Cost-effectiveness of response evaluation after chemoradiation in patients with advanced oropharyngeal cancer using ¹⁸F–FDG-PET-CT and/or diffusion-weighted MRI

We developed a decision-analytic model to evaluate the effects and costs of four strategies for local response evaluation in patients with OPSCC who underwent CRT. In the first strategy under consideration, i.e. the reference strategy, all patients undergo EUA 3 months after completion of CRT for response evaluation. EUA is considered positive if histopathological proof of viable cancer has been found in the biopsy. The indication for EUA is considered unnecessary if 6 months of follow-up after response evaluation did not show residual disease.

In the three other strategies, response evaluation is performed by either PET-CT (strategy 2), DW-MRI (strategy 3) or a combination of PET-CT and DW-MRI (strategy 4). Only patients with a positive imaging test are referred to EUA. In strategy 4, patients are referred to EUA based on a combined assessment by a radiologist and nuclear medicine physician. The four strategies are depicted by decision trees in Fig. 1. Each end node reflects the diagnostic status of a patient who followed that specific branch as well as the associated costs.

Costs of the different diagnostic instruments were based on official tariff lists [5]. As shown in Table 1, combined PET-CT and DW-MRI was with 1313 Euros the most expensive test. Test characteristics were obtained from a prospective trial (2012–2014) in which patients with advanced but resectable OPSCC who underwent CRT were subjected to PET-CT, DW-MRI and EUA for response evaluation 3 months after end of CRT (Dutch Trial Register: NTR4111/NL39181.000.11). Patient and tumour characteristics are summarized in Table 2. PET-CT and DW-MRI images were interpreted by respectively two nuclear medicine physicians (OH, EC) and two radiologists (JC, PG). For PET-CT, we requested the observers individually to score the PET-CT using the Hopkins criteria (a 5-point scale in which scores 1, 2 and 3 are considered negative for tumour and scores 4 and 5 are considered positive) [6]. DW-MRI observers scored signal intensity on b1000 images and the corresponding ADC-map. A residual mass was considered ‘suspicious for residual disease’ if increased signal intensity on the b1000 images was present, in an area of contrast-enhancement on post-contrast T1WI and corresponding to low ADC-values. For DW-MRI, we requested the observers individually to classify the MRI-examinations using a dichotomous system, i.e. suspicious for a local residue or not, based on signal intensity of the DW-images. In case readings were discrepant, consensus was reached between the observers of either PET-CT or DW-MRI. For strategy 4, combined reading of PET-CT and DW-MRI with visual correlation by a radiologist and nuclear medicine physician was performed in all patients with discrepancies between the scoring of the two modalities. In total, 46 patients were included of whom five (11%) had residual tumour. Test characteristics of each diagnostic test are shown in Table 2. Sensitivities were 60% or higher, with the combined PET-CT and DW-MRI strategy having the highest sensitivity. Specificity was lowest for PET-CT with 83%.

Using the decision trees, we calculated the expected health effects of each response evaluation strategy, i.e. the expected proportion of correctly diagnosed patients (true positives and true negatives). Based on the costs of each diagnostic instrument, the average costs accumulated by a patient when following a specific branch in the decision tree were estimated. Subsequently, for each branch costs were multiplied by the probability that a patient will follow this branch. Summing up the expected costs of each branch of the decision tree results in the overall expected costs for that strategy. In addition, the number of EUA indications as well as the number of unnecessary EUA indications per response evaluation strategy were calculated. It was not possible to correctly estimate quality-adjusted life-years in this study. As an alternative we estimated the costs per true-positive case for the different strategies.

Due to the small sample size of this trial, we repeated the base-case analysis using test characteristics based on the literature. Sensitivity and specificity for PET-CT and DW-MRI were derived from respectively a systematic review by Gupta et al. (2011) [7] and the study of Vaid et al. (2017) [8]. Test characteristics for EUA and combined PET-CT and DW-MRI are not reported in the literature.

We further explored the impact of uncertainty regarding the test characteristics of the diagnostic instruments in univariate sensitivity analyses in which we increased and decreased the sensitivity and specificity of each instrument with 10% (absolute change). In the strategies in which a positive imaging test was followed by EUA, only the test characteristics of the imaging test were varied.

In addition, in clinical practice a positive EUA is usually followed by MRI and PET-CT to assess if surgical intervention is feasible and if any distant metastases are present, respectively. Therefore, in a sensitivity analysis we included the costs of these additional tests in the EUA strategy. Similarly, we added costs of an MRI or whole body PET-CT (in case of a positive EUA) to those of the “head and neck” PET-CT and DW-MRI, respectively. Finally, we assessed the impact of uncertainty surrounding the prevalence of residual tumour by increasing and decreasing the prevalence to 15% and 5%, respectively [9].

The proportion of correctly diagnosed patients and the expected costs per patient for each strategy are shown in Table 3. The combined PET-CT and DW-MRI strategy and the EUA strategy led to the highest proportion of correctly diagnosed patients, i.e. 96%. However, the expected costs of the EUA strategy were 927 Euros per patient lower than those of the combined PET-CT and DW-MRI strategy. The strategy with DW-MRI led to the lowest expected costs per patient but also to the lowest proportion of correct diagnoses. The PET-CT strategy and the combined PET-CT and DW-MRI strategy were dominated by the EUA strategy because these strategies led to a smaller or equal proportion of correct diagnoses, at higher costs.

Figure 2 shows the proportion of correct diagnoses as well as the proportion of unnecessary EUA indications per strategy. All imaging strategies led to a considerably lower proportion of unnecessary EUA indications compared to the EUA strategy. The combined PET-CT and DW-MRI strategy led to the lowest proportion of unnecessary EUA indications, i.e. 38%.

In Fig. 3, the total number of EUA indications, the number of unnecessary EUA indications and the expected costs per patient are shown for 1000 patients. In the EUA strategy, all patients underwent EUA, of which 891 indications were unnecessary. All imaging strategies substantially reduced the number of required EUAs as well as the number of unnecessary EUA indications. The DW-MRI required the lowest number of EUAs, i.e. 109 EUAs of which 43 indications were unnecessary. However, this strategy also had the highest number of missed residual disease. Please note that the combined PET-CT and DW-MRI required 65 additional EUAs compared to the DW-MRI strategy, but a slightly lower proportion of these EUA indications was unnecessary.

The costs per true-positive case were for EUA 7175 Euros, for PET-CT 24,058 Euros, for DW-MRI 7588 Euros and for combined PET-CT and DW-MRI 21,387 Euros. Although EUA and DW-MRI are much cheaper, they detect less recurrences than PET-CT leading to delayed salvage treatment with potentially poorer outcome. The addition of DW-MRI to PET-CT lowered the costs per true-positive case.

When the test characteristics of DW-MRI were based on the literature, the proportion of correct diagnoses increased from 0.93 to 0.95. On the other hand, also the expected costs and proportion of unnecessary EUA indications increased. For the PET-CT strategy, the proportion of correct diagnoses remained 0.95 whereas the expected costs and proportion of unnecessary EUA indications decreased when we based the test characteristics on the literature.

In the majority of sensitivity analyses in which we varied test characteristics, additional testing after a positive EUA and the prevalence of residual disease, the ordering of the strategies based on the proportion of correct diagnoses, expected costs and proportion of unnecessary EUA indications did not change, as shown in Table 3. Only in the analysis in which the specificity of the diagnostic instruments was lowered with 10%, the ordering of the strategies changed; the EUA strategy led to the lowest proportion of correct diagnoses.