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Year : 2023  |  Volume : 39  |  Issue : 1  |  Page : 75-76

Adjuvant intravesical chemohyperthermia or conventional chemotherapy in an era of bacillus Calmette-Guérin shortage for non-muscle invasive bladder cancer: The HIVEC-II trial

Department of Urology, All India Institute of Medical Sciences, Jodhpur, Rajasthan, India

Date of Submission08-Oct-2022
Date of Decision22-Nov-2022
Date of Acceptance01-Dec-2022
Date of Web Publication29-Dec-2022

Correspondence Address:
Priyank Bhargava
Department of Urology, All India Institute of Medical Sciences, Jodhpur, Rajasthan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/iju.iju_351_22

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How to cite this article:
Bhargava P. Adjuvant intravesical chemohyperthermia or conventional chemotherapy in an era of bacillus Calmette-Guérin shortage for non-muscle invasive bladder cancer: The HIVEC-II trial. Indian J Urol 2023;39:75-6

How to cite this URL:
Bhargava P. Adjuvant intravesical chemohyperthermia or conventional chemotherapy in an era of bacillus Calmette-Guérin shortage for non-muscle invasive bladder cancer: The HIVEC-II trial. Indian J Urol [serial online] 2023 [cited 2023 Jan 30];39:75-6. Available from:

   Summary Top

HIVEC-II was a multicentre, open label, two-arm, phase 2 randomised controlled trial (RCT) which compared adjuvant intravesical mitomycin C (MMC) given at 43°C i.e., chemohyperthermia (CHT) versus standard passive instillation of MMC in patients of intermediate risk (IR) nonmuscle invasive bladder cancer (NMIBC), stratified as per the European Association of Urology guidelines.[1],[2] The patients were recruited between May 2014 and December 2017. Eligible patients underwent complete transurethral resection of bladder tumor (TURBT) and patients with pT1 disease who had confirmation of deep muscle at histology did not undergo a repeat resection. Patients were randomised using a 1:1 allocation ratio and a stratified block randomisation size of 4 by the treating hospital to receive either 6 once-weekly instillations of MMC with CHT at a temperature of 43°C ± 1°C or conventional 6 once-weekly doses with patients asked to restrict fluid intake before treatment. Patients were followed with cystoscopy and cytology every 3 months for the first 12 months and then at 18 and 24 months. The primary outcome measure was disease-free survival (DFS) and secondary outcomes were recurrence rate at 3 months, recurrence-free survival (RFS), progression-free survival, disease-specific survival, overall survival (OS) and treatment safety and tolerability. A total of 259 patients were randomised, of whom 252 were ultimately treated – CHT: 127 and control: 125. Of these, 75 patients completed the treatment in the CHT arm and 111 in the control arm. At a median follow-up of 24 months, the DFS rates were 61% (95% confidence interval [CI] 51%–69%) in the CHT arm and 60% (95% CI = 50%–68%) in the control arm (Hazard ratio [HR] = 0.92, 95% CI = 0.62–1.37; P = 0.8). On individual analysis of NMIBC risk factors between arms, the treatment efficacy did not differ. Per-protocol analysis revealed that the 24-month DFS rate was better in the CHT arm (65%, 95% CI = 52%–75%) than in the control arm (59%, 95% CI = 48%–68%), although not statistically significant (HR = 0.75, 95% CI = 0.46–1.22; P = 0.4). Four patients, all with initial G2 pTa histology, in the CHT arm experienced disease progression and 8 patients in the CHT arm with 4 in the control arm died during follow-up without disease progression. Disease progression was significantly more likely in the CHT arm (HR = 3.44, 95% CI = 1.09–10.8; P = 0.02). OS was similar between arms (HR = 2.55, 95% CI = 0.77–8.40; P = 0.09). As far as adverse effects and tolerability is concerned, a smaller number of patients treated with CHT completed their protocolised treatment when compared to the control group (75 [59%] CHT, 111 [89%] control). The most common reasons cited in the CHT arm were equipment issues (n = 19) and bladder spasm/urgency (n = 10) and in the control arm were allergic reactions/rash (n = 5). The most common treatment-related adverse events included urinary tract pain, urinary frequency, haematuria, urinary urgency, and rash.

   Comments Top

This RCT compares CHT versus conventional chemotherapy for IR NMIBC. Traditionally, adjuvant intravesical chemotherapy is advocated for 1 year but in this study only induction doses, once weekly for 6 weeks were given. Further, adjuvant intravesical chemotherapy is associated with relatively higher rates of recurrence as compared to intravesical bacillus Calmette-Guérin (BCG) therapy.[2] Thus, some of the interventions in this study may not be the standard of care.

In the study, patients who had pT1 disease after first TURBT, did not undergo a repeat resection if deep muscle was identified in the specimen. This is usually not a standard practice as repeat resection is indicated in these patients and few patients may get upstaged to pT2 disease, which may be a possible confounding factor. While patients were asked to restrict their fluid intake before treatment to minimise dilution, asking them to void before intravesical instillation to avoid drug dilution and possible effect on drug concentration may have been better. In both the arms, 40 mg of MMC was diluted in 40 mL of sterile water, leading to a final concentration of 1 mg/mL. However, additional primer is routinely used during the heat exchange process in CHT given via the combat bladder recirculating system used in this study, which may itself contribute to drug dilution.[1],[3]

Disease recurrence was defined as the presence of urothelial carcinoma histologically or positive urinary cytology, and DFS was the primary with RFS as the secondary endpoint. It would be prudent to define both of these separately to have a clear understanding of the results. 41% of patients randomised to the CHT arm did not complete their treatment according to protocol, and the most common reason cited was equipment issues. Considering that HIVEC-II was an international multi-centre RCT, equipment issues leading to failure to complete treatment should have been minimised so that efficacy could have been compared in a better way between arms. CHT requires specialised equipment which may add to the cost. Bladder spasms/urgency was the reason for stopping treatment in 10 patients in CHT arm and only 2 patients in MMC arm. It should have been discussed whether CHT leads to increased bladder spasms. 28 patients suffered treatment related toxicities leading to not completing treatment in CHT arm, compared to 10 patients in control arm. So, to conclude that adverse events were common in both arms, without taking this point into consideration, may be erroneous.

Conductive hyperthermia did not show any oncological benefit. Radiofrequency induced thermotherapy effect (RITE) is another standard technique in use and multiple studies, including RCTs have reported its use in IR NMIBC with significantly higher recurrence free survival.[4],[5] Considering contrasting results of these two different techniques of CHT, more studies are required on CHT, including RITE to definitely identify its place in the management of IR NMIBC, especially in the era of shortage of BCG being faced in the European continent.

Financial support and sponsorship: Nil.

Conflicts of interest: There are no conflicts of interest.

   References Top

Tan WS, Prendergast A, Ackerman C, Yogeswaran Y, Cresswell J, Mariappan P, et al. Adjuvant intravesical chemohyperthermia versus passive chemotherapy in patients with intermediate-risk non-muscle-invasive bladder cancer (HIVEC-II): A phase 2, open-label, randomised controlled trial. Eur Urol 2022;Aug 20:S0302-0.  Back to cited text no. 1
Babjuk M, Burger M, Capoun O, Cohen D, Compérat EM, Dominguez Escrig JL, et al. European association of urology guidelines on non-muscle-invasive bladder cancer (Ta, T1, and Carcinoma in Situ). Eur Urol 2022;81:75-94.  Back to cited text no. 2
Tan WS, Kelly JD. Intravesical device-assisted therapies for non-muscle-invasive bladder cancer. Nat Rev Urol 2018;15:667-85.  Back to cited text no. 3
Colombo R, Salonia A, Leib Z, Pavone-Macaluso M, Engelstein D. Long-term outcomes of a randomized controlled trial comparing thermochemotherapy with mitomycin-C alone as adjuvant treatment for non-muscle-invasive bladder cancer (NMIBC). BJU Int 2011;107:912-8.  Back to cited text no. 4
Arends TJ, Nativ O, Maffezzini M, de Cobelli O, Canepa G, Verweij F, et al. Results of a randomised controlled trial comparing intravesical chemohyperthermia with mitomycin C versus bacillus calmette-guérin for adjuvant treatment of patients with intermediate and high-risk non-muscle-invasive bladder cancer. Eur Urol 2016;69:1046-52.  Back to cited text no. 5


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