Is robotic approach useful to palliate advanced bladder cancer? A monocentric single surgeon experience.

INTRODUCTION: The aim of this study was to assess surgical and functional outcomes of 17 consecutive patients undergoing robot- assisted radical cystectomy (RARC) with palliative intent in a monocentric single surgeon series.
MATERIAL AND METHODS: We collected data from 17 consecutive patients who underwent RARC with palliative intent performed by a single surgeon at our institution. Patients undergoing palliative RARC were those with advanced bladder cancer (BC) or advanced comorbidities. Clinical, surgical and functional outcomes were prospectively collected. Patients completed a specific questionnaire (Functional Assessment of Cancer Therapy-Bladder Cancer, FACT-BL) before and after surgery to assess the role of palliative RARC in terms of quality of life improvement.
RESULTS: Median age at surgery was 78 years, with median Charlson Comorbidity Index (CCI) and age-adjusted CCI of 3 and 7, respectively. Clinical stage was T2, T3 or T4 in 7, 8 and 2 patients respectively, with 52.9% and 29.4% with cN+ and cM+ disease. Median estimated blood loss was 200 ml, with 1 patient requiring intra-operative blood transfusion. Median hospital stay was 7 days. A total of 3 and 2 patients were re-hospitalized during the first 30 and 30-90 post-operative days, respectively. One major Clavien grade complication was recorded.At median follow-up of 8 months, 9 and 2 patients succumbed due to tumor progression and other causes. Pre-operative and post-operative FACT-BL scores improved significantly in each domain.
CONCLUSIONS: A RARC is a safe and feasible technique which could be offered as part of palliative care in patients with advanced BC or comorbidities. Precise guidelines for palliating BC patients should be better.

INTRODUCTION

Bladder cancer (BC) represents the 9th most commonly diagnosed cancer and the 13th cause of death in the world, with increasing incidence among elderly patients [1].

In western countries, about 25% of newly diagnosed BC are muscle-invasive BC (MIBC) and 10–30% of non-muscle-invasive BC (NMIBC) will progress to muscle-invasive disease, with nearly half of these patients succumbing due to tumor progression [2, 3, 4]. 5% to 15% present unresectable or metastatic disease at time of diagnosis [5]. Patients succumbing due to BC often present with disseminated disease and symptomatic metastases [6, 7]. Prognosis of advanced and/or metastatic BC is generally extremely poor and treatment is palliative. Patients with advanced bladder cancer often present with hardly bearable symptoms, such as chronic pelvic pain, urgency, hematuria and palliative cystectomy is performed to ease symptoms and perhaps improve their quality of life (QoL).

Palliative care has been widely described for other malignancies, but we still lack precise guidelines about palliation in BC patients [8, 9, 10].

Robot-assisted radical cystectomy (RARC) was firstly described in 2003 aiming to minimize invasiveness and trying to reduce surgical complications [11]. Nonetheless, despite a gradual increase of tertiary centers routinely performing RARC we still lack a clear evidence of superiority of robotic approach as compared to laparotomy, with open radical cystectomy (ORC) still representing the gold standard [12]. A recent randomized controlled trial reported reduced estimated blood loss (EBL), inferior transfusion rates and shorter hospital stay of RARC vs. ORC, with longer operative times, higher costs, and comparable complications rates and oncologic control [13].

The aim of this study is to present data from 17 consecutive patients who underwent RARC with palliative intent at our institution, to assess the potential role of minimally invasive surgery in this subset of BC patients.

MATERIAL AND METHODS

We prospectively collected data from 17 consecutive patients who underwent RARC with palliative intent at our institution between January 2015 and November 2018. Each patient received uretero-cutaneostomy as urinary derivation. Patients undergoing palliative RARC were those with advanced BC or serious comorbidities, namely clinical T3b/T4, N+ or M+ disease or Charlson Comorbidity Index (CCI) ≥3. CCI is the most commonly used score to assess comorbidities and to assess overall life expectancy of patients undergoing surgical procedures [14]. Local, nodal and systemic status were assessed with whole body contrast enhanced computed tomography (CE-CT), magnetic resonance imaging (MRI) and bone scan.

Each case was discussed in a multi-disciplinary meeting (including a urologist, oncologist, radiologist, radiotherapist and dedicated pathologist) and a proper informative consent was expressed by each patient. Neo-adjuvant chemotherapy was given according to multi-disciplinary decision and consisted of 4 cycles of platinum-based chemotherapy. Each surgical procedure was performed by a single surgeon (A.P.), after attending an intensive modular training program at a referral European tertiary center, supervised by a worldwide recognized mentor (P.W.) [15]. During our series, surgeons from another tertiary center participated as table assistants as a part of a modular training. Surgical procedure was performed as previously described without major modifications [16]. Female patients also received hysteroannessiectomy as part of the surgical procedure, although one patient already underwent laparoscopic hysteroannessiectomy. Patients with a carcinoma in situ (CIS) at the urethral frozen section also underwent perineal urethrectomy at the end of the surgical procedure. A validated specific questionnaire, Functional Assessment for Cancer Therapy – Bladder Cancer (FACT-BL) version 4 was translated in Italian and administered to patients before surgery and a month after surgery [17].

For each patient we reported clinical, peri-operative data, post-operative complication within 3 months graded according to Clavien-Dindo classification, pre- and post-operative FACT-BL scores, cancer specific and overall survival status. Post-operative complications were labelled as ‘early’ or ‘late’ if occurred within 30 days after surgery or between 30 and 90 post-operative days, respectively.

Statistical analyses

Statistical elaborations were performed using SPSS® version 21.0 (IBM Corp, Armonk, NY) for Macintosh ®. Continuous variables were reported as medians with interquartile ranges and means+/-standard deviation, whereas categorical variables were expressed as frequencies with proportions. Wilcoxon signed-ranked test was used to compare medians of pre- and post-operative scores of FACT-BL domains. An alpha value of 5% was set to be the threshold to determine statistical significance.

RESULTS

Table 1 reports demographics of 17 patients who underwent RARC with palliative intent.

Table 1

Overall demographic and clinical features of patients undergoing RARC with palliative intent

Number of patients (%)	17 (100)
Sex (%) Male Female	13 (76.5)4 (23.5)
Age at surgery Median IQR	7873-82
CCI Median IQR	32-4
BMI Median IQR	2422.5-26.1
Related symptoms (%) Haematuria Pelvic pain Frequent urination Weight loss	5 (29.4)6 (35.3)3 (29.4)4 (23.5)
Pre-operative stage (%) T1 T2 T3 T4	0 (0)7 (41.2)8 (47.1)2 (11.8)
cN+	9 (52.9)
cM+	5 (29.4)
Concomitant CIS (%)	3 (17.6)
Previous BCG instillation (%)	4 (23.5)
Neo-adjuvant CHT (%)	4 (23.5)

RARC – robot-assisted radical cystectomy; IQR – interquartile range; CCI – Charlson Comorbidity Index; BMI – body mass index; cN – clinical nodal status; cM – clinical metastases status; CIS – carcinoma in situ; BCG – bacillus of Calmette Guérin; CHT – chemotherapy

Median age at surgery was 78 years, 13 (76.5%) patients were male, median body mass index was 24 with median CCI and age-adjusted CCI of 3 and 7, respectively.

A total of 41.2%, 47.1% and 23.5% patients had a T2, T3 or T4 stage respectively, 52.9% patients had clinical node positive disease and 29.4% had bone/organ metastasis at surgery.

Carcinoma in situ (CIS) was associated in 17.6%, 4 (23.5%) previously received bladder instillations with bacillus of Calmette-Guérin and 4 (23.5%) received neo-adjuvant chemotherapy.

Patients reported persistent hematuria, unresponsive pelvic pain, frequent urination and sudden weight loss in 29.4%, 35.3%, 29.4% and 23.5% of cases respectively.

Median operative time was 320 minutes, urethrectomy was performed in 3 patients, with median EBL of 200 ml and only 1 individual receiving intra-operative blood transfusion (Table 2). Three (75%) women underwent hysteroannessiectomy as part of the surgical procedure, with no uterine or ovarian tumor detected at pathologic examination. Pathologic stage was T2, T3, T4a and T4b in 2 (11.8%), 5 (29.4%), 9 (52.9%) and 1 (5.9%) patients, respectively. Prostate cancer (PCa) was detected in 7 (23%) male patients, each with International Society of Urological Pathology (ISUP) grade 1 disease, respectively. Positive surgical BC margins were 11.8%, whereas no surgical margins were detected for PCa.

Table 2

Surgical and pathologic data of 17 consecutive patients who underwent palliative RARC at our Institution

	Overall
Total operative time (min) Median  IQR	320260-370
Estimated blood loss (ml) Median  IQR	200160-250
Intraoperative blood transfusions (%)	1 (5.9)
Urethrectomy (%)	3 (17.6)
Hysteroannessectomy (%)°	3 (75)
Pathologic stage (%) T0-T1 T2 T3 T4a T4b	0 (0)2 (11.8)5 (29.4)9 (52.9)1 (5.9)
Positive surgical margins (%)	2 (11.8)
Histotype (%)TCCSCC	16 (94.1)1 (5.9)
Incidental PCa (%)*	3 (23)
Gleason grade group** 1 2 3-5	3 (100)0 (0)0 (0)
Positive PCa margins (%)***	0 (0)

IQR – interquartile range; UCS: uretero-cutaneostomy; CIS – carcinoma in situ;

TCC – transitional cell carcinoma; SCC – squamous cell carcinoma; PCa – prostate cancer

among male patients

among male patients with concurrent PCa

patients with positive lymph nodes

among female patients

Median hospital stay was 7 days (Table 3). During the first 30 post-operative days, 8 patients developed low- grade complications, with 3 individuals re-admitted for receiving intra-venous antibiotics for urinary tract infections. Two patients developed late post-operative complications, with 1 requiring further hospitalization for receiving intravenous antibiotics and percutaneous nephrostomy placement. 2 patients died at 2 months due to tumor progression.

Table 3

Post-operative outcomes and complications of patients who underwent palliative RARC

	Overall
Hospital stay (days)  Median  IQR	76–9
Early p.o. Clavien grade complications I II III IV V	5 (29.4)3 (17.6)0 (0)0 (0)0 (0)
Early p.o. complications (%) UTI Paralytic ileus	5 (9.5)3 (9.5)
<30-day readmission rate (%)	3 (17.6)
Late p.o. Clavien grade complications (%) I II III IV V	1 (0)1 (11.8)1 (5.9)0 (0)0 (0)
Late p.o. complications (%) UTI Ureteral stenosis	2 (11.8)1 (5.9)
>30 and <90-day re-admission rate (%)	2 (11.8)
90-day mortality (%)	2 (11.8)*
CSM (%)	9 (52.3)
OCM (%)	2 (11.8)
Follow up (months) Median  IQR	85–11

IQR – interquartile range; p.o.: post-operative; UTI – urinary tract infection; CSM – cancer specific mortality; OCM – other causes of mortality

deceased due to tumor progression

At the median follow-up of 8 months, 9 (52.9%) and 2 (11.8%) patients died due to tumor progression and other causes, respectively.

Table 4 reports pre- and post-operative FACT-BL scores. Functional well-being (pre- vs. post- operative 18 vs. 15, respectively, p. <0.001), social well-being (12 vs. 14, p = 0.001), emotional well-being (16 vs. 12, p <0.001) and functional well-being (14 vs. 18, p <0.001) significantly improved after palliative RARC.

Table 4

Pre- and post-operative FACT-BL scores of patients who underwent palliative RARC

	Pre-operative	Post-operative	p-value
Physical well-being Median IQR	1816–22	1511–16	<0.001*
Social well-being Median IQR	1210–15	1412–16	0.001*
Emotional well-being Median IQR	1614–18	1210–14	<0.001*
Functional well-being Median IQR	1413–17	1816–19	<0.001*

FACT-BL – functional assessment cancer therapy-bladder cancer; IQR – interquartile range

CSM – cancer-specific mortality; SD – standard deviation; IQR – interquartile range; OCM –other causes of mortality

DISCUSSION

Palliative care for BC is a still highly uncharacterized issue, with no precise guidelines and indications. American Society of Clinical Oncology recommends early palliative care for patients affected by advanced malignancies, late-stage disease, distant metastasis or life expectancy of 624 months [8, 18]. Hugar et al. recently reported, though, that only 4% with patients affected by advanced BC or advanced comorbidities actually undergo palliative treatments among Medicare beneficiaries [8].

One-fifth of BC in western countries presents as inoperable or metastatic at first diagnosis [19]. The current gold standard for treatment of locally advanced or metastatic bladder cancer remains cisplatin-based chemotherapy with increase in overall survival from 3–6 months to 14 months, with a 40–70% response rate [20]. The best response rate was observed in BC patients with good performance status, preserved renal function, complete response and nodal metastasis as compared to those with visceral metastasis [3, 21]. Surgery is sometimes used to consolidate a good response to first line chemo-therapy, even in cases with limited lymph node (LN) metastases or sometimes solitary lung metastasis [3]. Immunotherapy has further increased the role of surgery to reduce the tumor burden.

As evidenced by Herr et al., in a series of 80 patients with an unresectable tumor (T4NxMx) or an inoperable tumor (T3-T4, N2-N3, M0-M1) immunotherapy allowed tumor resection in 32 patients, of those half received a complete tumor resection and one third of them survived at 5 years [22]. Patients with T4b disease or intractable hematuria may require surgery to relieve symptoms, but due to high morbidity other less invasive treatments such a radiotherapy should be considered as the first line of therapy [3, 23]. Lebret et al. concluded that surgery alone for advanced/metastatic BC is not enough to eradicate a systemic disease and to reduce symptoms, as it should always be a complement to chemotherapy [24]. In our relatively small series we aimed to evaluate the role of RARC in a series of 17 advanced/metastatic BC. Robotic cystectomy was firstly introduced to reducing surgical distress of BC patients undergoing surgery when compared to ORC, aiming at decreasing surgical complications and hospital stay with comparable oncologic outcomes to laparotomic approach.

Parekh et al., recently reported data from the first randomized trial comparing RARC to ORC and thus confirming a non-inferiority of robotic approach, with reduced EBL, blood transfusion, hospital stay but similar complication to ORC.

Though, as reported for prostate cancer treatment, despite being related to significantly higher costs, it could still improve functional and emotional outcomes of patients affected by a neoplastic disease [25, 26, 27].

In our study we attempted to assess the benefit of robotic surgery in a palliative care context. Hence, our goal wasn't curative, but we aimed to palliate symptoms and reduce general distress in a subset of patients with very poor life expectancy.

Despite a small number of patients included, some results should be underlined. First, when considering surgical outcomes median EBL (200 ml), the number of intra-operative transfusion (5.9%), positive surgical margins (11.8%), median operative time, despite advanced local, with median hospital stay of 7 days are remarkable. Pasadena Consensus Panel indicated that RARC surgical proficiency is reached generally after 20–30 procedures, with EBL <400 ml with <15% of positive surgical margins and operative time <400 minutes as proofs of proficiency [28]. Our series was performed throughout the learning curve of a single surgeon, thus further affirming the need of a skilled mentorship to begin performing this highly challenging procedure and the importance of a high surgical volume to master this technique [29]. In fact, RARC, especially in case of advanced BC, should be limited to only tertiary high-volume centers.

Second, complication rates were quite low, with 9 (42.9%) complications overall during first 90 post-operative days, of those only 3 were high Clavien grade and required a further surgical procedure. According to many authors [30, 31, 32], despite mini-invasiveness, RARC is nonetheless related to a 60–80% post-operative complications. Furthermore, the only randomized controlled trial available comparing RARC to ORC confirmed a comparable rate of post-operative complications between laparotomic and robotic approach [13]. Patients included in our study, though, shared a poor prognosis given advanced BC and/or comorbidities, with most deemed as unfit for neo-adjuvant chemotherapy, with only 6 individuals still alive at 8 post-operative months. A short hospital-stay and low complication rates could afford a relatively quicker recover and the chance of undergoing eventual further therapies. The only high-grade late complication recorded was ureteral stenosis, which is one of the most common late complication after RC. Despite open surgery being still considered as the gold standard, its management could still be ‘less-invasive’ with good surgical results, as reported by other authors [33, 34], without adding further surgical distress.

Third, pre- and post-operative FACT-BL scores significantly improved despite a nonetheless poor prognosis. FACT-BL is a validated, bladder cancer specific questionnaire, with different items exploring physical, social, emotional and functional well-being [17]. The removal of the primary tumor in some cases partially palliated symptoms, thus improving overall quality of life.

A significant proportion of patients undergoing palliative RARC in our series reported pre-operative chronic hematuria, unbearable pelvic pain or frequent urination and, despite being adequately informed about potential surgical complications and the palliative nature of surgery itself, still were strongly determined to undergo RARC.

On the other hand, despite acknowledging a short life expectancy, the chance of receiving a palliative treatment without major surgical drawback improved patients' morale and perhaps improved their quality of life.

Our study presents several limitations, including the low number of patients enrolled, the lack of a control group, the high costs of robotic procedures related to minimal survival advantage.

CONCLUSIONS

Robot- assisted radical cystectomy is a feasible and relatively safe technique, with potential indications also for advanced/metastatic bladder cancer (BC), though with a palliative and not curative purpose. Palliation care for BC should be more extensively evaluated and further studies should be needed to define precise guidelines, as already described for other tumors.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.