC (methotrexate, vinblastine, doxorubicin and cisplatin) considered the standard regimen. Gemcitabine plus cisplatin (GC) has similar efficacy and less toxicity than MVAC in metastatic disease, but is untested as neoadjuvant treatment.
The authors retrospectively evaluated patients with muscle-invasive urothelial carcinoma who received neoadjuvant GC before radical cystectomy between November 2000 and December 2006 at Memorial Sloan-Kettering Cancer Center. Post-therapy pathological downstaging to either residual disease at cystectomy (pT0) or no residual muscle-invasion (<pT2, ie, pT0, pTIS, pT1), chemotherapy delivery, and disease-free survival were the endpoints of interest. For comparison, similar endpoints were assessed in a historical cohort treated with neoadjuvant MVAC.
Four cycles of neoadjuvant GC were given over 12 weeks (n = 42). Thirty-nine (93%) of 42 patients received 4 cycles, with a median 91% drug delivery for cisplatin and 90% for gemcitabine. The pT0 proportion was 26% (95% confidence interval [CI], 14-42), and no residual muscle-invasive disease proportion (<pT2) was 36% (95% CI, 21-52); pT0 was achieved in 28% (95% CI, 16-42) and <pT2 in 35% (95% CI, 23-49) of 54 MVAC-treated patients. All 15 GC patients achieving <pT2 pathologic stage remained disease-free at a median follow-up of 30 months.
Neoadjuvant GC is feasible and allows for timely drug delivery. The proportion of GC-treated patients whose primary tumors were downstaged, with prolonged disease-free survival and minimal or no residual disease, was similar to MVAC-treated patients. Cancer 2008. © 2008 American Cancer Society.
Despite surgery with curative intent (radical cystectomy and a bilateral pelvic lymph node dissection), approximately 50% of patients with muscle-invasive transitional cell carcinoma of the bladder will develop distant metastases and die of the disease.1 Attempts to improve survival have focused on perioperative chemotherapy in an attempt to eradicate micrometastases. A meta-analysis of over 3000 patients from neoadjuvant studies demonstrated a statistically superior survival benefit from neoadjuvant cisplatin-based combination chemotherapy compared with surgery alone.2
The most successful neoadjuvant regimen reported in the literature is MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin), a standard of care for treatment of patients with metastatic cancer.3 This consensus is supported by the Southwest Oncology Group (SWOG)-8710 trial that randomized patients with stage T2-T4a bladder cancer to receive either radical cystectomy alone or 3 cycles of MVAC followed by cystectomy.4 Disease-specific survival was superior for the patients receiving neoadjuvant MVAC (hazard ratio, 1.66; 95% confidence interval [CI], 1.22-2.45; P = .002). There was a trend toward superior overall survival (overall survival, 1.33; 95% CI, 1.00-1.76) for MVAC-treated patients, with a 5-year survival of 57% compared with 43% for patients treated with surgery alone (P = .06). Pathologic response to neoadjuvant therapy also yields useful prognostic information. In the SWOG study, patients without residual disease (pT0) at cystectomy had an improved 5-year survival (85%) over those who had residual disease, and patients in the MVAC arm more frequently achieved pT0 status (38% vs 15%; P < .001).4
Despite these data, neoadjuvant chemotherapy has met resistance in the oncology community.5 Commonly cited reasons for lack of neoadjuvant therapy is that MVAC toxicity is too severe for routine clinical use,3 or that delaying cystectomy leads to progression.6 Better-tolerated neoadjuvant chemotherapy may encourage greater utilization and potentially better outcomes. Cisplatin and gemcitabine therapy (GC) demonstrates efficacy similar to MVAC in terms of response and long-term survival for metastatic disease, but with far less toxicity.7, 8 It therefore appears to be an excellent candidate for neoadjuvant therapy, but little information is available regarding optimum drug delivery, pathological response, and disease-free survival.9
Here, we report our experience with neoadjuvant GC before cystectomy in patients with clinical stage pT2-pT4a, N0 bladder cancer. Our main outcome of interest was the rate of pathologic downstaging to either pT0 or <pT2, because these endpoints are directly related to 5-year survival. To provide side-by-side assessments of similar therapy, we describe this experience in the context of a historical cohort of patients treated with neoadjuvant MVAC at our institution.
MATERIALS AND METHODS
Approval was obtained from the institutional review board (IRB) of Memorial Sloan-Kettering Cancer Center (MSKCC) to review patients who had been treated at MSKCC with neoadjuvant chemotherapy, either MVAC or GC. For GC neoadjuvant therapy, both the pharmacy database and the institutional surgical database were queried for all patients who received this chemotherapy at MSKCC's Sidney Kimmel Center for Prostate and Urologic Cancers. Then, medical records of bladder cancer patients treated with GC chemotherapy between November 2000 and December 2006 were reviewed. These records were cross-validated with a surgical database of MSKCC patients undergoing radical cystectomy. The IRB approval allowed us to capture patients with muscle-invasive disease seen at our center who met 2 criteria: 1) they were referred to a MSKCC medical oncologist for neoadjuvant therapy from an outside physician or an MSKCC urologist; and, 2) they received their chemotherapy at our center with GC. During the time period of this study and continuing to the present, it has been our practice in medical oncology to discuss neoadjuvant cisplatin-based regimens such as MVAC and GC with patients who have muscle-invasive disease and who are eligible for neoadjuvant therapy. Despite this discussion, no patients were treated with MVAC during the actual study period.
Patients referred to the Center for muscle-invasive urothelial cancer identified at transurethral resection of the bladder tumor (TURBT) had an independent MSKCC pathology review by dedicated genitourinary pathologists. Patients were then clinically staged with either computed tomography (CT) or magnetic resonance imaging, and a repeat examination under anesthesia (EUA) by a MSKCC urologist. A repeat TURBT was performed at the time of EUA at the surgeon's discretion. All patients underwent postchemotherapy radical cystectomy with pelvic lymphadenectomy. Pathologic staging was retrieved from the postoperative pathology reports. The study included patients with locally advanced disease clinically suspicious for tumor involving the anterior vagina or prostate (clinical stage T4a seen in 3 patients), but excluded patients with cT4b disease. Patients were excluded if there was clinical indication of metastatic disease, eg, any adenopathy >2 cm on pretreatment imaging, or if they had nontransitional cell carcinoma. These ineligible patients with more advanced disease were recommended to have 6 cycles of systemic chemotherapy, the choice of which depended on renal function and medical comorbidities, interest in conventional or investigational therapy, and perceived tolerance of chemotherapy.
Patients were evaluated for chemotherapy by an MSKCC medical oncologist, typically recommending GC chemotherapy consisting of 4 cycles at 21-day intervals over 12 weeks. The 21-day schedule was based on the evidence of greater drug exposure of both cisplatin and gemcitabine compared with the original 28-day schedule, with completion of 4 rather than 3 cycles in 12 weeks.10, 11 Two 21-day schedules predominated: standard single-dose and “split-dose” cisplatin. The former consisted of 4 cycles of GC with cisplatin at 70 mg/m2 and gemcitabine at 1000 mg/m2 on Day 1, and gemcitabine at 1000 mg/m2 on Day 8.12 Split-dose GC consisted of 4 cycles of cisplatin at 35 mg/m2 and gemcitabine at 1000 mg/m2 on Days 1 and 8 of each cycle.13 Two patients received all chemotherapy at local institutions, and 2 received the initial cycle at our institution but completed therapy locally. Specific drug doses were not retrievable in 1 patient, who was excluded from the dose-intensity analysis.
For the comparator cohort, our institutional database was accessed for a previously reported cohort of 111 patients treated with 4 cycles of MVAC chemotherapy at 28-day intervals before cystectomy. These patients had heterogeneous surgical management.14 In that study, some patients refused cystectomy or deferred surgery until progression. We were able to identify 54 of 111 who underwent either a partial or a radical cystectomy after MVAC. Our institutional database did not include complete data regarding the delivered chemotherapy doses and the toxicity related to the MVAC chemotherapy regimen, thus precluding a toxicity comparison with GC. However, it did contain the dates of initiating MVAC chemotherapy, the number of cycles, the date and extent of cystectomy, and pathological endpoints.
Descriptive statistics were used for all endpoints of interest, including pathological outcome and survival. Disease-free survival was chosen as the endpoint of interest because of the relatively short follow-up in the GC cohort. Kaplan-Meier analysis was used to describe disease-free survival, but the GC and MVAC groups were not compared statistically. Disease-free survival was defined as the time from first chemotherapy to the appearance of local or regional disease, metastases, or death. Superficial urothelial cancer recurrences were not considered events. Drug intensity over time was analyzed for 4 planned cycles of therapy in 41 patients, as previously reported by our group15 and others.11 The last 2 cycles in the 2 patients treated with 6 cycles before cystectomy were not included in the calculations.
Forty-two patients received neoadjuvant GC, and 54 received MVAC. Both cohorts had similar clinical characteristics at presentation (Table 1). The GC cohort of 42 patients was selected from a surgical database of over 700 patients undergoing cystectomy for all stages of bladder cancer during the study period. Forty-one patients received GC on the 21-day schedule; 26 patients received standard-dose cisplatin, and 15 patients received the split-dose cisplatin schedule. One patient was treated with the original 28-day GC schedule (Days 1, 8, 15).7 Two patients received 6 rather than the usual 4 cycles of GC. Three patients received only 3 of 4 planned cycles. Reasons for early discontinuation were worsening renal function, dehydration with hypotension, and progressive urinary symptoms without tumor response (1 patient). No patient who received neoadjuvant GC as a bimodal approach to treating muscle-invasive bladder cancer refused cystectomy. Nine patients were hospitalized during treatment. The most common causes were thromboembolic disease (3 patients) followed by emesis (2 patients).
|Characteristics||GC, n=42||MVAC, n=54|
|Age (median, y) at first chemotherapy||64 (56-70)||63 (58-67)|
|Age (median, y) at RC||64 (57-70)||63 (58-68)|
|Sex (men), No. (%)||32 (76)||43 (80)|
|Clinical stage at presentation, No. (%)|
|T2||19 (45)||32 (59)|
|T3||19 (45)||15 (28)|
|T4||4 (10)||7 (13)|
|Days to cystectomy from first chemotherapy dose, median [range]||138 [123-155]||125 [89-175]|
|RC||138 [23-155]||96 [80-163], n=33|
|PC||NA||155 [118-182], n=21|
Pathologic outcomes at cystectomy were contrasted with prechemotherapy clinical stage for GC patients. (Table 2). Twenty-six percent (95% CI, 14-42) of patients achieved pT0 stage and 36% (95% CI, 21-52) had <pT2 disease at cystectomy. Achievement of <pT2 status was achieved in 13 of 27 patients treated with standard-dose cisplatin and 2 of 15 receiving split-dose cisplatin; the small numbers of patients precluded statistical analysis (Table 3). All patients underwent pelvic lymphadenectomy, with a median lymph node count of 15. Lymph node positivity (despite normal postchemotherapy scans) was seen in 2 pT2 patients and 9 pT3 patients. Although all patients had transitional cell carcinoma histology at diagnosis, the cystectomy specimens showed 2 patients with residual squamous differentiation and 1 with residual small cell carcinoma.
|Prechemotherapy Clinical Stage||Pathologic Stage at Cystectomy||Total|
|Dosing Regimen||Pathologic Stage at Cystectomy|
|Clinical stage, No.|
Of the 54 patients treated with neoadjuvant MVAC and surgery, 33 underwent radical cystectomy, and 21 underwent partial cystectomy after chemotherapy. The rate at which pT0 stage and <pT2 were achieved was 28% (95% CI, 16-42) and 35% (95% CI, 23-49), respectively. Because these patients underwent either radical or partial cystectomy based on response to chemotherapy, 15% of 33 patients (95% CI, 5-32) who underwent radical cystectomy were pT0, but 48% of 21 patients (95% CI, 26-70) were stage pT0 after partial cystectomy.
Disease-free survival was assessed in relation to pathological outcome. At last follow-up in the GC cohort, 15 patients had developed recurrent disease, of whom 10 died of disease, and 5 were alive with disease. Twenty-six patients were without evidence of disease. One patient died of unknown causes 3½ years after initial chemotherapy. All 15 patients who were <pT2 stage at cystectomy remained disease-free at last follow-up, with a median follow-up of 30 months (interquartile range [IQR], 14-37). All 11 patients with positive lymph nodes at cystectomy recurred; 7 subsequently died of disease. Disease-free survival curves for the GC and MVAC cohorts are presented in Figure 1. The median follow-up for survivors was 24.2 months in the GC cohort and 48.1 months in the MVAC cohort.
In evaluating the ability to deliver the planned GC chemotherapy, we found that the median time from the first day of GC chemotherapy to the last date of therapy was 77 days (IQR, 70-89). The median time from the date of the last drug administration to the date of radical cystectomy was 57 days (IQR, 46-76). The median interval from first chemotherapy treatment to radical cystectomy was 138 days (IQR, 123-155). No significant differences were observed in the duration of therapy for patients treated with conventional cisplatin dosing (n = 27) versus a split-dose schedule (n = 15) (Table 4).
|Therapy Span||Conventional Dose Schedule, Median Days (Range), n=27||Split Dose Cisplatin, Median Days (Range), n=15|
|Start of chemotherapy to cystectomy||147 (123-169)||129 (112-145)|
|Start to end of chemotherapy||77 (70-97)||75 (70-84)|
|End of chemotherapy to cystectomy||62 (47-82)||49 (40-66)|
The median time from first MVAC chemotherapy to radical cystectomy was 126 days (IQR, 89-175). This interval was 96 days (IQR, 80-163) among the 33 patients who underwent radical cystectomy versus 155 days (IQR, 118-182) among the 21 patients who underwent partial cystectomy.
Dose-intensity of GC chemotherapy was reviewed for a planned 4 cycles to be given over 12 weeks. All 42 study patients received at least 3 cycles of neoadjuvant GC, 39 (93%) received 4 cycles, and 2 received 6 cycles. The achieved dose intensity for cisplatin was 90% (IQR, 75-100), translating into a median weekly cisplatin dose of 21 mg/m2/week (IQR, 18-23). The achieved dose intensity for gemcitabine was 90% (IQR, 68-100), with a median dose of 615 mg/m2/week (IQR, 542-667). Cisplatin dose intensity was slightly greater in patients receiving split-dose cisplatin (93%) compared with conventional single-dose cisplatin (88%).
This is the first comprehensive study demonstrating that neoadjuvant GC chemotherapy can downstage muscle-invasive bladder tumors to a degree observed with MVAC.14 The proportion of patients with complete eradication of tumor (pT0) was 26% for GC in this study and 28% for patients treated with MVAC in our prior study. Elimination of muscle-invasive disease (<pT2) was also similar: 36% for GC and 35% for MVAC. Although these results do not come from a direct random comparison, the similarity of responses in primary bladder tumors across 1 institution's studies is not surprising, given the comparable activity of these 2 regimens in metastatic cancer.7, 8
Pathologic response to neoadjuvant therapy yields useful prognostic information. In the SWOG study, patients without residual disease (pT0) at cystectomy had an improved 5-year survival (85%) over those who had residual disease, and patients in the MVAC arm more frequently achieved pT0 status (38% vs 15%; P < .001).4 However, even less complete downstaging to non–muscle-invasive disease (<T2) is still prognostic. One analysis reported that patients with only residual “superficial” disease (including pT0, pTcis, pTa, and pT1) after neoadjuvant chemotherapy experienced a 75% survival at 5 years, compared with 20% for those with residual muscle-invasive or lymph node–positive disease.16 Thus, chemotherapy downstaging defines chemotherapy efficacy and is a surrogate for long-term survival.
At first glance, the pathologic complete response rate (pT0) of 26% achieved with GC in this study appears inferior to other studies in which 38% of patients were reported to have achieved pT0 with MVAC and 32% with CMV (cisplatin, methotrexate, and vinblastine).4, 17 A closer look at these trials suggests that the pT0 rates across studies are actually similar. In the neoadjuvant CMV trial, only 206 of 246 patients receiving chemotherapy had surgery; 35 had tumor progression precluding cystectomy.18 Thus, the reported pT0 rate of 32% drops to 27% (95% CI, 21-33) if the results are evaluated using an intent-to-treat analysis. SWOG-8710 reported a pT0 rate of 38% (48 of 126) in patients undergoing surgery,4 but that drops to 32% (48 of 150; 95 CI, 25-40) using an intent-to-treat analysis when all 150 patients receiving MVAC are included. Thus, these data suggest that GC chemotherapy has activity within the range of other neoadjuvant regimens known to improve survival.
Similar to prior observations with MVAC,4, 14 GC patients with an excellent pathological response to therapy did well. All 15 GC patients achieving <pT2 disease in this study remain disease-free. Although the median follow-up is shorter than the previously reported MVAC series, these results support the concept that sustained benefit in disease-free survival follows downstaging to <pT2, and is similar across active cisplatin-based regimens.16 Moreover, no patient failed to undergo cystectomy because of progression during 12 weeks of neoadjuvant GC chemotherapy.
Drug delivery with the 21-day schedule of GC was excellent. Forty-two patients received at least 3 cycles, and 39 (93%) received 4 cycles. This delivery appears to be better than MVAC and CMV as reported in randomized trials. SWOG-8710 reported that 87% of patients randomized to MVAC received 1 full cycle of chemotherapy.4 The CMV trial reported that 20% of patients received less than the 3 intended cycles, and approximately half the patients received the planned dose of cisplatin.18 These observations suggest that the GC regimen, better tolerated than MVAC in advanced disease, is superior to CMV in the delivered number of cycles and possibly better than MVAC.
In this study, dose intensity was higher using a 21-day schedule for GC than the original 28-day schedule. The achieved dose intensity for cisplatin was 90% (IQR, 75-100), translating into a median weekly cisplatin dose of 21 mg/m2/week (IQR, 18-23), higher than cisplatin delivery seen in a prior MVAC study from our center.15 Our results for GC are similar to other studies following the 21-day GC regimen of 70 mg/m2/cycle and a delivered cisplatin dose of 21 mg/m2/week in bladder cancer and 23 mg/m2/week in nonsmall lung cancer.10, 12, 19 The achieved dose intensity for gemcitabine was 90% (IQR, 68-100), with a median dose of 615 mg/m2/week (IQR, 542-667), exceeding that observed for the 28-day GC schedule, with observed medians of 593 to 600 mg/m2/week.7, 11 We also report on 15 patients treated with split-dose cisplatin who achieved a 93% dose intensity. Although fewer responses in the primary tumors were seen after split-dose cisplatin than single-dose cisplatin (2 of 15 vs 13 of 27), the numbers of patients are too small to compare statistically or draw inferences. More study of the regimens is indicated to address whether or not there is a schedule impact on tumor response.
The neoadjuvant GC regimen was generally well tolerated, but there were 9 hospitalizations among the 42 patients. Thromboembolic events accounted for 1 third of the complications, 2 were incidental emboli detected on routine postchemotherapy CTs, and no complication was life-threatening. Thromboembolic complications have been reported to occur in 13% of urothelial cancer patients on cisplatin-based chemotherapy, so the rate of 7% seen in our study is consistent with that observed in the literature.20
There are limitations to our study. This is a retrospective study with selection biases, and a comparison between the GC and MVAC cohorts is limited because of historic rather than randomized comparisons. As with all retrospective analyses, this study may have missed patients receiving bimodality therapy or patients who did not undergo cystectomy despite cross-validation of the pharmacy and surgical datasets. Outside of hospitalization rates, we did not have complete chemotherapy toxicity data. However, this regimen has previously been studied in urothelial and nonsmall lung cancer, and the toxicity profile has been well characterized.
In conclusion, this study demonstrates that GC for muscle-invasive bladder cancer produces definitive clinical activity in the neoadjuvant setting, with a pathological complete response rate similar to that of MVAC and an excellent disease-free survival in responding patients. By using the 21-day schedule, GC could be given for 4 cycles in 12 weeks, with a higher dose intensity than the typical 28-day schedule. This well-tolerated regimen is worthy of more extended use and evaluation in the neoadjuvant setting.
- 9Phase II trial of gemcitabine and cisplatin as neoadjuvant chemotherapy for invasive bladder cancer: preliminary results [abstract]. J Clin Oncol. 2006; 24( suppl): 644S. Abstract 14590., , , et al.
- 17on behalf of the International Collaboration of Trialists of the MRC Advanced Bladder Cancer Group, MRC Clinical Trials Unit, London, UK. Updated results of a randomised controlled trial of neoadjuvant cisplatin (C), methotrexate (M) and vinblastine (V) chemotherapy for muscle-invasive bladder cancer [abstract]. Proc Am Soc Clin Oncol. 2002; 21: 178A. Abstract 710.,
- 18Neoadjuvant cisplatin, methotrexate and vinblastine chemotherapy for muscle-invasive bladder cancer: a randomised controlled trial. International collaboration of trialists. Lancet. 1999; 354: 533–540.
- 19A 3-week gemcitabine-cisplatin regimen for metastatic urothelial cancer. Can J Urol. 2004; 11: 2445–2449., , , et al.