The Legacy of RTOG/NRG Protocols in Shaping Current Bladder Preservation Therapy in North America

There are an estimated 81,180 new cases of urinary bladder cancer for 2022 in the United States (US), along with an estimated 17,100 new deaths.1 Urinary bladder cancer, at clinical presentation, can be broadly bucketed into 3 categories: superficial, invasive (of lamina propria or muscle), and metastatic. For bladder tumors that are superficial or invasive of lamina propria alone, treatment consists of transurethral resection of bladder tumor (TURBT) followed by intravesical therapies in the bladder to prevent recurrence and progression of disease. Metastatic disease is managed with systemic therapies, which consist of chemotherapy or immunotherapies. The Radiation Therapy Oncology Group (RTOG)/NRG Oncology has a long and storied history of conducting prospective trials in North America using radiation therapy as part of trimodality therapy (TMT) for bladder preservation, primarily for muscle-invasive disease. TMT consists of maximal TURBT followed by chemoradiation. Radical cystectomy has traditionally been the gold standard treatment for muscle-invasive bladder cancer (MIBC). The legacy of RTOG/NRG bladder preservation trials are largely phase II studies because of general lack of acceptance of TMT. Unfortunately, there are no completed direct head-to-head randomized comparisons between the TMT and cystectomy and no plan for any in the foreseeable future, as the only randomized trial (the UK Selective Bladder Preservation against Radical Excision trial) closed due to poor accrual.2 However, data from the RTOG/NRG prospective protocols provided the foundation for this treatment paradigm and modern series demonstrate similar long-term clinical outcomes compared to radical cystectomy, particularly with contemporary treatment, firmly establishing TMT as an alternative option for well-selected patients.3, 4, 5 Herein, we discuss the evolution of RTOG/NRG bladder preservation trials that have helped to firmly establish TMT and bladder preservation as a viable and accepted treatment option for patients with bladder cancer. Furthermore, we look ahead to the future of organ-preservation therapy in bladder cancer, including new indications for bladder preservation, the incorporation of novel therapies to further improve upon clinical outcomes, the improvement of radiation techniques, and the personalization of therapy using precision medicine technologies.

Bladder preservation protocols have been ongoing since 1985,6, 7, 8, 9, 10, 11, 12, 13, 14 enrolling a total of 570 patients in published trials (Table 1). All trials have evaluated the use of TMT with various chemotherapies and varying radiation doses and fractionation. The published RTOG series includes eight Phase I/II trials, and one Phase III trial. In general, all RTOG protocols utilized small pelvic radiation fields, which consisted of a 4-field technique and included the whole bladder, bladder tumor, prostate in men, and pelvic lymph nodes. The fields extended superiorly to the S2-3 junction (mid-sacrum), inferiorly to the lower pole of the obturator foramen, and 1cm lateral to the bony margin of the pelvis at the widest point. Eligibility criteria for each trial has been previously described but in general included clinical stage T2-4a and excluded patients with biopsy-proven nodal and metastatic disease. Most trials excluded patients with hydronephrosis as well.

The first trial by the RTOG evaluated TMT in patients who were candidates for cystectomy.6 Patients received cisplatin in combination with induction radiation therapy (40 Gy to the pelvis). After a 2-week break, patients went on to have restaging, including cystoscopy and tumor site biopsy, along with restaging scans of the pelvis. Those who did not have a complete response went on have a cystectomy. For those who had a complete response, they went on to receive an additional 24 Gy to the bladder with concurrent cisplatin. The radiation break was initially introduced to avoid delaying a salvage cystectomy and avoid full dose radiation to the pelvis prior to embarking on a cystectomy in nonresponders. This was the first RTOG trial to evaluate cisplatin concurrently with radiation for safety and efficacy in patients suitable for cystectomy, based on the promising data from a trial pioneered by Dr. William Shipley in patients unsuitable for cystectomy.15 Complete response was achieved in 66% of patients, and overall, 3-year actuarial survival was 64%. This trial set the standard for the classic TMT approach for patients who are cystectomy candidates, which consisted of TURBT + induction chemoradiation, followed by response evaluation with cystoscopy, followed by consolidation chemoradiation for those with complete response versus radical cystectomy for those with incomplete response.

After the success of RTOG 85-12, the RTOG developed protocol 88-02, led by Dr. William Shipley,7 which included neoadjuvant methotrexate, cisplatin, and vinblastine (MCV) chemotherapy prior to the TMT regimen, based on results of a pilot study performed at the Massachusetts General Hospital.16 Patients underwent induction chemoradiation with concurrent cisplatin. Radiation was given daily in 1.8 Gy fractions to a total dose of 39.6 Gy to the pelvis. After 2 weeks, patients were restaged with cystoscopy and tumor site biopsy, along with staging scans of the pelvis. Consolidation therapy consisted of radiation to 25.2 Gy in daily 1.8 Gy/fraction to the bladder tumor volume along with cisplatin. In this trial, 75% of the enrolled 91 patients achieved a complete response, and 4-year overall survival was 62%. In terms of toxicity, there were more toxicities in this trial compared to the earlier RTOG study of concurrent cisplatin and radiotherapy alone, without the addition of MCV. The addition of neoadjuvant MCV led to increased incidence of diarrhea, leukopenia, and mucositis.

Based on the results of RTOG 88-02, Dr. Shipley and the RTOG team developed RTOG 89-038 as a randomized Phase III trial to further evaluate the effectiveness of 2 cycles of neoadjuvant MCV. Based on study design, a projected accrual was 174 patients, however, this trial was stopped earlier due to poor patient tolerance of MCV. There was an unexpectedly high rate of severe neutropenia and sepsis. Three patients died due to severe leukopenia and sepsis from induction MCV therapy. Initial inclusion criteria were more permissive, with creatinine clearance of 50 mL/min, and required level of serum creatinine upon entry of 2.0 mg/dL or less. These eligibility requirements were later modified to 60 mL/min creatinine clearance and an entry level serum creatinine of 1.7 mg/dL or less. Following this change, only 1 patient had severe neutropenic sepsis. Induction chemoradiation consisted of radiation to the pelvis to 39.6 Gy in daily doses of 1.8 Gy along with concurrent cisplatin. After a 4-week break, patients were restaged with cystoscopy, tumor site biopsy, and urine cytology. Consolidation radiation therapy consisted of treatment to the bladder tumor only to a total dose of 64.8 Gy in 1.8 Gy/fraction, along with concurrent cisplatin. For the 123 patients enrolled, the 5-year overall survival rate was 49%; 48% in arm 1 (neoadjuvant MCV) versus 49% in arm 2. There were no other significant differences in outcomes, including 5-year distant metastasis rate (33% arm 1 vs 39% arm 2) and 5-year survival with a functioning bladder (36% arm 1 vs 40% arm 2). Thus, it was concluded that neoadjuvant MCV was not beneficial for TMT bladder preservation.

In RTOG 95-06, the RTOG began to evaluate twice daily fractionation, or accelerated fractionation, in combination with concurrent chemotherapy (5-fluorouracil, 5-FU, and cisplatin).9 This study excluded patients with hydronephrosis given that prior studies had found that these patients had poorer overall outcomes with TMT. Thirty-four patients were included in the analysis. After induction treatment (which consisted of twice-daily 3 Gy fractions to a total dose of 24 Gy to the pelvis), 67% of patients achieved a complete response (upon evaluation with cystoscopy, tumor site biopsy, and urine cytology 3-4 weeks after completion of induction therapy). Patients then went on to receive consolidative chemoradiation with twice-daily 2.5-Gy fractions to 20 Gy to the bladder and bladder tumor volume, thus for a total of 44 Gy to the bladder and bladder tumor. Three-year overall survival was 83%. Three-year bladder-intact survival was 66%. However, within 29 months of median follow-up, of the 20 patients who achieved a complete response, 9 patients (45%) developed superficial recurrence. In addition, 21% of patients developed grade 3 or 4 hematologic toxicity.

In this trial,10 Dr. Shipley and the RTOG sought to evaluate the utility of adjuvant MCV chemotherapy, given that neoadjuvant MCV chemotherapy was too toxic. Patients received induction chemoradiation with concurrent cisplatin. The induction radiation therapy consisted of 12 days of twice-daily radiation, 1.8 Gy to the pelvis in the morning followed by 1.6 Gy to the tumor 4-6 hours later (40.8 Gy to the tumor, and 21.6 Gy to the pelvis). After a 3-week break, patients were restaged with cystoscopy, tumor site biopsy, and urine cytology. In this study, out of 47 patients, 74% achieved a complete response and went on to receive consolidation chemoradiation. Consolidation consisted of 1.5 Gy twice-daily treatments for a total dose of 24 Gy to the pelvis (64.8 Gy total to the tumor, 45.6 Gy to the pelvis). Afterwards, patients then went on to receive 3 cycles of adjuvant MCV chemotherapy. In those with an incomplete response, a cystectomy was performed, followed by adjuvant MCV chemotherapy. However, only 45% of patients were able to complete 3 cycles of MCV chemotherapy. Approximately 41% of patients experienced Grade 3 or higher toxicity during adjuvant chemotherapy, again highlighting its poor tolerability. Three-year distant metastasis rate was 29%, while the overall survival rate was 61%. The bladder-intact survival rate was 48%.

The goal of this trial11 was to enhance radiosensitizing chemotherapy with the addition of paclitaxel as part of the concurrent chemotherapy that is given along with cisplatin during induction and consolidation radiotherapy. In addition, the protocol sought to explore a different adjuvant chemotherapy regimen (cisplatin and gemcitabine), given the toxicity associated with MCV chemotherapy. The use of cisplatin 70mg/m2 and gemcitabine 1000mg/m2 previously demonstrated comparable cancer control to a regimen of methotrexate, doxorubicin, vinblastine, and cisplatin with improved patient tolerance,17 thus it was felt that the replacement of MCV with cisplatin and gemcitabine would be beneficial for patients undergoing TMT. Induction radiation was given over 13 days, twice-daily, with 1.6 Gy given to the pelvis in the morning, followed by 1.5 Gy to the bladder for 5 treatments, followed by 1.5 Gy to the tumor for eight treatments. Total dose was 20.8 Gy to the pelvis, 28.3 Gy to the bladder, and 40.3 Gy to the bladder tumor. This was delivered along with cisplatin and paclitaxel. Patients who achieved a complete response based on restaging, which consisted of cystoscopy, tumor site biopsy, and cytology 3 weeks after completion of induction chemoradiation, then went on to receive consolidation chemoradiation. This consisted of 1.5 Gy pelvic radiation delivered twice-daily to a total of 24 Gy along with the concurrent chemotherapy, thus the final radiation doses were 64.3 Gy to the tumor and 44.8 Gy to the pelvis. The patients then went on to receive adjuvant gemcitabine and cisplatin. Of 80 eligible patients enrolled, the complete response rate after induction was 81% (65/80 patients). The 5-year overall and disease-specific survival rates were 56% and 71%, respectively. The addition of paclitaxel resulted in a greater percentage of grade 3-4 toxicity during chemoradiation, specifically diarrhea. There were still hematologic toxicities associated with adjuvant chemotherapy (46% with grade 3 toxicity), however, the higher response and cancer control rates were promising. This led to the follow-up protocol, RTOG 02-33, which randomized patients to this regimen compared to a regimen consisting of 5-FU in place of paclitaxel along with cisplatin.

In order to further assess the optimal concurrent chemotherapy regimen to improve efficacy for induction and consolidation radiation, RTOG 02-33,12 a randomized phase 2 study, was performed. Patients were randomized to receive either paclitaxel along with cisplatin concurrently with radiation versus 5FU along with cisplatin concurrent with radiation. Adjuvant chemotherapy was the same for both arms and consisted of adjuvant cisplatin/gemcitabine/paclitaxel. The radiation protocol was similar to the protocol described for RTOG 99-06. Forty-six patients were in the paclitaxel group and 47 patients were in the 5FU group. Overall, with a median follow-up of 5 years, cancer control rates were comparable between the 2 regimens. After induction chemoradiation, 33 patients (72%) in the paclitaxel group achieved a complete response, compared to 30 patients (62%) in the 5FU group. Five-year overall survival was 71% and 75%, respectively. The trial was not designed to compare the 2 regimens to each other directly. However, in general, the 2 regimens were tolerated well, with more acute side-effects in the paclitaxel regimen (metabolic), and with the 5FU regimen causing more genitourinary/gastrointestinal side effects, particularly during the consolidative phase. This study provides information for clinicians weighing different chemotherapy regimens to select for patients undergoing TMT.

RTOG then embarked on a protocol evaluating patients unsuitable for cystectomy, recognizing that salvage cystectomy may not be possible for a significant number of MIBC patients, along with the addition of trastuzumab to the concurrent chemotherapy.13 Prior studies suggested a high rate of her2/neu positive tumors among patients with bladder cancer, and that these patients may have worse outcomes with traditional therapies.18 Thus, investigators analyzed tumors for her2/neu expression, and added trastuzumab to the radiosensitizing chemotherapy regimen of paclitaxel. Radiation was administered daily at 1.8 Gy fractions for a total of 36 fractions and a total dose of 64.8 Gy. There was no break to assess for response, given that these patients were ineligible for a cystectomy, thus there would be no reason to not complete the chemoradiation therapy. Overall, there were 20 patients with her2/neu overexpression who received the addition of trastuzumab (arm 1) and 46 patients without her2/neu overexpression who received standard radiation and paclitaxel (arm 2). Overall, the complete response rate at 1 year was 72% for arm 1 and 68% for arm 2. There were acute treated-related adverse events in 7 of 20 patients in arm 1 and 14 of 46 patients in arm 2. Overall, this protocol demonstrated that daily radiation with paclitaxel is effective in patients unsuitable for cystectomy with moderate toxicity and good response rates. Separately, in those with her2/neu overexpression, a group that traditionally has poor outcomes, the addition of trastuzumab may improve outcomes with comparable efficacy and complete response rates to patients not overexpressing her2/neu.

Radiosensitization with cisplatin is standard for bladder preservation, however, not all patients are fit for cisplatin. Those with impaired renal function and hearing loss are not good candidates. Thus, NRG/RTOG 07-12 sought to evaluate gemcitabine (twice-a-week low-dose of 27mg/m2) along with once daily radiation compared to 5FU/cisplatin and twice daily radiation (as per RTOG 02-33 above).14 The incorporation of low-dose gemcitabine came from a phase I trial from the University of Michigan, establishing safety of the regimen with high response rates and clinical outcomes comparable seen in prior series.19 The primary end point was freedom from the distant metastasis at 3 years (DMF3). The daily radiation consisted of 2 Gy per day delivered to the pelvis for 10 fractions, followed by 2 Gy to the bladder for 4 fractions, and 2 Gy to the bladder tumor for 6 fractions. Thus, total induction doses were 20 Gy to the pelvis, 28 Gy to the bladder, and 40 Gy to the bladder tumor. Consolidation therapy consisted of 2 Gy per day delivered to the pelvis for 12 fractions (24 Gy total). Thus, final total doses were 44 Gy to the pelvis, 52 Gy to the bladder, and 64 Gy to the bladder tumor. Thirty-three patients were included in each arm. Median follow-up was 5.1 years. For twice daily radiation with 5FU/cisplatin, the DMF3 was 78%, while the DFM3 was 84% for daily radiation with gemcitabine. Bladder-intact distant metastasis-free survival at 3 years was 67% and 72% for each arm, respectively. Complete response rates were 88% and 78%, respectively. In the 5FU/cisplatin arm, 21/33 patients (64%) of patients experienced grade 3 and 4 toxicities during treatment. In the gemcitabine arm, 18/33 (55%) of patients experienced grade 3 and 4 toxicities during treatment. This trial demonstrated excellent DMF3 for both arms, and somewhat fewer toxicities in the gemcitabine arm, suggesting that both regimens are good options for bladder preservation with TMT, and that gemcitabine along with daily radiation can be viable alternative in patients who are unsuitable for cisplatin-based chemotherapy.

As discussed above, bladder preservation in each individual trial appears to achieve effective local control and good clinical outcomes, although long-term bowel and bladder toxicity remained a concern. The long-term effects of chemoradiation to the bladder and pelvis were evaluated using a pooled analysis of RTOG trials 89-03, 95-06, 97-06, and 99-06.20 Between 1990 and 2002, there were 157 patients evaluable who underwent bladder-preservation therapy, surviving ≥2 years from start of treatment with bladder intact. Late toxicity was defined as toxicity ≥180 days after consolidation chemoradiation. With a median follow-up of 5.4 years (range, 2.0-13.2 years), 7% of patients (n = 11) experienced late grade ≥3 pelvic toxicity. This was defined as 5.7% (n = 9) genitourinary toxicity and 1.9% (n = 3) gastrointestinal toxicity (1 patient experienced both a late grade 3 genitourinary and gastrointestinal toxicity). There were no late grade 4 toxicities and no treatment-related deaths, thus concluding that there is low incidence of late pelvic morbidity associated with TMT in patients who retain their bladder.

Separately, long-term outcomes of bladder-preservation for MIBC were evaluated using a pooled analysis of RTOG trials 88-02, 89-03, 95-06, 97-06. 99-06, and 02-33.4 Between 1988 and 2007, 468 patients were enrolled onto these trials. Complete response to TMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients evaluated, and 7.8 years among 205 survivors, overall survival rates at 5- and 10-years were 57% and 36% respectively. The disease-specific survival rates were 71% and 65% respectively. Five- and ten-year estimates of local failures, muscle-invasive versus non-muscle-invasive, were 13% and 14% for muscle-invasive and 31% and 36% for non-muscle-invasive, respectively. The estimated rates of distant metastases were 31% at 5-year and 35% at 10-year. This pooled analysis thus demonstrated that long-term disease-specific survival rates were comparable to those from radical cystectomy, solidifying its role as a suitable alternative to radical cystectomy for patients with MIBC.

There have been efforts to move bladder preservation into earlier disease stages such as clinical stage T1 bladder cancer, particularly in the recurrent NMIBC setting. For this patient population, the standard treatment after failed BCG (bacillus Callamette-Guerin) intravesical therapy is radical cystectomy. Effective second-line therapy using intravesical agents is not well established, with studies demonstrating poor results.21, 22, 23 There is a need to improve upon the clinical outcomes in this patient population. RTOG embarked on a phase II trial evaluating bladder preservation TMT therapy in patients with recurrent high-grade T1 bladder tumors following BCG treatment.24 Thirty-seven patients were enrolled between 2009 and 2017, with 34 evaluable. With a median follow-up of 4.2 years, the 3-year freedom from cystectomy rate was 88%. Overall survival at 3 and 5 years was 69% (95% CI 53%-85%) and 53% (95% CI 35%-72%), respectively. Grade 3 adverse events occurred in 20 patients, and consisted of anemia, gastrointestinal issues, urinary tract infections, lymphopenia, metabolism/nutrition disorders, or hematuria. Trial results have only been presented at the American Society for Radiation Oncology Annual Conference in 2021, but these early data demonstrate that trimodality therapy for bladder preservation may be reasonable in this patient population and should be considered for select patients. This represents an area of opportunity for further exploration and additional research to compare to established modalities in this disease state to understand appropriate patient selection.

In order to improve upon the current expected clinical long-term outcomes for bladder cancer patients treated with chemoradiation, current TMT protocols need to continue to evolve Table 2).

In recent years, immune checkpoint inhibitors (ICI) have been approved for advanced/metastatic bladder cancer, demonstrating activity in those who are initially cisplatin-ineligible, as well as in those who have progressed after first-line platinum-based chemotherapy.25, 26, 27, 28 Other data have suggested that the combination of radiation and ICI therapy may improve outcomes in localized muscle-invasive bladder cancer.29, 30, 31, 32 This is being studied in the cooperative group setting in both the INTACT: SWOG/NRG 1806 study, which evaluates chemoradiotherapy +/- atezolizumab in muscle-invasive bladder cancer (NCT03775265), as well as the INSPIRE: ECOG-ACRIN/NRG EA8185 trial, which evaluates chemoradiotherapy +/- durvalumab in node-positive bladder cancer (NCT04216290). In the SWOG/NRG 1806 study, which is currently planned to be the largest US-based trial of bladder-preservation to date (enrollment goal of 475 patients), the permissive radiation design is highly pragmatic to ensure accrual, allowing physicians to treat 1-3 phases and to include the pelvis or not, given the ongoing evolution of radiation fields. Thus, this highly contemporary design will allow findings to be interpreted with the modern use of radiation therapy for MIBC. Separately, INSPIRE is also novel given the nodal treatment design, which can help to answer the question of whether regional nodal involvement can be considered curable with the use of chemoradiation.

When using immunotherapy in combination with radiation therapy for earlier disease stages, the safety and tolerability is important to assess given the synergistic relationship between the 2 treatments. Two early phase 1 studies evaluated ICI in combination with hypofractionated radiation treatment to the bladder.33,34 The PLUMMB trial (NCT02560636) was a Phase I study of 5 patients with locally advanced/metastatic bladder cancer, treated with 36 Gy in 6 weekly fractions along with pembrolizumab starting 2 weeks prior to radiation and concurrently with radiation.34 This trial was stopped early as 2 patients experienced severe bladder irritation (cystitis or pain). These were determined to be protocol-defined dose-limiting toxicities judged to be related to treatment. A separate phase 1 trial evaluated atezolizumab along with weekly gemcitabine for 4 weeks concurrent with hypofractionated radiation (50 Gy in 20 fractions) for localized MIBC.33 The protocol included radiation to the pelvic lymph nodes. There were a total of 8 patients enrolled. The first give patients received atezolizumab at 1200 mg intravenously every 3 weeks for 16 cycles. Three patients developed grade 3 side effects (gastrointestinal), two of which qualified as dose-limiting toxicity. Thus, the dose of atezolizumab was decreased to 840 mg for the remaining 3 patients. However, the study was ultimately terminated due to the development of additional grade 3 toxicity in 2 patients treated with the reduced dose. The toxicities were mostly gastrointestinal. Four patients developed grade 3 colitis. Due to these severe toxicities observed when combining hypofractionated RT and ICI, the SWOG/NRG 1806 trial does not allow for hypofractionation currently. An early analysis of safety data of 73 patients enrolled onto the trial (36 receiving standard TMT, 37 receiving TMT + atezolizumab) found reasonable toxicity rates, with 11 grade 3 or higher toxicities on the standard arm versus 23 on the experimental arm.35 The most common toxicity was hematological and considered non-immune related, with none of the grade 3 or higher toxicities considered to be immune-related in this early safety analysis. Thus, the combination of conventionally fractionated radiation and ICI appears to be safe with acceptable early toxicity.

Going forward, deep understanding of molecular features of bladder tumors can lead to discover of predictive and prognostic biomarkers that can aid with appropriate patient selection for bladder preservation.36 Many of the previously discussed RTOG/NRG trials have a component of biospecimen collection for translational discovery. There are several promising candidates that have been studied using RTOG/NRG samples, but these need to be further evaluated prospectively (Table 3). For example, MRE11, as measured by immunohistochemistryin a cohort of patients treated with radiation alone, demonstrated that patients with low MRE11 staining had associated worse 3-year cancer-specific survival.37 A pooled analysis using tissue from patients enrolled on 6 NRG/RTOG bladder-sparing trials validated this finding.38 Separately, investigations into DNA repair pathway alterations found that deleterious mutations in ERCC2 were associated with improved outcomes after chemoradiation for bladder cancer.39,40 Additional work using whole exome sequencing/gene expression profiling from tissues from patients enrolled in NRG/RTOG bladder-sparing trials is ongoing. Alterations in signal transduction pathways have also been associated with outcomes after chemoradiation for MIBC. In a study using tissue from patients enrolled on RTOG 88-02, 89-03, 95-06, and 97-06, EGFR expression (assessed by immunohistochemistry) was associated with improved outcomes after treatment. Conversely, HER2 expression via immunohistochemistry was associated with poorer outcomes.41 Due to this observation, RTOG 05-24 was designed to evaluate the use of trastuzumab in patients with HER2/neu overexpression, finding that the addition of trastuzumab may have mitigated the worse prognosis associated with HER2 overexpression.

The promise of potential synergy when combining ICIs with radiation therapy for MIBC may be more evident in certain subsets of patients with immune-activated disease. In a large study of patients receiving TMT for bladder preservation evaluating immune signatures based on gene expression, signatures associated with T-cell activation and interferon-gamma signaling were associated with improved disease-specific survival. A comparison cohort of patients treated with neoadjuvant chemotherapy and radical cystectomy did not find this same association.42 Thus, as part of NRG/SWOG 1806, multiple translational studies are planned with the goal of identifying/validating biomarkers related to ICI response in combination with radiation for MIBC.

As ongoing trials with planned translational studies close, and prior translational studies are completed, data will help inform an improved selection and treatment of candidates with bladder cancers.

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