Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care

Clinical Nutrition xxx (2014) 1e9

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Clinical Nutrition journal homepage: http://www.elsevier.com/locate/clnu

Original article

Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care Eran Ben-Arye a, b, c, *, Michal Livne Aharonson a, d, Elad Schiff e, f, Noah Samuels a, g a

Integrative Oncology Program, The Oncology Service and Lin Medical Center, Clalit Health Services, Haifa and Western Galilee District, Israel Complementary and Traditional Medicine Unit, Department of Family Medicine, Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel c Clalit Health Services, Haifa and Western Galilee District, Israel d Dietary Service, Clalit Health Services, Haifa and Western Galilee District, Israel e Department of Internal Medicine, and Integrative Medicine Service, Bnai-Zion Hospital, Haifa, Israel f The Department for Complementary Medicine, Law and Ethics, The International Center for Health, Law and Ethics, Haifa University, Israel g Tal Center for Integrative Medicine, Institute of Oncology, Sheba Medical Center, Tel Hashomer, Israel b

a r t i c l e i n f o

s u m m a r y

Article history: Received 25 July 2014 Accepted 16 December 2014

Background & aims: Chemotherapy-induced gastrointestinal (GI) toxicities often impair quality-of-life (QOL) and require reduction of the chemotherapy dose intensity. We explored the effects of a complementary integrative medicine (CIM) therapeutic process, administered in conjunction with conventional supportive care, on GI-related symptoms and concerns in patients undergoing chemotherapy. Patients and methods: We conducted a prospective, pragmatic study among patients undergoing chemotherapy referred by their healthcare providers to a CIM-trained integrative physician (IP) for consultation, followed by CIM treatments. Symptom severity and patient concerns were assessed at baseline and at an IP follow-up visit at 6e12 weeks, using the Edmonton Symptom Assessment Scale (ESAS) and the Measure Yourself Concerns and Wellbeing (MYCAW) questionnaires. Adherence to the integrative care (AIC) program was defined as attendance of
4 CIM treatments, with 30 days between sessions. Results: Of the 308 patients referred to the IP consultation, 275 (89.3%) expressed GI symptoms and concerns, 189 of whom attended the follow-up IP assessment. Of these, 144 (46%) were found to be adherent to the treatment plan (AIC group). Repeated measure analysis indicated a statistical interaction between baseline and follow-up scores, for ESAS (appetite, p ¼ 0.005; drowsiness, p ¼ 0.027; shortness of breath, p ¼ 0.027; and sleep, p ¼ 0.034) and for MYCAW outcomes. This when comparing the AIC to the non-AIC group responses. Reduction of GI concerns (p ¼ 0.024) was greater among patients in the AIC group (MYCAW questionnaire), with significantly less chemotherapy-related hospitalizations found in this group (p ¼ 0.008). The participation of a registered dietitian during CIM treatments led to greater reduction in nausea (from 4.24 to 1.85 vs. 2.73 to 1.36, respectively; p ¼ 0.017). Conclusions: Integration of CIM with standard supportive care, especially in patients adhering to the CIM treatment regimen, may help reduce chemotherapy-induced GI symptoms and concerns, as well as QOLrelated non-GI symptoms. Further research is needed in order to explore the effects of specific CIM modalities on GI symptoms and concerns during chemotherapy. © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Keywords: Integrative medicine Complementary and alternative medicine Nutrition Chemotherapy Quality of life Appetite

1. Introduction

* Corresponding author. The Oncology Service, Lin Medical Center, 35 Rothschild St., Haifa, Israel. Tel.: þ972 (5) 28709282; fax: þ972 (4) 8568249. E-mail address: [email protected] (E. Ben-Arye).

Supportive care for patients with cancer undergoing chemotherapy has improved significantly, largely the result of an enhanced awareness of the importance of quality-of-life (QOL)related issues and improved symptom control, such as the newly available anti-emetic agents [1]. Yet the toxic effects of anti-cancer treatments continue to present a significant challenge to both

http://dx.doi.org/10.1016/j.clnu.2014.12.011 0261-5614/© 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

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E. Ben-Arye et al. / Clinical Nutrition xxx (2014) 1e9

patients and their healthcare providers. These include gastrointestinal (GI) concerns such as nausea, appetite and taste alteration, mouth sores, constipation, diarrhea, abdominal pain and bloating. Other treatment-related toxicities, such as chemotherapy-related fatigue and peripheral neuropathy, as well as a wide range of emotional and physical issues, can all cause significant distress and exacerbate one another. Treatment-related symptoms often lead to the cessation or delay of treatment regimens, necessitating a reduction in dose density with reduced efficacy [2,3]. There is therefore a need to search out new treatment options which are both safe and effective in improving QOLrelated outcomes, which would allow for the completion of treatment regimens as planned. The use of complementary and integrative medicine (CIM) in conjunction with chemotherapy is widespread, with many patients turning to these therapies for the relief of symptoms which are not addressed in conventional supportive care [4]. There is a large body of evidence supporting the benefits of a number of CIM modalities, including for the treatment of GI-related symptoms. For example, Chinese herbal medicine, acupuncture and acupressure have all been found to be effective in reducing chemotherapy-induced nausea and vomiting (CINV) [5e8]. In addition, mind-body medicine (e.g., hypnosis, yoga, guided imagery, progressive muscle relaxation training) have also been found to be of benefit for CINV [9e11], and xerostomia can be reduced by hypnosis [12] and acupuncture [13]; oral mucositis by nutritional supplements such as Carob (Ceratonia siliqua L.), Rhodiola algida, glutamine, and honey [14e17]; taste alteration following irradiation with zinc supplementation [18]; and diarrhea with probiotics and the Japanese Kampo medicinal herb Hangeshashin-to [19e21]. The growing awareness of the conventional medical establishment regarding the potential benefits of CIM in supportive care has led to the establishment of a number of integrative medicine programs within leading U.S. cancer centers [22,23], as well as in other Western countries [24]. CIM consultations and subsequent treatments play an integral role at these centers, and are geared toward improving QOL while ensuring safety (i.e., side effects, negative interactions with anti-cancer therapies, etc.). The integrative oncology environment is characterized by a patient-centered, biopsycho-social-spiritual approach which guides a multiple-modality treatment plan tailored to the patient's specific concerns. This integrative approach requires the cooperation of other supportive care-healthcare practitioners, including nutritional consultants and psycho-oncologists. The goal of the present study was to explore the impact of an integrative oncology program, in which CIM treatments are provided in addition to conventional supportive care therapies, on chemotherapy-induced GI-related toxicities and patients' concerns, as well as other QOL-related outcomes. For this purpose we chose a pragmatic methodological approach, reflecting the real-world clinical setting of the CIM program which serves as an integral part of a public conventional-care oncology service. 2. Methods

Patients age 18 years and older who were undergoing chemotherapy in the outpatient oncology service at the Lin and Zebulon Medical Centers in northern Israel (between July 2009 and July 2012) were eligible for study inclusion. Chemotherapy regimens were either adjuvant or neo-adjuvant protocols for local disease, or else palliative for advanced disease. Patients presenting to the study centers were referred by their oncologists, nurse oncologists, or psycho-oncologists to the integrative physician (IP) for consultation. Referrals were based on a structured list of specific QOLrelated concerns, including gastro-intestinal symptoms such as nausea and vomiting, mouth sores and gingivitis, alteration of taste, reduced appetite, weight change, dietary concerns, constipation, diarrhea, abdominal pain/flatulence/bloating, and heartburn. NonGI-related concerns included fatigue, pain and emotional distress. 2.2. Assessment of patients' QOL and gastro-intestinal concerns The initial (baseline) IP consultation lasts approximately an hour. IPs are medical doctors with extensive training in CIM treatment modalities, as well as in conventional supportive cancer care. A follow-up visit to the IP is scheduled at 6 and 12 weeks following the initial consultation. At the initial IP consultation, treatment-related symptoms and QOL-related outcomes are evaluated using the Edmonton Symptom Assessment Scale (ESAS), a Likert-like study tool scoring 10 symptoms, of which two are related to GI concerns (nausea and appetite) and the remainder either general (fatigue, depression, anxiety, drowsiness, feeling of well-being, and sleep) or specific non-GI-related symptoms (pain, shortness of breath). The severity of symptoms is self-scored by patients, and ranges from 0 (no symptoms) to 10 (worst possible symptoms) [26]. Baseline and follow-up ESAS scores are also analyzed following categorization to one of the following 4 groups: 0, no symptoms; 1e3, mildly severe symptoms; 4e6, moderately severe symptoms; and 7e10, severe symptoms. At the same time, GI-related and other concerns are evaluated using the Measure Yourself Concerns and Wellbeing (MYCAW) tool. The MYCAW is a Likert-like questionnaire in which patients are asked to list their two most important concerns, which are then scored from 0 (of no concern) to 6 (of greatest concern). In addition to addressing their symptoms, patients are also asked to score their general feeling of well-being (0, as good as it could be; 6, as bad as it could be), followed by two open-ended questions regarding “other issues related to your health” and “what has been the most important issue for you?” [27]. GI concerns are considered to be significant if they fulfill one or more of the following criteria: 1. the presence of nausea or a lack of appetite, with an ESAS score of
4; 2. a score of
3 on the MYCAW questionnaire for one or two of the following GI-related concerns: nausea/vomiting; mouth sores and/or pain; heartburn; abdominal flatulence and/or pain; diarrhea or constipation; reduced appetite; weight change; or 3. an expressed interest in nutritional counseling. Patients for whom the referring healthcare provider listed a GI-related concern as an indication for the referral were included as well.

2.1. Study design and location 2.3. CIM treatments The study was designed as a prospective pragmatic trial, examining patients' preferences and the impact of a CIM intervention on chemotherapy-induced GI toxicity, as well as other QOLrelated outcomes. The study took place at the Integrative Oncology Program (IOP) at the Haifa and Western Galilee Oncology Service of Clalit Healthcare services. The IOP approach is patient-centered, addressing concerns regarding QOL-related outcomes during chemotherapy and advanced disease [25].

At the end of the initial IP consultation the goals of treatment are established and a treatment plan is designed in accordance with the patient's expectations and main concerns. The IP presents the patients an updated in-depth explanation regarding the level of research-based evidence on the efficacy and safety of the CIM treatment options. CIM treatments are provided by qualified and experienced practitioners, with the following therapeutic

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

E. Ben-Arye et al. / Clinical Nutrition xxx (2014) 1e9

interventions offered: 1. an IP consultation on the use of dietary supplements and herbal remedies, emphasizing the evidencebased research findings on the safety of supplement use during chemotherapy (e.g., supplement-chemotherapy interactions) and effectiveness on QOL-related outcomes; 2. a consultation with a registered dietitian; 3. participation in a 3-h cuisine group workshop led by the study IP, along with an occupational therapist (trained in CIM), a spiritual consultant and a registered dietitian who, together with the patient, design a nutritional strategy for improving QOL and daily functioning; and 4 weekly acupuncture sessions, often in combination with mind-body (guided imagery) or manual (e.g. acupressure, reflexology) techniques. 2.4. Standard conventional supportive cancer care Standard conventional supportive care is prescribed by the treating oncologists and nurse oncologist. Standard supportive care includes both preventive treatment (e.g. MASCC and ESMO clinical practice guidelines for the prevention of acute or delayed chemotherapyeinduced nausea and vomiting, in accordance with the level of emetic risk) [28], as well as treatment of acute gastrointestinal symptoms (e.g. anti-emetics for the treatment of refractory or breakthrough nausea) and other QOL-related concerns. 2.5. Assessment of patient adherence to CIM treatments Patients undergoing CIM treatments are grouped in accordance with their adherence to the integrative care (AIC) program. AIC is defined as attendance of
4 CM treatment sessions, with an interval of no more than 30 days between each interaction. The definition of AIC was formulated by a multi-disciplinary team of researchers in a prior multi-step design study [29]. 2.6. Data analysis Data from the registry protocol were gathered and subsequently analyzed using the SPSS software program (version 18; SPSS Inc., Chicago, IL). A Pearson's chi-square test and Fisher's exact test were used to examine any variations in demographic data, as well as the prevalence of categorical variables among patients in the AIC and non-AIC groups. A t-test was used to examine the differences between continuous variables in cases where normality was assumed, and a ManneWhitney U test was used for non-normal distribution. Statistical significance was considered with a p value of 0.05. Sample size calculation was performed using the WIN EPISCOPE 2.0 software. The sample size was determined with the allocation of at least 50 patients to each group, allowing for an alpha-error of 0.05 and beta-error of 0.2 (power 80%) in order to detect a 25% difference in the ESAS 11-point scale, between AIC and non-AIC participants. A Repeated Measure Analysis (RMA) was conducted in order to determine changes in ESAS and MYCAW scores. The ESAS and MYCAW scores are dependent variables, while the within-subjects factor was the change in ESAS and MYCAW scores as documented during the initial and follow-up IP consultations. Adherence to integrative care was considered to be an independent parameter, reflecting between-subject factor. Each of the 10 ESAS scales (representing a different symptom) was evaluated, comparing scores obtained at the initial and at the follow-up IP sessions. Since the ESAS questionnaires contain independent symptom scores (with no overall total questionnaire score), we performed 10 separate RMAs. An additional analysis of the ESAS score change was performed by grouping ESAS scores, as recorded in the initial 1st and follow-up IP assessments, into one of 4 categories: 0, symptom not present;

3

1e3, mild symptom severity; 4e6, moderately severe symptom; and 7e10, severe symptom. Analysis of the changes between the four categories (no change, improved or worsened) was performed for each of the 10 ESAS symptoms for the AIC and non AIC groups, using a Marginal Homogeneity test. Analysis of the change in category shifts was also performed, comparing the AIC and non-AIC groups using a Fisher's Exact test. 2.7. Ethical considerations The protocol of the present study was submitted to and approved by the Ethics Review Board (Helsinki Committee) of the Carmel Medical Center in Haifa, Israel. The study protocol was conducted on a strictly voluntary basis, with no monetary or other incentive offered for participation. In order to ensure privacy, no identifying information or other factors were entered into the data analysis. The study protocol was registered at ClinicalTrials.gov (NCT01860365). 3. Results 3.1. Characteristics of the study group During the study period a total of 308 patients were referred by their oncology healthcare practitioner to the IP consultation. Of these, 275 (89.3%) had significant GI concerns, with 189 attending the follow-up IP assessments at 6e12 weeks. The remaining 86 patients did not return for follow-up for the following reasons: an unwillingness to continue with IP follow-up assessment (n ¼ 30); no interest in undergoing CIM treatment (n ¼ 46); death before the scheduled visit (n ¼ 7); or attendance at the follow-up assessment which was either too early or too late, according to the prescribed schedule (n ¼ 3). The demographic, treatment- and cancer-related characteristics of patients with significant GI concerns are presented in Table 1. No significant differences were found between those who attended the follow-up IP visit and those who did not, this with respect to demographic, medical or treatment-related characteristics or selfreported use of CIM for cancer-related outcomes. However, prior use of CIM for non-cancer-related outcomes was reported more frequently among those who attended the IP follow-up visit than among those who did not (54.3% vs. 37.2%; p ¼ 0.009). Table 2 presents the characteristics of the study group, based on their adherence to the CIM treatment regimens. Of the 189 who attended a follow-up IP assessment, 144 were found to be adherent to the treatment plan (AIC group) and 45 non-adherent (non-AIC group). No significant differences were found between these two groups with respect to most demographic or medical characteristics, as well as prior use of CIM for non-cancer-related indications. However, patients in the AIC group tended to reside closer to the cancer center (43.1% vs. 24.4%, p ¼ 0.034) and reported lower rates of CIM use for cancer-related indications (48.6% vs. 68.9%, p ¼ 0.025). 3.2. Referral, CIM treatment characteristics and IP assessment timing The AIC and non-AIC groups did not differ significantly with respect to the oncology healthcare professional (oncologist, nurse oncologist, or psycho-oncologist) who had referred them or the specific indications given for referral to the IP consultation. These included gastro-intestinal symptoms, fatigue, emotional distress, and general well-being (Table 2). Clinical assessment was conducted by the study IPs during the baseline and 6e12 week followup visit, using both ESAS and MYCAW questionnaires. Rates of

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

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E. Ben-Arye et al. / Clinical Nutrition xxx (2014) 1e9

Table 1 Demographic, treatment, and cancer-related characteristics of patients with GI symptoms and concerns. Characteristic

Total cohort N ¼ 275 n (%)

Completed follow-up assessmentc N ¼ 189 n (%)

Did not complete follow-up assessment N ¼ 86 n (%)

P Value

Age [Mean in years ± SD (median)] Gender: Male Female Main language:a Hebrew Other Place of birth:a Israel Other Residence distanceb Haifa Suburbs Periphery Cancer sites:a Breast Gynecological Gastro-intestinal Prostate Urological Lung Other Cancer recurrence:a Yes No Evidence for metastasis:a Yes No Chemotherapy setting:a Neo-Adjuvant & Adjuvant Palliative Non-cancer related CIM use:a Yes No Cancer-related CIM use:a Yes No

62.23 ± 12.75 (64)

61.86 ± 12.88 (63)

63.03 ± 12.75 (65)

0.48

66 (24.0) 209 (76.0)

45 (23.8) 144 (76.2)

21 (24.4) 65 (75.6)

1.00

194 (71.1) 79 (28.9)

137 (72.9) 51 (27.1)

57 (61.7) 28 (32.9)

0.38

122 (46.6) 140 (53.4)

82 (45.3) 99 (54.7)

40 (49.4) 41 (50.6)

0.59

108 (39.3) 108 (39.3) 59 (21.5)

73 (38.6) 73 (38.6) 43 (22.8)

35 (40.7) 35 (40.7) 16 (18.6)

0.74

112 51 64 9 15 16 8

79 35 43 7 10 9 6

33 16 21 2 5 7 2

(38.4) (18.6) (24.4) (2.3) (5.8) (8.1) (2.3)

0.69 1.00 0.76 0.72 1.00 0.27 1.00

(40.7) (18.5) (23.3) (3.3) (5.5) (5.8) (2.9)

(41.8) (18.5) (22.8) (3.7) (5.3) (4.8) (3.2)

67 (24.4) 208 (75.6)

44 (23.3) 145 (76.7)

23 (26.7) 63 (73.3)

0.55

128 (46.5) 147 (53.5)

88 (46.4) 101 (53.4)

40 (46.5) 46 (53.5)

1.00

167 (64.5) 92 (35.5)

121 (66.9) 60 (33.1)

46 (59.0) 32 (41.0)

0.25

134 (48.9) 140 (51.1)

102 (54.3) 86 (45.7)

32 (37.2) 54 (62.8)

0.009

142 (52.0) 131 (48.0)

101 (53.4) 88 (46.6)

41 (48.8) 43 (51.2)

0.51

SD, standard deviation, CIM, complementary and integrative medicine. Data analysis was performed by t-test, Fisher's exact test, and Pearson Chi-square test, as needed. a Data limited to the number of respondents who reported this information. b In relation to residential distance from Haifa: suburbs e up to 20 km from Haifa; periphery ebeyond 20 km from Haifa. c IP assessments were conducted at baseline and between 6 and 12 weeks after the initial consultation.

attendance at the follow-up visit did not differ significantly between the AIC and non-AIC groups (median: 57.5 vs. 46 days, p ¼ 0.72). However, attendance at the CIM treatment sessions, from the initial to the concluding assessment, differed significantly between the two groups (median 7 vs. 4 sessions), as per definition. The CIM modalities provided to patients in both groups were similar, and included advice on herbal/nutritional supplement use, nutritional consultation, mind-body (e.g. guided imagery, breathing, and relaxation and exercises) and manual therapies (e.g., acupressure, reflexology) (Table 2). In contrast, the AIC group received significantly more treatments with acupuncture, and was more likely to participate in the cuisine workshops than those in the non-AIC group. 3.3. Impact of CIM treatments on GI symptoms and well-being (ESAS tool) Table 3 presents the mean scores of the 10 ESAS symptoms for both the AIC and non-AIC groups, at the initial IP consultation and at the follow-up visit. Baseline scores were similar in both groups for all 10 ESAS symptoms (p > 0.05). However, the AIC group demonstrated a more significant improvement in symptom severity and well-being (p < 0.001), when comparing baseline-to-

follow up scores. Scores improved significantly in the non-AIC group as well for most symptoms, except for drowsiness, shortness of breath, appetite and sleep. Repeated Measure Analysis indicated a statistical interaction between baseline and follow-up scores with respect to drowsiness (p ¼ 0.027), shortness of breath (p ¼ 0.027), appetite (P ¼ 0.005) and sleep (p ¼ 0.034), in the variable of AIC vs. non-AIC. Analysis of the 4 ESAS score categories indicated a percent increase (i.e., improvement) among patients showing improved scores. This was more pronounced in the AIC group than in the nonAIC group with respect to improved appetite (52% vs. 31%, p ¼ 0.016). However, the percent increase in patients with severe drowsiness was greater in the non-AIC group (20% in the AIC vs. 35% in the non-AIC group; p ¼ 0.04). Percent increase in symptom improvement was similar in both AIC and non-AIC groups for the following symptoms: pain (improved in 38% vs. 41%, p ¼ 0.72; worsened in 9% vs. 20%, p ¼ 0.06); fatigue (improved in 56% vs. 49%, p ¼ 0.39; worsened in 11% vs. 22%, p ¼ 0.08); nausea (p ¼ 0.30, p ¼ 0.33); depression (p ¼ 0.16, p ¼ 0.46); anxiety (p ¼ 0.23, p ¼ 0.41); shortness of breath (p ¼ 0.12, p ¼ 0.37); sleep (compared improvement, p ¼ 0.16; worsening 14% vs. 27%, p ¼ 0.07); and overall feeling of well-being (compared improvement, p ¼ 0.16; worsening 11% vs. 22%, p ¼ 0.08).

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

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Table 2 Comparison of demographic, treatment- and cancer-related variables of patients with significant GI symptoms and concerns, according to their adherence to the CIM treatment regimen. Characteristic

Cohort of patients assessed in both initial and follow-up visit N ¼ 189 n (%)

Age [Mean in years ± SD (median)] 61.86 ± 12.88 Gender: Male 45 Female 144 Main language:b Hebrew 137 Other 51 Place of birth:b Israel 82 Other 99 c Residence distance Haifa 73 Suburbs 73 Periphery 43 Cancer sites:b Breast 79 Gynecological 35 Gastro-intestinal 43 Prostate 7 Urological 10 Lung 9 Other 6 b Cancer recurrence: Yes 44 No 145 Evidence for metastasis:b Yes 88 No 101 Chemotherapy setting:b Neo-Adjuvant & Adjuvant 121 Palliative 60 b Non-cancer related CM use: Yes 102 No 86 Cancer-related CM use:b Yes 101 No 88 b Referrer's profession: Oncologist 72 Nurse oncologist 78 Psycho-oncologist 32 Referral's indication:b Gastro-intestinal 52 Fatigue 38 Emotional 29 General well-being 84 CIM modalities provided following IP assessment: Herbal consultation 147 Dietitian consultation 37 Cuisine workshop 26 Acupuncture 175 Mind-body therapies 102 Manual therapies 106

(63)

AICa group N ¼ 144 n (%)

Non AIC group N ¼ 45 n (%)

62.41 ± 13.19 (63)

60.11 ± 11.80 (65)

P Value

0.29

(23.8) (76.2)

39 (27.1) 105 (72.9)

6 (13.3) 39 (86.7)

0.07

(72.9) (27.1)

104 (72.7) 39 (27.3)

33 (73.3) 12 (26.7)

1.00

(45.3) (54.7)

59 (42.4) 80 (57.6)

23 (54.8) 19 (45.2)

0.21

(38.6) (38.6) (22.8)

62 (43.1) 50 (34.7) 32 (22.2)

11 (24.4) 23 (51.1) 11 (24.4)

0.03 0.05 0.81

(41.8) (18.5) (22.8) (3.7) (5.3) (4.8) (3.2)

56 28 35 5 10 7 3

23 7 8 2

0.17 0.66 0.42 0.67 0.12 1.00 0.15

(38.9) (19.4) (24.3) (3.5) (6.9) (4.9) (2.1)

(51.1) (15.6) (17.8) (4.4)

e 2 (4.4) 3 (6.7)

(23.3) (76.7)

36 (25.0) 108 (75.0)

8 (17.8) 37 (82.2)

0.42

(46.4) (53.4)

66 (45.8) 78 (54.2)

22 (48.9) 23 (51.1)

0.73

(66.9) (33.1)

88 (63.8) 50 (36.2)

33 (76.7) 10 (23.3)

0.14

(54.3) (45.7)

80 (55.9) 63 (44.1)

22 (48.9) 23 (51.1)

0.49

(53.4) (46.6)

70 (48.6) 74 (51.4)

31 (68.9) 14 (31.1)

0.025

(39.6) (42.9) (17.6)

56 (40.3) 61 (43.9) 22 (15.8)

16 (37.2) 17 (39.5) 10 (23.3)

0.85 0.72 0.26

(28.3) (20.7) (15.8) (45.7)

38 29 23 64

(27.0) (20.6) (16.3) (45.4)

14 9 6 20

(32.6) (20.9) (14.0) (46.5)

0.56 1.00 0.82 1.00

(77.8) (19.6) (13.8) (92.6) (54.0) (56.1)

110 32 24 140 80 86

(76.4) (22.2) (16.7) (97.2) (55.6) (59.7)

37 5 2 35 22 20

(82.2) (11.1) (4.4) (77.8) (48.9) (44.4)

0.54 0.13 0.046 <0.0001 0.49 0.086

SD, standard deviation, CIM, complementary integrative medicine. Data analysis was performed by t-test, Fisher's exact test, and Pearson Chi-square test, as needed. a AIC, adherence to the integrative care treatments; defined as at least 4 consecutive integrative care sessions following initial IP assessment with less than 30 days of interval between the sessions. b Data limited to the number of respondents who reported this information. c In relation to residential distance from Haifa: suburbs e up to 20 km from Haifa; periphery ebeyond 20 km from Haifa.

3.4. Impact of CIM interventions on GI-related concerns (MYCAW questionnaire) Patients in both AIC and non-AIC groups scored similarly at baseline with respect to GI-related concerns, as measured by the MYCAW questionnaire (5.27 vs. 5.24, p ¼ 0.89). In both groups, scores significantly improved by the follow-up IP visit (p < 0.0001), with no significant difference found between the adherent and

non-adherent patient groups (2.66 vs. 2.47, p ¼ 0.69). Baseline MYCAW scores were similar for the 50 AIC and 5 non-AIC patients who had specified GI concerns among their two most important symptoms. However, scores improved more significantly at followup in the AIC group (from 5.16 ± 1.20 to 2.84 ± 1.42) than they did in the non-AIC group (from 5.60 ± 0.55 to 4.40 ± 1.52; p < 0.0001). Repeated Measure Analysis indicated a statistical interaction between MYCAW scores at baseline and at follow-up, based on a

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

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Table 3 Comparison of Edmonton Symptom Assessment Scores (ESAS) questionnaire mean scores, between patients adherent (AIC) and non-adherent (non-AIC) to the CIM treatment regimen. P values*

Non-AIC group N ¼ 45 Mean score ± SD

Symptom

AIC group N ¼ 144 Mean score ± SD Baseline assessment

Follow-up assessment

Baseline assessment

Follow-up assessment

Pain

4.01 ± 3.36

2.54 ± 2.85

3.89 ± 3.45

2.96 ± 3.10

Fatigue

5.80 ± 2.62

3.86 ± 2.51

5.78 ± 2.87

4.71 ± 2.83

Nausea

3.16 ± 3.16

1.50 ± 2.15

2.38 ± 2.88

1.51 ± 2.54

Depression

3.61 ± 3.10

2.15 ± 2.61

3.00 ± 2.78

2.18 ± 2.54

Anxiety

3.78 ± 3.23

2.07 ± 2.43

3.71 ± 3.32

2.18 ± 2.76

Drowsiness

4.05 ± 3.03

2.66 ± 2.67

3.60 ± 2.99

3.47 ± 3.03

Shortness of breath

2.54 ± 3.11

1.68 ± 2.25

1.67 ± 2.66

1.89 ± 2.73

Appetite

5.01 ± 3.01

3.28 ± 2.68

4.20 ± 3.20

4.16 ± 2.92

Sleep

4.79 ± 3.36

3.46 ± 2.59

4.07 ± 3.36

3.89 ± 2.71

Feeling of well-being

5.40 ± 2.49

3.73 ± 2.28

5.11 ± 2.77

4.16 ± 2.58

P ¼ 0.84 P ¼ 0.40 P < 0.001 P < 0.001 P ¼ 0.97 P ¼ 0.056 p < 0.0001 P ¼ 0.033 P ¼ 0.14 P ¼ 0.98 P < 0.001 P < 0.001 P ¼ 0.24 P ¼ 0.95 P < 0.001 P < 0.001 P ¼ 0.90 P ¼ 0.81 P < 0.001 P < 0.001 P ¼ 0.39 P ¼ 0.09 P < 0.001 P ¼ 0.81 P ¼ 0.092 P ¼ 0.61 P < 0.001 P ¼ 0.59 P ¼ 0.12 P ¼ 0.06 P < 0.001 P ¼ 0.94 P ¼ 0.21 P ¼ 0.34 P < 0.001 P ¼ 0.76 P ¼ 0.51 P ¼ 0.29 P < 0.001 P < 0.001

*P values are presented concerning the following comparisons. Comparing baseline scores of AIC vs. non-AIC groups. Comparing follow-up (6e12 weeks) scores of AIC vs. non-AIC groups. Comparing baseline to follow-up scores in AIC group. Comparing baseline to follow-up scores in non-AIC group.

significant difference found in the final scores, as reported by patients at follow-up (p ¼ 0.024).

3.5. Adherence to CIM therapeutic process and treatment-related outcomes Of the total cohort of patients who attended the follow-up IP assessment (n ¼ 188), 71 patients (46 in the AIC group, 25 in the non-AIC group) were hospitalized during the study period as a result of one of the following chemotherapy-related complications: nausea or vomiting, neutropenic fever, dehydration, deep vein thrombosis and severe fatigue. Patients in the AIC group had significantly less chemotherapy-related hospitalizations (AIC vs. non AIC: 46/143, or 32.2% vs. 25/45, or 55.6%; p ¼ 0.008), as well as higher one-year survival rates following the initial IP assessment, though this was not of statistical significance (AIC, 85.4% vs. nonAIC, 73.3%; p ¼ 0.073).

3.6. Participation of a registered dietitian in CIM treatments In a sub-group analysis of patients expressing GI concerns who adhered to the CIM treatment plan (AIC group; n ¼ 144), ESAS scores of those who were treated by a CIM practitioners alone (n ¼ 103) were compared to those for whom a registered dietitian was integrated into the CIM therapeutic process (n ¼ 41). Both groups had similar demographic (age, gender, languages spoken, country of birth, distance of residence from the oncology center) and medical characteristics. The two groups also shared a similar distribution of cancer sites, though breast cancer was less prevalent among patients in the dietician's group (21.4% vs. 78.6%, p ¼ 0.019). Patients in both groups were undergoing similar chemotherapy regimens, and had similar rates of reported use of complementary medicine for both cancer and non-cancer-related outcomes. The group of patients who were seen by the combined CIM practitioner-dietician team had more severe baseline ESAS scores for nausea (p ¼ 0.009). These patients showed a greater reduction

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

E. Ben-Arye et al. / Clinical Nutrition xxx (2014) 1e9

in nausea severity than those in the CIM practitioner-only group (from 4.24 ± 3.41 to 1.85 ± 2.32 versus from 2.73 ± 2.97 to 1.36 ± 2.07, respectively; p ¼ 0.017). No difference was observed between the two groups for other ESAS parameters, including appetite, fatigue, drowsiness, and general well-being. 4. Discussion Improving patients' well-being in general and gastro-intestinal symptoms in particular is an important treatment goal during chemotherapy, both for the patients themselves as well as for the oncology healthcare practitioners responsible for their care. We present the findings of a prospective, pragmatic study which examined the impact of CIM treatments on chemotherapy-induced GI toxicities and concerns, as well as impaired QOL-related outcomes. ESAS scores improved more significantly in patients who adhered to the CIM treatment regimen (AIC group) with respect to appetite, drowsiness, dyspnea and sleep, as did the MYCAW scores for GI-related concerns. In addition, for patients treated by the CIM practitioner-dietician team ESAS scores for nausea showed a significantly greater improvement than in patients treated by a CIM practitioner alone. We also found that patients in the AIC group had significantly less chemotherapy-related hospitalizations, with a trend for higher rates of one-year survival. The findings of the present study need to be further explored in. T, The cost-effective implications of the integrative support care process, as shown here with patients receiving adjuvant/neoadjuvant or palliative chemotherapy, need to be examined as well. Conventional treatments for chemotherapy-related toxicities have been examined elsewhere for this outcome, and despite their proven efficacy they have not been found to be cost-effective [30] Such an analysis was not possible in the present study format due to the concurrent use of conventional supportive care treatments, as well as variations in dose density and patient adherence to the chemotherapy regimen. The findings of the present study nonetheless illustrate the potential benefits of integrating CIM therapies into standard conventional supportive care. We examined the effects CIM treatments on chemotherapy-related gastro-intestinal symptoms and concerns, using a structured referral process of patients by their oncology healthcare professionals to an IP for a baseline and follow-up consultation. This format provides a unique integrative setting for examining the effects of these modalities, and the use of a pragmatic research model allows for a better understanding of this process than would be possible in an explanatory (randomized, controlled) trial. Firstly, CIM treatment regimens are based on patients' preferences and not on a random allocation to a specific and pre-defined treatment arm. Secondly, the treatment modalities being offered are tailored to the main concerns of the patient, taking into account effectiveness and safety, as opposed to a uniform and standardized regimen. The pragmatic research design reflects real-world patient care and focuses on the many challenges facing both clinicians and patients alike. The present study examined the outcomes of a patient-centered integrative approach, incorporating a multi-faceted therapeutic process individually tailored for symptom relief, specifically gastro-intestinal concerns. The present research has a number of limitations, many of which are the result of the pragmatic methodological design. The study set out to evaluate the effectiveness of a patient-tailored integrative approach on the concerns and well-being of patients undergoing chemotherapy. This approach may lead to a referral and selection bias resulting from the fact that oncology healthcare providers refer only certain patients to the IP consultation; a patient preference bias, based on the accepting (or rejecting) of the CIM

7

treatment regimen; and an adherence bias, reflecting patient satisfaction with treatments and immediate outcomes (nonrespondent bias). In addition, study withdrawal from CIM treatments and/or non-attendance at follow-up IP visits may have resulted from the toxic effects of chemotherapy, progression of disease or even death. Chemotherapy-induced toxicities are an important factor to consider, since they can potentially prevent adherence to and attendance by patients at follow-up visits. And while lower rates of chemotherapy-related hospital admission rates were observed in the AIC group, this may reflect the beneficial effects of adherence to the CIM regimen, as well as the study's limitations, as described. We therefore recommend that the findings of our research be interpreted cautiously, until more rigorous studies are conducted in order to clarify the relationship between adherence to and effectiveness of the CIM therapeutic process. During the design process of the study, we made an attempt to address these many limitations of the study format. First, we evaluated the entire cohort of 308 patients who had been referred to the IP consultation, as well as the 275 patients for whom their GI concerns were addressed at the initial IP consultation. We compared the groups of patients who attended a follow-up assessment with the IP (n ¼ 189) with those who did not (n ¼ 86), and found no significant difference between the two with respect to demographic, disease- or chemotherapy-related variables. We found that prior use of complementary medicine for non-cancer-related outcomes was significantly more prevalent in the group attending the follow-up IP assessment. While these findings may reflect a patient preference bias, it should be noted that other more significant potential bias-creating factors (e.g. local versus advanced cancer, chemotherapy setting) were not apparent. In addition to the above steps, and based on findings reported in a previous study of the integrative setting [29], we compared those patients who attended the IP follow-up assessment based on their adherence to the CIM treatment regimen. Although attending the follow-up visit may reflect a patient bias, no significant difference was found between those who adhered and those who did not for most outcomes, except for the distance of residence from the cancer center and, surprisingly, lower rates of CM use for cancerrelated indications (higher in the AIC group). This may suggest a preference bias reflecting prior experience with complementary medicine, though this linkage is not clear. Another point to consider is that although patients in both AIC and non-AIC groups were offered the same CIM modalities (including herbal/supplement and dietitian counseling), patients in the AIC group received more acupuncture treatments and participated more frequently in the cuisine workshops. This difference may have been caused by the greater overall number of CIM visits among the patients in the AIC group, though more research is needed in order to better understand this discrepancy. Another important point to take into consideration when trying to understand the findings of the present study is related to the consultation given on herbal/nutritional supplement use, which was provided to both groups of patients (AIC and non-AIC). The findings on present and past use of supplements in the study setting have been reported elsewhere [31]. Providing patients with the most recent evidence on the safety and effectiveness of these supplements is of primary importance. This is especially true in societies such as Israel, where significant cross-cultural challenges can be found, and where a large number of patients are reportedly using traditional herbal medicine. While we do not have an extensive list of all the herbs and supplements which were being used by patients, we did not find any difference in the number of herbal/supplement-oriented consultations between the two groups.

Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011

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E. Ben-Arye et al. / Clinical Nutrition xxx (2014) 1e9

The study also did not provide any data on the adherence of patients to standard conventional supportive care treatments, as prescribed by their oncologist and/or nurse oncologists. It is possible that significant differences exist between the AIC and nonAIC groups with respect to this aspect of care, which would most likely have significant implications for the general well-being as well as symptom severity. The impact on symptoms and concerns would most likely be affected by the level and intensity of conventional supportive care, thereby influencing the effects of the CIM treatment process. Nevertheless, patients who were seen at follow-up by the study IP, whether adherent to the CIM treatment regimen or not, showed a significant improvement for most symptoms (as measured by ESAS), as well as for GI concerns (as measured by MYCAW). It is most likely that the reduction of symptom severity resulted from a number of factors, such as the effects of conventional supportive care; improved patients' perceived control and coping ability with the side effects of chemotherapy [32]; reductions in chemotherapy dose intensity during the study period [33]; the timing of follow-up visits (proximity to chemotherapy treatments) [34]; non-specific effects of the IP intervention, which may have empowered the patient [35]; an enhanced sense of affective communication by patients with their oncology healthcare provider [36]; or the result of regression to the mean, as hypothesized in other CIM studies [37]. At the same time, however, the greater reduction in symptom severity observed in the AIC group may reflect a specific effect associated with the ongoing CIM therapeutic process. Both AIC and non-AIC groups showed beneficial effects from the CIM treatments. In both groups, GI symptoms and concerns were found to be reduced following CIM treatments, and an improvement was observed for general QOL and non-GI outcomes such as drowsiness, shortness of breath, and sleep. The AIC group, however, showed a greater improvement with respect to appetite (as measured by ESAS) and GI concerns (measured by MYCAW) than did patients in the non-AIC group. In addition, the reduction in the severity of nausea (on ESAS) was found to be more pronounced in patients who were treated in the combined CIM practitioner/dietician format. This may have been the result of a number of conventional supportive care variables (e.g. anti-emetic use, adjustment of chemotherapy doses). Further studies are therefore needed, which would control for elements of conventional supportive care and thus provide a clearer picture as to the role of the dietitian in an integrative setting of care. Future research will also need to explore the integration of registered dietitians in the CIM therapeutic intervention, which may increase the effectiveness of the CIM treatments for GI-related concerns, in either an additive or synergistic fashion. In conclusion, the integration of CIM treatments with conventional supportive care may help alleviate GI concerns such as a reduced appetite, as well as other QOL-related outcomes and nonGI symptoms. The participation of a registered dietitian in CIM practitioner-administered treatments may further promote symptom improvement. CIM treatments may also reduce oncologytreatment-related hospitalizations. Further research, both pragmatic and explanatory, is needed in order to better understand the benefits of integrative CIM patient-tailored treatments for reducing GI and other toxic effects of chemotherapy. The large scale implications for the applicability of the present integrative oncology setting in other socio-cultural arenas in developed and developing countries need to be explored. Finally, the integrative oncology approach presented here may serve as additional venue for conventional nutritionists who provide counseling aimed at improving patients' quality of life and alleviating their gastro-intestinal concerns during chemotherapy.

Disclosure No funding was provided for the study, and no conflict of interest exists for any of the authors. Authorship Dr. Ben-Arye: Conception and design of the study, acquisition of the data, analysis and interpretation of the data, drafting the article and revising it critically for important content, and final approval of the version to be submitted. Ms. Livne Aharonson: Conception and design of the study, acquisition of the data, final approval of the version to be submitted. Dr. Schiff: Conception and design of the study, analysis and interpretation of the data, drafting the article and revising it critically for important content, and final approval of the version to be submitted. Dr. Samuels: Conception and design of the study, analysis and interpretation of the data, drafting the article and revising it critically for important content, and final approval of the version to be submitted. Conflict of interest The authors state that there are neither actual nor potential conflicts of interest, including any financial, personal or other relationships with other people or organizations whatsoever. Acknowledgments We thank Ms. Ronit Leiba for the statistical analysis. References [1] Grunberg SM, Warr D, Gralla RJ, Rapoport BL, Hesketh PJ, Jordan K, et al. Evaluation of new antiemetic agents and definition of antineoplastic agent emetogenicityestate of the art. Support Care Cancer 2011;19(Suppl. 1):S43e7. [2] Neymark N, Crott R. Impact of emesis on clinical and economic outcomes of cancer therapy with highly emetogenic chemotherapy regimens: a retrospective analysis of three clinical trials. Support Care Cancer 2005;13(10): 812e8. [3] Vavra KL, Saadeh CE, Rosen AL, Uptigrove CE, Srkalovic G. Improving the relative dose intensity of systemic chemotherapy in a community-based outpatient cancer center. J Oncol Pract 2013;9(5):e203e11. [4] Ben-Arye E, Massalha E, Bar-Sela G, Silbermann M, Agbarya A, Saad B, et al. Stepping from traditional to integrative medicine: perspectives of Israeli-Arab patients on complementary medicine's role in cancer care. Ann Oncol 2014;25(2):476e80. [5] Li SG, Chen HY, Ou-Yang CS, Wang XX, Yang ZJ, Tong Y, et al. The efficacy of Chinese herbal medicine as an adjunctive therapy for advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One 2013;8(2): e57604. [6] Mok TS, Yeo W, Johnson PJ, Hui P, Ho WM, Lam KC, et al. A double-blind placebo-controlled randomized study of Chinese herbal medicine as complementary therapy for reduction of chemotherapy-induced toxicity. Ann Oncol 2007;18(4):768e74. [7] Garcia MK, McQuade J, Haddad R, Patel S, Lee R, Yang P, et al. Systematic review of acupuncture in cancer care: a synthesis of the evidence. J Clin Oncol 2013;31(7):952e60. [8] Molassiotis A, Helin AM, Dabbour R, Hummerston S. The effects of P6 acupressure in the prophylaxis of chemotherapy-related nausea and vomiting in breast cancer patients. Complement Ther Med 2007;15(1):3e12. [9] Richardson J, Smith JE, McCall G, Richardson A, Pilkington K, Kirsch I. Hypnosis for nausea and vomiting in cancer chemotherapy: a systematic review of the research evidence. Eur J Cancer Care (Engl) 2007;16(5):402e11. [10] Raghavendra RM, Nagarathna R, Nagendra HR, Gopinath KS, Srinath BS, Ravi BD, et al. Effects of an integrated yoga programme on chemotherapyinduced nausea and emesis in breast cancer patients. Eur J Cancer Care (Engl) 2007;16(6):462e74. [11] Yoo HJ, Ahn SH, Kim SB, Kim WK, Han OS. Efficacy of progressive muscle relaxation training and guided imagery in reducing chemotherapy side effects in patients with breast cancer and in improving their quality of life. Support Care Cancer 2005;13(10):826e33.

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Please cite this article in press as: Ben-Arye E, et al., Alleviating gastro-intestinal symptoms and concerns by integrating patient-tailored complementary medicine in supportive cancer care, Clinical Nutrition (2014), http://dx.doi.org/10.1016/j.clnu.2014.12.011