*3.3. Association of Handgrip with Adverse Outcomes*

In a second step, we investigated the prognostic value of HGS in this population of cancer patients stratified by sex (Table 3). In our overall adjusted statistical model, a 10 kg decrease in HGS was associated with a 50% increase in the risk of 180-day all-cause mortality (adjusted OR 1.52 (95% CI 1.19 to 1.94), *p* = 0.001). The effect was similar among male and female patients, but the association was only significant in male patients (adjusted OR 1.59 (95% CI 1.19 to 2.12), *p* = 0.002 vs. adjusted OR 1.54 (95% CI 0.89 to 2.65), *p* = 0.122 for female patients).


**Table 3.** Association of handgrip strength with short- and long-term outcomes stratified by sex.


**Table 3.** *Cont.*

Abbreviations: OR, odds ratio; Coef, coefficient; SD, standard deviation; EQ-5D, EuroQol Group 5-Dimension Self-Report Questionnaire; HGS, handgrip strength; VAS, visual analogue scale. \* Adjusted for randomization, age, weight, height, NRS 2002, center, main diagnosis (cardiovascular, infection, renal disease, failure to thrive) and comorbidities (hypertension, chronic kidney failure, chronic heart failure, diabetes mellitus) and for randomization group.

We also found significant associations between HGS and other clinical endpoints, namely 30-day all-cause mortality (adjusted OR 1.59 (95% CI 1.13 to 2.22), *p* = 0.007), admission to ICU (adjusted OR 2.58 (95% CI 1.08 to 6.16), *p* = 0.033), major complications (adjusted OR 1.65 (95% CI 1.09 to 2.51), *p* = 0.018), mean Barthel Index score (points) (adjusted Coef −1.44 (95% CI-2.56 to −0.33), *p* = 0.011) and incidence of one or more falls within 180 days (adjusted OR 1.58 (1.02 to 2.46), *p* = 0.04).

#### **4. Discussion**

This secondary analysis of a large, randomized trial found HGS to be highly predictive of long- and short-term mortality and other adverse outcomes among cancer patients. In line with previous research, HGS values depended on sex and patient age [26,27,36], but we additionally found important differences among different types of cancers. Our data provide important HGS reference values for the specific population of cancer patients, which may help future counseling of patients and interpretation of HGS results.

Through the additional stratification by tumor entity, a more precise assessment of functional status and muscle strength via HGS measurements is possible within the population of malnourished cancer patients. It may help to better understand the value of a single HGS measurement in an individual cancer patient and puts this measurement in the perspective of what is expected of the specific population. For this reason, our HGS data from a large, randomized controlled trial may contribute to a better classification of the functional status of malnourished cancer patients by HGS values. Nevertheless, our analysis is still limited by sample size within the different tumor entities, and larger studies would be useful to provide better estimates. Further investigations should also focus on the predictive value of HGS in different tumor entities stratified by age and sex.

Our analysis also showed a significant association of HGS in cancer patients and different clinical outcomes, such as all-cause mortality within 180 days, which is consistent with findings from our research group including other patient populations [36]. In fact, an incremental decrease in HGS by 10 kg resulted in more than doubling the risk for 180-d all-cause mortality among all tumor entities and sexes. These results persisted after adjustment for important cofounders, such as randomization, age, weight, height, NRS 2002, main diagnosis and comorbidities. These findings underline the prognostic value of HGS in malnourished cancer patients and are consistent with results from studies that also included patients with different diseases [36,41,46,47]. Additionally, our results show that, in the overall population, there is a significant association between the Barthel Index score and a decrease in HGS. As both are instruments for assessing functional status, this is an expected result, which was not stable in sex-specific subgroups. A decrease in HGS by 10 kg was also associated with other short-term endpoints, as shown in Table 3.

While the role of nutrition in cancer patients has received little attention, several studies observed a strong increase in mortality in patients with higher nutritional risk [41,48–50]. Indeed, patients with an NRS of ≥5 points had a 19% higher risk of long-term mortality compared to those with 3 points in a previous analysis [41]. Our data now suggest that, in addition to clinical information about weight and low appetite included in the NRS score, HGS is an additional parameter that helps providers understand the risk of a patient and may also help with decisions regarding the start of nutritional interventions. Importantly, we recently found that HGS was also predictive for treatment response, with patients in the lowest HGS ranges showing the best response rates [36].

The present analysis has several strengths worth mentioning, including the rather large population of patients with different types of cancer and the prospective gathering of data as part of the EFFORT trial [31,32]. High adherence to the study protocol in the main trial further increases the value of data collected. Limitations include the secondary analysis with limited power and the exploratory nature of our analyses, with the risk for model overfitting and type I error. Validation of our results is thus necessary. Further, we did not include critically ill and surgical cancer patients, which makes our findings only applicable to medical cancer patients. Since we had only limited information about the CKD stages, we did not consider a further stratification.

#### **5. Conclusions**

Our data provide evidence about the prognostic implications of HGS measurement in cancer patients and validate the prognostic value of HGS in regard to long-term mortality. In addition, our results provide expected HGS values in the population of hospitalized malnourished cancer patients, which may allow better interpretation of values in individual patients.

**Author Contributions:** Conceptualization, P.S., P.T. and N.K.-B.; Methodology, P.S., P.T. and N.K.-B.; Formal Analysis, P.S., P.T. and N.K.-B.; Investigation, P.S., P.T. and N.K.-B.; Data Curation, P.S., P.T. and N.K.-B.; Writing—Original Draft Preparation, P.T., C.G., N.K.-B., A.B., K.-H.W., Z.S. and P.S.; Writing—Review and Editing, P.T., N.K.-B. and C.G.; Visualization, P.T.; Supervision, P.S. and K.-H.W.; Project Administration, P.S.; Funding Acquisition, P.S. and Z.S. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Swiss National Science Foundation (SNSF professorship, PP00P3\_150531 and PP00P3\_176972) and the Research Council of the Kantonsspital Aarau, Switzerland (1410.000.058 and 1410.000.044).

**Institutional Review Board Statement:** The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee Northwest/Central Switzerland (EKNZ) in January 2014 (EKNZ; 2014\_001).

**Informed Consent Statement:** Informed consent was obtained from all subjects involved in the study.

**Data Availability Statement:** The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

**Acknowledgments:** We thank all patients and hospital staff for support of our trial.

**Conflicts of Interest:** Unrelated to this trial, Nestlé Health Science and Abbott Nutrition previously provided unrestricted grant money to the institution of P.S. The institution of Z.S. received research support from Nestlé Health Science, Abbott Nutrition, B. Braun and Fresenius Kabi. All other authors report no conflict of interest.
