Advances in surgical management of muscle invasive bladder cancer.

INTRODUCTION: Bladder cancer remains a disease of the elderly with relatively few advances that have improved survival over the last 20 years. Radical cystectomy (RC) has long remained the principal treatment for muscle-invasive bladder cancer (MIBC).
METHODS: A literature search of PubMed was performed. The content was reviewed for continuity with the topic of surgical advances in MIBC. Articles and society guidelines were included in this review.
RESULTS: Despite the associated morbidity, even in the elderly, RC is still a reasonable option. Modifications during RC may have a positive or negative impact on survival and quality of life. The extent of pelvic lymph node dissection is one such factor which may positively impact survival outcomes. In addition, preservation of pelvic organs, robotic surgery and the adoption of enhanced recovery after surgery principles continues to improve the postoperative recovery and quality of life in RC patients.
CONCLUSION: There are some ongoing studies in many of these areas, but overall the new advances in MIBC may improve patient quality and quantity of life. The advances in surgical treatment of MIBC are important and the focus of the review here.

INTRODUCTION

Bladder cancer remains a disease of the elderly with relatively few advances that have improved survival over the last 20 years.[123] Radical cystectomy (RC) has long remained the principal treatment for muscle-invasive bladder cancer (MIBC).[4] Despite the associated morbidity, even in the elderly, RC is still a reasonable option.[5] Modifications during RC may have a positive or negative impact on survival and quality of life. The extent of pelvic lymph node dissection (ePLND) is one such factor which may positively impact survival outcomes.[6] In addition, preservation of pelvic organs, robotic surgery, and the adoption of enhanced recovery after surgery (ERAS) principles continues to improve the postoperative recovery and quality of life in RC patients.[789] The advances in surgical treatment of MIBC are important and the focus of the review here.

METHODS

Literature review was completed by searching the PubMed database with the term “cystectomy or bladder cancer” in addition to one of the following terms: “lymph node dissection,” “organ sparing,” “chemotherapy,” “robotic,” “laparoscopic,” or “enhanced recovery.” Included studies were available in English language and full text from institutional subscription or PubMed. Relevant studies and guideline publications were included if they were published in the last 3 years.

ADVANCES IN SURGERY FOR MUSCLE INVASIVE BLADDER CANCER

Integration of systemic chemotherapy

Survival after RC for MIBC is dependent not only on surgical techniques but also on the thoughtful integration of systemic therapy. Neoadjuvant chemotherapy (NAC) before RC is supported by level I evidence and continues to be recommended by multiple guidelines.[101112] With increasing awareness and recommendations from urology and oncology organizations, there seems to be improved utilization of NAC in the MIBC patients.[1314] Interestingly, for many years methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) has been thought to have oncological equivalence to gemcitabine and cisplatin (GC). However, a recent meta-analysis of over 3000 patients rekindles the question of which regimen is superior.[15] Yin et al. reported a possible advantage to MVAC compared to GC for overall survival, however, this was not statistically significant, (hazard ratio [HR], 1.31; 95% confidence interval [CI], 0.99–1.74).[15] Even in those where NAC is omitted, there is increasing evidence to support the use of adjuvant chemotherapy.[16] As new immunotherapies arise, they may provide survival advantages when combined with RC, but only future studies will be able to provide answers.[1718]

Extended lymph node dissection

Pelvic lymph node dissection remains integral to RC for MIBC. It is clear that a pelvic lymph node dissection with RC provides a survival advantage compared to RC alone.[19] There are many studies which suggest a direct correlation between the increasing numbers of lymph nodes removed and improved survival.[1920] Hence, the remaining question is: does a formal ePLND provide a survival advantage? In a recent meta-analysis reported on over 2800 patients who underwent pelvic lymph node dissection, those who had ≥ pT3 disease had a significant benefit in recurrence-free survival with ePLND, HR: 0.61 (95% CI: 0.52–0.73), P < 0.001, but the same did not hold true for those with ≤ pT2 disease, HR: 0.95 (95% CI 0.64–1.41), P = 0.81.[20] An additional report noted patients may have more morbidity associated, specifically greater blood loss (P < 0.001), with ePLND, but the ePLND does result in a decrease in local recurrences.[21] In patients with micrometastatic disease, the ePLND may provide greater survival benefit (HR: 0.52; 95% CI 0.43–0.64) compared to those without any occult lymph node metastasis.[22] Ongoing studies, such was SWOG 1011 phase III trial and the German Association of Urologic Oncology trial are randomized trials to compare ePLND to standard lymph node dissection and will help provide more definitive data and possibly stratify which patients benefit the most from ePLND.[1023]

Organ sparing

For patients who are carefully selected, sparing of the peritoneum, prostate, vagina, and uterus can provide several advantages without compromising the oncological outcomes.[2425] Organ-sparing cannot only provide improved sexual function; it may augment urinary function.[26] An additional technique during RC which may improve the quality of life is the readaptation of the dorsolateral peritoneal layers after ePLND. The readaptation of these peritoneal layers has been explored as an option to reduce postoperative ileus.[27] Vatolomei et al. reported outcomes of a randomized study looking at 200 patients with and without readaptation.[27] They found that there was less pain and better bowel function at both 3 and 24 months postoperatively.[27] In addition to the peritoneal readaptation, different degrees of other pelvic organ preservation may also be beneficial.

For men, sexual preservation has been described in several variations. For any prostate sparing treatment, it is recommended that there be no tumor at the bladder neck, a prostatic urethral biopsy is obtained before RC, and prostate specific antigen checked.[28] In addition, a transrectal ultrasound-guided prostate biopsy should be performed.[28] The first form of male preservation is nerve sparing. As with radical prostatectomy, nerve sparing does help maintain sexual function.[102930] In a highly selected group, nerve sparing and seminal vesicle sparing may help preserve functional outcomes with over 70% reporting potency within 12 months of surgery; however, long-term oncological data are not available at this time, and this should be done with caution.[30] In addition, nerve sparing reports with short follow-up report oncologic outcomes are not compromised with this technique.[10] The second variation of male organ sparing is prostate capsule sparing. Sparing the prostatic capsule is supported by some and may provide theoretical advantages, however, a recent randomized control trial comparing the prostatic capsule sparing to the traditional nerve sparing at cystectomy with neobladder creation showed no benefit at 12 months in sexual or urinary function.[31] However, full prostate sparing may provide a safe oncological result with superior urinary and sexual function, in highly selected patients.[28] The last method for male sexual organ sparing reported is the bilateral nerve sparing along with the prostatic apex.[32] This approach in younger RC patients has improved sexual function; however, oncological outcomes are yet to be determined.[32]

For women absence of trigonal and bladder floor involvement, lack of palpable posterior masses on bimanual exam and absence of enlarged lymph nodes has been associated with lack of bladder cancer extension to the pelvic organs. These factors may help stratify which women should be offered nerve, vaginal, and uterine sparing RC during preoperative counseling.[33] Specifically, uterine preservation allows for avoidance of vaginal shortening, which may improve healthcare-related quality of life (HRQoL).[34] Importantly, the avoidance of vaginal shortening has been reported to improve sexual function for women.[24] In addition, uterine preservation allows for improved urinary function in women with continent diversions.[34] Urinary function may also be improved with intentional nerve sparing in women.[35]

Although the idea of sparing pelvic organs is appealing, it should be done only in selected patients. The overall quality of evidence related to organ sparing RC is not robust. Thus, RC with sparing of pelvic organs is not routinely recommended.[10]

Robotic surgery

The role of robotic cystectomy remains controversial.[36] However, robotic RC has become an acceptable alternative to open surgery by some guideline organizations, including the European Association of Urology.[10]

There appear to be no compromised outcomes in survival for robotic RC patients. Multiple studies report similar oncological outcomes at 5 years for robotic RC compared to open RC.[37383940] Oncological outcomes have been subject to heavy criticism because of selection bias.[4142] However, multiple studies have reported advanced pathology treated with robotic RC has similar oncological outcomes to advanced pathology treated with open RC.[3738394041] In addition, there is no difference in lymph node yield between the two modalities.[43]

The Memorial Sloan Kettering trial, the only randomized clinical trial to date comparing open and robotic RC, only included open urinary diversions.[44] An experienced robotic surgeon can often perform an intracorporeal urinary diversion of any type and may be able to avoid postoperative gastrointestinal side effects as well as other postoperative morbidity.[10454647] There are no randomized trials comparing complete robotic intracorporeal urinary diversion with open RC. Robotic RC seems to be safe for patients; no studies have been published demonstrating an increase in perioperative complications.[48] Importantly, there are many reports of robotic RC having less blood loss than open RC.[3649]

With some benefits and no oncologic compromise, the ideal patient population for robotic RC is yet to be determined. Winter et al. recently published a study where elderly patients specifically may be offered a benefit by robotic surgery.[49] To date, few have looked at patient-reported HRQoL outcomes. Improved physical wellbeing may be found in robotic RC when compared to open RC patients.[50] The randomized multicenter open versus robotic cystectomy (RAZOR) trial outcomes are anxiously awaited to see what advantages or disadvantages are seen with robotic RC.[51] In the meantime, robotic RC is considered effective and safe with comparable oncological outcomes.[52]

Enhanced recovery after surgery

ERAS pathways for cystectomy have become gradually more popular to aid in the recovery of patients after surgery.[953] ERAS pathways have been long used in colorectal surgery. This has become the foundation on which enhanced recovery for RC patients was built. There are many components to these pathways to help alleviate the physical and psychological stress RC brings to these patients.[79] A recent meta-analysis reported a reduction in complications and length of stay in the hospital.[8] Important components of ERAS for RC patients include: patient education, prehabilitation, carbohydrate loading, maintenance of euvolemia, maintenance of normothermia, early enteral feeding, early mobilization, opioid avoidance, multimodal pain control, and venous thromboembolism prevention.[795455]

Part of ERAS is a focus on euvolemia. Euvolemia can be maintained by the use of hemodynamic monitoring and norepinephrine to prevent postoperative fluid overload.[56] Further, norepinephrine has been associated with decreased intraoperative blood loss and a faster return of bowel function.[5657] One study reported improved urinary and sexual function outcomes with norepinephrine use and fluid restriction.[58]

Despite the practice of ERAS becoming more popular, there still exists a gap between the perception of practicing ERAS principles and clinical practice.[59] Only improved awareness will help urologists advance ERAS implementation which will lead to increased patient benefit.[959]

FUTURE DIRECTIONS

The future of MIBC surgery will continue to be shaped by a multidisciplinary team. Integration of systemic immunotherapy for MIBC and RC will likely be important, especially in platinum ineligible patients. Furthermore, markers to predict patient recovery after RC and measures of RC patients' symptoms burden will give us insight into how to better counsel and prepare patients for RC. As robotic surgeons gain urinary diversion experience, this may allow streamlining of the operation and lead to an overall decrease in complications. Finally, RC currently is reserved for those who can be cured of their MIBC; the question remains as to whether there may be a life prolonging advantage in cytoreductive RC.

CONCLUSION

Overall, there are some advances in MIBC surgery which can prolong survival and improve the quality of life after RC. There are still many unanswered questions in the area of surgery for MIBC, but hopefully ongoing research will provide us with more data in the near future.