Changes in upper extremity function, ADL, and HRQoL in colorectal cancer patients after the first chemotherapy cycle with oxaliplatin: a prospective single-center observational study

Changes in upper extremity function, ADL, and HRQoL in colorectal cancer patients after the first... Purpose Oxaliplatin, an important chemotherapeutic agent in colorectal cancer, causes chemotherapy-induced peripheral neurop- athy (CIPN), for which prophylactic or therapeutic interventions are lacking. We aimed to investigate changes in upper extremities, activities of daily living (ADL), and health-related quality of life (HRQoL) parameters after the first chemotherapy cycle. Methods Thirty-eight colorectal cancer patients scheduled to receive the leucovorin, 5′-fluorouracil, oxaliplatin (FOLFOX) therapy or the capecitabine, oxaliplatin (CAPOX) therapy, participated. Patients underwent objective assessment of sensory function, mus- cular strength, and manual dexterity and answered the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Disabilities of the Arm, Shoulder, and Hand-Disability/Symptom (DASH-DS) questionnaires for subjective assessment. The CIPN was assessed at baseline and prior to the second drug cycle. Results Light touch sensation in both hands worsened significantly after the first drug cycle, though no significant changes were observed in muscular strength and manual dexterity. The QLQ-C30 analysis showed that Physical Functioning, Role Functioning, Nausea and Vomiting, and Dyspnea were significantly worse, whereas Emotional Functioning was improved. The DASH-DS analysis revealed significant worsening of dysfunction and subjective symptoms. Conclusions Our results suggest that light touch sensation may worsen even in the absence of multiple chemotherapy cycles. Even if arm and hand function (muscular strength and manual dexterity) is apparently intact, patients may experience dysfunction and decreased HRQoL. For preserving or improving patients’ ADL and HRQoL, it is imperative to provide support at chemo- therapy initiation. . . . Keywords Chemotherapy-induced peripheral neuropathy (CIPN) Upper extremity function Activities of daily living (ADL) . . Health-related quality of life (HRQoL) Oxaliplatin (L-OHP) Colorectal cancer Introduction However, chemotherapy side effects may decrease patient health-related quality of life (HRQoL), with serious clinical The recent development of multidisciplinary therapy has led implications, such as the need for dose reduction, treatment to improved survival and reduced relapse in cancer patients. delays, or treatment discontinuation [1]. Oxaliplatin (L-OHP), an important chemotherapeutic agent in colorectal cancer, causes acute and chronic chemotherapy- induced peripheral neuropathy (CIPN). Chronic CIPN leads to * Ami Tabata dose-limiting toxicity [2, 3], and a cumulative dose ≥ 540– fuguku@kuhp.kyoto-u.ac.jp 850 mg/m increases risk of subjective symptoms such as numbness, and that of functional disorders which may affect Department of Human Health Sciences, Graduate School of patient activities of daily living (ADL) [2–6]. Patients often Medicine, Kyoto University, 53, Kawahara-cho, Syogoin, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan experience CIPN symptoms in their fingers [7], which can interfere with ADL and HRQoL [8–11]. However, there is Rehabilitation Unit, Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan no standardized effective therapy for prevention and treatment of CIPN [12–18]. Commonly used measures of CIPN include Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan the National Cancer Institute Common Terminology Criteria 2398 Support Care Cancer (2018) 26:2397–2405 (NCI-CTCAE) v4.0, and physician-based instruments [19]. Procedures However, CIPN symptoms are largely subjective, and the lack of a universally recognized standard for quantifying CIPN The CIPN measurements were collected before initiation of symptoms [17, 20–22] makes it difficult to capture changes the first chemotherapy cycle (baseline) and again before start in sensory function, ADL, and HRQoL, in detail [23–25]. of the second drug cycle, to investigate changes in chronic Chronic platinum-induced neuropathy is believed to manifest sensory neuropathy, manual dexterity, ADL, and HRQoL after as secondary axonal degeneration or axonal damage accom- the first chemotherapy cycle. Following that, CIPN measure- panying dorsal root ganglion neuronopathy [26–28]. ments were collected 2 or 3 weeks after baseline just before Although L-OHP-induced neuropathy is sensory rather than the second drug cycle depending on the regimen, because motor in nature, the intensity of dysfunction can impair phys- FOLFOX therapy was administered every 2 weeks and ical functions, resulting in symptoms such as sensory ataxia CAPOX therapy was administered every 3 weeks (Fig. 1). [1]. The negative influence of CIPN on upper extremity Measures function, ADL, and HRQoL can be detected only in advanced stages of dysfunction. Once CIPN symptoms Objective assessments occur, they usually persist for a year or more after treat- ment termination [29–31]. In severe cases, sensory Sensory evaluation was performed by light touch sensation, nerve fiber damage may become irreversible [16]. moving two-point discrimination (m2PD), and proprioceptive Therefore, it is important that interventions or self-care sensation assessments. Motor function was evaluated by man- strategies are offered to patients prior to the appearance ual dexterity, grip strength, and pinch strength tests. of obvious CIPN symptoms. We aimed to investigate changes in chronic sensory Evaluation of sensory function neuropathy, manual dexterity, ADL, and HRQoL after the first cycle of L-OHP-based chemotherapy in Evaluation of light touch sensation We employed the widely colorectal cancer patients who were scheduled to receive used Semmes-Weinstein monofilament test (SWMT) (2.83, initial chemotherapy. We focused on the period after the 3.22, 3.61, 4.31, 4.56, and 6.65 mg monofilaments) first chemotherapy cycle when CIPN symptoms were (Aesthesio®, Precise Tactile Sensory Evaluator), to evaluate expected to be milder, rather than during the period light touch sensation [32]. The evaluation was conducted ac- when the cumulative L-OHP dose was 540–850 mg/m cording to the operation manual [33] by an experienced occu- or higher, when functional disorders caused by chronic pational therapist. The testing procedure was explained to the CIPN are likely to appear. patients, and they were instructed to respond verbally by say- ing Btouch^ or Byes^ when a stimulus was felt. Subsequently, in a quiet area conducive to minimize distractions, two evalu- ations were performed under similar conditions. Light touch Methods sensation was assessed in the right and left index finger pad (a half beyond the distal interphalangeal joint). Perception levels Study design and participants were interpreted based on the monofilament labels as follows: 2.83 (normal), 3.22 or 3.61 (diminished light touch), 4.31 We conducted a prospective single-center observational study, (diminished protective sensation), 4.56 or 6.65 (loss of pro- approved by the Kyoto University Graduate School and tective sensation), and 6.65 undetected (nonmeasurable). Faculty of Medicine, Ethics Committee (E1571). Colorectal cancer patients scheduled to receive initial chemotherapy with Moving two-point discrimination test [34, 35] Pressure per- the leucovorin, 5′-fluorouracil, oxaliplatin (FOLFOX) or the ception of right and left index fingers was evaluated using a capecitabine, oxaliplatin (CAPOX) therapy at the Kyoto two-point discriminator. One or two points of the discrimina- University Hospital were surveyed. tor were vertically pressed onto the long axis of the finger pad Study eligibility criteria included (a) diagnosis of colorectal until it bent slightly, were held for about 2 s, and then slowly cancer, (b) scheduled FOLFOX or CAPOX therapy, (c) ability moved distally to the fingertip. The subject was asked whether to fill a questionnaire, and (d) written informed consent pro- he/she was being touched at one point or at two points. Testing vided. Study exclusion criteria were (a) pre-existing neuro- began with 5-mm spacing between discriminator tips, which pathic disease (peripheral neuropathy and/or a disease of the was narrowed in a stepwise manner. The subject was required central nervous system), (b) prior chemotherapy, and (c) to respond to two out of three stimuli before the distance was unsuitability as deemed by the researchers and/or the attend- recorded as the minimum separable distance between two points. ing physician. Support Care Cancer (2018) 26:2397–2405 2399 Fig. 1 Schedule of CIPN a FOLFOX therapy measurements baseline prior to the second drug cycle CIPN measurements 2 weeks FOLFOX therapy 2 weeks first chemothearapy second b CAPOX therapy baseline prior to the second drug cycle CIPN measurements 3weeks CAPOX therapy 3 weeks first chemothearapy second Evaluation of proprioceptive test The flexion and extension the preceding week. The DASH-DS is part of DASH, with 30 movements of the metacarpophalangeal (MP) joints of the items assessing: pain and subjective symptoms (5 items), the right and left index fingers were repeated ten times passively. degree of difficulty when performing various physical activi- A tenth and a half of normal range of motion (ROM) move- ties (21 items), and the effect of upper extremity dysfunction ment was repeated five times each. The subject was asked on social activities (1 item), on work and daily life (1 item), on whether his/her MP joints were being moved to the flexion sleep (1 item), and the psychological effect on self-image (1 or extension direction. The number of times the patient an- item). Each item is scored on a scale of 1 to 5, for a total score swered correctly was recorded as the proprioceptive acuity ranging from 0 to 100, calculated as per the DASH-DS scor- score. ing manual. Higher scores indicate higher severity. In this study, the total score was calculated from 29 items after ex- Evaluation of motor function cluding an item pertaining to sexual function. This informa- tion was not obtained since it is not pertinent to upper extrem- Manual dexterity test We used the Purdue Pegboard Test [36] ity function, and in addition, would be difficult for the elderly to evaluate manual dexterity. The number of pins a patient patient group to provide. could place in the holes of the relevant column using their dominant hand and their nondominant hand in 30 s was re- EORTC QLQ-C30 (version 3) The EORTC QLQ-C30 (version corded as a function of manual dexterity. 3) (QLQ-C30) is a 30-item patient self-administered question- naire assessing HRQoL [38], with a global health status/QOL Grip strength test The grip strength of both hands was mea- (global QOL) scale, 5 functional scales (physical functioning, sured using a Smedley-type digital hand dynamometer role functioning, emotional functioning, cognitive function- (TSUTSUMI) in the sitting and the elbow-extended positions. ing, and social functioning), and 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, Pinch strength test Pinch force between the index finger and constipation, diarrhea, and financial difficulties). The QOL thumb of both hands (i.e., pulp pinch strength) was measured. scores were calculated as per the EORTC Scoring Manual. During the pulp pinch strength measurement with a hydraulic Higher scores on the global QOL scale and the functional pinch gauge (North Coast), the subjects were seated upright scale indicate favorable conditions. Conversely, higher scores with the elbow flexed at a 90° angle. on the symptom scale indicate poor conditions. Subjective assessments Statistical analyses Subjective assessments of the ADL and HRQoL were per- formed using the Japanese Society for Surgery of the Hand Scores from the Purdue Pegboard Test, grip strength test, and (JSSH) version of the Disabilities of the Arm, Shoulder, and the pinch strength test were compared using paired t tests. Hand (DASH), and the European Organization for the Scores obtained from the Semmes-Weinstein monofilament Research and Treatment of Cancer Quality of Life test, m2PD test, DASH-DS, and the QLQ-C30 were com- Questionnaire C30 (EORTC QLQ-C30) version 3. pared using the Wilcoxon signed rank test. All statistical anal- yses were performed using the IBM SPSS, ver. 20 software The DASH disability/symptom (DASH-DS) [37] The DASH is a (International Business Machines Corporation, Armonk, NY). patient self-administered questionnaire to assess upper ex- A p value < 0.05 (two-tailed test) was considered statistically tremity dysfunction and relevant subjective symptoms during significant. 2400 Support Care Cancer (2018) 26:2397–2405 Results cycle due to malaise, pain, or other unfavorable health condi- tions. Thus, the sample size differed by time point. Forty-eight colorectal cancer patients scheduled to receive ini- tial FOLFOX/CAPOX therapy at the Kyoto University Evaluation of sensory function Hospital who provided informed consent and were enrolled between November 2012 and June 2014. Ten patients were Semmes-Weinstein monofilament test There was a significant excluded due to the following reasons: chemotherapy difference in the median SWMT readings for the right index discontinued during the assessment period (3), poor health finger at baseline (2.83 mg), and those prior to the second drug conditions (3), prior history of peripheral neuropathy or upper cycle (3.61 mg) (p = 0.000, Table 2(a)). Likewise, the median extremity disorders (2); difficulty in baseline assessment (1), reading for the left index finger at baseline was 2.83 mg, while and difficulty in assessment due to time constraints (1). Thirty- that prior to the second drug cycle was 2.83 mg, which were eight patients who satisfied study eligibility criteria were in- also significantly different (p =0.009). cluded in this study (Table 1). Moving two-point discrimination test There was no statisti- cally significant change between m2PD test values at baseline Patient characteristics and those prior to the second drug cycle (Table 2(b)). Thirty-eight patients (22 men, 16 women) were included in the study (median age 65 years; range 33–76 years). All pa- Proprioceptive test There was no statistically significant tients were right-handed and received either the FOLFOX change between proprioceptive test results at baseline and (n = 19) or the CAPOX therapy (n =19). those prior to the second drug cycle (Table 2(c)). Objective assessments Evaluation of motor function All patients provided data for all items at baseline. However, Manual dexterity test There was no significant change in one patient did not provide data for the manual dexterity, grip manual dexterity test values at baseline and those prior to strength, or the pinch strength tests prior to the second drug the second drug cycle (Table 3(a)). Table 1 Characteristics of study subjects Grip strength test There was no significant difference between mean values for the right hand at baseline (28.3 ± 9.2 kg) and Characteristics those prior to the second drug cycle (28.0 ± 8.7 kg). Likewise, Age (median, range) 65 (33–76) the mean value for the left hand at baseline was 26.6 ± 9.1 kg, while that prior to the second drug cycle was 26.2 ± 8.6 kg, N (%) and this change was not statistically significant (Table 3(b)). In addition, 36/37 patients (97.3%) had lower mean grip strength Gender Men 22 (57.9) at any time compared to that of age- and gender-matched Women 16 (42.1) individuals as per the FY2014 Survey on Physical Fitness Treatment Neoadjuvant 12 (31.6) and Motor Abilities conducted by the Ministry of Education, Adjuvant 15 (39.5) Culture, Sports, Science and Technology [39]. Palliative 11 (28.9) Regimen FOLFOX 19 (50.0) Pinch strength test No significant changes in pinch strength CAPOX 19 (50.0) test results were observed between the two time points Stage (initial diagnosis) I 1 (2.6) (Table 3(c)). II 5 (13.2) III 12 (31.6) Subjective assessments IV 20 (52.6) Location of tumor Ascending colon 8 (21.1) DASH-DS Transverse colon 7 (18.4) Descending colon 1 (2.6) The median DASH-DS score at baseline was 2.6, while that Sigmoid colon 11 (28.9) prior to the second drug cycle was 5.2, showing significant Rectum 9 (23.7) worsening of dysfunction and subjective symptoms (p = Cecum 1 (2.6) 0.007) (Table 4). There was a significant difference between Appendix 1 (2.6) median scores for pain and subjective symptoms at baseline Support Care Cancer (2018) 26:2397–2405 2401 Table 2 Assessment of sensory Baseline Prior to the second drug cycle function 25% Median 75% 25% Median 75% zp (a) Semmes-Weinstein monofilament test (mg) (N =38) Right hand 2.83 2.83 2.83 2.83 3.61 3.61 − 4.053 0.000* Left hand 2.83 2.83 3.32 2.83 2.83 3.61 − 2.619 0.009* (b) Moving two-point discrimination test (mm) (N =38) Right hand 2.00 3.00 3.00 2.00 3.00 3.00 − 0.229 0.819 Left hand 2.00 3.00 3.00 2.00 2.00 3.00 − 0.785 0.433 (c) Propriceptive test (trials) (N =38) Right hand 10.00 10.00 10.00 10.00 10.00 10.00 0.000 1.000 Left hand 10.00 10.00 10.00 10.00 10.00 10.00 0.000 1.000 Wilcoxon signed rank test, *p <0.05 (median score 5), and that prior to the second drug cycle Discussion (median score 6) (p =0.036). This study examined the changes in sensory dysfunction, manual dexterity, ADL, and HRQoL after the first chemother- QLQ-C30 apy drug cycle in colorectal cancer patients from both objec- tive and subjective points of view, by combining six assess- The scores for each QLQ-C30 scale were compared between ment tools on upper extremity function and two subjective baseline and prior to the second drug cycle (Table 5). There assessment tools on ADL and HRQoL. were no significant changes in the scores on the global health In this study, light touch sensation worsened after the first status/QOL scale. However, physical functioning (p =0.049) drug cycle, but neither m2PD nor proprioception showed clear and role functioning (p = 0.014) significantly worsened. worsening. The light touch sensation receptor is a slow-adapting However, emotional functioning improved significantly (p = mechanoreceptor that affects grip force adjustment ability such 0.003). Cognitive functioning and social functioning did not as while continuously holding an object without squashing or change significantly. Nausea and vomiting (p = 0.045) and dropping it. On the other hand, the m2PD receptor is a quick- dyspnea (p = 0.020) significantly worsened. There were no adapting mechanoreceptor that affects the identification of ma- significant changes in fatigue, pain, insomnia, appetite loss, terials and dexterity. Thus, our results imply that slow-adapting constipation, diarrhea, and financial difficulties. mechanoreceptors are more likely to be damaged than are quick- Table 3 Assessment of motor Baseline Prior to the second drug cycle function Mean SD Mean SD tp (a) Changes in the results of manual dexterity test (pins) (N =37) Right hand 14.22 2.213 14.38 1.861 − 0.589 0.560 Left hand 13.22 1.858 13.57 1.951 − 1.412 0.166 (b) Changes in the results of the grip strength test (kg) (N =37) Right hand 28.27 9.204 28.02 8.653 0.450 0.655 Left hand 26.61 9.098 26.24 8.602 0.744 0.462 (c) Changes in the results of the pinch strength test (N) (N =37) Right hand 33.54 16.77 32.65 15.46 0.550 0.586 Left hand 30.80 15.75 29.51 15.01 0.736 0.467 Paired t tests, *p < 0.05 2402 Support Care Cancer (2018) 26:2397–2405 Table 4 The results of the Baseline Prior to the second drug cycle DASH-DS (N =38) 25% Median 75% 25% Median 75% zp DASH-DS 0.0 2.6 8.8 2.4 5.2 13.1 − 2.708 0.007* Subjective symptoms 5.0 5.0 6.0 5.0 6.0 8.0 − 2.094 0.036* Difficulty of ADL 20.0 23.0 29.3 21.0 25.0 32.3 − 1.806 0.071 Influence on social Activity 1.0 1.0 1.0 1.0 1.0 1.0 − 0.378 0.705 Influence on job 1.0 1.0 1.0 1.0 1.0 1.0 − 1.633 0.102 Influence on sleep 1.0 1.0 1.0 1.0 1.0 1.0 − 1.000 0.317 Psychological influence 1.0 1.0 1.0 1.0 1.0 2.0 − 1.620 0.105 Wilcoxon signed rank test, *p <0.05 DASH-DS (range 0-100 points), pain and subjective symptoms (range 5-25 points), the degree of difficulty when performing various physical activities (range 20-100 points), the effect of upper extremity problem on social activities (range 1-5 points), work and daily life (range 1-5 points), sleep (range 1-5 points), and the psychological effect on self-image (range 1-5 points)Higher scores indicate higher severity adapting mechanoreceptors, during low total dose of chemother- study. However, studies suggest that sensory ataxia may occur apy. Thus, manual dexterity, dependent on quick-adapting as symptoms become severe [1]. Thus, as the total L-OHP dose mechanoreceptors did not worsen, while light touch sensation, increases, both the slow and the quick-adapting mechanorecep- a function of slow-adapting mechanoreceptors worsened, in our tors may be damaged. Therefore, continuous assessments of sensory function and manual dexterity are indicated. The signif- Table 5 The results of the QLQ-C30 (version 3) (N =38) icant change in the SWMT median for the right hand (2.83 vs. 3.61 mg) suggests clinically relevant dysfunction because the Baseline Prior to the perception level changes from Bnormal^ to Bdiminished light second drug cycle touch.^ However, the median left hand scores at baseline and at follow-up were similar, implying absence of clinically rele- Mean SD Mean SD zp vant dysfunction. The 75th percentile of SWMT scores before Global QOL 64.0 24.2 63.2 22.1 − 0.657 0.511 the second course of chemotherapy was 3.61 mg. These results Functional scales indicate that an increase in patients with diminished light touch in the left hand as well. We cannot ascertain if this left hand Physical functioning 91.6 12.8 86.8 13.6 − 1.969 0.049* dysfunction is clinically relevant based on these results alone, so Role functioning 91.7 19.3 83.8 21.4 − 2.451 0.014* there is a need to investigate the correlation between these results Emotional functioning 79.6 18.6 87.2 16.8 − 2.937 0.003* and everyday life as a topic for future research. Cognitive functioning 85.1 13.9 85.5 13.5 − 0.334 0.739 L-OHP-induced peripheral neuropathy symptoms are not Social functioning 79.4 25.2 78.9 24.4 − 0.245 0.807 considered to be due to motor neuropathy [40]. This is Symptom scales/items consistent with the findings of this study which indicated that Fatigue 23.4 21.1 26.9 21.9 − 0.950 0.342 motor function did not worsen after one cycle of chemother- Nausea/vomiting 1.8 5.2 5.7 12.4 − 2.008 0.045* apy. On the other hand, the mean grip strength test score in Pain 11.4 19.8 8.8 13.3 − 0.634 0.526 97.3% of patients was lower than that in age- and gender- Dyspnea 7.9 14.4 15.8 21.6 − 2.324 0.020* matched subjects according to the FY2014 Survey on Insomnia 14.0 18.4 14.0 26.4 − 0.675 0.500 Physical Fitness and Motor Abilities [39], suggesting a lower Appetite loss 13.2 22.6 14.9 25.3 − 0.472 0.637 muscle strength in colorectal cancer patients receiving chemo- Constipation 9.6 15.3 12.3 18.0 − 0.728 0.467 therapy. There were 12 patients receiving neoadjuvant therapy Diarrhea 20.2 23.9 18.4 22.9 − 0.843 0.399 (31.6%), 15 patients receiving adjuvant therapy (39.5%), and Financial difficulties 19.3 25.3 18.4 25.3 − 1.040 0.298 11 patients receiving palliative therapy (28.9%) in this study. Wilcoxon signed rank test, *p <0.05 In 52.6% of patients with advanced stage IV disease with Global QoL and the functional scale (physical functioning, role function- distant metastasis, there was a risk of reduced physical ing, emotional functioning, cognitive functioning, and social function- function due to disease progression in addition to that due to ing): Higher scores indicate better conditions. Symptom scale (fatigue, chemotherapy side effects. Because this study examined nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, changes in chronic sensory dysfunction, manual dexterity, diarrhea, and financial difficulties): Higher scores indicate poor conditions ADL, and HRQoL after the first chemotherapy cycle, Support Care Cancer (2018) 26:2397–2405 2403 objective assessment tools specialized for upper extremity study, these results cannot be compared with previously pub- function were selected. While we were unable to objectively lished results. Previous studies [42] have not reported worsen- evaluate the possible effect of deterioration of general patient ing of physical functioning or role functioning after the first condition on test results, it is unlikely that disease progression cycle of chemotherapy. Thus, worsening of physical and role or rapid deterioration of the general condition of patients had functioning may be due to changes in HRQoL at the early an effect on test scores because: only patients receiving che- stages of chemotherapy. Role functioning tools assess the de- motherapy for the first time were studied; included patients gree of difficulty in work, daily life, hobbies, and leisure but were deemed testable by a doctor; the second evaluation time cannot address specific areas of difficulty. So, in the rehabilita- point was 2–3 weeks after the first (thus still being in the initial tion of cancer patients, identifying specific areas of difficulty stage of chemotherapy); and data from patients who were and offering individualized support may be important. unable to be evaluated a second time were not included in this Although 48 colorectal cancer patients were initially en- study. However, DASH-DS and QLQ-C30 used to assess rolled in this study, ten withdrew due to poor physical condi- ADL and HRQoL are not specialized for the assessment of tion, and 38 patients were included in the final analysis. CIPN symptoms, and reduced physical function can affect the Accordingly, the results of this study are based on patients scores, so these results need to be interpreted with caution. with relatively good systemic conditions, and hence, caution The objective assessment results did not reveal worsening is required while interpreting the results. In addition, in this of upper extremity function, except in the case of light touch study, the results show worsening of light touch sensation and sensation. This implied that no causative dysfunction was de- subjective symptoms, and changes in scores on the symptom tected after the first drug cycle, which might affect ADL. On scale and the functional scale. The objective of this study was the other hand, DASH-DS, a subjective assessment tool, to determine changes in upper limb function, ADL, and showed dysfunction and worsening of subjective symptoms HRQoL after initiating chemotherapy, when the total after the first drug cycle. Thus, the standard clinical assessment oxaliplatin dose is still low. It is difficult to determine the tools for upper extremity function showed that chemotherapy long-term prognosis based on this time results alone. While can adversely affect daily life activities and cause worsening of there are functional changes during the initial stage of chemo- subjective symptoms in cancer patients receiving chemothera- therapy, it is not clear how this is related to long-term func- py even at a stage where compromised muscle strength or tional disability. This topic will be included in our future re- upper extremity dysfunction are not likely. This indicates that search. A possible limitation of the study is that, since multiple it is necessary to support cancer patients on chemotherapy statistical comparisons were made with a small sample size, a from the most initial stages, even in the absence of any appar- family-wise error (type I error) may have occurred. It is im- ent dysfunction. It is important to note that, to provide individ- portant to conduct additional large-scale and long-term studies in the future to verify the reliability of this finding. ualized support while accommodating unique symptoms and backgrounds during treatment, care should be taken even dur- ing the initial stages of treatment. Additionally, patients may have decreased sensory perception post-chemotherapy initia- Conclusions tion, so it is also necessary to focus on patient education and providing guidance for daily living, early on. Our results suggested that light touch sensation may worsen According to the EORTC QLQ-C30 scoring manual [41], after the first drug cycle even during low total dose chemo- patients who reported Ba little^ change for better or worse on a therapy. In addition, m2PD and proprioception were main- particular scale (function or symptom) had QLQ-C30 changes tained, and dysfunction that can affect ADL such as reduced of about 5 to 10. The changes in means for role functioning, manual dexterity did not occur. However, our results also emotional functioning, and dyspnea suggest minimal changes showed that L-OHP may cause worsening of ADL and clinically. The QLQ-C30 assessment revealed that emotional HRQoL in patient-subjective assessments. Our results imply functioning significantly improved while physical functioning that it is necessary to support cancer patients on chemotherapy and role functioning significantly worsened after the first drug from the most initial stages, even in absence of any apparent cycle. According to a HRQoL study conducted 1 year post- dysfunction. surgery in colorectal cancer patients who did not undergo che- motherapy, emotional functioning significantly improved Acknowledgements We deeply appreciate patients at Kyoto University 2 months post-surgery, compared with that pre-surgery [42]. Hospital for their contribution to this study. We would like to thank Editage (www.editage.jp) for English language editing. These results are consistent with the findings of the present Funding information This work was partially supported by the study which showed improved emotional functioning after Promotion Plan for the Platform of Human Resource Development for the first drug cycle. However, since patients on post-operative Cancer administered by the Ministry of Education, Culture, Sports, adjuvant therapy as well as those on pre-operative neoadjuvant Science and Technology in Japan (grant no. 12 to TT). The funder did therapy or mitigation therapy were included in the current not have a role in the study design; collection, analysis, or interpretation 2404 Support Care Cancer (2018) 26:2397–2405 of the data; the writing of the report; or the decision to submit the article 12. Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, for publication. Kalofonos HP (2008) A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev 34(4):368–377. https://doi.org/10. 1016/j.ctrv.2008.01.003 Compliance with ethical standards 13. Beijers AJ, Jongen JL, Vreugdenhil G (2012) Chemotherapy- induced neurotoxicity: the value of neuroprotective strategies. 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Kaneko A, Asai N, Kanda T (2005) The influence of age on pres- sure perception of static and moving two-point discrimination in http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Supportive Care in Cancer Springer Journals

Changes in upper extremity function, ADL, and HRQoL in colorectal cancer patients after the first chemotherapy cycle with oxaliplatin: a prospective single-center observational study

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Medicine & Public Health; Oncology; Nursing; Nursing Research; Pain Medicine; Rehabilitation Medicine
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Abstract

Purpose Oxaliplatin, an important chemotherapeutic agent in colorectal cancer, causes chemotherapy-induced peripheral neurop- athy (CIPN), for which prophylactic or therapeutic interventions are lacking. We aimed to investigate changes in upper extremities, activities of daily living (ADL), and health-related quality of life (HRQoL) parameters after the first chemotherapy cycle. Methods Thirty-eight colorectal cancer patients scheduled to receive the leucovorin, 5′-fluorouracil, oxaliplatin (FOLFOX) therapy or the capecitabine, oxaliplatin (CAPOX) therapy, participated. Patients underwent objective assessment of sensory function, mus- cular strength, and manual dexterity and answered the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and the Disabilities of the Arm, Shoulder, and Hand-Disability/Symptom (DASH-DS) questionnaires for subjective assessment. The CIPN was assessed at baseline and prior to the second drug cycle. Results Light touch sensation in both hands worsened significantly after the first drug cycle, though no significant changes were observed in muscular strength and manual dexterity. The QLQ-C30 analysis showed that Physical Functioning, Role Functioning, Nausea and Vomiting, and Dyspnea were significantly worse, whereas Emotional Functioning was improved. The DASH-DS analysis revealed significant worsening of dysfunction and subjective symptoms. Conclusions Our results suggest that light touch sensation may worsen even in the absence of multiple chemotherapy cycles. Even if arm and hand function (muscular strength and manual dexterity) is apparently intact, patients may experience dysfunction and decreased HRQoL. For preserving or improving patients’ ADL and HRQoL, it is imperative to provide support at chemo- therapy initiation. . . . Keywords Chemotherapy-induced peripheral neuropathy (CIPN) Upper extremity function Activities of daily living (ADL) . . Health-related quality of life (HRQoL) Oxaliplatin (L-OHP) Colorectal cancer Introduction However, chemotherapy side effects may decrease patient health-related quality of life (HRQoL), with serious clinical The recent development of multidisciplinary therapy has led implications, such as the need for dose reduction, treatment to improved survival and reduced relapse in cancer patients. delays, or treatment discontinuation [1]. Oxaliplatin (L-OHP), an important chemotherapeutic agent in colorectal cancer, causes acute and chronic chemotherapy- induced peripheral neuropathy (CIPN). Chronic CIPN leads to * Ami Tabata dose-limiting toxicity [2, 3], and a cumulative dose ≥ 540– fuguku@kuhp.kyoto-u.ac.jp 850 mg/m increases risk of subjective symptoms such as numbness, and that of functional disorders which may affect Department of Human Health Sciences, Graduate School of patient activities of daily living (ADL) [2–6]. Patients often Medicine, Kyoto University, 53, Kawahara-cho, Syogoin, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan experience CIPN symptoms in their fingers [7], which can interfere with ADL and HRQoL [8–11]. However, there is Rehabilitation Unit, Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan no standardized effective therapy for prevention and treatment of CIPN [12–18]. Commonly used measures of CIPN include Kyoto University Hospital, 54, Kawahara-cyo, Syogoin, Sakyo-ku, Kyoto City, Kyoto 606-8507, Japan the National Cancer Institute Common Terminology Criteria 2398 Support Care Cancer (2018) 26:2397–2405 (NCI-CTCAE) v4.0, and physician-based instruments [19]. Procedures However, CIPN symptoms are largely subjective, and the lack of a universally recognized standard for quantifying CIPN The CIPN measurements were collected before initiation of symptoms [17, 20–22] makes it difficult to capture changes the first chemotherapy cycle (baseline) and again before start in sensory function, ADL, and HRQoL, in detail [23–25]. of the second drug cycle, to investigate changes in chronic Chronic platinum-induced neuropathy is believed to manifest sensory neuropathy, manual dexterity, ADL, and HRQoL after as secondary axonal degeneration or axonal damage accom- the first chemotherapy cycle. Following that, CIPN measure- panying dorsal root ganglion neuronopathy [26–28]. ments were collected 2 or 3 weeks after baseline just before Although L-OHP-induced neuropathy is sensory rather than the second drug cycle depending on the regimen, because motor in nature, the intensity of dysfunction can impair phys- FOLFOX therapy was administered every 2 weeks and ical functions, resulting in symptoms such as sensory ataxia CAPOX therapy was administered every 3 weeks (Fig. 1). [1]. The negative influence of CIPN on upper extremity Measures function, ADL, and HRQoL can be detected only in advanced stages of dysfunction. Once CIPN symptoms Objective assessments occur, they usually persist for a year or more after treat- ment termination [29–31]. In severe cases, sensory Sensory evaluation was performed by light touch sensation, nerve fiber damage may become irreversible [16]. moving two-point discrimination (m2PD), and proprioceptive Therefore, it is important that interventions or self-care sensation assessments. Motor function was evaluated by man- strategies are offered to patients prior to the appearance ual dexterity, grip strength, and pinch strength tests. of obvious CIPN symptoms. We aimed to investigate changes in chronic sensory Evaluation of sensory function neuropathy, manual dexterity, ADL, and HRQoL after the first cycle of L-OHP-based chemotherapy in Evaluation of light touch sensation We employed the widely colorectal cancer patients who were scheduled to receive used Semmes-Weinstein monofilament test (SWMT) (2.83, initial chemotherapy. We focused on the period after the 3.22, 3.61, 4.31, 4.56, and 6.65 mg monofilaments) first chemotherapy cycle when CIPN symptoms were (Aesthesio®, Precise Tactile Sensory Evaluator), to evaluate expected to be milder, rather than during the period light touch sensation [32]. The evaluation was conducted ac- when the cumulative L-OHP dose was 540–850 mg/m cording to the operation manual [33] by an experienced occu- or higher, when functional disorders caused by chronic pational therapist. The testing procedure was explained to the CIPN are likely to appear. patients, and they were instructed to respond verbally by say- ing Btouch^ or Byes^ when a stimulus was felt. Subsequently, in a quiet area conducive to minimize distractions, two evalu- ations were performed under similar conditions. Light touch Methods sensation was assessed in the right and left index finger pad (a half beyond the distal interphalangeal joint). Perception levels Study design and participants were interpreted based on the monofilament labels as follows: 2.83 (normal), 3.22 or 3.61 (diminished light touch), 4.31 We conducted a prospective single-center observational study, (diminished protective sensation), 4.56 or 6.65 (loss of pro- approved by the Kyoto University Graduate School and tective sensation), and 6.65 undetected (nonmeasurable). Faculty of Medicine, Ethics Committee (E1571). Colorectal cancer patients scheduled to receive initial chemotherapy with Moving two-point discrimination test [34, 35] Pressure per- the leucovorin, 5′-fluorouracil, oxaliplatin (FOLFOX) or the ception of right and left index fingers was evaluated using a capecitabine, oxaliplatin (CAPOX) therapy at the Kyoto two-point discriminator. One or two points of the discrimina- University Hospital were surveyed. tor were vertically pressed onto the long axis of the finger pad Study eligibility criteria included (a) diagnosis of colorectal until it bent slightly, were held for about 2 s, and then slowly cancer, (b) scheduled FOLFOX or CAPOX therapy, (c) ability moved distally to the fingertip. The subject was asked whether to fill a questionnaire, and (d) written informed consent pro- he/she was being touched at one point or at two points. Testing vided. Study exclusion criteria were (a) pre-existing neuro- began with 5-mm spacing between discriminator tips, which pathic disease (peripheral neuropathy and/or a disease of the was narrowed in a stepwise manner. The subject was required central nervous system), (b) prior chemotherapy, and (c) to respond to two out of three stimuli before the distance was unsuitability as deemed by the researchers and/or the attend- recorded as the minimum separable distance between two points. ing physician. Support Care Cancer (2018) 26:2397–2405 2399 Fig. 1 Schedule of CIPN a FOLFOX therapy measurements baseline prior to the second drug cycle CIPN measurements 2 weeks FOLFOX therapy 2 weeks first chemothearapy second b CAPOX therapy baseline prior to the second drug cycle CIPN measurements 3weeks CAPOX therapy 3 weeks first chemothearapy second Evaluation of proprioceptive test The flexion and extension the preceding week. The DASH-DS is part of DASH, with 30 movements of the metacarpophalangeal (MP) joints of the items assessing: pain and subjective symptoms (5 items), the right and left index fingers were repeated ten times passively. degree of difficulty when performing various physical activi- A tenth and a half of normal range of motion (ROM) move- ties (21 items), and the effect of upper extremity dysfunction ment was repeated five times each. The subject was asked on social activities (1 item), on work and daily life (1 item), on whether his/her MP joints were being moved to the flexion sleep (1 item), and the psychological effect on self-image (1 or extension direction. The number of times the patient an- item). Each item is scored on a scale of 1 to 5, for a total score swered correctly was recorded as the proprioceptive acuity ranging from 0 to 100, calculated as per the DASH-DS scor- score. ing manual. Higher scores indicate higher severity. In this study, the total score was calculated from 29 items after ex- Evaluation of motor function cluding an item pertaining to sexual function. This informa- tion was not obtained since it is not pertinent to upper extrem- Manual dexterity test We used the Purdue Pegboard Test [36] ity function, and in addition, would be difficult for the elderly to evaluate manual dexterity. The number of pins a patient patient group to provide. could place in the holes of the relevant column using their dominant hand and their nondominant hand in 30 s was re- EORTC QLQ-C30 (version 3) The EORTC QLQ-C30 (version corded as a function of manual dexterity. 3) (QLQ-C30) is a 30-item patient self-administered question- naire assessing HRQoL [38], with a global health status/QOL Grip strength test The grip strength of both hands was mea- (global QOL) scale, 5 functional scales (physical functioning, sured using a Smedley-type digital hand dynamometer role functioning, emotional functioning, cognitive function- (TSUTSUMI) in the sitting and the elbow-extended positions. ing, and social functioning), and 9 symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, Pinch strength test Pinch force between the index finger and constipation, diarrhea, and financial difficulties). The QOL thumb of both hands (i.e., pulp pinch strength) was measured. scores were calculated as per the EORTC Scoring Manual. During the pulp pinch strength measurement with a hydraulic Higher scores on the global QOL scale and the functional pinch gauge (North Coast), the subjects were seated upright scale indicate favorable conditions. Conversely, higher scores with the elbow flexed at a 90° angle. on the symptom scale indicate poor conditions. Subjective assessments Statistical analyses Subjective assessments of the ADL and HRQoL were per- formed using the Japanese Society for Surgery of the Hand Scores from the Purdue Pegboard Test, grip strength test, and (JSSH) version of the Disabilities of the Arm, Shoulder, and the pinch strength test were compared using paired t tests. Hand (DASH), and the European Organization for the Scores obtained from the Semmes-Weinstein monofilament Research and Treatment of Cancer Quality of Life test, m2PD test, DASH-DS, and the QLQ-C30 were com- Questionnaire C30 (EORTC QLQ-C30) version 3. pared using the Wilcoxon signed rank test. All statistical anal- yses were performed using the IBM SPSS, ver. 20 software The DASH disability/symptom (DASH-DS) [37] The DASH is a (International Business Machines Corporation, Armonk, NY). patient self-administered questionnaire to assess upper ex- A p value < 0.05 (two-tailed test) was considered statistically tremity dysfunction and relevant subjective symptoms during significant. 2400 Support Care Cancer (2018) 26:2397–2405 Results cycle due to malaise, pain, or other unfavorable health condi- tions. Thus, the sample size differed by time point. Forty-eight colorectal cancer patients scheduled to receive ini- tial FOLFOX/CAPOX therapy at the Kyoto University Evaluation of sensory function Hospital who provided informed consent and were enrolled between November 2012 and June 2014. Ten patients were Semmes-Weinstein monofilament test There was a significant excluded due to the following reasons: chemotherapy difference in the median SWMT readings for the right index discontinued during the assessment period (3), poor health finger at baseline (2.83 mg), and those prior to the second drug conditions (3), prior history of peripheral neuropathy or upper cycle (3.61 mg) (p = 0.000, Table 2(a)). Likewise, the median extremity disorders (2); difficulty in baseline assessment (1), reading for the left index finger at baseline was 2.83 mg, while and difficulty in assessment due to time constraints (1). Thirty- that prior to the second drug cycle was 2.83 mg, which were eight patients who satisfied study eligibility criteria were in- also significantly different (p =0.009). cluded in this study (Table 1). Moving two-point discrimination test There was no statisti- cally significant change between m2PD test values at baseline Patient characteristics and those prior to the second drug cycle (Table 2(b)). Thirty-eight patients (22 men, 16 women) were included in the study (median age 65 years; range 33–76 years). All pa- Proprioceptive test There was no statistically significant tients were right-handed and received either the FOLFOX change between proprioceptive test results at baseline and (n = 19) or the CAPOX therapy (n =19). those prior to the second drug cycle (Table 2(c)). Objective assessments Evaluation of motor function All patients provided data for all items at baseline. However, Manual dexterity test There was no significant change in one patient did not provide data for the manual dexterity, grip manual dexterity test values at baseline and those prior to strength, or the pinch strength tests prior to the second drug the second drug cycle (Table 3(a)). Table 1 Characteristics of study subjects Grip strength test There was no significant difference between mean values for the right hand at baseline (28.3 ± 9.2 kg) and Characteristics those prior to the second drug cycle (28.0 ± 8.7 kg). Likewise, Age (median, range) 65 (33–76) the mean value for the left hand at baseline was 26.6 ± 9.1 kg, while that prior to the second drug cycle was 26.2 ± 8.6 kg, N (%) and this change was not statistically significant (Table 3(b)). In addition, 36/37 patients (97.3%) had lower mean grip strength Gender Men 22 (57.9) at any time compared to that of age- and gender-matched Women 16 (42.1) individuals as per the FY2014 Survey on Physical Fitness Treatment Neoadjuvant 12 (31.6) and Motor Abilities conducted by the Ministry of Education, Adjuvant 15 (39.5) Culture, Sports, Science and Technology [39]. Palliative 11 (28.9) Regimen FOLFOX 19 (50.0) Pinch strength test No significant changes in pinch strength CAPOX 19 (50.0) test results were observed between the two time points Stage (initial diagnosis) I 1 (2.6) (Table 3(c)). II 5 (13.2) III 12 (31.6) Subjective assessments IV 20 (52.6) Location of tumor Ascending colon 8 (21.1) DASH-DS Transverse colon 7 (18.4) Descending colon 1 (2.6) The median DASH-DS score at baseline was 2.6, while that Sigmoid colon 11 (28.9) prior to the second drug cycle was 5.2, showing significant Rectum 9 (23.7) worsening of dysfunction and subjective symptoms (p = Cecum 1 (2.6) 0.007) (Table 4). There was a significant difference between Appendix 1 (2.6) median scores for pain and subjective symptoms at baseline Support Care Cancer (2018) 26:2397–2405 2401 Table 2 Assessment of sensory Baseline Prior to the second drug cycle function 25% Median 75% 25% Median 75% zp (a) Semmes-Weinstein monofilament test (mg) (N =38) Right hand 2.83 2.83 2.83 2.83 3.61 3.61 − 4.053 0.000* Left hand 2.83 2.83 3.32 2.83 2.83 3.61 − 2.619 0.009* (b) Moving two-point discrimination test (mm) (N =38) Right hand 2.00 3.00 3.00 2.00 3.00 3.00 − 0.229 0.819 Left hand 2.00 3.00 3.00 2.00 2.00 3.00 − 0.785 0.433 (c) Propriceptive test (trials) (N =38) Right hand 10.00 10.00 10.00 10.00 10.00 10.00 0.000 1.000 Left hand 10.00 10.00 10.00 10.00 10.00 10.00 0.000 1.000 Wilcoxon signed rank test, *p <0.05 (median score 5), and that prior to the second drug cycle Discussion (median score 6) (p =0.036). This study examined the changes in sensory dysfunction, manual dexterity, ADL, and HRQoL after the first chemother- QLQ-C30 apy drug cycle in colorectal cancer patients from both objec- tive and subjective points of view, by combining six assess- The scores for each QLQ-C30 scale were compared between ment tools on upper extremity function and two subjective baseline and prior to the second drug cycle (Table 5). There assessment tools on ADL and HRQoL. were no significant changes in the scores on the global health In this study, light touch sensation worsened after the first status/QOL scale. However, physical functioning (p =0.049) drug cycle, but neither m2PD nor proprioception showed clear and role functioning (p = 0.014) significantly worsened. worsening. The light touch sensation receptor is a slow-adapting However, emotional functioning improved significantly (p = mechanoreceptor that affects grip force adjustment ability such 0.003). Cognitive functioning and social functioning did not as while continuously holding an object without squashing or change significantly. Nausea and vomiting (p = 0.045) and dropping it. On the other hand, the m2PD receptor is a quick- dyspnea (p = 0.020) significantly worsened. There were no adapting mechanoreceptor that affects the identification of ma- significant changes in fatigue, pain, insomnia, appetite loss, terials and dexterity. Thus, our results imply that slow-adapting constipation, diarrhea, and financial difficulties. mechanoreceptors are more likely to be damaged than are quick- Table 3 Assessment of motor Baseline Prior to the second drug cycle function Mean SD Mean SD tp (a) Changes in the results of manual dexterity test (pins) (N =37) Right hand 14.22 2.213 14.38 1.861 − 0.589 0.560 Left hand 13.22 1.858 13.57 1.951 − 1.412 0.166 (b) Changes in the results of the grip strength test (kg) (N =37) Right hand 28.27 9.204 28.02 8.653 0.450 0.655 Left hand 26.61 9.098 26.24 8.602 0.744 0.462 (c) Changes in the results of the pinch strength test (N) (N =37) Right hand 33.54 16.77 32.65 15.46 0.550 0.586 Left hand 30.80 15.75 29.51 15.01 0.736 0.467 Paired t tests, *p < 0.05 2402 Support Care Cancer (2018) 26:2397–2405 Table 4 The results of the Baseline Prior to the second drug cycle DASH-DS (N =38) 25% Median 75% 25% Median 75% zp DASH-DS 0.0 2.6 8.8 2.4 5.2 13.1 − 2.708 0.007* Subjective symptoms 5.0 5.0 6.0 5.0 6.0 8.0 − 2.094 0.036* Difficulty of ADL 20.0 23.0 29.3 21.0 25.0 32.3 − 1.806 0.071 Influence on social Activity 1.0 1.0 1.0 1.0 1.0 1.0 − 0.378 0.705 Influence on job 1.0 1.0 1.0 1.0 1.0 1.0 − 1.633 0.102 Influence on sleep 1.0 1.0 1.0 1.0 1.0 1.0 − 1.000 0.317 Psychological influence 1.0 1.0 1.0 1.0 1.0 2.0 − 1.620 0.105 Wilcoxon signed rank test, *p <0.05 DASH-DS (range 0-100 points), pain and subjective symptoms (range 5-25 points), the degree of difficulty when performing various physical activities (range 20-100 points), the effect of upper extremity problem on social activities (range 1-5 points), work and daily life (range 1-5 points), sleep (range 1-5 points), and the psychological effect on self-image (range 1-5 points)Higher scores indicate higher severity adapting mechanoreceptors, during low total dose of chemother- study. However, studies suggest that sensory ataxia may occur apy. Thus, manual dexterity, dependent on quick-adapting as symptoms become severe [1]. Thus, as the total L-OHP dose mechanoreceptors did not worsen, while light touch sensation, increases, both the slow and the quick-adapting mechanorecep- a function of slow-adapting mechanoreceptors worsened, in our tors may be damaged. Therefore, continuous assessments of sensory function and manual dexterity are indicated. The signif- Table 5 The results of the QLQ-C30 (version 3) (N =38) icant change in the SWMT median for the right hand (2.83 vs. 3.61 mg) suggests clinically relevant dysfunction because the Baseline Prior to the perception level changes from Bnormal^ to Bdiminished light second drug cycle touch.^ However, the median left hand scores at baseline and at follow-up were similar, implying absence of clinically rele- Mean SD Mean SD zp vant dysfunction. The 75th percentile of SWMT scores before Global QOL 64.0 24.2 63.2 22.1 − 0.657 0.511 the second course of chemotherapy was 3.61 mg. These results Functional scales indicate that an increase in patients with diminished light touch in the left hand as well. We cannot ascertain if this left hand Physical functioning 91.6 12.8 86.8 13.6 − 1.969 0.049* dysfunction is clinically relevant based on these results alone, so Role functioning 91.7 19.3 83.8 21.4 − 2.451 0.014* there is a need to investigate the correlation between these results Emotional functioning 79.6 18.6 87.2 16.8 − 2.937 0.003* and everyday life as a topic for future research. Cognitive functioning 85.1 13.9 85.5 13.5 − 0.334 0.739 L-OHP-induced peripheral neuropathy symptoms are not Social functioning 79.4 25.2 78.9 24.4 − 0.245 0.807 considered to be due to motor neuropathy [40]. This is Symptom scales/items consistent with the findings of this study which indicated that Fatigue 23.4 21.1 26.9 21.9 − 0.950 0.342 motor function did not worsen after one cycle of chemother- Nausea/vomiting 1.8 5.2 5.7 12.4 − 2.008 0.045* apy. On the other hand, the mean grip strength test score in Pain 11.4 19.8 8.8 13.3 − 0.634 0.526 97.3% of patients was lower than that in age- and gender- Dyspnea 7.9 14.4 15.8 21.6 − 2.324 0.020* matched subjects according to the FY2014 Survey on Insomnia 14.0 18.4 14.0 26.4 − 0.675 0.500 Physical Fitness and Motor Abilities [39], suggesting a lower Appetite loss 13.2 22.6 14.9 25.3 − 0.472 0.637 muscle strength in colorectal cancer patients receiving chemo- Constipation 9.6 15.3 12.3 18.0 − 0.728 0.467 therapy. There were 12 patients receiving neoadjuvant therapy Diarrhea 20.2 23.9 18.4 22.9 − 0.843 0.399 (31.6%), 15 patients receiving adjuvant therapy (39.5%), and Financial difficulties 19.3 25.3 18.4 25.3 − 1.040 0.298 11 patients receiving palliative therapy (28.9%) in this study. Wilcoxon signed rank test, *p <0.05 In 52.6% of patients with advanced stage IV disease with Global QoL and the functional scale (physical functioning, role function- distant metastasis, there was a risk of reduced physical ing, emotional functioning, cognitive functioning, and social function- function due to disease progression in addition to that due to ing): Higher scores indicate better conditions. Symptom scale (fatigue, chemotherapy side effects. Because this study examined nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, changes in chronic sensory dysfunction, manual dexterity, diarrhea, and financial difficulties): Higher scores indicate poor conditions ADL, and HRQoL after the first chemotherapy cycle, Support Care Cancer (2018) 26:2397–2405 2403 objective assessment tools specialized for upper extremity study, these results cannot be compared with previously pub- function were selected. While we were unable to objectively lished results. Previous studies [42] have not reported worsen- evaluate the possible effect of deterioration of general patient ing of physical functioning or role functioning after the first condition on test results, it is unlikely that disease progression cycle of chemotherapy. Thus, worsening of physical and role or rapid deterioration of the general condition of patients had functioning may be due to changes in HRQoL at the early an effect on test scores because: only patients receiving che- stages of chemotherapy. Role functioning tools assess the de- motherapy for the first time were studied; included patients gree of difficulty in work, daily life, hobbies, and leisure but were deemed testable by a doctor; the second evaluation time cannot address specific areas of difficulty. So, in the rehabilita- point was 2–3 weeks after the first (thus still being in the initial tion of cancer patients, identifying specific areas of difficulty stage of chemotherapy); and data from patients who were and offering individualized support may be important. unable to be evaluated a second time were not included in this Although 48 colorectal cancer patients were initially en- study. However, DASH-DS and QLQ-C30 used to assess rolled in this study, ten withdrew due to poor physical condi- ADL and HRQoL are not specialized for the assessment of tion, and 38 patients were included in the final analysis. CIPN symptoms, and reduced physical function can affect the Accordingly, the results of this study are based on patients scores, so these results need to be interpreted with caution. with relatively good systemic conditions, and hence, caution The objective assessment results did not reveal worsening is required while interpreting the results. In addition, in this of upper extremity function, except in the case of light touch study, the results show worsening of light touch sensation and sensation. This implied that no causative dysfunction was de- subjective symptoms, and changes in scores on the symptom tected after the first drug cycle, which might affect ADL. On scale and the functional scale. The objective of this study was the other hand, DASH-DS, a subjective assessment tool, to determine changes in upper limb function, ADL, and showed dysfunction and worsening of subjective symptoms HRQoL after initiating chemotherapy, when the total after the first drug cycle. Thus, the standard clinical assessment oxaliplatin dose is still low. It is difficult to determine the tools for upper extremity function showed that chemotherapy long-term prognosis based on this time results alone. While can adversely affect daily life activities and cause worsening of there are functional changes during the initial stage of chemo- subjective symptoms in cancer patients receiving chemothera- therapy, it is not clear how this is related to long-term func- py even at a stage where compromised muscle strength or tional disability. This topic will be included in our future re- upper extremity dysfunction are not likely. This indicates that search. A possible limitation of the study is that, since multiple it is necessary to support cancer patients on chemotherapy statistical comparisons were made with a small sample size, a from the most initial stages, even in the absence of any appar- family-wise error (type I error) may have occurred. It is im- ent dysfunction. It is important to note that, to provide individ- portant to conduct additional large-scale and long-term studies in the future to verify the reliability of this finding. ualized support while accommodating unique symptoms and backgrounds during treatment, care should be taken even dur- ing the initial stages of treatment. Additionally, patients may have decreased sensory perception post-chemotherapy initia- Conclusions tion, so it is also necessary to focus on patient education and providing guidance for daily living, early on. Our results suggested that light touch sensation may worsen According to the EORTC QLQ-C30 scoring manual [41], after the first drug cycle even during low total dose chemo- patients who reported Ba little^ change for better or worse on a therapy. In addition, m2PD and proprioception were main- particular scale (function or symptom) had QLQ-C30 changes tained, and dysfunction that can affect ADL such as reduced of about 5 to 10. The changes in means for role functioning, manual dexterity did not occur. However, our results also emotional functioning, and dyspnea suggest minimal changes showed that L-OHP may cause worsening of ADL and clinically. The QLQ-C30 assessment revealed that emotional HRQoL in patient-subjective assessments. Our results imply functioning significantly improved while physical functioning that it is necessary to support cancer patients on chemotherapy and role functioning significantly worsened after the first drug from the most initial stages, even in absence of any apparent cycle. According to a HRQoL study conducted 1 year post- dysfunction. surgery in colorectal cancer patients who did not undergo che- motherapy, emotional functioning significantly improved Acknowledgements We deeply appreciate patients at Kyoto University 2 months post-surgery, compared with that pre-surgery [42]. Hospital for their contribution to this study. We would like to thank Editage (www.editage.jp) for English language editing. These results are consistent with the findings of the present Funding information This work was partially supported by the study which showed improved emotional functioning after Promotion Plan for the Platform of Human Resource Development for the first drug cycle. However, since patients on post-operative Cancer administered by the Ministry of Education, Culture, Sports, adjuvant therapy as well as those on pre-operative neoadjuvant Science and Technology in Japan (grant no. 12 to TT). The funder did therapy or mitigation therapy were included in the current not have a role in the study design; collection, analysis, or interpretation 2404 Support Care Cancer (2018) 26:2397–2405 of the data; the writing of the report; or the decision to submit the article 12. Argyriou AA, Polychronopoulos P, Iconomou G, Chroni E, for publication. Kalofonos HP (2008) A review on oxaliplatin-induced peripheral nerve damage. Cancer Treat Rev 34(4):368–377. https://doi.org/10. 1016/j.ctrv.2008.01.003 Compliance with ethical standards 13. Beijers AJ, Jongen JL, Vreugdenhil G (2012) Chemotherapy- induced neurotoxicity: the value of neuroprotective strategies. 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