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Impact of Partial Nephrectomy and Percutaneous Cryoablation on Short-term Health-related Quality of Life—A Prospective Comparative Cohort Study

Take Home Message Patients receiving percutaneous cryoablation (PCA) had lower baseline scores on physical functioning but were comparable with those receiving partial nephrectomy (PN) with regard to Global Health Status. Significant differences in health-related quality of life were reported from baseline to 14 d postoperatively between PN and PCA, but were no longer evident after 90 d.


Introduction
In recent decades, increases in the incidence of renal cell carcinoma (RCC) stage cT1 have been reported, with the majority being incidental findings, with increasing age [1]. Partial nephrectomy (PN) is considered the gold standard treatment; however, ablation therapy, including percutaneous cryoablation (PCA), is an alternative minimally invasive treatment mostly preferred in elderly patients or those with severe comorbidity and not suitable candidates for surgery [2]. The increasing pace of an aging population highlights the need to expand the surgical treatment paradigm [3]. Treatment of small renal masses should take into account several factors, including oncological status, healthrelated quality of life (HRQoL), and healthy life expectancy. Patient-reported HRQoL contributes valuable information on factors otherwise challenging to measure, including emotional and cognitive functioning.
Previous studies on RCC have focused on HRQoL after PN [4][5][6] or compared PN with radical nephrectomy (RN) [7][8][9][10]. However, only a few studies have assessed HRQoL after cryoablation, and these often pooled ablative therapies (eg, cryoablation and radiofrequency ablation) [11] and minimally invasive procedures (eg, percutaneous and laparoscopic) [12]. Furthermore, many studies were retrospective, and either these used HRQoL as a secondary outcome or HRQoL was inconsistently measured or reported [13]. Thus, it remains challenging to discuss HRQoL outcomes when advising patients with RCC stage cT1 on treatment decisions.
The aim of this prospective study was to assess and compare short-term HRQoL and self-reported health status after PN and PCA in patients treated for RCC stage cT1.

Patients and methods
The details of this comparative, prospective cohort study have been reported according to the ''Strengthening the Reporting of Observational Studies in Epidemiology'' (STROBE) guidelines [14]. In addition, this study is registered on ClinicalTrials.gov (NCT04040530).

2.1.
Setting and participants  [17]. The latter scale was not analyzed in this study.
The scores were calculated based on the EORTC scoring manual [16].
All scale scores range from 0 to 100, with a high score on the functional scales indicating a high level of functioning and a high score on the symptom scales indicating greater severity of individual symptoms. were collected with additional questions. Clinical information was collected from patients' medical records and through patient interviews, including: ECOG performance status [18], complications graded according to the Clavien-Dindo classification [19], histopathology according to the American Joint Committee on Cancer eighth edition for RCC tumor node metastasis (TNM) staging system [20], Charlson Comorbidity Index (CCI) [21], and radius-endophytic-nearness-anterior-location (RENAL) nephrometry score [22].

Ethical considerations
Prior to inclusion, patients were informed about the purpose of the study, the anonymity and confidentiality of their personal data, and their right to withdraw from the study at any time.

Results
A total of 184 patients with RCC stage cT1N0M0 were scheduled to undergo NSS during the inclusion period. Seven patients, who planned to receive PN, were excluded due to conversion to RN, benign tumor pathology, or metastasis before operation. Three patients who planned to receive PCA had repeated NSS for another tumor within 3 mo of the first treatment, leaving 173 patients eligible to participate in the study. Eight patients either misplaced or did not return the baseline questionnaire, resulting in 165 remaining patients (PN, n = 79 and PCA, n = 86) included in the analysis (CONSORT flowchart, Fig. 1). Patients receiving PCA were significantly older, were more frequently unemployed due to retirement, had worse performance status, had higher CCI, and were more likely to have other malignities at the time of treatment than patients who underwent PN (Table 1). Patients receiving PCA had significantly smaller tumors than those receiving PN. RENAL scores and histological subtypes were comparable between PN and PCA. Patients receiving PN had significantly higher scores on PF and RF, and reported significantly lower levels of fatigue and insomnia at baseline than those who received PCA. Otherwise, the groups were comparable on HRQoL scores and self-reported symptoms at baseline (Table 1). In addition, 90-d postoperative complications were comparable between PCA and PN.
The completion rates of the questionnaire were 98% at 14-d and 96% at 90-d follow-up. Patients lost to follow-up were considered random for both PN and PCA.
A statistically significant difference between baseline and 14-d follow-up was found for Global health status, PF, RF, and EF, suggesting that PCA either increased or did not decrease as much as PN. Likewise, patients who underwent PN had a significant increase in fatigue, pain, dyspnea, appetite loss, and diarrhea at 14-d follow-up compared with PCA patients (Fig. 2). Overall, the data show that all significant differences observed from baseline to 14-d follow-up were not significant compared with those from baseline to 90-d follow-up. Adjusting for age and sex did not change the results on any scales or symptoms. Table 2 shows the differences from baseline to follow-up between PN and PCA in global health status, the five functioning scales, and the eight symptom scales after 14 and 90 d. For the mean scores for PN and PCA for each scale, the difference between the groups, and the difference from baseline to each followup, see Supplementary Table 1.

Discussion
In this prospective comparative study, we found that patients receiving PN had a statistically significant decrease in global health status, PF, RF, and EF at 14-d follow-up compared with patients receiving PCA. This finding was accompanied by PN having a significant increase in symptom scores on fatigue, pain, dyspnea, appetite loss, and diarrhea at 14-d follow-up. However, this difference was not present at 90-d follow-up in any of the HRQoL scales or self-reported symptoms scores. These results corroborate those reported by Sandbergen et al. [12], who found an initial decrease in HRQoL following surgical treatment of RCC after 1 mo, which gradually improved up to or above baseline after 1 yr, regardless of procedural approaches or treatment modality. The same findings were reported by Becker et al. [23], who found no significant difference in long-term HRQoL outcomes following laparoscopic PN and OPN. Moreover, Breau et al. [6] reported that patients receiving OPN recovered to baseline HRQoL after 12 mo. These previous findings suggest that treatment procedure has a smaller effect on long-term HRQoL. In the present study, we confirmed these findings at 90-d follow-up. Watanabe et al. [5] recently reported a significant or small improvement in HRQoL scores following RAPN after 6-12 mo except for mental health, which improved significantly at 3-mo follow-up. The significant differences observed at 14-d follow-up in the present study may reflect the nature of the treatment, as PCA is less invasive than PN. Similar results were reported by Sandbergen et al. [12], who found that short-term HRQoL favors minimally invasive procedures. The more significant change in symptom burden observed in the PN group could also affect the changes observed in the functional scales. However, statistical significance does not necessarily indicate a clinically relevant change [16]. Several authors have investigated how to interpret the meaning of small and significant changes in HRQoL scores measured by the EORTC. Osoba et al. [24] used an anchor-based approach that inves-tigated the correlation between patients' subjective significance and changes in mean scores in the EORTC questionnaire when administered to a population of women treated for breast cancer. The authors reported that a mean change in scores between 5 and 10 corresponded to ''a little'' change, a mean change in scores between 10 and 20 corresponded to ''a moderate'' change, and a mean change above 20 corresponded to ''very much'' change. They did not distinguish between the HRQoL scales [24]. Cocks et al. [25], by contrast, reported that changes in mean scores on the EORTC scales should be interpreted differently with regard to mean changes over time when associated with the minimal clinically important difference (MCID). Furthermore, they showed that estimates of improvements   were smaller than those of worsening. Applying the thresholds by Cocks et al. [25] to the results in this study, the changes at 14-d follow-up in the domains of global health status, PF, RF, and pain were medium, whereas the changes in EF, dyspnea, appetite loss, and diarrhea were small. Thus, only the difference in fatigue could be classified as a large change. We found a significant difference within the range of MCID between PN and PCA at 14-d follow-up. A finding that could, however, be considered less relevant for patients when compared with that over a lifespan. Nevertheless, it could aid patients and clinicians in decision-making. Furthermore, given the nonrandomized design, this study cannot conclude whether a comorbid and elderly patient receiving PN would recover to baseline HRQoL after 90 d.
Previous reviews exploring quality of life following surgical treatment of RCC have observed that evidence in this field is sparse, partially due to the over-representation of retrospective studies [13,26]. This situation creates an issue when comparing treatments such as PN and PCA in which, as we have reported in this study, patients have different baseline HRQoL scores. Another factor, when comparing HRQoL results across the literature, is the variety of instruments used, as we recently addressed in a systematic review [27]. To our knowledge, a disease-specific instrument is not yet available to assess HRQoL in patients with localized RCC. Therefore, we chose the EORTC questionnaire based on relevance and the recall period that fit the followup period. The high response compliance by patients in this study (98% and 96%) suggests that patients found the EORTC questionnaire a meaningful assessment tool for reporting HRQoL.
Studies have shown that PCA could be associated with an increased risk of treatment failure or recurrence of RCC [28,29]. Given that this study focused on short-term HRQoL, we did not include information regarding oncological out-comes. However, we reported a mean difference between PN and PCA at 90-d follow-up below the MCID on all HRQoL scales. Thus, a possibly more significant concern regarding whether treatment was successful or not in the PCA group was not detectable in the HRQoL outcome measured in this study.
Patient selection and decision-making in the treatment of RCC stage cT1 have been debated since the use of ablation therapies have become more widespread [30][31][32]. We found that patients receiving PCA were significantly older and had worse performance status and more severe comorbidity than patients receiving PN. In addition, patient frailty has been reported to impact perioperative and oncological outcomes [33]. Therefore, preoperative frailty assessment could optimize patient outcomes and is a factor to consider in decision-making. Whereas the most discussed factors revolve around clinical outcomes, this study proposes that patient-reported outcomes in terms of HRQoL should also be considered as part of clinical decision-making when treating RCC stage cT1.

Limitations
A limitation of the present study is that patients were not randomized, which poses a risk of confounding by indication, potentially compromising internal validity. However, the design followed the clinical practice of providing information about HRQoL outcomes from a broader patient perspective. We argue that this feature, combined with a high response rate throughout the study, contributes to the external and internal validity. Therefore, the magnitude of the indication bias is limited. The inclusion of open procedures poses another limitation since postoperative outcomes after minimally invasive procedures such as RAPN, compared with open PN, may differ, especially in the  short-term outcome. However, this study reflects the standard clinical practice and real-life data. It would have strengthened the results if more patients had been included, generating a larger sample size. However, patients treated with NSS were consecutively recruited for almost 2 yr, from an uptake area covering 2 million people.

Conclusions
This prospective multicenter study found a significant difference between baseline and a 14-d follow-up in several HRQoL and symptom scales, favoring PCA over PN. However, we found no significant differences between baseline and 90-d follow-up in HRQoL scales and self-reported symptoms between patients who underwent PN and those who received PCA to treat stage cT1 RCC.
Author contributions: Theresa Junker had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.