Abstract
Background:
Chemo-radiation is a well-established alternative to radical cystectomy in patients with muscle-invasive bladder cancer. Many patients due to age or medical comorbidity are unfit for either radical cystectomy, or standard cisplatin- or 5-fluorouracil–based chemoradiation, and do not receive appropriate treatment with curative intent. We treated patients with a less aggressive protocol employing seven weekly doses of paclitaxel and daily irradiation. In those whose tumors showed overexpression of her2/neu, seven weekly doses of trastuzumab were also administered.
Objective:
To report the long-term survival outcomes and toxicity results of the of NRG Oncology RTOG 0524 study.
Design, setting, and participants:
Seventy patients were enrolled and 65 (median age: 76 yr) were deemed eligible. Patients were assigned to daily radiation and weekly paclitaxel + trastuzumab (group 1, 20 patients) or to daily radiation plus weekly paclitaxel (group 2, 45 patients) based on tumor her2/neu overexpression. Radiation was delivered in 1.8 Gy fractions to a total dose of 64.8 Gy.
Outcome measurements and statistical analysis:
The primary endpoint was unresolved treatment-related toxicity. The secondary endpoints were complete response rate, protocol completion rate, and disease-free and overall survival.
Results and limitations:
Protocol therapy was completed by 60% (group 1) and 76% (group 2); complete response rates at 12 wk were 62% in each group. Acute treatment-related adverse events (AEs) of grade ≥3 were observed in 80% in group 1 and 58% in group 2. There was one treatment-related grade 5 AE in group 1. Unresolved acute treatment-related toxicity was 35% in group 1 and 31% in group 2. The median follow-up was 2.3 yr in all patients and 7.2 yr in surviving patients. Overall survival at 5 yr was 25.0% in group 1 and 37.8% in group 2 (33.8% overall). At 5 yr, disease-free survival was 15.0% in group 1 and 31.1% in group 2.
Conclusions:
In a cohort of patients with muscle-invasive bladder cancer who are not candidates for cystectomy or cisplatin chemotherapy, chemoradiation therapy offers a treatment with a significant response rate and 34% 5-yr overall survival. While there were many AEs in this medically fragile group, there were few grade 4 events and one grade 5 event attributable to therapy.
Patient summary:
Patients with invasive bladder cancer who cannot tolerate surgery were treated with radiation and systemic therapy without surgically removing their bladders. Most patients tolerated the treatment, were able to keep their bladders, and showed a significant treatment response rate.
Keywords: Bladder cancer, Chemotherapy, Radiation therapy, Targeted therapy
1. Introduction
Organ-sparing therapy for cancer has widely been adopted in such cancers as those in the upper airway and anus. Offering comparable survival to radical surgery with improved quality of life, combination therapy with chemotherapy and radiation is also a proven approach in muscle-invasive bladder cancer [1-3]. Radical cystectomy with urinary diversion is the mainstay of treatment, but many patients are not fit for this highly morbid procedure. Cisplatin-based chemotherapy with twice daily radiation has been demonstrated in several cooperative group trials to offer good success. It is estimated that, in the USA, over 25% of patients with muscle-invasive bladder cancer do not receive any definitive treatment at all [4]. This is likely due to the substantial number of patients with significant medical comorbidity or advanced age, which makes them ineligible for radical surgery. Many of these patients are also medically ineligible to receive cisplatin, the most well-established chemotherapy agent. NRG Oncology RTOG 0524 was designed to assess the toxicity and efficacy of chemoradiation with transurethral resection of the bladder tumor in patients ineligible for radical cystectomy and cisplatin-based chemotherapy. Patients received weekly paclitaxel for 7 wk and daily radiation to the bladder and pelvis. In those whose tumor demonstrated her2/neu overexpression, a putative biomarker in bladder cancer for inferior outcomes with traditional therapy, weekly trastuzumab was administered for seven doses [5]. Toxicity and early efficacy have previously been reported [6]. We report here the long-term outcomes of toxicity, disease-free survival (DFS), overall survival (OS), and bladder preservation of NRG Oncology RTOG 0524.
2. Patients and methods
2.1. Study design and participants
Patients with muscle-invasive bladder cancer were nonrandomly assigned to treatment with paclitaxel, radiation therapy (XRT), and trastuzumab (group 1) if their tumors expressed her2/neu on an immunohistochemical (IHC) analysis (2+ or 3+ on HercepTest). Patients with IHC negative or 1+ expression of her2/neu were treated with paclitaxel and radiotherapy (group 2). Eligible patients had confirmed urothelial cancer invasive into the muscularis propria (stage ≥T2). The patients had no clinical or radiographic evidence of metastases. The patients underwent maximal transurethral resection of the bladder tumor. The full eligibility criteria have previously been described [1]. The designation of a patient as unfit for cystectomy or not able to tolerate cisplatin chemotherapy was the discretion of the participating treating physicians based on the assessment of the patient’s whole clinical scenario. The study was registered with ClinicalTrials.gov (number NCT00238420).
2.2. Treatment
All patients were treated with daily XRT and weekly paclitaxel. Radiation was administered in 1.8 Gy daily fractions for 36 treatments delivered 5 d/wk; 1.8 Gy in 22 fractions was administered to small pelvic fields. The bladder received 1.8 Gy to the whole bladder, then a reduced field to the bulky tumor with partial sparing of the bladder, if possible, for six fractions at 1.8 Gy. The total dose was 64.8 Gy. A full description of the treatment protocol has previously been published [6].
In group 1 (her2/neu positive), patients were additionally treated with trastuzumab once weekly for 7 wk. The trastuzumab dosage was 4 mg/kg loading dose, and subsequent doses were 2 mg/kg intravenously. Dose reductions were not permitted.
History and physical examination, including vital signs and laboratory studies, were performed weekly.
Patients continued treatment until the completion of 7 wk of chemotherapy and 36 fractions of radiation unless there was progression of disease, unacceptable toxicity, treatment delay of >3 wk, inability to comply with study requirements, or withdrawal of informed consent. Since the original report, one patient in group 2 was deemed to be ineligible.
Adverse events (AEs) were graded according to the Common Terminology Criteria for Adverse Events v 3.0. Serious AEs were reported through the Adverse Event Expedited Reporting System application accessed from the Cancer Therapy Evaluation Program website.
Upon completion of treatment, patients were followed with cystoscopy and urinary cytology. Follow-up included regular imaging of the chest, abdomen, and pelvis. After the 1st year, it was recommended that patients undergo regular cystoscopic evaluation.
2.3. Statistical methods and sample-size considerations
The sample size was calculated based on testing the null hypothesis that the true toxicity rate is ≥25% versus the alternative hypothesis that the toxicity rate is no more than 10%, under one-sided alpha of 0.10 and 90% power. Using Fleming’s [7] one-sample multiple testing procedure (a multi-stage stopping rule was employed), 40 analyzable cases were required in each group. At the current sample sizes, there was 67% power to detect the planned toxicity difference in the paclitaxel/trastuzumab group and 92% power for the paclitaxel-alone group, setting aside multiple testing issues. Exact 95% confidence intervals (CIs) are presented using the Clopper-Pearson method. DFS and OS were estimated using the Kaplan-Meier procedure [8].
2.4. Outcomes
The study primary endpoint, acute treatment-related toxicity, was defined as toxicity that did not resolve to grade ≤1 within 7 d or a reasonable time frame as determined by the study chairs and treating physicians.
The secondary endpoints included the complete response rate of the primary tumor, DFS and OS, and ability of patients who were not cystectomy candidates to complete treatment.
2.5. Study enrollment
This study required a total of 88 patients in order to achieve 40 analyzable patients in each of the two groups. The study was subsequently joined by the NCIC CTG in Canada. Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group also endorsed this study through the Clinical Trials Support Unit. Details of protocol amendments and patient exclusions are available in our original report. Since the original publication, one additional patient in group 2 was deemed to be ineligible, leaving 65 for the current analysis.
3. Results
Pretreatment characteristics of the 65 eligible participants are shown in Table 1. The median ages of group 1 and 2 patients were 79.5 and 73 yr, respectively. The majority of patients in both groups were non-Hispanic and White, with Zubrod performance status 0 or 1, and tumor stage of T2, N0, and M0. Twelve patients were female and 53 were male.
Table 1 –
Pretreatment characteristics
| Patient or tumor characteristic | RT + paclitaxel + trastuzumab (n = 20) |
RT + paclitaxel (n = 45) |
Total (n = 65) |
|---|---|---|---|
| Age | |||
| Median | 79.5 | 73 | 76 |
| Min-Max | 51–86 | 55–90 | 51–90 |
| Q1-Q3 | 72.5–81.5 | 66–80 | 68–81 |
| Gender, n (%) | |||
| Male | 18 (90.0) | 35 (77.8) | 53 (81.5) |
| Female | 2 (10.0) | 10 (22.2) | 12 (18.5) |
| Race, n (%) | |||
| Asian | 0 (0.0) | 1 (2.2) | 1 (1.5) |
| White | 20 (100.0) | 44 (97.8) | 64 (98.5) |
| Ethnicity, n (%) | |||
| Not Hispanic or Latino | 20 (100.0) | 43 (95.6) | 63 (96.9) |
| Unknown | 0 (0.0) | 2 (4.4) | 2 (3.1) |
| Zubrod performance status, n (%) | |||
| 0 | 7 (35.0) | 25 (55.6) | 32 (49.2) |
| 1 | 12 (60.0) | 16 (35.6) | 28 (43.1) |
| 2 | 1 (5.0) | 4 (8.9) | 5 (7.7) |
| T stage, n (%) | |||
| T1 | 1 (5.0) | 2 (4.4) | 3 (4.6) |
| T2 | 15 (75.0) | 39 (86.7) | 54 (83.1) |
| T3 | 3 (15.0) | 2 (4.4) | 5 (7.7) |
| T4 | 1 (5.0) | 2 (4.4) | 3 (4.6) |
| N stage, n (%) | |||
| N0 | 18 (90.0) | 37 (82.2) | 55 (84.6) |
| N1 | 0 (0.0) | 4 (8.9) | 4 (6.2) |
| NX | 2 (10.0) | 4 (8.9) | 6 (9.2) |
| M stage, n (%) | |||
| M0 | 20 (100.0) | 45 (100.0) | 65 (100.0) |
RT = radiotherapy.
Data on AEs are shown in Tables 2-6. In group 1, the worst AEs definitely, probably, or possibly related to treatment were 15 (75.0%) patients with grade 3, zero (0.0%) patients with grade 4, and one (5.0%) patient with grade 5 AEs, respectively. For group 2, there were 22 (48.9%) patients with grade 3, four (8.9%) patients with grade 4, and zero (0.0%) patients with grade 5 AEs (Table 2). Table 3 reports the system organ class details of all AEs regardless of the relationship to treatment. All grade 5 AEs are listed in Table 4. There was one grade 5 colonic perforation (reported as possibly related to protocol treatment) in group 1, and one grade 5 aspiration and one sudden death (both reported as unrelated to protocol treatment) in group 2.
Table 2 –
Summary of worst adverse event per patient
| Relationship to treatment | Adverse event | Grade | RT + paclitaxel + trastuzumab (n = 20), n (%) |
RT + paclitaxel (n = 45), n (%) |
|---|---|---|---|---|
| Definitely, probably, or possibly | Worst nonhematological | 1 | 4 (20.0) | 10 (22.2%) |
| 2 | 4 (20.0) | 9 (20.0%) | ||
| 3 | 8 (40.0) | 7 (15.6%) | ||
| 4 | 1 (5.0) | 1 (2.2%) | ||
| 5 | 1 (5.0) | 0 (0%) | ||
| Worst overall | 1 | 0 (0.0) | 4 (8.9%) | |
| 2 | 4 (20.0) | 15 (33.3%) | ||
| 3 | 15 (75.0) | 22 (48.9%) | ||
| 4 | 0 (0.0) | 4 (8.9%) | ||
| 5 | 1 (5.0) | 0 (0.0%) | ||
| Any a | Worst nonhematological | 1 | 5 (25.0) | 10 (22.2%) |
| 2 | 4 (20.0) | 11 (24.4%) | ||
| 3 | 9 (45.0) | 10 (22.2%) | ||
| 4 | 1 (5.0) | 1 (2.2%) | ||
| 5 | 1 (5.0) | 0 (0%) | ||
| Worst overall | 1 | 0 (0.0) | 2 (4.4%) | |
| 2 | 4 (20.0) | 9 (20.0%) | ||
| 3 | 15 (75.0) | 26 (57.8%) | ||
| 4 | 0 (0.0) | 6 (13.3%) | ||
| 5 | 1 (5.0) | 2 (4.4%) |
CTCAE = Common Terminology Criteria for Adverse Events; RT = radiotherapy.
Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0.
Table 6 –
Acute treatment-related toxicity: RT + paclitaxel arm
| Acute toxicities | RT + paclitaxel All patients |
RT + paclitaxel first 40 patients | ||
|---|---|---|---|---|
| n = 45 | p value a | n = 40 | p value a | |
| YES | 14 (31.1%) | 0.87 | 11 (27.5%) | 0.72 |
| (18.2%, 46.7%) b | (14.6%, 43.9%) b | |||
| NO | 31 (68.9%) | 29 (72.5%) | ||
RT = radiotherapy.
One-sided binomial exact test.
95% Clopper-Pearson exact confidence interval.
Table 3 –
Number of patients with an adverse event by category and grade any relationship to protocol treatment
| Category | RT + paclitaxel + trastuzumab (n = 20) Grade |
RT + paclitaxel (n = 45) Grade |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | 2 | 3 | 4 | 5 | 1 | 2 | 3 | 4 | 5 | |
| Allergy/immunology, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (2.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Auditory/ear, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 8 (17.8) | 8 (17.8) | 1 (2.2) | 0 (0.0) |
| Blood/bone marrow, n (%) | 5 (25.0) | 4 (20.0) | 9 (45.0) | 1 (5.0) | 0 (0.0) | 9 (20.0) | 3 (6.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Cardiac arrhythmia, n (%) | 2 (10.0) | 0 (0.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 14 (31.1) | 9 (20.0) | 6 (13.3) | 0 (0.0) | 0 (0.0) |
| Cardiac general, n (%) | 2 (10.0) | 4 (20.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 3 (6.7) | 1 (2.2) | 1 (2.2) | 0 (0.0) | 0 (0.0) |
| Coagulation, n (%) | 3 (15.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 8 (17.8) | 8 (17.8) | 3 (6.7) | 1 (2.2) | 0 (0.0) |
| Constitutional symptoms, n (%) | 4 (20.0) | 1 (5.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 3 (6.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Death, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 8 (17.8) | 15 (33.3) | 5 (11.1) | 0 (0.0) | 0 (0.0) |
| Dermatology/skin, n (%) | 1 (5.0) | 2 (10.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 12 (26.7) | 1 (2.2) | 5 (11.1) | 1 (2.2) | 1 (2.2) |
| Gastrointestinal, n (%) | 4 (20.0) | 7 (35.0) | 6 (30.0) | 0 (0.0) | 1 (5.0) | 11 (24.4) | 11 (24.4) | 11 (24.4) | 1 (2.2) | 0 (0.0) |
| Hemorrhage/bleeding, n (%) | 1 (5.0) | 4 (20.0) | 4 (20.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (2.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Hepatobiliary/pancreas, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Infection, n (%) | 0 (0.0) | 6 (30.0) | 2 (10.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (4.4) | 2 (4.4) | 1 (2.2) | 0 (0.0) |
| Lymphatics, n (%) | 1 (5.0) | 2 (10.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 1 (2.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Metabolic/laboratory, n (%) | 4 (20.0) | 9 (45.0) | 4 (20.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 8 (17.8) | 8 (17.8) | 1 (2.2) | 0 (0.0) |
| Musculoskeletal/soft tissue, n (%) | 0 (0.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 9 (20.0) | 3 (6.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Neurology, n (%) | 4 (20.0) | 3 (15.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 14 (31.1) | 9 (20.0) | 6 (13.3) | 0 (0.0) | 0 (0.0) |
| Ocular/visual, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (6.7) | 1 (2.2) | 1 (2.2) | 0 (0.0) | 0 (0.0) |
| Pain, n (%) | 5 (25.0) | 3 (15.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 8 (17.8) | 8 (17.8) | 3 (6.7) | 1 (2.2) | 0 (0.0) |
| Pulmonary/upper respiratory, n (%) | 2 (10.0) | 3 (15.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 3 (6.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Renal/genitourinary, n (%) | 1 (5.0) | 1 (5.0) | 5 (25.0) | 0 (0.0) | 0 (0.0) | 8 (17.8) | 15 (33.3) | 5 (11.1) | 0 (0.0) | 0 (0.0) |
| Sexual/reproductive function, n (%) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 12 (26.7) | 1 (2.2) | 5 (11.1) | 1 (2.2) | 1 (2.2) |
| Syndromes, n (%) | 1 (5.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 11 (24.4) | 11 (24.4) | 11 (24.4) | 1 (2.2) | 0 (0.0) |
| Vascular, n (%) | 0 (0.0) | 0 (0.0) | 1 (5.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (2.2) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
CTCAE = Common Terminology Criteria for Adverse Events; RT = radiotherapy.
Includes adverse events where relationship to protocol treatment is missing. Adverse events were graded with CTCAE version 3.0.
Table 4 –
Grade 5 adverse events
| Treatment arm | Patient | Category | Term | Relationship to treatment |
Days from start of treatment |
Days from end ofM treatment |
|---|---|---|---|---|---|---|
| RT + paclitaxel + trastuzumab | A | Gastrointestinal | Colonic perforation | Possibly | 53 | 10 |
| RT + paclitaxel | B | Pulmonary/upper respiratory | Aspiration | Unrelated | 31 | 2 |
| C | Death | Sudden death | Unrelated | 47 | 4 |
CTCAE = Common Terminology Criteria for Adverse Events; RT = radiotherapy.
Adverse events were graded with CTCAE version 3.0.
Tables 5 and 6 summarize the primary endpoint, protocol-specified acute treatment-related toxicity. In group 1, seven (35%) of 20 patients experienced one or more of the acute treatment-related toxicities. A one-sided binomial exact test of the null hypothesis (toxicity rate of >25%) is not significant (one-sided p = 0.90), with a 95% CI ranging from 15.4% to 59.2%. In group 2, 14 (31.1%) of 45 patients experienced one or more of the acute treatment-related toxicities (Table 6). A one-sided binomial exact test of the null hypothesis is again not statistically significant, whether applied to all 45 patients or to the first 40 enrolled patients per the study design (one-sided p = 0.87 and 0.72, respectively). The 95% CI ranged from 18.2% to 46.7% (all 45 patients) or from 14.6% to 43.9% (40 patients). Thus, in neither group could we conclude that the true toxicity rate was < 25%.
Table 5 –
Acute treatment-related toxicity: RT + paclitaxel + trastuzumab arm
| Acute toxicities | RT + paclitaxel + trastuzumab (n = 20) |
p value a |
|---|---|---|
| Yes | 7 (35.0%) | 0.90 |
| (15.4%, 59.2%) b | ||
| No | 13 (65.0%) |
RT = radiotherapy.
One-sided binomial exact test.
95% Clopper-Pearson exact confidence interval.
3.1. Response, OS, and DFS
The median follow-up time was 2.3 yr for all 65 eligible patients and 7.2 yr for the 14 surviving patients. Table 7 summarizes the information about a complete response to protocol therapy, where a complete response is defined as negative for either gross tumor in cystoscopy or carcinoma in tumor biopsy, or for both. Patients were not evaluable if either cystoscopy or tumor biopsy was not done. Thirteen out of 18 patients (72.2%) in group 1 and 25 out of 37 (67.6%) in group 2 had a complete response to the treatment within the 1st year (Table 7). Ten patients were not evaluable for response at 1 yr (all died without a response evaluation).
Table 7 –
Complete response to treatment within the 1st year
| RT + paclitaxel + trastuzumab (n = 18) |
RT + paclitaxel (n = 37) | |||
|---|---|---|---|---|
| n (%) | 95% CI | n (%) | 95% CI | |
| Complete response | 13 (72.2) | (46.5%, 90.3%) | 25 (67.6) | (50.2%, 82.0%) |
| No response | 5 (27.8) | 12 (32.4) | ||
CI = confidence interval; RT = radiotherapy.
Ten patients were not evaluable for response; the reasons are as follows: ten patients died without a response evaluation (two trastuzumab patient and eight no trastuzumab patients).
OS and DFS rates are plotted in Figures 1 and 2, respectively. At the time of this updated analysis, 18 deaths in group 1 and 33 deaths in group 2 have been reported. Eleven and 16, respectively, were cancer related, with the remaining non–cancer related. The 3-yr OS rates were 50.0% (95% CI: 27.1–69.2%) for group 1 and 42.2% (95% CI: 27.8–56.0%) for group 2, while the 5-yr OS rates were 25.0% (95% CI: 9.1–44.9%) for group 1 and 37.8% (95% CI: 23.9–51.6%) for group 2. The median survival time was 2.8 yr (95% CI: 1.1–4.4) for group 1 and 2.0 yr (95% CI: 1.1–8.5) for group 2. In group 1, 11 of the total 18 deaths were due to cancer. For group 2, 16 of 33 deaths were due to cancer. Almost all patients (19 of 20 in group 1, and 44 of 45 in group 2) experienced either disease progression or death to date.
Fig. 1 –
Overall survival in group 1 (paclitaxel/trastuzumab) and group 2 (paclitaxel) in years since enrollment.
Fig. 2 –
Disease-free survival in group 1 (her2/neu+, paclitaxel/trastuzumab) and group 2 (her2/neu−, paclitaxel) in years since enrollment.
The 3-yr DFS rates were 25.0% (95% CI: 9.1–44.9%) in group 1 and 35.6% (95% CI: 22.0–49.3%) in group 2; the 5-yr rates were 15.0% (95% CI: 3.7–33.5) in group 1 and 31.1% (95% CI: 18.4–44.7) in group 2. The median DFS was 1.1 yr (95% CI: 0.6–2.8) in group 1 and 0.8 yr (95% CI: 0.4–3.0) in group 2 (Fig. 2). Although at study entry these patients were deemed unfit for radical surgery, a total of five patients eventually underwent cystectomy. Bladder preservation was achieved in most patients. Among patients who survived to year 2 and beyond, the significant majority (31 of 34) had not undergone cystectomy (91.2%). Figure 3 graphically depicts bladder intact survival, that is, the time to cystectomy or death.
Fig. 3 –
Bladder intact survival in group 1 (her2/neu+, paclitaxel/trastuzumab) and group 2 (her2/neu−, paclitaxel) in years since enrollment.
3.2. Biopsy, cystoscopy, and disease recurrence findings
In group 1, nine patients underwent one or more biopsies: three were negative for carcinoma on all biopsies, three had a positive biopsy, and three had both positive and negative biopsies. Sixteen patients had one or more cystoscopies, of whom 15 were negative for gross tumor on all examinations. In group 2, 21 patients underwent one or more biopsies: 15 were negative for carcinoma on all biopsies, five had a positive biopsy, and one had both positive and negative biopsies. Thirty-two patients had one or more cystoscopies, of whom 15 were negative for gross tumor on all examinations.
In group 1, 13 patients had a local recurrence, zero a pelvic node recurrence, and eight had a distant recurrence (five had more than one type of recurrence). In group 2, these numbers were 18, 2, and 11, respectively (with eight having more than one type of recurrence).
Bladder intact survival at 2 yr was 91.2%.
4. Discussion
This phase 2 study was designed to assess a novel chemoradiation protocol in combination with biological therapy for patients with muscle-invasive bladder cancer who were medically unfit or ineligible for radical surgery and cisplatin-based chemotherapy. Paclitaxel was chosen as a radiation sensitizing chemotherapy with a lower risk of renal toxicity. Patients whose tumors expressed her2/neu were additionally treated with trastuzumab. Results show that the treatment was tolerated well, with <9% experiencing therapeutic toxicity of grade 4 and just one treatment-related death. We could not, however, rule out that the overall toxicity rate exceeds 25%. The primary endpoint of toxicity was thoroughly discussed in our prior publication.
There was one death in this population, which was probably treatment related. A bowel perforation occurred 12 d after the completion of the protocol. Rates of grade 3 and 4 AEs were consistent with prior experience in RTOG studies. Gastrointestinal toxicity was the most common significant adverse reaction to therapy, and is likely related to both paclitaxel and radiation. The radiation fields employed in this study antedated the introduction of intensity-modulated XRT, adaptive therapy, and image-guided radiation techniques, which may reduce gastrointestinal toxicity [9,10]. The addition of trastuzumab did not increase radiation/paclitaxel local toxicity. In group 1, there were 18 deaths, 11 due to cancer. There were 33 deaths in Group 2, 16 due to cancer.
The majority of the patients had a complete response to therapy. Despite this, 65% of patients had recurred or died by year 2. DFS shows that most events occurred within the 1st year. Although the study was not designed to assess efficacy, these results appear to be inferior to standard radical chemoradiation employing concurrent cisplatin or gemcitabine chemotherapy [11,12]. This is particularly likely as over 85% of the patients in this study had T2 disease, unlike other studies in which there are higher proportions of T3 and T4 tumors [2]. The most active chemotherapeutic agents against bladder cancer, cisplatin and gemcitabine, were not a component of this regimen [12,13]. The study does not suggest that paclitaxel has substantial activity and the control rates are comparable with those historically reported for radiation alone [11,14,15]. We believe that different chemosensitizing regimens such as single-agent gemcitabine or combination mitomycin C/5-fluorouracil are feasible in this patient population and likely superior to radiotherapy alone. The value of the trastuzumab given to the her2/neu-positive patients is a matter of speculation. Since early reports that it predicted the outcome of radiation-treated patients, little has been added to the literature [5]. Trastuzumab appeared to add little in terms of toxicity, but response rates were similar to the nontrastuzumab cohort, and thus it appeared to add little in terms of cancer outcome. These data cannot, therefore, be used to argue either for or against its use. It is possible that different assays and criteria for Her-2 status from those we employed may have yielded different results.
There were important differences between this and the more standard bladder-sparing protocols that went beyond the choice of systemic therapy. An opportunity for salvage cystectomy is usually built into most bladder-preserving protocols as a “safety net” and is partly responsible for the high survival rates reported [2]. This was not a component of this investigation as patients had already been deemed ineligible. Interval cystoscopy during therapy to assess response was thus not mandated. The enrolment criteria required that a transurethral resection of the bladder tumor be completed as thoroughly as possible, as visibly complete transurethral resection of the bladder tumor has been associated with improved prognosis in trimodality therapy in prior studies. Details of the completeness of tumor resection, however, were not available for this cohort. As the patients were elderly, it is likely that less aggressive efforts were made to resect all visible tumors. There were patients, despite being deemed ineligible at study enrollment, who later underwent cystectomy. Of the patients, 91.2% did not have the bladder removed.
This protocol employing radiation and paclitaxel was originally developed to be a tolerable approach for the elderly and medically unfit. Since its conception, however, a number of newer radiation approaches for the elderly have been tested in phase 2 studies, which have been shown to combine efficacy with tolerability. These include the use of hypofractionation and adaptive radiotherapy with partial bladder radiation, and the omission of elective lymph node treatment. While it is not possible to directly compare these approaches with our protocol, these have the advantage of convenience (fewer fractions) and may thus be preferable from a patient perspective [16,17].
5. Conclusions
The elderly and frail represent a very challenging subset of patients with significant cancer who cannot be managed with standard radical therapies. Indeed, they are frequently not treated with any kind of curative intent at all [4]. This protocol offers insights into the efficacy and side effects of an option for this subgroup of patients. We observed a high complete response rate with few grade 4 and one grade 5 events. Long-term tumor control appears inferior to more standard treatments available to medically fit patients. Newer radiation fractionations and technologies, immunotherapeutic medication, and nonchemotherapy radiation adjuvants that have been studied may offer either an improved therapeutic response or better tolerability and convenience [16].
We studied a modified chemoradiotherapy regimen to treat a group of patients with invasive bladder cancer who were unfit for conventional radical cystectomy or chemotherapy. One group had tumors that overexpressed her2/neu. We found that patients could reasonably tolerate the treatment despite their frail medical conditions with moderate control of their cancer. Trastuzumab therapy in the her2/neu tumors did not improve treatment response.
Acknowledgments:
The authors acknowledge Richard Whittington, MD (deceased), for contribution as the PI for ECOG.
Funding/Support and role of the sponsor:
This project was supported by grants U10CA180868 (NRG Oncology Operations) and U10CA180822 (NRG Oncology SDMC) from the National Cancer Institute (NCI).
Footnotes
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Financial disclosures: Douglas M. Dahl certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Drs. Brian K. Chang, Douglas M. Dahl, Richard L. Deming, John A. Ellerton, R. Jeffrey Lee, M. Dror Michaelson, Huong T. Pham, William U. Shipley, and Gregory P. Swanson, and Mr. Joseph P. Rodgers have nothing to disclose. Dr. Jason A. Efstathiou declares in the past 36 mo consulting fees from Blue Earth Diagnostics, Boston Scientific, AstraZeneca, and Taris Biomedical; participation in a data safety monitoring board or an advisory board of Merck, Roviant Pharma, Myovant, Sciences, Progenics, Janssen, and Bayer Healthcare. Dr. Felix Y. Feng declares in the past 36 mo consulting for Janssen, Bayer, PFS Genomics (termed April 2021), Myovant Sciences, Roivant, Astellas, Foundation Medicine, Varian, Bristol, Meyers Squibb, Exact Sciences, and Novartis; receiving stock options from Serimmune from serving on their scientific advisory board in 2020; being a cofounder of Artera, a company focused on digital pathology biomarkers in prostate cancer; holding a leadership position with NRG Oncology as the Chair of the Genitourinary Cancer Committee—the role of helping investigators design proposals for clinical trials that are then evaluated by the NCI for funding; all funding decisions are made by the NCI and not by NRG or by Dr. Feng. Dr. Theodore G. Karrison, since the initial planning of the work GRANT SDMC from NCI provides salary support. Dr. Howard M. Sandler declares in the past 36 mo consulting fees from Janssen, ASTRO Board of Directors—unpaid, and stock in Radiogel. Dr. Luis Souhami declares in the past 36 mo support for attending meetings and/or travel from Varian Medical, and participation in a data safety monitoring board or an advisory board of AbbVie and Janssen. Dr. Jacqueline Vuky declares in the past 36 mo research funding from Merck, Roche/Genentech, Innocrin, Celldex, Novartis, Fortis, and Arvinas; advisory fee from BMS, AstraZeneca, and Seattle Genetics/Astellas. Dr. Chin-Lee Wu declares in the past 36 mo consulting fee from OrigiMed. Dr. Anthony L. Zietman declares in the past 36 mo Chair of steering committees for UK randomized trials: PACE, RAIDER, and CHHIP; stipend from Elsevier Publishing: Editor in Chief, International Journal Radiation Oncology Biology Physics.
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