- Email: [email protected]
Consolidative Radiotherapy in Metastatic Urothelial Cancer
Original Study
Consolidative Radiotherapy in Metastatic Urothelial Cancer Sumit Shah,1 Chiyuan Amy Zhang,2 Steven Hancock,3 Alice Fan,1 Eila Skinner,2 Sandy Srinivas1 Abstract We analyzed a group of 22 patients with metastatic urothelial carcinoma who had received consolidative radiation after chemotherapy. Patients who received consolidative radiotherapy achieved a 19-month progression-free survival and 49-month overall, with 36% of patients disease-free after 6 years. The 5-year overall survival rate for this cohort was 50%. This suggests that consolidative radiation is feasible and might contribute to long-term disease control. Background: We report outcomes of a retrospective, single-institution experience with consolidative radiation after chemotherapy in metastatic urothelial cancer (MUC). Patients and Methods: From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with MUC who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. Overall survival (OS) was defined as time from start of chemotherapy to death or last follow-up. Results: In the selected group of patients with MUC, the median age was 67 years; 59% had received previous cisplatin-based chemotherapy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases. Median survival from diagnosis to cystectomy was 48 months. Median PFS was 13 months and median OS was 29 months. Eight patients (36%) were alive and disease-free 6 years after radiation therapy. Patients who were rendered disease-free were those with nodal metastases and delivery of radiation to a single site of metastasis. Conclusion: In this highly selective cohort of patients with MUC treated with consolidative radiation after chemotherapy, 36% were rendered disease-free. This suggests that radiation is feasible and might contribute to long-term disease control. Further prospective studies are needed to better characterize the benefit of combined modality treatment. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Combined modality treatment, Consolidation, Cystectomy, Radiation
Introduction Although rarely curative, chemotherapy remains the mainstay of treatment for locally advanced/metastatic urothelial carcinoma. Multiagent first-line cisplatin-based combination chemotherapy such as MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or cisplatin and gemcitabine carries a response rate of 45% to 55% and median overall survival (OS) of 13 months.1 Most 1
Division of Oncology Department of Urology 3 Department of Radiation Oncology, Stanford Hospital, Stanford, CA 2
Submitted: Jan 4, 2017; Revised: Mar 24, 2017; Accepted: Apr 3, 2017 Address for correspondence: Sumit Shah, MD, MPH, Division of Oncology, Stanford Hospital, 875 Blake Wilbur Drive, Palo Alto, CA 94304 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.04.007
patients with locally advanced urothelial carcinoma will have disease relapse within 1 year, including patients who achieve a complete response to initial chemotherapy.2 Because most recurrences occur in the same nodal field as the initial site of clinical tumor involvement, several studies have evaluated the role of surgical consolidation after preoperative cisplatinbased chemotherapy for node-positive disease.3,4 In patients with metastatic urothelial cancer who achieve either a partial or complete response to chemotherapy, surgical consolidation has been shown to improve outcomes compared with chemotherapy alone with 5-year OS rates ranging from 33% to 58%.5 Although radiotherapy is known to play a significant role in muscle-invasive bladder cancer,6,7 there is a paucity of data regarding the role of consolidative radiation in metastatic urothelial cancer.
Clinical Genitourinary Cancer Month 2017
-1
Consolidative Radiotherapy in Metastatic Urothelial Cancer In this study, we report on our single-institution experience with consolidative radiation for metastatic urothelial cancer.
Patients and Methods From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with metastatic urothelial carcinoma who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. The sites of metastasis included regional lymphadenopathy (N1, N2, and N3) as well as distant nodal and visceral metastases (M1). Patients who received radiation to multiple fields were included in the analysis. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Patients who received radiation for a palliative intent were excluded from the cohort. After approval from our institutional review board, a retrospective medical record review was performed and data on age, sex, stage, chemotherapy regimen, date and site of relapse, and dose of radiation were collected. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. OS was defined as time from start of chemotherapy to death or last follow-up. Continuous variables are presented in mean and range; categorical variables are expressed in frequencies with percentage. KaplaneMeier curves illustrate the overall and PFS in months, stratified according to single versus multiple nodes. Cox proportional hazard models are incorporated to assess relative risks of subjects in numbers of nodes and different stages of cancer. A multivariate logistic regression model was built to predict the likelihood of one being an overall survivor.
Results Patients In the 22 selected patients with metastatic urothelial carcinoma who underwent consolidative radiation therapy, the median age was 67 (range, 27-82) years with 64% of the cohort being men. Fifteen patients (68%) had primary bladder disease whereas 7 patients (32%) had upper tract disease. At the time of initial diagnosis, 10 patients (53%) had stage IV disease, of which 2 patients had M1 disease at the time of diagnosis and 8 patients had regional nodal involvement. Five patients (26%) had stage III disease, 2 patients (10.5%) had stage II disease, and 2 patients had stage I disease (10.5%).
Relapse Of the 22 patients, 17 (77%) had disease relapse with nodal involvement. Fifteen patients had disease relapse to either pelvic or retroperitoneal lymph nodes and 2 patients had disease relapse to distant nodes (mediastinal and supraclavicular nodes). Three patients (14%) had metastatic disease relapse to the lung. Twelve patients (55%) had multiple sites of relapse.
Treatment at First Relapse Of the 20 patients who had metastatic disease relapse, 13 (59%) patients received cisplatin-based chemotherapy, 5 (23%) received carboplatin-based therapy, and 4 (18%) received a nonplatinumbased chemotherapy. The 2 patients who received neoadjuvant chemotherapy (cisplatin-based and dose-dense MVAC, respectively) for their metastatic disease at the time of diagnosis did not receive further chemotherapy. All patients achieved a partial response to chemotherapy. All 22 patients underwent consolidative intensity modulated radiation therapy to the remaining metastatic foci with doses ranging from 25 to 56 Gy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases.
Response The median PFS for all patients from the time of radiotherapy consolidation to the time of relapse or last follow-up was 19 months (95% confidence interval [CI], 9-61 months; Figure 1). Median OS for all patients from time of first relapse to death or last follow-up was 49 months (95% CI, 27-63 months; Figure 2).
Table 1 Patient Characteristics Characteristic Median Age (Range), y Sex: Male/Female, n (%)
2
-
All patients in this cohort underwent cystectomy or nephrouretectomy. Three patients completed neoadjuvant chemotherapy and 10 patients underwent adjuvant therapy after resection. Six patients were initially treated with surgery alone, with chemotherapy given at the time of relapse as discussed in the Treatment at First Relapse section. In total, 19 patients with either local (stage I) or locally advanced disease (stage II-III, or stage IV, M0 disease), had metastatic relapse, with a mean time to relapse of 22 months (range, 2-90 months), and were treated with chemotherapy at the time of relapse. Three patients with stage IV disease were treated with chemotherapy after cystectomy for residual disease after surgery. Previous treatments are summarized in Table 1.
Clinical Genitourinary Cancer Month 2017
67 (27-82) 14/8 (64/36)
Primary, n (%) Bladder RP/ureter
15 (68) 7 (32)
Initial Therapy Surgery alone Surgery with adjuvant chemotherapy Neoadjuvant chemotherapy with surgery Time to Recurrence (Range), mo
Previous Treatment
Value
6 (27) 13 (59) 3 (27) 22 (0-90)
Chemotherapy at First Relapse or for Residual Disease, n (%) Cisplatin combination
13 (59)
Carboplatin combination
5 (23)
Nonplatin combination
4 (18)
Sites of Metastases, n (%) Nodes
17 (77)
Lung
3 (14)
Adrenal
1 (4.5)
Omentum Single vs. Multiple Nodes, n (%) Abbreviation: RP ¼ retroperitoneal.
1 (4.5) 10/12 (45/55)
Sumit Shah et al Figure 1 Progression-Free Survival (PFS)
Cox hazard models were performed to stratify PFS and OS according to number of nodes (single vs. multiple), age, sex, and stage. Survival analysis showed that patients with multiple nodes had 17.84 greater odds of disease relapse after radiation compared with single-node metastases (95% CI, 2.28-139.7; P ¼ .0061). Patients with multiple nodes at the time of first relapse had a 2.28 times greater likelihood of death, however this was not statistically significant (95% CI, 0.605-8.616; P ¼ .2232). Stratification according to age, sex, and stage was not statistically significant. Eight patients (36%) were alive and disease-free 6 years after radiation therapy and were deemed the long-term responders. Six of the 8 patients received radiation to regional lymph nodes (including retroperitoneal lymph nodes). Two of the 8 patients received radiation to distant sites—1 to a single mediastinal lymph node and the other patient received radiation to a single lung metastasis. A responder versus nonresponder analysis was conducted to identify important predictors for OS. We examined sex, nodal status (nonregional, regional, visceral), number of nodes (single vs. multiple), and duration between the time of cystectomy to first relapse. In this analysis, having only 1 metastatic lymph node proved to be a statistically favorable predictive factor (Table 2).
months and 5-year cancer-specific survival of 33% for those who achieved a partial response to chemotherapy.9 Compared with the surgical consolidation literature, little is known regarding the role of radiotherapy consolidation treatment. To date, this is the largest known study of patients with metastatic urothelial carcinoma who underwent radiation consolidation treatment. One previous retrospective Canadian study of 12 patients who achieved a partial response to chemotherapy followed by radiation showed a median OS of 15.6 months.10 In the current study, we evaluated 22 patients who had undergone consolidative radiation for metastatic urothelial carcinoma. All patients had previously undergone cystectomy or nephrouretectomy, and most patients had disease relapse in the metastatic Figure 2 Overall Survival
Discussion The treatment and prognosis for metastatic urothelial carcinoma has evolved considerably with the use of multimodality treatment. Early studies on consolidative surgery from Herr et al showed a significant benefit of postchemotherapy radical cystectomy for regionally metastatic bladder cancer with a 5-year OS rate of 32%. Patients who had declined surgery had a 5-year OS rate of only 8%.8 More recent prospective data of patients from M.D. Anderson who underwent surgical consolidation for node-positive metastatic bladder cancer showed a median cancer-specific survival of 26
Clinical Genitourinary Cancer Month 2017
-3
Consolidative Radiotherapy in Metastatic Urothelial Cancer randomized study would thus be needed to quantify the benefit of consolidative radiation.
Table 2 Responder Versus Nonresponder Analysis
Variable
Not Long-Term Long-Term Responder Responder (n [ 14) (n [ 8)
P
Age, y
63.3 3.8
64.6 4.0
.82
Sex: Male/Female, n (%)
9/5 (64/36)
5/3 (63/37)
.93
Duration From Cystectomy to First Relapse, mo
24.3 7.6
30.8 7.6
.58
Nonregional
2 (14.3)
1 (12.5)
.95
Visceral
4 (28.6)
1 (12.5)
Regional
8 (57.1)
6 (75.0)
Node Status, n (%)
Node Number, n (%) Single Multiple
3 (21.4)
7 (87.5)
11 (78.6)
1 (12.5)
.011
setting with a median time to first relapse of 22 months. Patients received chemotherapy at the time of first relapse and subsequently achieved a partial response. Consolidative radiation was then given for residual disease at the sites of relapse. In this study we showed a 19-month PFS after radiation and 49month OS for patients who underwent consolidative radiation, with 36% of patients disease-free after 6 years. The 5-year OS rate for this cohort was 50%. Multivariate analysis showed that multiple nodes (> 1) predicted significantly worse outcomes with regard to PFS (hazard ratio [HR], 17.84) and a trend toward poorer OS (HR, 2.28). Stage at the time of diagnosis did not correlate with outcomes at a statistically significant level, likely because of small numbers. Interestingly, although most long-term survivors underwent radiation to a single recurrent regional lymph node, 2 patients did have distant disease including 1 patient with a biopsy proven visceral lung metastasis and 1 patient with mediastinal lymphadenopathy, which was clinically evident but not biopsy proven before receiving radiation. Overall, our data are consistent with surgical consolidation outcomes, which show similar 5-year OS rates. There were no significant complications due to radiation in this cohort, which raises the possibility of consolidative radiation as an alternative to surgery. Limitations of the study include the retrospective nature of the series with a heterogenous patient population with patients who presented at different stages and who received different chemoradiation regimens. Many of patients in this series received chemotherapy in the adjuvant setting, whereas more recent data have shown benefit of neoadjuvant therapy for locally advanced urothelial cancer.11 The role of consolidative radiation after immunotherapy was not evaluated in this study. Furthermore, although this is, to our knowledge, the largest cohort in the literature to have undergone consolidative radiation for metastatic urothelial carcinoma, the numbers are limited, especially for subgroup analysis. We also acknowledge that patients who received consolidative radiation were a highly selective population with small tumor burden after chemotherapy, so it is possible that a survival benefit might be reflective of a more indolent biology of their disease. A
4
-
Clinical Genitourinary Cancer Month 2017
Conclusion Multimodality therapy with consolidative radiation for metastatic urothelial carcinoma has curative potential. In this highly selective cohort of patients with metastatic urothelial cancer treated with consolidative radiation after chemotherapy, 36% were rendered disease-free without complications due to radiation. This suggests that radiation is feasible and might contribute to long-term disease control and those with single nodal disease fare best. Further prospective studies should be undertaken to better characterize who would best benefit from this combined modality treatment strategy.
Clinical Practice Points There is currently no consensus on the optimal treatment
strategy for the management of residual disease after chemotherapy in metastatic urothelial cancer. Consolidative radiation after chemotherapy can result in longterm durable remissions. Having radiation treatment to only 1 metastatic lymph node was associated with a better prognosis than treatment to multiple metastatic sites.
Acknowledgments This study was supported by the Division of Oncology at Stanford University.
Disclosure The authors have stated that they have no conflicts of interest.
References 1. von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. J Clin Oncol 2005; 23:4602-8. 2. Dimopoulos MA, Finn L, Logothetis CJ. Pattern of failure and survival of patients with metastatic urothelial tumors relapsing after cis-platinum-based chemotherapy. J Urol 1994; 151:598-600 [discussion: 600-1]. 3. Herr HW, Donat SM. Outcome of patients with grossly node positive bladder cancer after pelvic lymph node dissection and radical cystectomy. J Urol 2001; 165: 62-4. 4. Sweeney P, Millikan R, Donat M, et al. Is there a therapeutic role for postchemotherapy retroperitoneal lymph node dissection in metastatic transitional cell carcinoma of the bladder? J Urol 2003; 169:2113-7. 5. Yafi FA, Kassouf W. Management of patients with advanced bladder cancer following major response to systemic chemotherapy. Expert Rev Anticancer Ther 2009; 9:1757-64. 6. James ND, Hussain SA, Hall E, et al. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med 2012; 366:1477-88. 7. Coen JJ, Zietman AL, Kaufman DS, Shipley WU. Benchmarks achieved in the delivery of radiation therapy for muscle-invasive bladder cancer. Urol Oncol 2007; 25:76-84. 8. Herr HW, Donat SM, Bajorin DF. Post-chemotherapy surgery in patients with unresectable or regionally metastatic bladder cancer. J Urol 2001; 165:811-4. 9. Ho PL, Willis DL, Patil J, et al. Outcome of patients with clinically node-positive bladder cancer undergoing consolidative surgery after preoperative chemotherapy: the M.D. Anderson Cancer Center Experience. Urol Oncol 2016; 34:59.e1-8. 10. Passaperuma K, Ash R, Venkatesan V, Rodrigues G, Winquist E. Pelvic chemoradiotherapy after chemotherapy for metastatic bladder cancer. Can J Urol 2006; 13:3009-15. 11. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med 2003; 349:859-66.
Consolidative Radiotherapy in Metastatic Urothelial Cancer Sumit Shah,1 Chiyuan Amy Zhang,2 Steven Hancock,3 Alice Fan,1 Eila Skinner,2 Sandy Srinivas1 Abstract We analyzed a group of 22 patients with metastatic urothelial carcinoma who had received consolidative radiation after chemotherapy. Patients who received consolidative radiotherapy achieved a 19-month progression-free survival and 49-month overall, with 36% of patients disease-free after 6 years. The 5-year overall survival rate for this cohort was 50%. This suggests that consolidative radiation is feasible and might contribute to long-term disease control. Background: We report outcomes of a retrospective, single-institution experience with consolidative radiation after chemotherapy in metastatic urothelial cancer (MUC). Patients and Methods: From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with MUC who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. Overall survival (OS) was defined as time from start of chemotherapy to death or last follow-up. Results: In the selected group of patients with MUC, the median age was 67 years; 59% had received previous cisplatin-based chemotherapy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases. Median survival from diagnosis to cystectomy was 48 months. Median PFS was 13 months and median OS was 29 months. Eight patients (36%) were alive and disease-free 6 years after radiation therapy. Patients who were rendered disease-free were those with nodal metastases and delivery of radiation to a single site of metastasis. Conclusion: In this highly selective cohort of patients with MUC treated with consolidative radiation after chemotherapy, 36% were rendered disease-free. This suggests that radiation is feasible and might contribute to long-term disease control. Further prospective studies are needed to better characterize the benefit of combined modality treatment. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2017 Elsevier Inc. All rights reserved. Keywords: Chemotherapy, Combined modality treatment, Consolidation, Cystectomy, Radiation
Introduction Although rarely curative, chemotherapy remains the mainstay of treatment for locally advanced/metastatic urothelial carcinoma. Multiagent first-line cisplatin-based combination chemotherapy such as MVAC (methotrexate, vinblastine, adriamycin, and cisplatin) or cisplatin and gemcitabine carries a response rate of 45% to 55% and median overall survival (OS) of 13 months.1 Most 1
Division of Oncology Department of Urology 3 Department of Radiation Oncology, Stanford Hospital, Stanford, CA 2
Submitted: Jan 4, 2017; Revised: Mar 24, 2017; Accepted: Apr 3, 2017 Address for correspondence: Sumit Shah, MD, MPH, Division of Oncology, Stanford Hospital, 875 Blake Wilbur Drive, Palo Alto, CA 94304 E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2017 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2017.04.007
patients with locally advanced urothelial carcinoma will have disease relapse within 1 year, including patients who achieve a complete response to initial chemotherapy.2 Because most recurrences occur in the same nodal field as the initial site of clinical tumor involvement, several studies have evaluated the role of surgical consolidation after preoperative cisplatinbased chemotherapy for node-positive disease.3,4 In patients with metastatic urothelial cancer who achieve either a partial or complete response to chemotherapy, surgical consolidation has been shown to improve outcomes compared with chemotherapy alone with 5-year OS rates ranging from 33% to 58%.5 Although radiotherapy is known to play a significant role in muscle-invasive bladder cancer,6,7 there is a paucity of data regarding the role of consolidative radiation in metastatic urothelial cancer.
Clinical Genitourinary Cancer Month 2017
-1
Consolidative Radiotherapy in Metastatic Urothelial Cancer In this study, we report on our single-institution experience with consolidative radiation for metastatic urothelial cancer.
Patients and Methods From our single-institution database of 2597 patients with urothelial carcinoma treated since 1997, we identified 22 patients with metastatic urothelial carcinoma who underwent consolidative radiotherapy after a partial response to chemotherapy with the intent of rendering them disease-free. The sites of metastasis included regional lymphadenopathy (N1, N2, and N3) as well as distant nodal and visceral metastases (M1). Patients who received radiation to multiple fields were included in the analysis. All patients had undergone primary surgical therapy with either cystectomy or nephroureterectomy. Patients who received radiation for a palliative intent were excluded from the cohort. After approval from our institutional review board, a retrospective medical record review was performed and data on age, sex, stage, chemotherapy regimen, date and site of relapse, and dose of radiation were collected. Progression-free survival (PFS) was defined as time from completion of radiation therapy to relapse or last follow-up. OS was defined as time from start of chemotherapy to death or last follow-up. Continuous variables are presented in mean and range; categorical variables are expressed in frequencies with percentage. KaplaneMeier curves illustrate the overall and PFS in months, stratified according to single versus multiple nodes. Cox proportional hazard models are incorporated to assess relative risks of subjects in numbers of nodes and different stages of cancer. A multivariate logistic regression model was built to predict the likelihood of one being an overall survivor.
Results Patients In the 22 selected patients with metastatic urothelial carcinoma who underwent consolidative radiation therapy, the median age was 67 (range, 27-82) years with 64% of the cohort being men. Fifteen patients (68%) had primary bladder disease whereas 7 patients (32%) had upper tract disease. At the time of initial diagnosis, 10 patients (53%) had stage IV disease, of which 2 patients had M1 disease at the time of diagnosis and 8 patients had regional nodal involvement. Five patients (26%) had stage III disease, 2 patients (10.5%) had stage II disease, and 2 patients had stage I disease (10.5%).
Relapse Of the 22 patients, 17 (77%) had disease relapse with nodal involvement. Fifteen patients had disease relapse to either pelvic or retroperitoneal lymph nodes and 2 patients had disease relapse to distant nodes (mediastinal and supraclavicular nodes). Three patients (14%) had metastatic disease relapse to the lung. Twelve patients (55%) had multiple sites of relapse.
Treatment at First Relapse Of the 20 patients who had metastatic disease relapse, 13 (59%) patients received cisplatin-based chemotherapy, 5 (23%) received carboplatin-based therapy, and 4 (18%) received a nonplatinumbased chemotherapy. The 2 patients who received neoadjuvant chemotherapy (cisplatin-based and dose-dense MVAC, respectively) for their metastatic disease at the time of diagnosis did not receive further chemotherapy. All patients achieved a partial response to chemotherapy. All 22 patients underwent consolidative intensity modulated radiation therapy to the remaining metastatic foci with doses ranging from 25 to 56 Gy. The most common sites radiated were the regional lymph nodes (64%). Other radiated sites included the lung, adrenal glands, and omental metastases.
Response The median PFS for all patients from the time of radiotherapy consolidation to the time of relapse or last follow-up was 19 months (95% confidence interval [CI], 9-61 months; Figure 1). Median OS for all patients from time of first relapse to death or last follow-up was 49 months (95% CI, 27-63 months; Figure 2).
Table 1 Patient Characteristics Characteristic Median Age (Range), y Sex: Male/Female, n (%)
2
-
All patients in this cohort underwent cystectomy or nephrouretectomy. Three patients completed neoadjuvant chemotherapy and 10 patients underwent adjuvant therapy after resection. Six patients were initially treated with surgery alone, with chemotherapy given at the time of relapse as discussed in the Treatment at First Relapse section. In total, 19 patients with either local (stage I) or locally advanced disease (stage II-III, or stage IV, M0 disease), had metastatic relapse, with a mean time to relapse of 22 months (range, 2-90 months), and were treated with chemotherapy at the time of relapse. Three patients with stage IV disease were treated with chemotherapy after cystectomy for residual disease after surgery. Previous treatments are summarized in Table 1.
Clinical Genitourinary Cancer Month 2017
67 (27-82) 14/8 (64/36)
Primary, n (%) Bladder RP/ureter
15 (68) 7 (32)
Initial Therapy Surgery alone Surgery with adjuvant chemotherapy Neoadjuvant chemotherapy with surgery Time to Recurrence (Range), mo
Previous Treatment
Value
6 (27) 13 (59) 3 (27) 22 (0-90)
Chemotherapy at First Relapse or for Residual Disease, n (%) Cisplatin combination
13 (59)
Carboplatin combination
5 (23)
Nonplatin combination
4 (18)
Sites of Metastases, n (%) Nodes
17 (77)
Lung
3 (14)
Adrenal
1 (4.5)
Omentum Single vs. Multiple Nodes, n (%) Abbreviation: RP ¼ retroperitoneal.
1 (4.5) 10/12 (45/55)
Sumit Shah et al Figure 1 Progression-Free Survival (PFS)
Cox hazard models were performed to stratify PFS and OS according to number of nodes (single vs. multiple), age, sex, and stage. Survival analysis showed that patients with multiple nodes had 17.84 greater odds of disease relapse after radiation compared with single-node metastases (95% CI, 2.28-139.7; P ¼ .0061). Patients with multiple nodes at the time of first relapse had a 2.28 times greater likelihood of death, however this was not statistically significant (95% CI, 0.605-8.616; P ¼ .2232). Stratification according to age, sex, and stage was not statistically significant. Eight patients (36%) were alive and disease-free 6 years after radiation therapy and were deemed the long-term responders. Six of the 8 patients received radiation to regional lymph nodes (including retroperitoneal lymph nodes). Two of the 8 patients received radiation to distant sites—1 to a single mediastinal lymph node and the other patient received radiation to a single lung metastasis. A responder versus nonresponder analysis was conducted to identify important predictors for OS. We examined sex, nodal status (nonregional, regional, visceral), number of nodes (single vs. multiple), and duration between the time of cystectomy to first relapse. In this analysis, having only 1 metastatic lymph node proved to be a statistically favorable predictive factor (Table 2).
months and 5-year cancer-specific survival of 33% for those who achieved a partial response to chemotherapy.9 Compared with the surgical consolidation literature, little is known regarding the role of radiotherapy consolidation treatment. To date, this is the largest known study of patients with metastatic urothelial carcinoma who underwent radiation consolidation treatment. One previous retrospective Canadian study of 12 patients who achieved a partial response to chemotherapy followed by radiation showed a median OS of 15.6 months.10 In the current study, we evaluated 22 patients who had undergone consolidative radiation for metastatic urothelial carcinoma. All patients had previously undergone cystectomy or nephrouretectomy, and most patients had disease relapse in the metastatic Figure 2 Overall Survival
Discussion The treatment and prognosis for metastatic urothelial carcinoma has evolved considerably with the use of multimodality treatment. Early studies on consolidative surgery from Herr et al showed a significant benefit of postchemotherapy radical cystectomy for regionally metastatic bladder cancer with a 5-year OS rate of 32%. Patients who had declined surgery had a 5-year OS rate of only 8%.8 More recent prospective data of patients from M.D. Anderson who underwent surgical consolidation for node-positive metastatic bladder cancer showed a median cancer-specific survival of 26
Clinical Genitourinary Cancer Month 2017
-3
Consolidative Radiotherapy in Metastatic Urothelial Cancer randomized study would thus be needed to quantify the benefit of consolidative radiation.
Table 2 Responder Versus Nonresponder Analysis
Variable
Not Long-Term Long-Term Responder Responder (n [ 14) (n [ 8)
P
Age, y
63.3 3.8
64.6 4.0
.82
Sex: Male/Female, n (%)
9/5 (64/36)
5/3 (63/37)
.93
Duration From Cystectomy to First Relapse, mo
24.3 7.6
30.8 7.6
.58
Nonregional
2 (14.3)
1 (12.5)
.95
Visceral
4 (28.6)
1 (12.5)
Regional
8 (57.1)
6 (75.0)
Node Status, n (%)
Node Number, n (%) Single Multiple
3 (21.4)
7 (87.5)
11 (78.6)
1 (12.5)
.011
setting with a median time to first relapse of 22 months. Patients received chemotherapy at the time of first relapse and subsequently achieved a partial response. Consolidative radiation was then given for residual disease at the sites of relapse. In this study we showed a 19-month PFS after radiation and 49month OS for patients who underwent consolidative radiation, with 36% of patients disease-free after 6 years. The 5-year OS rate for this cohort was 50%. Multivariate analysis showed that multiple nodes (> 1) predicted significantly worse outcomes with regard to PFS (hazard ratio [HR], 17.84) and a trend toward poorer OS (HR, 2.28). Stage at the time of diagnosis did not correlate with outcomes at a statistically significant level, likely because of small numbers. Interestingly, although most long-term survivors underwent radiation to a single recurrent regional lymph node, 2 patients did have distant disease including 1 patient with a biopsy proven visceral lung metastasis and 1 patient with mediastinal lymphadenopathy, which was clinically evident but not biopsy proven before receiving radiation. Overall, our data are consistent with surgical consolidation outcomes, which show similar 5-year OS rates. There were no significant complications due to radiation in this cohort, which raises the possibility of consolidative radiation as an alternative to surgery. Limitations of the study include the retrospective nature of the series with a heterogenous patient population with patients who presented at different stages and who received different chemoradiation regimens. Many of patients in this series received chemotherapy in the adjuvant setting, whereas more recent data have shown benefit of neoadjuvant therapy for locally advanced urothelial cancer.11 The role of consolidative radiation after immunotherapy was not evaluated in this study. Furthermore, although this is, to our knowledge, the largest cohort in the literature to have undergone consolidative radiation for metastatic urothelial carcinoma, the numbers are limited, especially for subgroup analysis. We also acknowledge that patients who received consolidative radiation were a highly selective population with small tumor burden after chemotherapy, so it is possible that a survival benefit might be reflective of a more indolent biology of their disease. A
4
-
Clinical Genitourinary Cancer Month 2017
Conclusion Multimodality therapy with consolidative radiation for metastatic urothelial carcinoma has curative potential. In this highly selective cohort of patients with metastatic urothelial cancer treated with consolidative radiation after chemotherapy, 36% were rendered disease-free without complications due to radiation. This suggests that radiation is feasible and might contribute to long-term disease control and those with single nodal disease fare best. Further prospective studies should be undertaken to better characterize who would best benefit from this combined modality treatment strategy.
Clinical Practice Points There is currently no consensus on the optimal treatment
strategy for the management of residual disease after chemotherapy in metastatic urothelial cancer. Consolidative radiation after chemotherapy can result in longterm durable remissions. Having radiation treatment to only 1 metastatic lymph node was associated with a better prognosis than treatment to multiple metastatic sites.
Acknowledgments This study was supported by the Division of Oncology at Stanford University.
Disclosure The authors have stated that they have no conflicts of interest.
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