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ORIGINAL ARTICLE
Year : 2022 | Volume
: 18
| Issue : 7 | Page : 1884-1893
Efficacy and adverse reactions of intra-arterial chemotherapy in patients with bladder cancer: A systematic review and meta-analysis
Junjie Ji, Yu Yao, Fengju Guan, Lijiang Sun, Guiming Zhang
Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, China
Correspondence Address:
Guiming Zhang
Department of Urology, The Affiliated Hospital of Qingdao University, No. 16, Jiangsu Rd, Qingdao, 266003
China
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/jcrt.jcrt_2187_21
This meta-analysis investigated the efficacies of intra-arterial chemotherapy (IAC) plus intravesical chemotherapy (IVC) versus IVC alone in patients with non–muscle-invasive bladder cancer (NMIBC), and preoperative IAC versus preoperative intravenous chemotherapy (IV) in patients with bladder cancer. We also assessed the adverse reactions (ARs) of IAC. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for English articles published before April 2021. The qualities of cohort studies and randomized controlled trials were analyzed using the Newcastle–Ottawa Scale and Cochrane risk-of-bias tool, respectively. Effect outcomes were computed by random-effects and fixed-effects models. Statistical analyses were conducted using Stata 16.0 and RevMan v5.3.0. A total of seven articles were included. The analysis revealed that IAC plus IVC significantly prolonged recurrence-free survival (RFS) (hazard ratio [HR] = 0.55, 95% confidence interval [CI] = 0.40–0.76, I2 = 0%) and progression-free survival (PFS) (HR = 0.59, 95% CI = 0.37–0.97, I2 = 0%) compared with IVC alone in NMIBC patients after transurethral resection of bladder tumor (TURBT), but had no effect on overall survival (OS), tumor recurrence interval, or tumor-specific death rate. Preoperative IAC had no significant OS benefit compared with preoperative IV in bladder cancer patients. Regarding ARs, patients treated with IAC were significantly more likely to develop grade 1–2 ARs, including nausea/vomiting (odds ratio [OR] = 26.38, 95% CI = 1.88–370.79, I2 = 78%), neutropenia (OR = 10.15, 95% CI = 3.01–34.24, I2 = 0%), hypoleukemia (OR = 5.49, 95% CI = 1.38–21.82, I2 = 26%), and increased alanine aminotransferase (OR = 12.28, 95% CI = 2.24–67.43, I2 = 0%), but there was no significant difference between grade 1–2 ARs and grade 3–4 ARs in terms of increased creatinine in patients treated with IAC. Therefore, administration of IAC plus IVC after TURBT improved RFS and PFS compared with IAC alone in patients with NMIBC. IAC was associated with mild ARs and was well tolerated by most patients.
Keywords: Adverse Reactions, bladder cancer, intra-arterial chemotherapy, meta-analysis, prognosis
Bladder cancer is the 10th most common malignancy worldwide and the sixth most common malignancy in males.[1] Approximately 75% of patients with bladder cancer present with a disease confined to the mucosa or submucosa, which is also called non–muscle-invasive bladder cancer (NMIBC), associated with longer survival and a lower risk of cancer-specific mortality compared with muscle-invasive bladder cancer (MIBC).[2],[3] Although TaT1 tumors can be completely eradicated by transurethral resection of the bladder tumor (TURBT) alone, patients also need adjuvant therapy because of the high variability in 3-month recurrence rates.[4] TURBT followed by intravesical chemotherapy (IVC) or Bacille Calmette–Guérin (BCG) is recommended as a standard treatment for NMIBC by the European Association of Urology.[5] Although some meta-analyses have indicated that the administration of BCG after TURBT is superior to IVC after TURBT in terms of recurrence and complete response,[6],[7] BCG is associated with more local and systemic side effects, which may influence the treatment period.[8],[9] In addition, the wide application of BCG is hindered by its availability and expense.[10] There is thus an urgent need to find new therapeutic strategies to replace existing treatments.
Cisplatin-based neoadjuvant chemotherapy (NAC) has been used since the 1980s to improve the low 5-year survival of MIBC patients treated with radical cystectomy.[11],[12] A meta-analysis of patient data from 11 randomized trials indicated that cisplatin-based NAC resulted in a 9% absolute improvement in survival at 5 years,[13] indicating the need for chemotherapy before surgery. NAC is often administered intravenously in MIBC patients, and more methods should be considered to improve survival.
Intra-arterial chemotherapy (IAC), involving administration via the bladder-feeding artery, had been used in patients with bladder cancer for over 40 years.[14] Two animal experiments indicated that IAC had a better pharmacological profile and better tumor response in dogs with urogenital tumors, compared with intravenous chemotherapy (IV).[15],[16] IAC is being used increasingly because of local dose escalation to the tumor and the reduced availability of systemic drugs. Two studies indicated that IAC was effective in the treatment of retinoblastoma and oral cancer with less toxicities.[17],[18] However, the effects and adverse reactions (ARs) of IAC compared with other forms of therapy in patients with bladder cancer remain unclear. The current meta-analysis aimed to identify the efficacy of IAC plus IVC versus IVC alone in patients with NMIBC after TURBT and to compare preoperative IAC versus preoperative IV in patients with bladder cancer. We also assessed the ARs of IAC.
> Materials and MethodsLiterature search
We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for articles published in English before April 2021 using the following terms: (”Urinary Bladder Neoplasms” OR “bladder cancer” OR “bladder carcinoma” OR “bladder tumor” OR “Transitional Cell Carcinoma” OR “urothelial carcinoma”) AND (”Intra-arterial injection” OR “Intra-arterial infusion” OR “Intra-arterial chemotherapy” OR “Intra-arterial therapy”).
Study selection
We conducted a systematic search according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [Supplementary Table 1].[19] Studies were included if they met the following criteria: (1) population: patients diagnosed with primary bladder cancer; (2) intervention and comparator: compared IAC plus IVC with IVC alone in NMIBC patients, or preoperative IAC with preoperative IV in bladder cancer patients; (3) included one of the following outcomes: overall survival (OS), recurrence-free survival (RFS), progression-free survival (PFS), tumor recurrence interval (TRI), tumor-specific death rate (TSDR), and ARs of IAC; (4) provided hazard ratio (HR), odds ratio (OR), or mean difference (MD) with 95% confidence interval (CI), or sufficient data to calculate these; and (5) study design: randomized controlled trial (RCT) or cohort study.
The exclusion criteria were papers reporting non-original research, such as meta-analyses, reviews, commentaries, and conference abstracts. Two reviewers performed the study selection independently, and disagreements were resolved by a third reviewer.
Data extraction and quality assessment
The following items were extracted from each study and recorded: first author, publication year, country, institution, research period, study design, numbers of treatments and controls, median follow-up, interventions, inclusion criteria, treatments, controls, and outcomes. The main outcome for our research was OS, and the secondary outcomes were RFS, PFS, TRI, TSDR, and ARs. Definitions of the outcomes are listed in [Supplementary Table 2]. If HRs and 95% CIs were not provided, we extracted the required information from Kaplan–Meier curves using previously published methods.[20],[21] If the same outcome (e.g., OS, RFS, PFS, TRI, TSDR, ARs) in the same study population was reported in more than one article, we included the study with the longest research period without duplication. The quality of RCTs was evaluated using the Cochrane risk-of-bias tool.[22] This tool contains six domains of bias, including selection bias, performance bias, detection bias, attrition bias, reporting bias, and other bias. Assessments are made for one or more items in each domain. We assigned a judgment of high, low, or unclear risk of material bias for each item. The cohort studies were assessed for quality using the Newcastle–Ottawa Quality Assessment Scale (NOS).[23] The scale comprises nine points in total on the three parts of the NOS, including participant selection (0–4 points), comparability (0–2 points), and exposure or outcome assessment (0–3 points). Scores of ≥7 indicate a high quality. Two independent reviewers extracted the data and carried out quality assessment, and disagreements were discussed and resolved by a third reviewer.
Statistical analysis
The outcomes of IAC plus IVC versus IVC alone, and IAC versus IV were calculated separately. We performed meta-analyses to pool the HRs and 95% CIs of survival outcomes (OS, RFS, PFS) using Stata 16.0. For other outcomes (TRI, TSDR, ARs), we performed meta-analyses to pool the MDs with 95% CIs to evaluate continuous data, and ORs with 95% CIs to evaluate dichotomous data using RevMan v5.3.0. I2 and Q statistics were calculated to assess the degree of heterogeneity, with I2 > 50% or P < 0.1 reflecting significant heterogeneity. A random-effects or fixed-effects model was chosen according to the presence or absence of significant heterogeneity. Results were assessed using forest plots. All ARs were scored according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0.
> ResultsStudy selection and characteristics
The selection process and results of detailed searching of the articles are shown in [Figure 1]. We identified 688 candidate studies, including 361 in PubMed, 223 in Embase, 19 in Cochrane Library, and 85 in Web of Science. After excluding 240 duplications and reviewing the titles, abstracts, and full texts, seven articles were eligible for the meta-analysis. Of these, three studies analyzed IAC plus IVC versus IVC alone, two analyzed IAC versus IV, and five analyzed the ARs of IAC. The studies included two RCTs and five cohort studies, comprising patients from four institutions recruited from 1988 to 2020. The detailed characteristics of the seven eligible studies are presented in [Table 1].
Two RCTs were evaluated by the Cochrane risk-of-bias tool [Figure 2]. One study had high risk of reporting bias, but both showed low risks of all bias terms, except other bias. Four of the five cohort studies had an NOS score ≥7, indicating that they were of high quality, and the other, early published article had a final score of 6 [Table 2].
IAC plus IVC versus IVC alone
Three studies were included to investigate the role of IAC plus IVC in NMIBC patients after TURBT.[24],[25],[26] Two studies evaluated the effects of IAC plus IVC on OS,[25],[26] two on RFS,[24],[26] two on PFS,[24],[26] two on TRI,[25],[26] and two on TSDR.[25],[26] Another study[27] with the same study population that also reported OS, TRI, and TSDR was excluded in favor of the one with a longer research period and larger population.[25]
Two articles with a sample of 483 patients evaluated the effects on OS. IAC plus IVC did not significantly prolong OS in patients with NMIBC after TURBT (HR = 0.52, 95% CI = 0.14–1.98; high heterogeneity, I2 = 83%, P = 0.02) [Figure 3]a.
Figure 3: Forest plots of survival outcomes. (a) Overall survival, (b) recurrence-free survival, and (c) progression-free survival in patients with NMIBC treated with IAC plus IVC versus IVC after TURBT. CI = confidence interval, HR = hazard ratio, IAC = intra-arterial chemotherapy, IV = intravenous chemotherapy, IVC = intravesical chemotherapy, NMIBC = non–muscle-invasive bladder cancer, TURBT = transurethral resection of bladder tumorTwo articles with a sample of 432 patients evaluated the effects on RFS and PFS. IAC plus IVC significantly prolonged RFS (HR = 0.55, 95% CI = 0.40–0.76) and PFS (HR = 0.59, 95% CI = 0.37–0.97) in patients with NMIBC treated with TURBT, with low heterogeneity (I2 = 0%, P = 0.47 and I2 = 0%, P = 0.79, respectively) compared with IAC alone [Figure 3]b and [Figure 3]c.
Two articles with a sample of 483 patients assessed the effects on TRI and TSDR. IAC plus IVC did not significantly prolong TRI (MD = 4.07, 95% CI = –1.31 to 9.45; high heterogeneity, I2 = 90%, P = 0.002) [Figure 4]a or TSDR (OR = 0.55, 95% CI = 0.28–1.07; low heterogeneity, I2 = 24%, P = 0.25) [Figure 4]b in patients with NMIBC after TURBT.
Figure 4: Forest plots of (a) tumor recurrence interval and (b) tumor-specific death rate in patients with NMIBC after TURBT treated with IAC plus IVC versus IVC. CI = confidence interval, IAC = intra-arterial chemotherapy, IVC = intravesical chemotherapy, NMIBC = non–muscle-invasive bladder cancer, TURBT = transurethral resection of bladder tumorIAC versus IV
Two studies investigated the efficacy of preoperative IAC versus preoperative IV in a total of 142 patients with bladder cancer and evaluated the effects on OS.[28],[29] There was no significant survival benefit of preoperative IAC compared with preoperative IV in terms of OS (HR = 0.74, 95% CI = 0.37–1.49; medium heterogeneity, I2 = 42%, P = 0.19) in bladder cancer patients [Figure 5].
Figure 5: Forest plot of overall survival of preoperative IAC versus preoperative IV in bladder cancer patients. IAC = intra-arterial chemotherapy, IV = intravenous chemotherapyARs of IAC
CTCAE v4.0 was used to score the ARs of IAC in three articles.[26],[27],[30] ARs were graded from 1 to 5, based on the following guidelines: grade 1 = mild, grade 2 = moderate, grade 3 = severe, grade 4 = life-threatening, and grade 5 = death-related ARs. For this meta-analysis, we classified the ARs of IAC in the three articles as either mild (grade 1–2) or severe (grade 3–4). Patients treated with IAC had a significantly higher incidence of grade 1–2 ARs, including nausea/vomiting (OR = 26.38, 95% CI = 1.88–370.79; high heterogeneity, I2 = 78%, P = 0.01) [Figure 6]a, neutropenia (OR = 10.15, 95% CI = 3.01–34.24; low heterogeneity, I2 = 0%, P = 0.37) [Figure 6]b, hypoleukemia (OR = 5.49, 95% CI = 1.38–21.82; low heterogeneity, I2 = 26%, P = 0.25) [Figure 6]c, and increased alanine aminotransferase (OR = 12.28, 95% CI = 2.24–67.43; low heterogeneity, I2 = 0%, P = 0.86) [Figure 6]d, indicating that most ARs of IAC were mild. However, there was no significant difference between grade 1–2 ARs and grade 3–4 ARs in terms of increased creatinine in patients treated with IAC (OR = 5.21, 95% CI = 0.60–45.30; low heterogeneity, I2 = 0%, P = 0.69) [Figure 6]e.
Figure 6: Forest plots of IAC-related adverse reactions including (a) nausea/vomiting, (b) neutropenia, (c) hypoleukemia, (d) increased alanine aminotransferase, and (e) increased creatinine. (f) Forest plots for comparison of leukopenia incidence between IAC and IV. CI = confidence interval, IAC = intra-arterial chemotherapy, IV = intravenous chemotherapyTwo studies compared the difference in the incidence of leukopenia in patients treated with preoperative IAC versus preoperative IV.[28],[29] There was no significant difference in the incidence of leukopenia between the IAC and IV groups (OR = 0.80, 95% CI = 0.30–2.13; low heterogeneity, I2 = 0%, P = 0.68) [Figure 6]f.
> DiscussionChemotherapy-based treatment regimens are often ineffective and discontinued because of low penetration of the drug at the tumor site and intolerable side effects. Methods of achieving loco-regional drug delivery, such as IAC, have the potential to increase tumor penetration and reduce ARs, which may in turn increase the efficacy of chemotherapy.[31] Some studies demonstrated positive effects of IAC in several tumors, including liver metastatic cancer, retinoblastoma, squamous cell carcinoma of the cervix, and pelvic lymph node metastases.[32],[33],[34],[35] We, therefore, carried out this meta-analysis to identify the efficacy of IAC.
We analyzed the role of IAC plus IVC in patients with NMIBC who underwent TURBT, and found that this treatment significantly prolonged RFS and PFS. Three other articles also reported higher RFS and PFS rates in NMIBC patients treated with IAC compared with IVC.[36],[37],[38] Although the pooled results also showed beneficial trends in OS, TRI, and TSDR, the differences in outcomes were not significant, in contrast to the findings of Sun et al. for OS,[26] Huang et al. for TSDR,[25] and both these studies for TRI.[25],[26] We consider that our insignificant results may have been affected by the high heterogeneities for OS and TRI and by the low quantity of the included studies. One recently published study compared IAC plus IVC with BCG instillation in patients with NMIBC and found no significant difference in RFS and PFS.[30] Thus, there is a need for more high-quality studies to identify the clinical efficacy of IAC plus IVC in NMIBC.
Cisplatin-based NAC is a standard therapy for MIBC. In addition to traditional intravenous NAC administration, preoperative IAC has been increasingly applied in patients with bladder cancer. Two studies indicated that IAC plus radical cystectomy resulted in prolonged survival, decreased tumor stage, and increased quality of life in bladder cancer patients.[39],[40] We compared the efficacy of preoperative IAC versus preoperative IV and found a beneficial but not significant trend in OS, with medium heterogeneity. However, we only included two articles due to a lack of eligible studies, and all the included patients had MIBC, except for one case of carcinoma in situ in Kuriyama et al.[29] Further meta-analyses with more eligible articles should, therefore, be conducted to assess the benefits of IAC before surgery in patients with MIBC.
IV and BCG instillation are responsible for many systemic ARs, such as liver or kidney dysfunction and chemical cystitis.[8],[41] Some ARs prove intolerable, and many patients choose to reduce the dosage or even stop their treatment. However, reducing the dosage of chemotherapy may also reduce its anticancer effects in patients with MIBC,[42] and it is, therefore, important to consider the ARs of IAC. The current meta-analysis showed that patients treated with IAC had a significantly higher incidence of grade 1–2 ARs, including nausea/vomiting, neutropenia, hypoleukemia, and increased alanine aminotransferase, indicating that most ARs of IAC were mild and tolerable. It was reported that mild ARs observed in IAC patients were due to lower dosage compared with IVC and IV, and most grade 3/4 toxicities in IAC were blood system diseases such as thrombocytopenia, neutropenia, and anemia.[37],[38] One study also reported that BCG was associated with more serious ARs than IAC.[30] These results suggest that IAC can be used safely and for a long term, with no intolerable ARs. We also found no significant difference in the incidence of leukopenia between patients treated with preoperative IAC and preoperative IV, but more strictly performed studies are needed to assess the ARs of intra-arterial NAC. Other reported ARs of IAC, including fever, diarrhea, and thrombocytopenia,[27],[30] also need to be investigated in studies with more data.
To the best of our knowledge, this was the first meta-analysis to study the efficacy and ARs of IAC combined with IVC in patients with NMIBC after TURBT and in NAC for bladder cancer. The major strengths of this meta-analysis included the use of HRs and 95% CIs, instead of ORs, to analyze survival outcomes, encompassing temporal information, and thus more accurately reflecting the prognosis. Second, if more than one article with the same population reported the same outcome, we only included the study with the longest research period to avoid duplication of patients. Third, we analyzed the ARs of IAC and inferred that most ARs were tolerable. However, this meta-analysis also had several limitations. First, we only included seven articles and some comparisons only included two studies due to the lack of eligible research. This may have affected the analysis of heterogeneity and the validity of our conclusions. Second, the combined analysis of RCTs and cohort studies may have introduced methodological heterogeneity, and subgroup analysis should be conducted in the future according to the study design, with the inclusion of more high-quality studies.
> ConclusionThis meta-analysis demonstrated that IAC plus IVC improved RFS and PFS in patients with NMIBC after TURBT, compared with IAC alone. However, the addition of IVC had no significant effect on OS, TRI, TSDR, and the efficacy of preoperative IAC. In addition, the ARs of IAC seemed mild and were well tolerated by most patients. More strictly performed cohort studies and RCTs are needed to support our findings.
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Conflicts of interest
There are no conflicts of interest.
> References
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