Clinical and economic evaluation of modulated electrohyperthermia concurrent to dose-dense temozolomide 21/28 days regimen in the treatment of recurrent glioblastoma: a retrospective analysis of a two-centre German cohort trial with systematic comparison and effect-to-treatment analysis

Abstract

Objective: To assess the efficacy and cost-effectiveness of modulated electrohyperthermia (mEHT) concurrent to dose-dense temozolomide (ddTMZ) 21/28 days regimen versus ddTMZ 21/28 days alone in patients with recurrent glioblastoma (GBM).

Design: A cohort of 54 patients with recurrent GBM treated with ddTMZ+mEHT in 2000-2005 was systematically retrospectively compared with five pooled ddTMZ 21/28 days cohorts (114 patients) enrolled in 2008-2013.

Results: The ddTMZ+mEHT cohort had a not significantly improved mean survival time (mST) versus the comparator (p=0.531) after a significantly less mean number of cycles (1.56 vs 3.98, p<0.001). Effect-to-treatment analysis (ETA) suggests that mEHT significantly enhances the efficacy of the ddTMZ 21/28 days regimen (p=0.011), with significantly less toxicity (no grade III-IV toxicity vs 45%-92%, p<0.0001). An estimated maximal attainable median survival time is 10.10 months (9.10-11.10). Cost-effectiveness analysis suggests that, unlike ddTMZ 21/28 days alone, ddTMZ+mEHT is cost-effective versus the applicable cost-effectiveness thresholds €US$25 000-50 000/quality-adjusted life year (QALY). Budget impact analysis suggests a significant saving of €8 577 947/$11 201 761 with 29.1-38.5 QALY gained per 1000 patients per year. Cost-benefit analysis suggests that mEHT is profitable and will generate revenues between €3 124 574 and $6 458 400, with a total economic effect (saving+revenues) of €5 700 034 to $8 237 432 per mEHT device over an 8-year period.

Conclusions: Our ETA suggests that mEHT significantly improves survival of patients receiving the ddTMZ 21/28 days regimen. Economic evaluation suggests that ddTMZ+mEHT is cost-effective, budget-saving and profitable. After confirmation of the results, mEHT could be recommended for the treatment of recurrent GBM as a cost-effective enhancer of ddTMZ regimens, and, probably, of the regular 5/28 days regimen. mEHT is applicable also as a single treatment if chemotherapy is impossible, and as a salvage treatment after the failure of chemotherapy.

Keywords: cost-effectiveness analysis; dose-dense temozolamide (ddtmz; effect-to-treatment analysis (eta); modulated electro-hyperthermia (meht); oncothermia; recurrent glioblastoma.

Figure 1

Dose-escalating scheme of modulated electrohyperthermia. The tenth session attains the maximum escalation, the further sessions are the same.

Figure 2

CONSORT flow chart. White: COI, cohort of interest; light grey: CSA, cohorts of covariate survival analysis; dark grey: cohorts out of analysis; black: analyses; ddTMZ, dose-dense temozolomide; GBM, glioblastoma; mEHT, modulated electrohyperthermia; SAT, supportive and alternative treatments.

Figure 3

Kaplan-Meier survival function of the patients treated with ddTMZ+mEHT (n=54) since diagnosis (A) and since first mEHT session (A₁). C, censored; ddTMZ, dose-dense temozolomide; mEHT, modulated electrohyperthermia; S, survival function.

Figure 4

Survival (Kaplan-Meier estimate) since first mEHT session of ‘mEHT-only’ (A, n=18) and combination treatment (B, n=58) samples. α, probability of type I error; C, censored; mEHT, modulated electrohyperthermia; P, p value; S, survival function.

Figure 5

Survival (Kaplan-Meier estimate) since first mEHT session of patients treated with low-dose mEHT (A, n=24) and high-dose mEHT (B, n=52). α, probability of type I error; C, censored; mEHT, modulated electrohyperthermia; P, p value; S, survival function.

Figure 6

Survival (Kaplan-Meier estimate) since first mEHT session of patients with SAT (A, n=59) and without SAT (B, n=17). α, probability of type I error; C, censored; mEHT, modulated electrohyperthermia; P, p value; S, survival function; SAT, supportive and alternative treatments.

Figure 7

Survival (Kaplan-Meier estimate) since first mEHT session of all patients with GBM (A, n=76) and younger (<50 years) patients with high-dose mEHT (B, n=23). α, probability of type I error; C, censored; mEHT, modulated electrohyperthermia; P, p value; S, survival function.

Figure 8

Effect-to-treatment analysis, attenuation modelling. (A) CA=15.0%; (B) CA=19.3%. CA, coefficient of attenuation; MNC, median number of cycles; mNC, mean number of cycles; mST | ETR: dot, mean survival time, ETR, line segment effect-to-tretament ratio.

Figure 9

Cycles needed to treat per one life-month gained (CNTM) scale.