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ORIGINAL ARTICLE
Year : 2022  |  Volume : 35  |  Issue : 4  |  Page : 2069-2075

Neoadjuvant chemotherapy with radical cystectomy versus radical cystectomy alone for muscle-invasive bladder cancer


1 Department of Urology, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Urology, Ministry of Health, Menoufia University, Menoufia, Egypt
3 Department of Oncology, Faculty of Medicine, Menoufia University, Menoufia, Egypt

Date of Submission01-Jul-2022
Date of Decision13-Jul-2022
Date of Acceptance17-Jul-2022
Date of Web Publication04-Mar-2023

Correspondence Address:
Ahmed M El-Zeiny
Shebin El-Kom, Menoufia
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_185_22

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  Abstract 


Background
Radical cystectomy (RC) is the gold standard in the treatment of muscle-invasive bladder cancer.
Objectives
To compare the pathologic response and perioperative morbidity of neoadjuvant chemotherapy (NAC) with cystectomy against RC alone as a treatment for muscle-invasive bladder cancer.
Patients and methods
This randomized controlled clinical trial took place between December 2020 and December 2021. The study enrolled 40 patients with muscle-invasive transitional cell carcinoma of the urinary bladder. Patients were randomized into two treatment groups: group I (20 patients) was treated with RC alone, and group II (20 patients) received three cycles of NAC with cystectomy.
Results
Of 20 patients of group II, only 16 patients completed NAC. Pretreatment patient criteria were comparable between both groups. Downstaging in postcystectomy specimen was significantly higher in group II than group I (pT0 12.5 vs. 0% and pT1 12.5 vs. 0%, respectively). There was no significant difference in postoperative complications between patients undergoing NAC plus RC and RC alone, with an overall complication rate of 68.8 and 66.7% in groups II and I, respectively.
Conclusion
NAC with RC is helpful in downstaging of the bladder cancers without increasing the perioperative morbidity related to RC.

Keywords: bladder cancer, complication, cystectomy, neoadjuvant chemotherapy, pathology


How to cite this article:
Sultan SM, Badawy AA, El-Zeiny AM, Elsayed MA, Salman BM. Neoadjuvant chemotherapy with radical cystectomy versus radical cystectomy alone for muscle-invasive bladder cancer. Menoufia Med J 2022;35:2069-75

How to cite this URL:
Sultan SM, Badawy AA, El-Zeiny AM, Elsayed MA, Salman BM. Neoadjuvant chemotherapy with radical cystectomy versus radical cystectomy alone for muscle-invasive bladder cancer. Menoufia Med J [serial online] 2022 [cited 2024 Mar 28];35:2069-75. Available from: http://www.mmj.eg.net/text.asp?2022/35/4/2069/370968




  Introduction Top


Bladder cancer is the ninth most common cancer in the world, with an annual incidence of more than 430 000 cases and the 13th highest cancer-related fatality rate [1],[2].

The most prevalent subtype is urothelial bladder cancer. Muscle-invasive bladder cancer (MIBC) is usually treated with radical cystectomy (RC), multimodal therapy (transurethral resection of tumor, chemotherapy, and radiation therapy), or palliative care [3].

RC is the standard treatment for patients with MIBC and MIBC with different histologies. Despite advances in surgical and perioperative care, RC alone is associated with a 5-year survival rate of ∼ 50%, most likely owing to the existence of radiologically undetectable micrometastasis at the time of surgery [4],[5],[6].

Chemotherapy is used to treat unsuspected metastases, whereas RC is used to treat the main tumor locally. Most survivors have significant chemotherapeutic responses and a higher chance of having no residual tumor (pT0) in the cystectomy specimen [7].

Since the 1980s, cisplatin-based neoadjuvant chemotherapy (NAC) has been used to enhance these outcomes [4],[5],[6],[7],[8],[9]. At 5 years, neoadjuvant treatment based on cisplatin improves overall survival (OS) by 5–8% [4].

International guidelines recommend NAC for cT2–T4a non metastatic patients before RC [3],[10].

NAC before surgery has several advantages, including that it is better tolerated before surgery than after, toxicity in nonmetastatic patients is usually lower than in patients with metastatic disease, and patients with nonmetastatic disease have a better performance status. Furthermore, patients are frequently able to tolerate higher doses and more rounds of chemotherapy preoperatively than postoperatively, and NAC downstages tumors, making surgery technically easier [11].

Despite these findings, NAC is still underused, with only 15–20% of patients with MIBC receiving it [12]. According to the 2012 survey of the members of the Society for Urologic Oncology, the most common concerns of clinicians when recommending NAC to their patients were age and comorbidities (54%), followed by surgery delay (35%), marginal benefit (33%), and prolonged diagnosis and referral (22%) [12],[13].

The aim of the study was to compare the pathologic response and perioperative morbidity of NAC with RC against RC alone as a treatment for muscle-invasive bladder.


  Patients and methods Top


This randomized controlled clinical trial was done at the urology and oncology departments of Menoufia University hospitals between December 2020 and December 2021. The study design was ethically approved by the ethical committee of the Faculty of Medicine, Menoufia University Hospital.

The study included 40 patients who had pathologically proven nonmetastatic muscle-invasive transitional cell carcinoma of the urinary bladder after transurethral resection of a bladder tumor. The clinical stage of tumor-node-metastases ranges from cT2–cT4a N0 M0. All patients with nonurothelial bladder cancer and nonsurgical candidates with a major comorbid illness were excluded from the study.

All patients had adequate renal function (serum creatinine <2 mg/d1).

A written consent was obtained from all patients. All patients were thoroughly evaluated (at diagnosis and before RC in group I and before starting the NAC and the cystectomy in group II), including performance status according to Eastern Cooperative Oncology Group (ECOG) between 0 and 2, full history taking, and complete physical and local examination. Routine laboratory investigations and radiological investigations, including chest, abdominal, and pelvic computed tomography with i.v. contrast were done.

Patients were divided into two groups:

Group I included 20 patients who had RC only and were scheduled for surgery as soon as they were diagnosed.

Group II included 20 patients who received NAC before RC. Three cycles of gemcitabine-cisplatin treatment were administered. Each cycle lasted 21 days and included gemcitabine 1250 mg/m2 on days 1 and 8 and cisplatin 70 mg/m2 on day 1. Every cisplatin infusion was accompanied by adequate intravenous hydration supportive care in accordance with the recommendations (anti-emetics, hematopoietic growth factors, antidiarrhea, and prevention of mucositis), with close monitoring for any hematological, hepatic, or renal damage, and doses were modified accordingly.

All patients in both groups had RC via a lower midline incision with bilateral limited pelvic lymphadenectomy. Orthotopic neobladders or ileal conduits were used as urinary diversions.

Both groups were compared in terms of surgery type, operative time (time from the surgeon starting the procedure till ending it, which did not included anesthesia time), extent of pelvic node dissection, estimated blood loss and operative blood transfusion, concurrent procedure, and surgical complications.

The degree of tumor downstaging was assessed and compared in both groups, as well as the pathological T-stage and N-stage outcome of cystectomy specimens. Patients' overall short-term problems, duration of stay, readmission rate, and/or death after RC were noted as well.

Furthermore, the Clavien-Dindo classification (CDC) score was used to compare wound, lymphatic, gastrointestinal, hematological, pulmonary, cardiovascular, and genitourinary problems. We compared no problems (CDC 0) with any complications (CDC 1–5), as well as severe complications (CDC 3–5) with minor complications (CDC 1–2) in both groups.

Statistical analysis

The data were collected, edited, coded, and entered into the IBM SPSS Statistics for Windows, version 20.0. (IBM Corp., Armonk, New York, USA). When the distribution of qualitative data was determined to be parametric, it was provided as a number and a percentage, whereas quantitative data were presented as mean, SD, and ranges.

When the predicted count in any cell was less than 5, the χ2 test and/or Fisher exact test were employed instead of the χ2 test to compare two groups with qualitative data.

The independent t test was used to compare two independent groups with quantitative data and parametric distribution. The confidence interval was set at 95%, and the acceptable margin of error was set at 5%. As a result, the following P value was declared significant: P value less than 0.05.


  Results Top


Both groups of patients had similar preoperative patient criteria [Table 1]. The mean age was 61.00 ± 5.51 and 62.25 ± 7.13 years for groups I and II, respectively, with male predominance in both groups.
Table 1: Preoperative patient criteria

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There was no statistically significant difference between the two groups in terms of baseline creatinine (mg/dl), baseline hemoglobin (g/dl), or smoking, but there was a highly statistically significant difference between the two groups in terms of the interval from diagnosis to RC (week), which was longer in group II.

The most common clinical stage in the study participants was cT3 (70% in group I and 60% in group II), with no statistically significant difference between the two groups.

Four patients from group II were excluded from the study (three lost to follow-up and one patient decided not to undergo cystectomy). All male patients in group I and group II underwent cysto-prostatectomy, whereas female patients underwent cystectomy, and anterior exenteration was done in one female patient from group II. Ilial conduit was done in 11 (55%) patients from group I and in four (25%) patients from group II, whereas orthotopic neobladder was done in nine (45%) patients from group I and in 12 (75%) patients from group II, with no statistically significant difference (P = 0.069). There was no statistically significant difference found between the two groups regarding the duration of surgery and lymph-node dissection, but there was a highly statistically significant difference found between the two groups regarding the estimated blood loss (ml) and the length of hospital stay (day), which was more significant in group I [Table 2].
Table 2: Comparison between groups regarding surgery duration, estimated blood loss (ml), and length of stay (day)

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Regarding the pathological response after RC, six patients were excluded from the study (four patients from group II, and the other two patients were excluded from group I for nonurothelial pathology of cystectomy specimen, although the biopsy was urothelial). Therefore, the total numbers of patients who completed the chemotherapy course were 16 patients in group II and 18 patients in group I. Concerning our primary end point, histological analysis of the cystectomy specimen after RC showed the incidence of downstaging was significant in group II (25%) with two patients downstaged to pT0 (12.5%) and two patient downstaged to pT1 (12.5%) [Table 3] and [Table 4].
Table 3: Comparison between groups regarding pathology after radical cystectomy

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Table 4: Comparison regarding tumor downstaging between clinical stage at diagnosis and pathological stage after cystectomy in both groups

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Concerning pathological lymph-nodes, the median number of LN dissected was 10, and there was no statistically significant difference found between the two groups.

Complication rates within 30 days postoperatively were comparable between the two group according to CDC. The percentage of all Clavien stages combined (CDC 1–5) was 66.7% in group I versus 68.8% in group II, with more Clavien II stage complications in group I (44.4%) than group II (37.5%) [Table 5].
Table 5: Comparison between groups regarding short-term postoperative no versus all complications according to the Clavien-Dindo classification score

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Minor (CDC 0–2) versus major (CDC 3–5) complications postoperatively were comparable between the two group [Table 6].
Table 6 Comparison between groups regarding specific short-term postoperative minor versus major complication according to the Clavien-Dindo classification score

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The most common 30-day complications were gastrointestinal (need for re-intervention for repairing of the intestinal anastomosis leakage with wound dehiscence, postoperative intestinal anastomotic leakage, and ileus and/or postoperative 5 days with no signs of transit) (33.3 vs. 25%), genitourinary (infection, fistula) (27.7 vs. 18.7%), and wound-related complications (infection and wound dehiscence) (16.6 vs. 12.5%) for patients treated with RC and RC with NAC, respectively.

There was no local recurrence noted in the 30 days postoperatively. Our results showed no significant differences in the overall complication rate or proportion of major complications observed between the two groups.


  Discussion Top


Importantly, there is no universally accepted standard technique for providing optimal quality care for muscle-invasive illness, and treatment algorithms for MIBC differ greatly from institution to institution. Despite breakthroughs in therapeutics, there is still much need for improvement in providing consistent, evidence-based, and high-quality BC care [14].

Although patients with NMI urothelial carcinoma can often be safely managed with transurethral resection with intravesical chemotherapy or immunotherapy, the standard of care for patients with MIBC is NAC followed by RC with bilateral pelvic lymph-node dissection (PLND) [15].

The goal of RC is to remove all cancers from the bladder and surrounding tissues while keeping the margins as small as possible. Concurrent comprehensive PLND is both diagnostic and therapeutic, with PLND related with a significant increase in OS in nonmetastatic patients across all tumor stages [16].

Because of the disease's aggressive nature, early identification and surgical treatment are critical in MIBC care. Delay in diagnosis or cystectomy has a negative effect on the patient's outcome [17].

There was no statistically significant difference between group I and group II in terms of baseline creatinine (mg/dl), baseline hemoglobin (g/dl), or smoking, but there was a highly statistically significant difference in terms of the time between diagnosis and RC between the two groups (week).

In terms of T stage and N stage at presentation, we discovered that there was no statistically significant difference between the two groups in terms of T stage and N stage.

When comparing group I and group II in terms of operative procedure type, approach, and urinary diversion, there was no statistically significant difference between the two groups in terms of urinary diversion, but a highly statistically significant difference in terms of operative procedure type in male patients.

While comparing group I and group II we discovered that there was no statistically significant difference between the two groups in terms of surgery duration and PLND, but there was a highly statistically significant difference in terms of blood loss (ml) and length of stay (day).

Furthermore, clinical tumor staging differed significantly between the RC alone and NAC plus RC groups. We discovered a statistically significant difference in pathology following RC between the two groups.

Group I had significantly more pathological T3–T4 and pathological nodal disease (26 vs. 5%), whereas group II had significantly more pathological T0, T1, and T2a. However, these findings should be interpreted with caution, as the current study was insufficiently powered to detect such differences. Nonetheless, this could point to a possible survival benefit in our NAC-treated patients. Furthermore, when compared with patients who received NAC, a considerably larger number of patients who did not receive NAC had pT4 (50 vs. 6.2%, respectively). A low pT4 status is linked to a shorter lifespan.

Our data imply that clinicians should strongly consider using NAC to improve MIBC OS rates when needed. It is vital to emphasize, however, that patient selection is critical for optimizing the benefit-to-risk trade-off (e.g. toxicity, nonresponse, and delay in RC).

Individuals with substantial comorbidities and/or poor renal function should be avoided, according to previous research. Other related hurdles include advanced age and diminished performance status. If renal impairment, cardiac dysfunction, significant hearing loss, or grade 2 (or higher) polyneuropathy prevent cisplatin-based NAC, urgent surgery should be considered, as carboplatin-based regimens are inferior. Postoperative morbidity is also more likely in patients with comorbidities and advanced age [18].

According to another study, MIBC is a dangerous disease with a significant probability of recurrence owing to the presence of micrometastases at the time of diagnosis. Early (micrometastatic) systemic illness can be eradicated with NAC, which is unachievable with RC alone [19].

Multiple landmark trials and meta-analyses have already shown that platinum-based NAC improves 5-year OS in patients with MIBC by roughly 5–7%. However, incorporating NAC into regular urological practice has proven to be a challenging task [20].

Both patients and physicians believe that a 5–7% absolute OS gain over 5 years is insufficient to justify the use of NAC, despite its recognized toxicity, comorbidities, and discomfort. Despite this, systemic treatments that improve survival by 7% are often utilized in breast and colon malignancies. The majority of MIBC deaths occur within 5 years after diagnosis owing to quick growth and spread of metastases; hence, any delay in surgery is particularly feared [19].

Previous research, however, found no change in survival when surgery was postponed owing to the use of NAC. This shows that urologists have the misconception that the hazards do not exceed the benefits. In a matched group, we feel our study adds to the understanding that NAC does not predispose patients to increased perioperative and postoperative problems [21].

Only a few studies have looked at the effect of NAC on perioperative complications after RC to date. Mixed results have been reported, raising concerns regarding a rise in perioperative problems. There is a scarcity of past data to support or contradict this hypothesis.

Johnson et al. [22] and Gandaglia et al.[23], who were the first to address this issue, addressed it in their investigations. NAC with RC versus RC alone did not indicate a higher number of problems in the former (55.1 and 51.8%, respectively). NAC did not increase the rate of complications, readmissions, or mortality in the latter study.

Our research, like those of our colleagues, found no significant increase in perioperative morbidity in patients who took NAC before RC. NAC was not found to be an independent risk factor for prolonging the operation, hospital stay, or local problems (scar disruption and infection at the surgical site).

In our study, a median number of 10 lymph nodes were dissected in both groups. Despite having a lower clinical NO stage at diagnosis, group I (1 patient) had a lower pathological N1 stage than the cystectomy only group (5 patients). It was determined that neoadjuvant had an influence on disease in the nodes owing to its ability to downstage tumors in the bladder.

Badawy et al.[24], in a pooled analysis, observed that 29.7% of patients had pN1 disease after CG neoadjuvant therapy, which is greater than the findings reported in our study. This high pN1 could be owing to the study's lack of definition of the pretreatment N stage.


  Conclusion Top


When compared with RC alone, NAC plus RC is beneficial in downstaging bladder cancers.

In patients with MIBC, NAC combined with RC is not linked to an increased risk of short-term postoperative morbidity and mortality. Patients with comorbidities were shown to be at a higher risk of postoperative complications. Cystectomy, on the contrary, is a very morbid procedure that necessitates careful selection of patients who are candidates for NAC treatment.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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