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Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscle-invasive bladder cancer at a tertiary medical center
Journal Pre-proof Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscleinvasive bladder cancer at a tertiary medical center Kimberly R. Gergelis, MD, Cole R. Kreofsky, MD, Christopher S. Choo, MD, Jason Viehman, BS, W Scott Harmsen, MS, Scott C. Lester, MD, Thomas M. Pisansky, MD, Brian J. Davis, MD PhD, Bradley J. Stish, MD, Richard Choo, MD PII:
S1879-8500(20)30045-X
DOI:
https://doi.org/10.1016/j.prro.2020.02.008
Reference:
PRRO 1199
To appear in:
Practical Radiation Oncology
Received Date: 12 December 2019 Revised Date:
5 February 2020
Accepted Date: 12 February 2020
Please cite this article as: Gergelis KR, Kreofsky CR, Choo CS, Viehman J, Harmsen WS, Lester SC, Pisansky TM, Davis BJ, Stish BJ, Choo R, Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscle-invasive bladder cancer at a tertiary medical center, Practical Radiation Oncology (2020), doi: https://doi.org/10.1016/j.prro.2020.02.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscleinvasive bladder cancer at a tertiary medical center Short title: Radiotherapy for elderly with bladder cancer Kimberly R Gergelis MD1, Cole R Kreofsky MD2, Christopher S Choo MD3, Jason Viehman BS4, W Scott Harmsen MS4, Scott C Lester MD1, Thomas M Pisansky MD1, Brian J Davis MD PhD1, Bradley J Stish MD1, Richard Choo MD1 1
Department of Radiation Oncology, Mayo Clinic, Rochester, MN
2
Department of Radiation Oncology, Bismarck Cancer Center, Bismarck, ND
3
Department of Internal Medicine, University of Minnesota, Minneapolis, MN
4
Department of Biostatistics & Information, Mayo Clinic, Rochester, MN
Correspondence:
Richard Choo 200 First Street SW Rochester, MN 55905 507-284-3261 [email protected]
There are no potential conflicts of interest. There is no source of funding or financial support. W Scott Harmsen, MS and Jason Viehman, BS were responsible for statistical support.
Presented as an e-poster at the ASTRO annual meeting in Chicago, Illinois on September 16, 2019 [Int J Radiat Oncol Biol Phys 2019;105(1): E251-E252].
Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscleinvasive bladder cancer at a tertiary medical center
Key words: Bladder cancer, Radiotherapy, Chemotherapy, Tri-modality, Elderly
1
ABSTRACT
Purpose: To evaluate the outcomes and profiles of elderly patients with muscle-invasive bladder cancer (MIBC) treated with definitive radiotherapy (RT) +/- chemotherapy (CHT) at a tertiary medical center.
Methods and Materials: A retrospective study was conducted for elderly patients with MIBC who were ≥ 70 years old and underwent RT +/- CHT between 2000 and 2016. Overall survival (OS) was estimated using the Kaplan-Meier method. Disease-specific survival (DSS), cumulative incidence of progression, patterns of recurrence, and toxicities were examined. Univariate analyses were performed to identify variables associated with OS, DSS, and cumulative incidence of progression, using the Cox proportional hazards model.
Results: A total of 84 patients underwent definitive RT +/- CHT. Of these, only 29% were deemed medically fit to undergo radical cystectomy (RC), while the remainder were medically unfit and/or had surgically unresectable disease. Median age was 81 years. Sixty-one percent, 29%, 2
and 11% had clinical stage II, III, and IV disease, respectively. Eighty-six percent had maximal TURBT prior to RT. Seventy-three percent received CHT with RT, and 27% had RT alone.
Median follow-up was 5.7 years. Median OS was 1.9 years. OS was 42% and 25%, and DSS was 64% and 54% at 3 and 5 years, respectively. On univariate analysis, medical fitness to undergo RC, receipt of CHT, lower T stage, and maximal TURBT were associated with better OS; lower T stage was associated with better DSS. The cumulative incidence of progression was 44% and 49% at 3 and 5 years, respectively. Late grade 3 GU and GI toxicity were 15% and 4%, respectively. None had grade 4 or 5 toxicity.
Conclusions: Elderly patients with MIBC referred for RT were often medically unfit or had a surgically unresectable tumor. In these medically compromised patients, definitive RT+/- CHT was welltolerated and yielded encouraging treatment outcomes.
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INTRODUCTION
Bladder cancer predominately affects elderly patients, with a median age of diagnosis of 73 years in the United States [1]. While the majority of bladder cancers are superficial tumors, 21% are muscle-invasive at the time of diagnosis [2]. Radical cystectomy (RC) + neoadjuvant chemotherapy (CHT) is one of the standard treatment options for muscle-invasive bladder cancer (MIBC). However, RC carries a high incidence of perioperative complications, including a significant perioperative mortality risk [4] [5]. Furthermore, the risk of perioperative mortality increases with advancing age. Schiffmann et al. reported that a 90-day perioperative mortality of RC was 6.4 % for age 65-69, 10.1 % for age 70-79, and 12.6 % for age ≥ 80 year, based on the SEER (Surveillance, Epidemiology, and End Results) database [5].
Another treatment option for MIBC is tri-modality therapy (TMT), incorporating maximal transurethral resection of bladder tumor (TURBT), radiotherapy (RT), and CHT. TMT is an attractive alternative to RC, as it offers an opportunity to preserve the organ and its efficacy can be comparable to that of RC. Multiple prospective studies have shown that TMT can yield equivalent long-term disease control and overall survival (OS) for well-selected patients [6] [7] [8] [9]. Furthermore, TMT is generally well-tolerated, even among elderly patients or those who are poor surgical candidates due to comorbidities.
4
For elderly patients, RC poses significant peril since they often have significant medical comorbidities, including chronic lung or cardiovascular disease. Furthermore, safeguarding the quality of life with organ-preservation, whenever possible, is an important factor in treatment decision-making for the elderly. Considering these factors, TMT is an attractive treatment option, particularly for elderly patients who are not medically fit for RC or desire to pursue organ-preservation.
Gray et al. reported, using the National Cancer Database, that a high proportion of elderly patients with MIBC in the U.S.A. did not receive definitive therapy [10]. The use of a definitive therapy (RC or RT) progressively decreased with advancing age. Of patients aged 71-80 years, 81-90 years, and > 90 years, only 55%, 35% and 15% were treated definitively, respectively. It was also noted that the use of RC steadily decreased with advancing age, while RT was increasingly utilized with older age. However, the significant decrease in RC with advancing age was not offset by a proportional increase in the utilization of RT, resulting in a significant shortfall in the utilization of definitive treatment in older patients.
It has been reported that an aggressive local therapy is associated with improved OS in patients older than 80 [11]. Since TMT can be an effective curative treatment with a safer toxicity profile for elderly patients, there is need to further evaluate the utility and efficacy of TMT in the generally under-treated elderly population. The aim of this paper is to examine the profiles and
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outcomes of elderly patients with MIBC treated with definitive RT +/- CHT at a tertiary medical center.
MATERIALS AND METHODS
Patient selection: The XXXX XXXXX Department of Radiation Oncology database was queried for all patients receiving definitive RT +/- CHT for MIBC between 2000 and 2016. This retrospective study was approved by the Institutional Review Board. Included in the study were patients ≥ 70 years who met all of the following criteria: (1) histological diagnosis of urothelial or squamous carcinoma with pathological confirmation of muscularis propria involvement, (2) clinical stage T2-T4N03M0, based on AJCC 7th Edition staging, (3) attempted maximal TURBT, and (4) receipt of RT +/CHT with curative intent. Patients with a prior history of superficial bladder cancer treated with intravesicular therapy were included if the above criteria were met. All patients underwent an evaluation by a urologist to assess the resectability of their MIBC and medical fitness to withstand RC. Based on this evaluation, patients were classified into two groups: Group 1 consisted of patients who had a surgically resectable tumor and were medically fit for RC, but elected RT +/- CHT, and Group 2 were those that had an unresectable tumor and/or were medically unfit for RC. Radiologic studies for staging included CT of the abdomen and pelvis, chest x-ray or chest CT, and, in some circumstances, pelvic MRI.
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Treatment: All patients underwent attempted TURBT. Following TURBT, patients received RT alone or RT in combination with concurrent and/or neoadjuvant CHT. RT dose, fractionation, and treatment volumes were prescribed at the discretion of the attending radiation oncologist. The target volume of RT was limited to the bladder or expanded to include both the bladder and the regional pelvic lymph nodes. Radiation therapy was delivered with 3D conformal or intensity modulated radiotherapy (IMRT) techniques, using five-days-per-week, once-daily fractionation.
CHT regimens were determined by the attending medical oncologist and included single-agent cisplatin (100 mg/m2 every 3 weeks for 3 cycles or 30-40 mg/m2 weekly), 5-FU plus mitomycinC, carboplatin plus paclitaxel, carboplatin alone, paclitaxel alone, 5-FU alone, or no CHT if precluded by comorbidities.
Assessment of treatment response and follow-up: All patients were evaluated with serial cystoscopy, urine cytology, CT scan of abdomen and pelvis, or MRI of the pelvis, and chest x-ray (or CT scan) every 3 to 6 months in the first 2 years and every 6 months thereafter. Local failure in the bladder was determined by cystoscopy, CT scan of abdomen and pelvis, or MRI of the pelvis, and histological confirmation of tumor recurrence. Abnormal urine cytology alone was considered insufficient for local tumor 7
recurrence. Pelvic relapse outside the bladder, such as pelvic nodal metastasis, and distant failures were identified on imaging and not always confirmed with a biopsy. Presence of local, pelvic, and/or distant failures were assessed until the time of death and documented regardless of whether it occurred as an initial tumor recurrence or as a subsequent failure after initial tumor recurrence.
Statistical analysis Descriptive statistics are reported as median (range) for continuous variables and number (percent) for discrete variables. Baseline comparisons between Group 1 and Group 2 were performed using Chi Square tests. OS was estimated using the Kaplan-Meier method and measured from the date of diagnosis to the date of death or last documented follow-up. DSS was evaluated by the cumulative incidence of bladder cancer-specific death, treating death due to non-bladder cancer causes as a competing risk, from the date of diagnosis to the date of death or last documented follow-up. Patients with an unknown cause of death were classified as death due to bladder cancer. Cumulative incidence of progression was estimated, using death as a competing risk, from the date of initial diagnosis to the date of any failure or last follow-up. Similarly, cumulative incidences of local recurrence (LR), pelvic relapse, and distant metastasis (DM) were estimated, using death as a competing risk, from the date of initial diagnosis to the date of specified failure of interest or last follow-up. Univariate analyses were performed to identify variables associated with OS using a Cox proportional hazards model, and those associated with DSS, disease progression, LR, pelvic relapse, and DM, using Fine and 8
Gray’s extension of the Cox model. A p-value of <0.05 was considered significant. Statistical analyses were performed using SAS v9.4 (SAS Institute Inc, Cary, NC). Acute and late toxicity were assessed, using CTCAE v5.
RESULTS
Patient and treatment characteristics: Between 2000 and 2016, a total of 84 patients met the study inclusion criteria and underwent definitive RT +/- CHT at our center. Of these patients, 51 (61%), 24 (29%), and 9 (11%) patients had stage II, III, and IV disease, respectively. Eighty-two patients had urothelial carcinoma, and the remaining two had squamous cell carcinoma. There were 66 males (79%) and 18 females (21%) with a median age of diagnosis of 81 years. The characteristics of the 84 patients are depicted in Table 1.
RT was delivered to the bladder and regional pelvic lymph nodes in 58 patients (69%), and the remaining 26 (31%) had RT limited to the bladder. The median dose to the bladder tumor and pelvic lymph nodes was 6490 cGy (range: 5040 - 6700) and 4500 cGy (range: 3960 - 5400), respectively. The common dose-fractionation regimens utilized were 6500 cGy in 35 fractions to the bladder tumor with 4500 cGy in 25 fractions to the pelvic lymph nodes, and 5500 cGy in 20 fractions to the bladder tumor with 4400 cGy in 20 fractions to the remaining bladder. Patients 9
were treated with full bladder for most of the dose-fractionation regimens, except the regimen of 5500 cGy in 20 fractions where patients were treated with empty bladder. The median time from diagnosis to initiation of RT was 48 days (interquartile range [IQR]: [29, 75]). Two patients were unable to complete RT, one due to the development of a hemorrhagic stroke and the other due to failure to thrive and genitourinary symptoms.
A total of 61 patients (73%) received CHT with RT. Of these, 60 received concurrent CHT with the majority (26/60: 43%) receiving single agent cisplatin, and 1 received neoadjuvant CHT prior to RT. Twenty-three patients (27%) underwent RT alone. All underwent attempted TURBT, which provided maximal tumor debulking for 72 patients (86%).
Twenty-four patients (29%) were considered to have both medical fitness to withstand RC and a surgically resectable bladder tumor, and were assigned to Group 1. The remaining 60 patients (71%) were medically unfit for RC (58) and/or had a surgically unresectable tumor (9 with T4 disease; of these, 7 were also medically unfit), and were assigned to Group 2. A higher proportion of Group 1 received concurrent or neoadjuvant CHT (92%) and had maximal TURBT (100%), in comparison with Group 2 (65%, p=0.01; 80%, p=0.01, respectively). There was no difference between the two groups in the ability to complete RT or concurrent CHT.
Follow-up, overall survival, disease specific survival, and cumulative incidence of progression: 10
The median follow-up was 5.7 years (range: 0.3 - 11.3). Median survival was 1.9 years. At last follow-up, 68 patients (81%) had died. For the entire cohort, OS was 69%, 49%, 42% and 25%, at 1, 2, 3, and 5 years, respectively. DSS was 80%, 68%, 64%, and 54% at 1, 2, 3, and 5 years, respectively; six patients did not have a documented cause of death, and were classified as death due to bladder cancer. Figure 1 demonstrates all-cause mortality of our cohort which is divided into bladder cancer mortality and non-bladder cancer mortality.
Group 1 had better OS than Group 2 (79% vs. 65% at 1 year, 75% vs. 38% at 2 years, 70% vs. 31% at 3 years, and 37% vs. 20% at 5 years; Log-Rank p= 0.006) (Figure 2). However, there was no statistical difference in DSS between Group 1 and Group 2 (83% vs. 78% at 1 year, 79% vs. 63% at 2 years, 75% vs. 60% at 3 years, and 52% and 55% at 5 years Log-Rank p=0.93). On univariate analysis, Group 1 vs. Group 2 (HR 0.5, 95% CI: 0.3-0.8, p<0.01), concurrent and/or neoadjuvant CHT (HR 0.5, 95% CI: 0.3-0.9, p=0.01), T stage (HR 1.1, T3 vs. T2, 95% CI: 0.6-2.1; HR 2.2, T4 vs. T2, 95% CI: 1.3-3.8, p=0.02), and maximal TURBT (HR 0.5, 95% CI: 0.3-0.99, p=0.046) were associated with better OS. Only T stage was associated with better DSS (HR 1.4, T3 vs. T2, 95% CI: 0.7-3.0; HR 3.6, T4 vs. T2, 95% CI: 1.5-8.4, p=0.02).
Thirty-nine patients (46%) had disease relapse at the time of last follow-up or death. The cumulative incidence of progression was 25%, 37%, 44%, and 49% at 1, 2, 3, and 5 years, respectively, for the entire cohort. There was no difference in the cumulative incidence of progression between Group 1 and Group 2 (13% vs. 29% at 1 year, 22% vs. 43% at 2 years, 40% 11
vs. 49% at 3 years, and 47% vs. 49% at 5 years; Log-Rank p= 0.33) (Figure 3). On univariate analysis, none of the evaluated variables were associated with the cumulative incidence of progression. At 5 years, 23 patients (27%) experienced LR; of these, 12 were biopsy-proven, muscle-invasive disease, whereas the remainders were superficial or in situ disease. LR at 1, 2, 3, and 5 years was 18%, 24%, 28%, and 29%, respectively. Maximal TURBT was significantly associated with better local control (p=0.02) (Figure 4), whereas concurrent and/or neoadjuvant CHT had no impact. Pelvic relapse at 1, 2, 3, and 5 years was 5%, 8%, 8% and 9%, respectively. There was a trend towards less pelvic relapse with maximal TURBT (p=0.054), while other variables including RT volume (bladder + pelvic lymph nodes vs. bladder only) had no association. DM at 1, 2, 3 and 5 years was 12%, 21%, 27%, and 33%, respectively. No variable was correlated with a higher risk of DM, including the receipt of CHT. The three most common sites of DM were the lung, liver, and bones. Table 2 describes univariate analyses examining potential associations with OS, DSS, cumulative incidence of progression, LR, pelvic relapse, and DM.
Acute and late GU and GI side effects: Acute grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicity was seen in 38% and 26% of patients, respectively. Two patients (2%) had acute grade 3 GU toxicity (1 with urinary obstruction and frequency; 1 with urosepsis). One (1%) had acute grade 3 GI toxicity (diarrhea). None had grade 4 or 5 acute toxicity. No variable was associated with acute grade ≥ 2 GU or GI toxicity. Of 60 patients receiving concurrent CHT, 20 were unable to complete planned CHT, 12
primarily due to deteriorating renal function, hematologic toxicity, diarrhea, fatigue, unrelated medical illnesses, or a combination of the aforementioned. Two patients were unable to complete RT, one due to failure to thrive and GU symptoms, and the other due to a hemorrhagic stroke.
Late grade ≥ 2 GU and GI toxicity was seen in 31% and 5% of patients, respectively. Thirteen patients (15%) had late grade 3 GU toxicity (2 urinary incontinence; 6 radiation cystitis including hematuria; 5 ureteral obstruction). Three patients (4%) had late grade 3 GI toxicity (2 radiation proctitis; 1 stricture of sigmoid colon). None had grade 4 or 5 acute or late toxicity.
DISCUSSION
RC + neoadjuvant CHT has been considered one of the standard treatment options for MIBC in the United States. However, RC carries a high rate of perioperative complications, including mortality, and potential long-term toxicities, such as renal insufficiency, urinary tract infection, and ureteral obstruction [12]. A randomized study by Bochner et al. reported a 90-day perioperative grade 2-5 complication rate of 66% with open RC and 62% with robot-assisted laparoscopic RC [13] .
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A growing number of studies have reported that TMT is efficacious with a relatively low incidence of major toxicity for MIBC [7] [8]. As a result, TMT is a viable alternative for patients medically unfit for RC or those opting for bladder preservation. In particular, it is an attractive treatment option for elderly patients who often have major medical comorbidities and unfavorable perioperative risk of RC. The notion that TMT is generally well-tolerated in elderly or frail patients is reflected well in our series where 98% (82/84) and 67% (40/60) of our cohort were able to complete planned RT and concurrent CHT, respectively.
The underutilization of definitive therapies (RC or RT) in the elderly population for MIBC has been reported [10, 14]. Separately, Hollenbeck et al reported that an aggressive local therapy is associated with improved OS in patients ≥ 80 years [11]. These parallel remarks raise the concern for possible sub-optimal care of elderly patients with MIBC and call for further exploration of a less morbid therapeutic intervention. The reasons for the underutilization of a definitive therapy in the elderly are likely multifactorial and include the concern for the ability to withstand major surgical or medical treatment, the presence of competing medical comorbidities, the potential treatment-related toxicity, and the impact of treatment on the quality of life in an elderly patient with a limited life expectancy. The aim of our series was to provide additional data on the utility and efficacy of RT +/- CHT in an elderly population for whom it can be an effective curative therapy with a safer toxicity profile.
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The OS of 49% at 2 years, 42% at 3 years, and 25% at 5 years in our series is reasonable, considering that our cohort was primarily comprised of elderly, and often frail, patients. In our series, 71% of patients were deemed medically unfit for RC and/or had surgically unresectable MIBC. These clinical features likely represent the current landscape of patients with MIBC who are referred for the consideration of RT +/- CHT. The inability to undergo RC, either due to comorbidities or unresectable tumor, along with the median age of 81 years in our series, predicts a low overall survival, regardless of disease progression, due to competing risks of death in these elderly patients with poor performance status. In our cohort, Group 1 had better OS than Group 2 (Log-Rank p= 0.006). Better overall health status is likely a key factor for better OS in Group 1. Also, the difference in overall health status can explain the differences in the proportions of patients receiving concurrent/neoadjuvant CHT (92% in Group 1 vs. 65% in Group 2), although there was no statistically significant difference in the ability to complete planned concurrent CHT between the two groups.
The DSS of our cohort (68% at 2 years, 64% at 3 years, and 54% at 5 years) is much better than OS, with the overall and bladder cancer-specific mortality demonstrated in Figure 1. This discordance between OS and DSS illustrates the risk of dying from causes other than bladder cancer was substantial, and the cumulative incidence of progression may have been underestimated by a competing risk of death in our series.
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The OS of our series is comparable to other series evaluating the efficacy of TMT. The Southwest Oncology Group conducted a phase II study to evaluate TMT (RT plus concurrent 5FU + cisplatin) in patients with MIBC who were medically unfit/surgically unresectable (55%), or refusing RC (45%). In this series, the patients were younger, with a median age of 67 years, but had more advanced T stages (≥ T3: 68%) with a higher rate of nodal metastasis (N1-2: 22%), in comparison with our cohort. This study reported an OS of about 42% at 3 years and 32% at 5 years [15]. In another series of 39 elderly patients (median age: 78 years) treated with TMT or RT alone, Tran et al. reported an OS of 43% at 3 years and 29% at 5 years [3]. It is also noteworthy that the OS of our study is similar to a series evaluating RC in an elderly population. Boustani et al. reported an OS of 22% at 5 years for 92 patients treated with RC, with a median age of 82 years [16]. In the same series, the author also reported that there was no difference in 5-year OS between patients treated with RC and those receiving RT + CHT, 22% vs 25%, respectively.
In our series, maximal TURBT was associated with a decreased risk of LR and pelvic relapse. This finding is similar to other series [7] [17] . Concurrent CHT was not a statistically significant prognostic factor for local or pelvic control in our study, in contrast to phase III [18] [19] and phase II studies [20] [21] [22]. Additionally, RT to the pelvic lymph nodes and bladder did not yield better pelvic control, in comparison with RT to the bladder alone, in our series. None of the variables examined were associated with a higher risk of DM. However, given the retrospective nature and a relatively small sample size of our series, caution is needed when
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interpreting out data on prognostic variables associated with treatment outcomes and relapse patterns.
Treatment-related toxicity is a major concern in elderly or medically-compromised patients. In our series, RT +/- concurrent CHT was generally well-tolerated. Most patients (98%) were able to complete planned RT, and 67% completed planned concurrent CHT. Acute grade 3 GU (2%) and GI (1%) toxicity was uncommon. In addition, late grade 3 GU toxicity of 15% was reasonable, and late grade 3 GI toxicity was infrequent (4%). No patients had acute or late grade 4 or 5 GU or GI toxicity. However, the incidence of late toxicity was likely underestimated due to a competing risk of death.
There are several limitations in our series. First, this was a retrospective analysis, thus unrecognized biases and/or confounding factors as well as inherent shortcoming in evaluating treatment outcomes and treatment-related toxicities are present. Second, the total number of patients in this analysis was relatively small, thus the outcomes observed must be interpreted with caution. Third, our cohort of patients was compiled over an extended period of time (2000-2016) during which various CHT agents and RT regimens were utilized and evolved. Nevertheless, the data and analysis presented herein provide a useful resource for counseling elderly patients in whom management options are often limited.
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CONCLUSION Elderly patients with MIBC referred for RT +/- CHT are often medically unfit or have surgically unresectable bladder cancer. Our series demonstrates that RT +/- CHT can be a safe and effective treatment option for elderly patients with MIBC, who are often medically unfit for RC or interested in pursuing organ preservation. In our study, RT +/- CHT was generally welltolerated, with low acute and late GU and GI toxicities, and yielded reasonable treatment outcomes consistent with the reported literature.
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James, N.D., et al., Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med, 2012. 366(16): p. 1477-88.
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Gray, P.J., et al., Use of potentially curative therapies for muscle-invasive bladder cancer in the United States: results from the National Cancer Data Base. Eur Urol, 2013. 63(5): p. 823-9.
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Hollenbeck, B.K., et al., Aggressive treatment for bladder cancer is associated with improved overall survival among patients 80 years old or older. Urology, 2004. 64(2): p. 292-7.
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Parekh, D.J., et al., Robot-assisted radical cystectomy versus open radical cystectomy in patients with bladder cancer (RAZOR): an open-label, randomised, phase 3, noninferiority trial. Lancet, 2018. 391(10139): p. 2525-2536.
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Bochner, B.H., et al., Comparing Open Radical Cystectomy and Robot-assisted Laparoscopic Radical Cystectomy: A Randomized Clinical Trial. Eur Urol, 2015. 67(6): p. 1042-1050.
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Turgeon, G.A. and L. Souhami, Trimodality therapy for bladder preservation in the elderly population with invasive bladder cancer. Front Oncol, 2014. 4: p. 206.
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Hussain, M.H., et al., Combination cisplatin, 5-fluorouracil and radiation therapy for locally advanced unresectable or medically unfit bladder cancer cases: a Southwest Oncology Group Study. J Urol, 2001. 165(1): p. 56-60; discussion 60-1.
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Boustani, J., et al., Radical cystectomy or bladder preservation with radiochemotherapy in elderly patients with muscle-invasive bladder cancer: Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators. Acta Oncol, 2018. 57(4): p. 491-497.
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Efstathiou, J.A., et al., Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol, 2012. 61(4): p. 705-11.
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Huddart, R.A., et al., Randomized noninferiority trial of reduced high-dose volume versus standard volume radiation therapy for muscle-invasive bladder cancer: results of the BC2001 trial (CRUK/01/004). Int J Radiat Oncol Biol Phys, 2013. 87(2): p. 261-9.
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Coppin, C.M., et al., Improved local control of invasive bladder cancer by concurrent cisplatin and preoperative or definitive radiation. The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol, 1996. 14(11): p. 2901-7.
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Mitin, T., et al., Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol, 2013. 14(9): p. 863-72.
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FIGURE LEGENDS
Table 1: Baseline demographics, clinical characteristics, and treatment details Table 2: Variables associated with overall survival, disease specific survival, cumulative incidence of progression, local relapse, pelvic relapse, and distant metastasis Figure 1: Mortality with bladder cancer and non-bladder cancer mortality Figure 2: Overall survival Figure 3: Cumulative incidence of progression Figure 4: Cumulative incidence of local failure stratified by receipt of maximal TURBT
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Tables Table 1: Baseline demographics, clinical characteristics, and treatment details Overall
Age, median (range), y ≥ 80, No. (%) < 80, No. (%) Sex, No. (%) Male Female Histology, No. (%) Urothelial Squamous T stage, No. (%) T2 T3 T4 N stage, No. (%) N0 N1 N2 N3 Stage, No. (%) II III IV Tumor grade, No. (%) G1 G2 G3 Missing Hydronephrosis, No. (%) Yes No Maximal TURBT, No. (%) Yes No Concurrent CHT, No. (%) Yes
81 (70-94) 46 (54.8) 38 (45.2)
Medically fit and surgically resectable (Group 1) (n=24) 82 (70-90) 13 (54.2) 11 (45.8)
Medically unfit and/or surgically unresectable (Group 2) (n=60) 81 (70-94) 33 (55.0) 27 (45.0)
p value
66 (78.6) 18 (21.4)
19 (79.2) 5 (20.8)
47 (78.3) 13 (21.7)
0.93
82 (97.6) 2 (2.4)
23 (95.8) 1 (4.2)
59 (98.3) 1 (1.7)
0.50
53 (63.1) 22 (26.2) 9 (10.7)
14 (58.3) 7 (29.2) 3 (12.5)
39 (65.0) 15 (25.0) 6 (10.0)
78 (92.9) 3 (3.6) 2 (2.4) 1 (1.2)
22 (91.7) 2 (8.3) 0 (0) 0 (0)
56 (93.3) 1 (1.7) 2 (3.3) 1 (1.7)
51 (60.7) 24 (28.6) 9 (10.7)
14 (58.3) 7 (29.2) 3 (12.5)
37 (61.7) 17 (28.3) 6 (10.0)
1 (1.2) 1 (1.2) 81 (96.4) 1 (1.2)
0 (0) 0 (0) 24 (100) 0 (0)
1 (1.7) 1 (1.7) 57 (95.0) 1 (1.7)
27 (32.1) 57 (67.9)
6 (25.0) 18 (75.0)
21 (35.0) 39 (65.0)
0.38
72 (85.7) 12 (14.3)
24 (100) 0 (0)
48 (80.0) 12 (20.0)
0.02
60 (71.4)
22 (91.7)
38 (63.3)
0.91
0.85
0.34
0.94
0.66
0.01
No Concurrent or Neoadjuvant CHT, No. (%) Yes No Chemo agent for concurrent CHT (n=60), No. (%) Cisplatin Carboplatin + Taxol Carboplatin 5 FU + MMC Taxol 5 FU Ability to complete planned concurrent CHT, No. (%) Yes No Target volume of RT, No. (%) Bladder + pelvic lymph nodes Bladder only RT type 3-D IMRT RT dose, No. (%) PTV bladder tumor: median (range) PTV pelvic nodes: median (range)
24 (28.6)
2 (8.3)
22 (36.7)
61 (72.6) 23 (27.4)
22 (91.7) 2 (8.3)
39 (65.0) 21 (35.0)
26 (43.3) 13 (21.7) 10 (16.7) 5 (8.3) 4 (6.7) 2 (3.3)
8 (36.4) 7 (31.8) 2 (9.1) 2 (9.1) 2 (9.1) 1 (4.5)
18 (47.4) 6 (15.8) 8 (21.1) 3 (7.9) 2 (5.3) 1 (2.6)
40 (66.7) 20 (33.3)
14 (63.6) 8 (36.4)
26 (68.4) 12 (31.6)
58 (69.0) 26 (31.0)
19 (79.2) 5 (20.8)
39 (65.0) 21 (35.0)
0.21
26 (31.0) 58 (69.0)
6 (25.0) 18 (75.0)
20 (33.3) 40 (66.7)
0.46
6490 (5040-6700) 4500 (3960-5400)
6500 (5580-6700) 4500 (3960-5400)
6480 (5040-6700) 4500 (3960-5400)
0.01
0.46
0.70
Table 2: Variables associated with overall survival, disease specific survival, cumulative incidence of progression, local relapse, pelvic relapse, and distant metastasis Variables; HR, (95% CI), p value Age (<80 vs. ≥ 80) Gender
T stage with N0
N0 vs. N1-3
Group 1 vs. Group 2 IMRT vs. 3-D CRT1 RT volume2 CHT3 CHT agents4
Maximal TURBT Hydronephrosis 1
Overall survival
Disease specific survival
Cumulative incidence of progression
Local relapse
Pelvic relapse
Distant metastasis
1.4 (0.9-2.3) p=0.14 0.8 (0.5-1.4) p=0.42 T3: 1.1 (0.6-2.1) T4: 2.2 (1.3-3.8) p=0.02* 1.2 (0.7-2.0) p=0.56 0.5 (0.3-0.8) p<0.01* 1.1 (0.7-1.9) p=0.71 0.9 (0.5-1.4) p=0.55 0.5 (0.3-0.9) p=0.01* 1.2 (0.7-2.2) p=0.48 0.5 (0.3-0.99) p=0.046* 1.3 (0.8-2.2) p=0.28
1.0 (0.5-1.8) p=0.92 0.8 (0.4-1.7) p=0.58 T3: 1.4 (0.7-3.0) T4: 3.6 (1.5-8.4) p=0.02* 1.0 (0.4-2.7) p=0.99 1.0 (0.5-1.8) p=0.93 1.2 (0.6-2.2) p=0.65 1.5 (0.7-3.1) p=0.25 1.6 (0.7-3.7) p=0.31 1.8 (0.9-3.6) p=0.09 1.1 (0.4-3.0) P=0.81 1.1 (0.6-2.1) P=0.75
1.0 (0.6-1.9) p=0.91 0.8 (0.4-1.8) p=0.65 T3: 1.3 (0.6-2.8) T4: 2.5 (1.0-6.7) p=0.17 1.1 (0.4-3.2) p=0.93 0.7 (0.4-1.4) p=0.30 1.5 (0.8-2.9) p=0.22 1.2 (0.6-2.3) p=0.67 1.3 (0.6-2.8) p=0.57 1.0 (0.5-2.0) p=1.00 0.7 (0.3-1.8) p=0.47 0.9 (0.5-1.8) p=0.86
1.6 (0.7-3.8) p=0.26 1.2 (0.5-3.0) p=0.65 T3: 1.0 (0.4-2.9) T4: 3.0 (0.9-10.1) p=0.20 1.1 (0.3-3.7) p=0.91 0.5 (0.2-1.3) p=0.14 1.9 (0.8-4.5) p=0.14 1.8 (0.7-4.8) p=0.25 1.3 (0.5-3.7) p=0.58 0.6 (0.2-1.6) p=0.32 0.3 (0.1-0.8) p=0.02* 0.6 (0.2-1.5) p=0.27
0.7 (0.1-2.9) p=0.58 1.3 (0.3-6.2) p=0.76 T3: 0.5 (0.1-4.5) T4: 2.1 (0.2-17.6) p=0.62 0.8 (0.04-16.9) p=0.88 0.4 (0.05-3.3) p=0.40 1.0 (0.2-4.7) p=0.97 0.3 (0.07-1.4) p=0.13 0.5 (0.1-2.0) p=0.29 0.4 (0.04-3.5) p=0.38 0.5 (0.3-1.01) p=0.054 1.7 (0.4-7.3) p=0.49
0.7 (0.3-1.5) p=0.37 0.56 (0.2-1.6) p=0.28 T3: 0.8 (0.3-2.1) T4: 2.1 (0.7-6.3) p=0.31 1.2 (0.3-5.0) p=0.85 1.1 (0.5-2.4) p=0.89 1.3 (0.6-2.9) p=0.57 1.1 (0.5-2.4) p=0.89 2.3 (0.8-7.2) p=0.14 0.9 (0.4-2.2) p=0.90 1.2 (0.3-4.0) p=0.80 1.4 (0.6-3.0) p=0.42
: IMRT: intensity-modulated radiotherapy, 3-D CRT: three-dimensional conformal radiotherapy : RT volume: bladder only vs. bladder + pelvic lymph nodes 3 : CHT: concurrent and/or neoadjuvant CHT vs. no CHT
2
4
: CHT agents: Cisplatin or 5-fluorouracil + mitomycin vs. others *: p <0.05
S1879-8500(20)30045-X
DOI:
https://doi.org/10.1016/j.prro.2020.02.008
Reference:
PRRO 1199
To appear in:
Practical Radiation Oncology
Received Date: 12 December 2019 Revised Date:
5 February 2020
Accepted Date: 12 February 2020
Please cite this article as: Gergelis KR, Kreofsky CR, Choo CS, Viehman J, Harmsen WS, Lester SC, Pisansky TM, Davis BJ, Stish BJ, Choo R, Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscle-invasive bladder cancer at a tertiary medical center, Practical Radiation Oncology (2020), doi: https://doi.org/10.1016/j.prro.2020.02.008. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.
Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscleinvasive bladder cancer at a tertiary medical center Short title: Radiotherapy for elderly with bladder cancer Kimberly R Gergelis MD1, Cole R Kreofsky MD2, Christopher S Choo MD3, Jason Viehman BS4, W Scott Harmsen MS4, Scott C Lester MD1, Thomas M Pisansky MD1, Brian J Davis MD PhD1, Bradley J Stish MD1, Richard Choo MD1 1
Department of Radiation Oncology, Mayo Clinic, Rochester, MN
2
Department of Radiation Oncology, Bismarck Cancer Center, Bismarck, ND
3
Department of Internal Medicine, University of Minnesota, Minneapolis, MN
4
Department of Biostatistics & Information, Mayo Clinic, Rochester, MN
Correspondence:
Richard Choo 200 First Street SW Rochester, MN 55905 507-284-3261 [email protected]
There are no potential conflicts of interest. There is no source of funding or financial support. W Scott Harmsen, MS and Jason Viehman, BS were responsible for statistical support.
Presented as an e-poster at the ASTRO annual meeting in Chicago, Illinois on September 16, 2019 [Int J Radiat Oncol Biol Phys 2019;105(1): E251-E252].
Outcomes and profiles of elderly patients receiving definitive radiotherapy for muscleinvasive bladder cancer at a tertiary medical center
Key words: Bladder cancer, Radiotherapy, Chemotherapy, Tri-modality, Elderly
1
ABSTRACT
Purpose: To evaluate the outcomes and profiles of elderly patients with muscle-invasive bladder cancer (MIBC) treated with definitive radiotherapy (RT) +/- chemotherapy (CHT) at a tertiary medical center.
Methods and Materials: A retrospective study was conducted for elderly patients with MIBC who were ≥ 70 years old and underwent RT +/- CHT between 2000 and 2016. Overall survival (OS) was estimated using the Kaplan-Meier method. Disease-specific survival (DSS), cumulative incidence of progression, patterns of recurrence, and toxicities were examined. Univariate analyses were performed to identify variables associated with OS, DSS, and cumulative incidence of progression, using the Cox proportional hazards model.
Results: A total of 84 patients underwent definitive RT +/- CHT. Of these, only 29% were deemed medically fit to undergo radical cystectomy (RC), while the remainder were medically unfit and/or had surgically unresectable disease. Median age was 81 years. Sixty-one percent, 29%, 2
and 11% had clinical stage II, III, and IV disease, respectively. Eighty-six percent had maximal TURBT prior to RT. Seventy-three percent received CHT with RT, and 27% had RT alone.
Median follow-up was 5.7 years. Median OS was 1.9 years. OS was 42% and 25%, and DSS was 64% and 54% at 3 and 5 years, respectively. On univariate analysis, medical fitness to undergo RC, receipt of CHT, lower T stage, and maximal TURBT were associated with better OS; lower T stage was associated with better DSS. The cumulative incidence of progression was 44% and 49% at 3 and 5 years, respectively. Late grade 3 GU and GI toxicity were 15% and 4%, respectively. None had grade 4 or 5 toxicity.
Conclusions: Elderly patients with MIBC referred for RT were often medically unfit or had a surgically unresectable tumor. In these medically compromised patients, definitive RT+/- CHT was welltolerated and yielded encouraging treatment outcomes.
3
INTRODUCTION
Bladder cancer predominately affects elderly patients, with a median age of diagnosis of 73 years in the United States [1]. While the majority of bladder cancers are superficial tumors, 21% are muscle-invasive at the time of diagnosis [2]. Radical cystectomy (RC) + neoadjuvant chemotherapy (CHT) is one of the standard treatment options for muscle-invasive bladder cancer (MIBC). However, RC carries a high incidence of perioperative complications, including a significant perioperative mortality risk [4] [5]. Furthermore, the risk of perioperative mortality increases with advancing age. Schiffmann et al. reported that a 90-day perioperative mortality of RC was 6.4 % for age 65-69, 10.1 % for age 70-79, and 12.6 % for age ≥ 80 year, based on the SEER (Surveillance, Epidemiology, and End Results) database [5].
Another treatment option for MIBC is tri-modality therapy (TMT), incorporating maximal transurethral resection of bladder tumor (TURBT), radiotherapy (RT), and CHT. TMT is an attractive alternative to RC, as it offers an opportunity to preserve the organ and its efficacy can be comparable to that of RC. Multiple prospective studies have shown that TMT can yield equivalent long-term disease control and overall survival (OS) for well-selected patients [6] [7] [8] [9]. Furthermore, TMT is generally well-tolerated, even among elderly patients or those who are poor surgical candidates due to comorbidities.
4
For elderly patients, RC poses significant peril since they often have significant medical comorbidities, including chronic lung or cardiovascular disease. Furthermore, safeguarding the quality of life with organ-preservation, whenever possible, is an important factor in treatment decision-making for the elderly. Considering these factors, TMT is an attractive treatment option, particularly for elderly patients who are not medically fit for RC or desire to pursue organ-preservation.
Gray et al. reported, using the National Cancer Database, that a high proportion of elderly patients with MIBC in the U.S.A. did not receive definitive therapy [10]. The use of a definitive therapy (RC or RT) progressively decreased with advancing age. Of patients aged 71-80 years, 81-90 years, and > 90 years, only 55%, 35% and 15% were treated definitively, respectively. It was also noted that the use of RC steadily decreased with advancing age, while RT was increasingly utilized with older age. However, the significant decrease in RC with advancing age was not offset by a proportional increase in the utilization of RT, resulting in a significant shortfall in the utilization of definitive treatment in older patients.
It has been reported that an aggressive local therapy is associated with improved OS in patients older than 80 [11]. Since TMT can be an effective curative treatment with a safer toxicity profile for elderly patients, there is need to further evaluate the utility and efficacy of TMT in the generally under-treated elderly population. The aim of this paper is to examine the profiles and
5
outcomes of elderly patients with MIBC treated with definitive RT +/- CHT at a tertiary medical center.
MATERIALS AND METHODS
Patient selection: The XXXX XXXXX Department of Radiation Oncology database was queried for all patients receiving definitive RT +/- CHT for MIBC between 2000 and 2016. This retrospective study was approved by the Institutional Review Board. Included in the study were patients ≥ 70 years who met all of the following criteria: (1) histological diagnosis of urothelial or squamous carcinoma with pathological confirmation of muscularis propria involvement, (2) clinical stage T2-T4N03M0, based on AJCC 7th Edition staging, (3) attempted maximal TURBT, and (4) receipt of RT +/CHT with curative intent. Patients with a prior history of superficial bladder cancer treated with intravesicular therapy were included if the above criteria were met. All patients underwent an evaluation by a urologist to assess the resectability of their MIBC and medical fitness to withstand RC. Based on this evaluation, patients were classified into two groups: Group 1 consisted of patients who had a surgically resectable tumor and were medically fit for RC, but elected RT +/- CHT, and Group 2 were those that had an unresectable tumor and/or were medically unfit for RC. Radiologic studies for staging included CT of the abdomen and pelvis, chest x-ray or chest CT, and, in some circumstances, pelvic MRI.
6
Treatment: All patients underwent attempted TURBT. Following TURBT, patients received RT alone or RT in combination with concurrent and/or neoadjuvant CHT. RT dose, fractionation, and treatment volumes were prescribed at the discretion of the attending radiation oncologist. The target volume of RT was limited to the bladder or expanded to include both the bladder and the regional pelvic lymph nodes. Radiation therapy was delivered with 3D conformal or intensity modulated radiotherapy (IMRT) techniques, using five-days-per-week, once-daily fractionation.
CHT regimens were determined by the attending medical oncologist and included single-agent cisplatin (100 mg/m2 every 3 weeks for 3 cycles or 30-40 mg/m2 weekly), 5-FU plus mitomycinC, carboplatin plus paclitaxel, carboplatin alone, paclitaxel alone, 5-FU alone, or no CHT if precluded by comorbidities.
Assessment of treatment response and follow-up: All patients were evaluated with serial cystoscopy, urine cytology, CT scan of abdomen and pelvis, or MRI of the pelvis, and chest x-ray (or CT scan) every 3 to 6 months in the first 2 years and every 6 months thereafter. Local failure in the bladder was determined by cystoscopy, CT scan of abdomen and pelvis, or MRI of the pelvis, and histological confirmation of tumor recurrence. Abnormal urine cytology alone was considered insufficient for local tumor 7
recurrence. Pelvic relapse outside the bladder, such as pelvic nodal metastasis, and distant failures were identified on imaging and not always confirmed with a biopsy. Presence of local, pelvic, and/or distant failures were assessed until the time of death and documented regardless of whether it occurred as an initial tumor recurrence or as a subsequent failure after initial tumor recurrence.
Statistical analysis Descriptive statistics are reported as median (range) for continuous variables and number (percent) for discrete variables. Baseline comparisons between Group 1 and Group 2 were performed using Chi Square tests. OS was estimated using the Kaplan-Meier method and measured from the date of diagnosis to the date of death or last documented follow-up. DSS was evaluated by the cumulative incidence of bladder cancer-specific death, treating death due to non-bladder cancer causes as a competing risk, from the date of diagnosis to the date of death or last documented follow-up. Patients with an unknown cause of death were classified as death due to bladder cancer. Cumulative incidence of progression was estimated, using death as a competing risk, from the date of initial diagnosis to the date of any failure or last follow-up. Similarly, cumulative incidences of local recurrence (LR), pelvic relapse, and distant metastasis (DM) were estimated, using death as a competing risk, from the date of initial diagnosis to the date of specified failure of interest or last follow-up. Univariate analyses were performed to identify variables associated with OS using a Cox proportional hazards model, and those associated with DSS, disease progression, LR, pelvic relapse, and DM, using Fine and 8
Gray’s extension of the Cox model. A p-value of <0.05 was considered significant. Statistical analyses were performed using SAS v9.4 (SAS Institute Inc, Cary, NC). Acute and late toxicity were assessed, using CTCAE v5.
RESULTS
Patient and treatment characteristics: Between 2000 and 2016, a total of 84 patients met the study inclusion criteria and underwent definitive RT +/- CHT at our center. Of these patients, 51 (61%), 24 (29%), and 9 (11%) patients had stage II, III, and IV disease, respectively. Eighty-two patients had urothelial carcinoma, and the remaining two had squamous cell carcinoma. There were 66 males (79%) and 18 females (21%) with a median age of diagnosis of 81 years. The characteristics of the 84 patients are depicted in Table 1.
RT was delivered to the bladder and regional pelvic lymph nodes in 58 patients (69%), and the remaining 26 (31%) had RT limited to the bladder. The median dose to the bladder tumor and pelvic lymph nodes was 6490 cGy (range: 5040 - 6700) and 4500 cGy (range: 3960 - 5400), respectively. The common dose-fractionation regimens utilized were 6500 cGy in 35 fractions to the bladder tumor with 4500 cGy in 25 fractions to the pelvic lymph nodes, and 5500 cGy in 20 fractions to the bladder tumor with 4400 cGy in 20 fractions to the remaining bladder. Patients 9
were treated with full bladder for most of the dose-fractionation regimens, except the regimen of 5500 cGy in 20 fractions where patients were treated with empty bladder. The median time from diagnosis to initiation of RT was 48 days (interquartile range [IQR]: [29, 75]). Two patients were unable to complete RT, one due to the development of a hemorrhagic stroke and the other due to failure to thrive and genitourinary symptoms.
A total of 61 patients (73%) received CHT with RT. Of these, 60 received concurrent CHT with the majority (26/60: 43%) receiving single agent cisplatin, and 1 received neoadjuvant CHT prior to RT. Twenty-three patients (27%) underwent RT alone. All underwent attempted TURBT, which provided maximal tumor debulking for 72 patients (86%).
Twenty-four patients (29%) were considered to have both medical fitness to withstand RC and a surgically resectable bladder tumor, and were assigned to Group 1. The remaining 60 patients (71%) were medically unfit for RC (58) and/or had a surgically unresectable tumor (9 with T4 disease; of these, 7 were also medically unfit), and were assigned to Group 2. A higher proportion of Group 1 received concurrent or neoadjuvant CHT (92%) and had maximal TURBT (100%), in comparison with Group 2 (65%, p=0.01; 80%, p=0.01, respectively). There was no difference between the two groups in the ability to complete RT or concurrent CHT.
Follow-up, overall survival, disease specific survival, and cumulative incidence of progression: 10
The median follow-up was 5.7 years (range: 0.3 - 11.3). Median survival was 1.9 years. At last follow-up, 68 patients (81%) had died. For the entire cohort, OS was 69%, 49%, 42% and 25%, at 1, 2, 3, and 5 years, respectively. DSS was 80%, 68%, 64%, and 54% at 1, 2, 3, and 5 years, respectively; six patients did not have a documented cause of death, and were classified as death due to bladder cancer. Figure 1 demonstrates all-cause mortality of our cohort which is divided into bladder cancer mortality and non-bladder cancer mortality.
Group 1 had better OS than Group 2 (79% vs. 65% at 1 year, 75% vs. 38% at 2 years, 70% vs. 31% at 3 years, and 37% vs. 20% at 5 years; Log-Rank p= 0.006) (Figure 2). However, there was no statistical difference in DSS between Group 1 and Group 2 (83% vs. 78% at 1 year, 79% vs. 63% at 2 years, 75% vs. 60% at 3 years, and 52% and 55% at 5 years Log-Rank p=0.93). On univariate analysis, Group 1 vs. Group 2 (HR 0.5, 95% CI: 0.3-0.8, p<0.01), concurrent and/or neoadjuvant CHT (HR 0.5, 95% CI: 0.3-0.9, p=0.01), T stage (HR 1.1, T3 vs. T2, 95% CI: 0.6-2.1; HR 2.2, T4 vs. T2, 95% CI: 1.3-3.8, p=0.02), and maximal TURBT (HR 0.5, 95% CI: 0.3-0.99, p=0.046) were associated with better OS. Only T stage was associated with better DSS (HR 1.4, T3 vs. T2, 95% CI: 0.7-3.0; HR 3.6, T4 vs. T2, 95% CI: 1.5-8.4, p=0.02).
Thirty-nine patients (46%) had disease relapse at the time of last follow-up or death. The cumulative incidence of progression was 25%, 37%, 44%, and 49% at 1, 2, 3, and 5 years, respectively, for the entire cohort. There was no difference in the cumulative incidence of progression between Group 1 and Group 2 (13% vs. 29% at 1 year, 22% vs. 43% at 2 years, 40% 11
vs. 49% at 3 years, and 47% vs. 49% at 5 years; Log-Rank p= 0.33) (Figure 3). On univariate analysis, none of the evaluated variables were associated with the cumulative incidence of progression. At 5 years, 23 patients (27%) experienced LR; of these, 12 were biopsy-proven, muscle-invasive disease, whereas the remainders were superficial or in situ disease. LR at 1, 2, 3, and 5 years was 18%, 24%, 28%, and 29%, respectively. Maximal TURBT was significantly associated with better local control (p=0.02) (Figure 4), whereas concurrent and/or neoadjuvant CHT had no impact. Pelvic relapse at 1, 2, 3, and 5 years was 5%, 8%, 8% and 9%, respectively. There was a trend towards less pelvic relapse with maximal TURBT (p=0.054), while other variables including RT volume (bladder + pelvic lymph nodes vs. bladder only) had no association. DM at 1, 2, 3 and 5 years was 12%, 21%, 27%, and 33%, respectively. No variable was correlated with a higher risk of DM, including the receipt of CHT. The three most common sites of DM were the lung, liver, and bones. Table 2 describes univariate analyses examining potential associations with OS, DSS, cumulative incidence of progression, LR, pelvic relapse, and DM.
Acute and late GU and GI side effects: Acute grade ≥ 2 genitourinary (GU) and gastrointestinal (GI) toxicity was seen in 38% and 26% of patients, respectively. Two patients (2%) had acute grade 3 GU toxicity (1 with urinary obstruction and frequency; 1 with urosepsis). One (1%) had acute grade 3 GI toxicity (diarrhea). None had grade 4 or 5 acute toxicity. No variable was associated with acute grade ≥ 2 GU or GI toxicity. Of 60 patients receiving concurrent CHT, 20 were unable to complete planned CHT, 12
primarily due to deteriorating renal function, hematologic toxicity, diarrhea, fatigue, unrelated medical illnesses, or a combination of the aforementioned. Two patients were unable to complete RT, one due to failure to thrive and GU symptoms, and the other due to a hemorrhagic stroke.
Late grade ≥ 2 GU and GI toxicity was seen in 31% and 5% of patients, respectively. Thirteen patients (15%) had late grade 3 GU toxicity (2 urinary incontinence; 6 radiation cystitis including hematuria; 5 ureteral obstruction). Three patients (4%) had late grade 3 GI toxicity (2 radiation proctitis; 1 stricture of sigmoid colon). None had grade 4 or 5 acute or late toxicity.
DISCUSSION
RC + neoadjuvant CHT has been considered one of the standard treatment options for MIBC in the United States. However, RC carries a high rate of perioperative complications, including mortality, and potential long-term toxicities, such as renal insufficiency, urinary tract infection, and ureteral obstruction [12]. A randomized study by Bochner et al. reported a 90-day perioperative grade 2-5 complication rate of 66% with open RC and 62% with robot-assisted laparoscopic RC [13] .
13
A growing number of studies have reported that TMT is efficacious with a relatively low incidence of major toxicity for MIBC [7] [8]. As a result, TMT is a viable alternative for patients medically unfit for RC or those opting for bladder preservation. In particular, it is an attractive treatment option for elderly patients who often have major medical comorbidities and unfavorable perioperative risk of RC. The notion that TMT is generally well-tolerated in elderly or frail patients is reflected well in our series where 98% (82/84) and 67% (40/60) of our cohort were able to complete planned RT and concurrent CHT, respectively.
The underutilization of definitive therapies (RC or RT) in the elderly population for MIBC has been reported [10, 14]. Separately, Hollenbeck et al reported that an aggressive local therapy is associated with improved OS in patients ≥ 80 years [11]. These parallel remarks raise the concern for possible sub-optimal care of elderly patients with MIBC and call for further exploration of a less morbid therapeutic intervention. The reasons for the underutilization of a definitive therapy in the elderly are likely multifactorial and include the concern for the ability to withstand major surgical or medical treatment, the presence of competing medical comorbidities, the potential treatment-related toxicity, and the impact of treatment on the quality of life in an elderly patient with a limited life expectancy. The aim of our series was to provide additional data on the utility and efficacy of RT +/- CHT in an elderly population for whom it can be an effective curative therapy with a safer toxicity profile.
14
The OS of 49% at 2 years, 42% at 3 years, and 25% at 5 years in our series is reasonable, considering that our cohort was primarily comprised of elderly, and often frail, patients. In our series, 71% of patients were deemed medically unfit for RC and/or had surgically unresectable MIBC. These clinical features likely represent the current landscape of patients with MIBC who are referred for the consideration of RT +/- CHT. The inability to undergo RC, either due to comorbidities or unresectable tumor, along with the median age of 81 years in our series, predicts a low overall survival, regardless of disease progression, due to competing risks of death in these elderly patients with poor performance status. In our cohort, Group 1 had better OS than Group 2 (Log-Rank p= 0.006). Better overall health status is likely a key factor for better OS in Group 1. Also, the difference in overall health status can explain the differences in the proportions of patients receiving concurrent/neoadjuvant CHT (92% in Group 1 vs. 65% in Group 2), although there was no statistically significant difference in the ability to complete planned concurrent CHT between the two groups.
The DSS of our cohort (68% at 2 years, 64% at 3 years, and 54% at 5 years) is much better than OS, with the overall and bladder cancer-specific mortality demonstrated in Figure 1. This discordance between OS and DSS illustrates the risk of dying from causes other than bladder cancer was substantial, and the cumulative incidence of progression may have been underestimated by a competing risk of death in our series.
15
The OS of our series is comparable to other series evaluating the efficacy of TMT. The Southwest Oncology Group conducted a phase II study to evaluate TMT (RT plus concurrent 5FU + cisplatin) in patients with MIBC who were medically unfit/surgically unresectable (55%), or refusing RC (45%). In this series, the patients were younger, with a median age of 67 years, but had more advanced T stages (≥ T3: 68%) with a higher rate of nodal metastasis (N1-2: 22%), in comparison with our cohort. This study reported an OS of about 42% at 3 years and 32% at 5 years [15]. In another series of 39 elderly patients (median age: 78 years) treated with TMT or RT alone, Tran et al. reported an OS of 43% at 3 years and 29% at 5 years [3]. It is also noteworthy that the OS of our study is similar to a series evaluating RC in an elderly population. Boustani et al. reported an OS of 22% at 5 years for 92 patients treated with RC, with a median age of 82 years [16]. In the same series, the author also reported that there was no difference in 5-year OS between patients treated with RC and those receiving RT + CHT, 22% vs 25%, respectively.
In our series, maximal TURBT was associated with a decreased risk of LR and pelvic relapse. This finding is similar to other series [7] [17] . Concurrent CHT was not a statistically significant prognostic factor for local or pelvic control in our study, in contrast to phase III [18] [19] and phase II studies [20] [21] [22]. Additionally, RT to the pelvic lymph nodes and bladder did not yield better pelvic control, in comparison with RT to the bladder alone, in our series. None of the variables examined were associated with a higher risk of DM. However, given the retrospective nature and a relatively small sample size of our series, caution is needed when
16
interpreting out data on prognostic variables associated with treatment outcomes and relapse patterns.
Treatment-related toxicity is a major concern in elderly or medically-compromised patients. In our series, RT +/- concurrent CHT was generally well-tolerated. Most patients (98%) were able to complete planned RT, and 67% completed planned concurrent CHT. Acute grade 3 GU (2%) and GI (1%) toxicity was uncommon. In addition, late grade 3 GU toxicity of 15% was reasonable, and late grade 3 GI toxicity was infrequent (4%). No patients had acute or late grade 4 or 5 GU or GI toxicity. However, the incidence of late toxicity was likely underestimated due to a competing risk of death.
There are several limitations in our series. First, this was a retrospective analysis, thus unrecognized biases and/or confounding factors as well as inherent shortcoming in evaluating treatment outcomes and treatment-related toxicities are present. Second, the total number of patients in this analysis was relatively small, thus the outcomes observed must be interpreted with caution. Third, our cohort of patients was compiled over an extended period of time (2000-2016) during which various CHT agents and RT regimens were utilized and evolved. Nevertheless, the data and analysis presented herein provide a useful resource for counseling elderly patients in whom management options are often limited.
17
CONCLUSION Elderly patients with MIBC referred for RT +/- CHT are often medically unfit or have surgically unresectable bladder cancer. Our series demonstrates that RT +/- CHT can be a safe and effective treatment option for elderly patients with MIBC, who are often medically unfit for RC or interested in pursuing organ preservation. In our study, RT +/- CHT was generally welltolerated, with low acute and late GU and GI toxicities, and yielded reasonable treatment outcomes consistent with the reported literature.
18
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Mak, R.H., et al., Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: a pooled analysis of Radiation Therapy Oncology Group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol, 2014. 32(34): p. 3801-9.
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Giacalone, N.J., et al., Long-term Outcomes After Bladder-preserving Tri-modality Therapy for Patients with Muscle-invasive Bladder Cancer: An Updated Analysis of the Massachusetts General Hospital Experience. Eur Urol, 2017. 71(6): p. 952-960.
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James, N.D., et al., Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med, 2012. 366(16): p. 1477-88.
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Turgeon, G.A. and L. Souhami, Trimodality therapy for bladder preservation in the elderly population with invasive bladder cancer. Front Oncol, 2014. 4: p. 206.
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Boustani, J., et al., Radical cystectomy or bladder preservation with radiochemotherapy in elderly patients with muscle-invasive bladder cancer: Retrospective International Study of Cancers of the Urothelial Tract (RISC) Investigators. Acta Oncol, 2018. 57(4): p. 491-497.
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Efstathiou, J.A., et al., Long-term outcomes of selective bladder preservation by combined-modality therapy for invasive bladder cancer: the MGH experience. Eur Urol, 2012. 61(4): p. 705-11.
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FIGURE LEGENDS
Table 1: Baseline demographics, clinical characteristics, and treatment details Table 2: Variables associated with overall survival, disease specific survival, cumulative incidence of progression, local relapse, pelvic relapse, and distant metastasis Figure 1: Mortality with bladder cancer and non-bladder cancer mortality Figure 2: Overall survival Figure 3: Cumulative incidence of progression Figure 4: Cumulative incidence of local failure stratified by receipt of maximal TURBT
22
Tables Table 1: Baseline demographics, clinical characteristics, and treatment details Overall
Age, median (range), y ≥ 80, No. (%) < 80, No. (%) Sex, No. (%) Male Female Histology, No. (%) Urothelial Squamous T stage, No. (%) T2 T3 T4 N stage, No. (%) N0 N1 N2 N3 Stage, No. (%) II III IV Tumor grade, No. (%) G1 G2 G3 Missing Hydronephrosis, No. (%) Yes No Maximal TURBT, No. (%) Yes No Concurrent CHT, No. (%) Yes
81 (70-94) 46 (54.8) 38 (45.2)
Medically fit and surgically resectable (Group 1) (n=24) 82 (70-90) 13 (54.2) 11 (45.8)
Medically unfit and/or surgically unresectable (Group 2) (n=60) 81 (70-94) 33 (55.0) 27 (45.0)
p value
66 (78.6) 18 (21.4)
19 (79.2) 5 (20.8)
47 (78.3) 13 (21.7)
0.93
82 (97.6) 2 (2.4)
23 (95.8) 1 (4.2)
59 (98.3) 1 (1.7)
0.50
53 (63.1) 22 (26.2) 9 (10.7)
14 (58.3) 7 (29.2) 3 (12.5)
39 (65.0) 15 (25.0) 6 (10.0)
78 (92.9) 3 (3.6) 2 (2.4) 1 (1.2)
22 (91.7) 2 (8.3) 0 (0) 0 (0)
56 (93.3) 1 (1.7) 2 (3.3) 1 (1.7)
51 (60.7) 24 (28.6) 9 (10.7)
14 (58.3) 7 (29.2) 3 (12.5)
37 (61.7) 17 (28.3) 6 (10.0)
1 (1.2) 1 (1.2) 81 (96.4) 1 (1.2)
0 (0) 0 (0) 24 (100) 0 (0)
1 (1.7) 1 (1.7) 57 (95.0) 1 (1.7)
27 (32.1) 57 (67.9)
6 (25.0) 18 (75.0)
21 (35.0) 39 (65.0)
0.38
72 (85.7) 12 (14.3)
24 (100) 0 (0)
48 (80.0) 12 (20.0)
0.02
60 (71.4)
22 (91.7)
38 (63.3)
0.91
0.85
0.34
0.94
0.66
0.01
No Concurrent or Neoadjuvant CHT, No. (%) Yes No Chemo agent for concurrent CHT (n=60), No. (%) Cisplatin Carboplatin + Taxol Carboplatin 5 FU + MMC Taxol 5 FU Ability to complete planned concurrent CHT, No. (%) Yes No Target volume of RT, No. (%) Bladder + pelvic lymph nodes Bladder only RT type 3-D IMRT RT dose, No. (%) PTV bladder tumor: median (range) PTV pelvic nodes: median (range)
24 (28.6)
2 (8.3)
22 (36.7)
61 (72.6) 23 (27.4)
22 (91.7) 2 (8.3)
39 (65.0) 21 (35.0)
26 (43.3) 13 (21.7) 10 (16.7) 5 (8.3) 4 (6.7) 2 (3.3)
8 (36.4) 7 (31.8) 2 (9.1) 2 (9.1) 2 (9.1) 1 (4.5)
18 (47.4) 6 (15.8) 8 (21.1) 3 (7.9) 2 (5.3) 1 (2.6)
40 (66.7) 20 (33.3)
14 (63.6) 8 (36.4)
26 (68.4) 12 (31.6)
58 (69.0) 26 (31.0)
19 (79.2) 5 (20.8)
39 (65.0) 21 (35.0)
0.21
26 (31.0) 58 (69.0)
6 (25.0) 18 (75.0)
20 (33.3) 40 (66.7)
0.46
6490 (5040-6700) 4500 (3960-5400)
6500 (5580-6700) 4500 (3960-5400)
6480 (5040-6700) 4500 (3960-5400)
0.01
0.46
0.70
Table 2: Variables associated with overall survival, disease specific survival, cumulative incidence of progression, local relapse, pelvic relapse, and distant metastasis Variables; HR, (95% CI), p value Age (<80 vs. ≥ 80) Gender
T stage with N0
N0 vs. N1-3
Group 1 vs. Group 2 IMRT vs. 3-D CRT1 RT volume2 CHT3 CHT agents4
Maximal TURBT Hydronephrosis 1
Overall survival
Disease specific survival
Cumulative incidence of progression
Local relapse
Pelvic relapse
Distant metastasis
1.4 (0.9-2.3) p=0.14 0.8 (0.5-1.4) p=0.42 T3: 1.1 (0.6-2.1) T4: 2.2 (1.3-3.8) p=0.02* 1.2 (0.7-2.0) p=0.56 0.5 (0.3-0.8) p<0.01* 1.1 (0.7-1.9) p=0.71 0.9 (0.5-1.4) p=0.55 0.5 (0.3-0.9) p=0.01* 1.2 (0.7-2.2) p=0.48 0.5 (0.3-0.99) p=0.046* 1.3 (0.8-2.2) p=0.28
1.0 (0.5-1.8) p=0.92 0.8 (0.4-1.7) p=0.58 T3: 1.4 (0.7-3.0) T4: 3.6 (1.5-8.4) p=0.02* 1.0 (0.4-2.7) p=0.99 1.0 (0.5-1.8) p=0.93 1.2 (0.6-2.2) p=0.65 1.5 (0.7-3.1) p=0.25 1.6 (0.7-3.7) p=0.31 1.8 (0.9-3.6) p=0.09 1.1 (0.4-3.0) P=0.81 1.1 (0.6-2.1) P=0.75
1.0 (0.6-1.9) p=0.91 0.8 (0.4-1.8) p=0.65 T3: 1.3 (0.6-2.8) T4: 2.5 (1.0-6.7) p=0.17 1.1 (0.4-3.2) p=0.93 0.7 (0.4-1.4) p=0.30 1.5 (0.8-2.9) p=0.22 1.2 (0.6-2.3) p=0.67 1.3 (0.6-2.8) p=0.57 1.0 (0.5-2.0) p=1.00 0.7 (0.3-1.8) p=0.47 0.9 (0.5-1.8) p=0.86
1.6 (0.7-3.8) p=0.26 1.2 (0.5-3.0) p=0.65 T3: 1.0 (0.4-2.9) T4: 3.0 (0.9-10.1) p=0.20 1.1 (0.3-3.7) p=0.91 0.5 (0.2-1.3) p=0.14 1.9 (0.8-4.5) p=0.14 1.8 (0.7-4.8) p=0.25 1.3 (0.5-3.7) p=0.58 0.6 (0.2-1.6) p=0.32 0.3 (0.1-0.8) p=0.02* 0.6 (0.2-1.5) p=0.27
0.7 (0.1-2.9) p=0.58 1.3 (0.3-6.2) p=0.76 T3: 0.5 (0.1-4.5) T4: 2.1 (0.2-17.6) p=0.62 0.8 (0.04-16.9) p=0.88 0.4 (0.05-3.3) p=0.40 1.0 (0.2-4.7) p=0.97 0.3 (0.07-1.4) p=0.13 0.5 (0.1-2.0) p=0.29 0.4 (0.04-3.5) p=0.38 0.5 (0.3-1.01) p=0.054 1.7 (0.4-7.3) p=0.49
0.7 (0.3-1.5) p=0.37 0.56 (0.2-1.6) p=0.28 T3: 0.8 (0.3-2.1) T4: 2.1 (0.7-6.3) p=0.31 1.2 (0.3-5.0) p=0.85 1.1 (0.5-2.4) p=0.89 1.3 (0.6-2.9) p=0.57 1.1 (0.5-2.4) p=0.89 2.3 (0.8-7.2) p=0.14 0.9 (0.4-2.2) p=0.90 1.2 (0.3-4.0) p=0.80 1.4 (0.6-3.0) p=0.42
: IMRT: intensity-modulated radiotherapy, 3-D CRT: three-dimensional conformal radiotherapy : RT volume: bladder only vs. bladder + pelvic lymph nodes 3 : CHT: concurrent and/or neoadjuvant CHT vs. no CHT
2
4
: CHT agents: Cisplatin or 5-fluorouracil + mitomycin vs. others *: p <0.05