Medsci 11 00015 v2

medical
sciences
Systematic Review
Prevention and Treatment of Chemotherapy-Induced Peripheral
Neuropathy (CIPN) with Non-Pharmacological Interventions:
Clinical Recommendations from a Systematic Scoping Review
and an Expert Consensus Process
Nadja Klafke 1, *, Jasmin Bossert 1 , Birgit Kröger 2 , Petra Neuberger 3 , Ute Heyder 4 , Monika Layer 5 ,
Marcela Winkler 6 , Christel Idler 6 , Elke Kaschdailewitsch 7 , Rolf Heine 8 , Heike John 9 , Tatjana Zielke 9 ,
Beeke Schmeling 9 , Sosamma Joy 10 , Isabel Mertens 10 , Burcu Babadag-Savas 9 , Sara Kohler 11 ,
Cornelia Mahler 12 , Claudia M. Witt 13 , Diana Steinmann 9 , Petra Voiss 10 and Regina Stolz 2
1 Department of General Practice and Health Services Research, University Hospital Heidelberg,
69120 Heidelberg, Germany
2 Institute for General Practice and Interprofessional Care, University Hospital Tübingen,
72076 Tübingen, Germany
3 National Center for Tumor Diseases, University Hospital Heidelberg, 69120 Heidelberg, Germany
4 Women’s Clinic, Community Hospital Karlsruhe, 76133 Karlsruhe, Germany
5 Center for Integrative Medicine, Cantonal Hospital St. Gallen, 9007 St. Gallen, Switzerland
6 Department of Naturopathy and Integrative Medicine, Robert-Bosch-Krankenhaus, 70376 Stuttgart, Germany
7 Center for Integrative Oncology, Die Filderklinik, 70794 Filderstadt-Bonlanden, Germany
8 Anthroposophic Nursing Network in Germany, Academy for Nursing Professions at the Filderklinik,
Die Filderklinik, 70794 Filderstadt-Bonlanden, Germany
9 Clinic for Radiation Therapy and Special Oncology, Hannover Medical School, 30625 Hannover, Germany
10 Department of Internal and Integrative Medicine, Evang. Kliniken Essen-Mitte, Faculty of Medicine,
Citation: Klafke, N.; Bossert, J.; University of Duisburg-Essen, 45136 Essen, Germany
11 Department of Health, Zurich University of Applied Sciences, 8401 Winterthur, Switzerland
Kröger, B.; Neuberger, P.; Heyder, U.;
12 Department of Nursing Science, Institute of Health Sciences, University Hospital Tübingen,
Layer, M.; Winkler, M.; Idler, C.;
72076 Tübingen, Germany
Kaschdailewitsch, E.; Heine, R.; et al. 13 Institute for Complementary and Integrative Medicine, University Hospital Zürich and University of Zürich,
Prevention and Treatment of
8091 Zürich, Switzerland
Chemotherapy-Induced Peripheral
* Correspondence: nadja.klafke@med.uni-heidelberg.de
Neuropathy (CIPN) with
Non-Pharmacological Interventions:
Abstract: Background: Most individuals affected by cancer who are treated with certain chemother-
Clinical Recommendations from a
apies suffer of CIPN. Therefore, there is a high patient and provider interest in complementary
Systematic Scoping Review and an
Expert Consensus Process. Med. Sci.
non-pharmacological therapies, but its evidence base has not yet been clearly pointed out in the
2023, 11, 15. https://doi.org/ context of CIPN. Methods: The results of a scoping review overviewing the published clinical
10.3390/medsci11010015 evidence on the application of complementary therapies for improving the complex CIPN symp-
tomatology are synthesized with the recommendations of an expert consensus process aiming to
Academic Editor: Tracy Murray-Stewart
draw attention to supportive strategies for CIPN. The scoping review, registered at PROSPERO
Received: 2 August 2022 2020 (CRD 42020165851), followed the PRISMA-ScR and JBI guidelines. Relevant studies pub-
Revised: 14 December 2022 lished in Pubmed/MEDLINE, PsycINFO, PEDro, Cochrane CENTRAL, and CINAHL between
Accepted: 23 December 2022 2000 and 2021 were included. CASP was used to evaluate the methodologic quality of the studies.
Published: 30 January 2023 Results: Seventy-five studies with mixed study quality met the inclusion criteria. Manipulative
therapies (including massage, reflexology, therapeutic touch), rhythmical embrocations, movement
and mind–body therapies, acupuncture/acupressure, and TENS/Scrambler therapy were the most
frequently analyzed in research and may be effective treatment options for CIPN. The expert panel
Copyright: © 2023 by the authors.
Licensee MDPI, Basel, Switzerland.
approved 17 supportive interventions, most of them were phytotherapeutic interventions including
This article is an open access article external applications and cryotherapy, hydrotherapy, and tactile stimulation. More than two-thirds of
distributed under the terms and the consented interventions were rated with moderate to high perceived clinical effectiveness in ther-
conditions of the Creative Commons apeutic use. Conclusions: The evidence of both the review and the expert panel supports a variety of
Attribution (CC BY) license (https:// complementary procedures regarding the supportive treatment of CIPN; however, the application on
creativecommons.org/licenses/by/ patients should be individually weighed in each case. Based on this meta-synthesis, interprofessional
4.0/).
Med. Sci. 2023, 11, 15. https://doi.org/10.3390/medsci11010015 https://www.mdpi.com/journal/medsci

Med. Sci. 2023, 11, 15 2 of 34
healthcare teams may open up a dialogue with patients interested in non-pharmacological treatment
options to tailor complementary counselling and treatments to their needs.
Keywords: chemotherapy-induced peripheral neuropathy (CIPN); complementary therapies; sup-

portive therapy; scoping review; consensus process; cancer; integrative oncology; interprofessional
healthcare; non-pharmacological interventions
1. Introduction
Chemotherapy-induced peripheral neuropathy (CIPN) develops due to neurotoxic
treatments, in particular taxanes, vinca alkaloids, platinum agent, proteasome inhibitors,
and thalidomide [1]. Such treatments attack the cellular and sub cellular level and cause
altered ion channel activity (sodium, potassium, calcium) as well as changes in the in-
tracellular systems, which are responsible for oxidative stress, neuroinflammation, and
mitochondrial dysfunction [2,3]. In contrast to nociceptive pain, which occurs when a
painful stimulus activates the peripheral nociceptors, neuropathic pain is not the result of
damaged tissue, but is caused by inner structural deficits in the peripheral neurons and
sensory nerves [2,3]. Unpleasant CIPN symptoms appear in a variety of ways. Patients
often experience numbness in their feet and palms as well as paresthesia, acroataxia, and
the loss of motor functions, which contribute to the fact that patients with CIPN have a
high risk for falling injuries [4]. For many patients, even opening a water bottle is painful
or they feel like “walking on glass” [4] (a statement of some experts participating in the
symposium, see phase 2 under 2.2 “Structured expert consensus process”). Up to 71% of pa-
tients undergoing acute treatment (e.g., Oxaliplatin, Docetaxel) experience CIPN [5], and it
is one of the major symptoms that affects why patients may decide to cease their treatment.
Patients who develop CIPN are both at younger and older age, experience restrictions in
their quality-of-life functions, and therefore need effective treatment options [6]. Up to 42%
of patients experience CIPN two years after they started their taxane- and platinum-based
chemotherapy [7], and they are also in need for effective strategies for improving their
symptoms and increasing their quality of life [8].
Currently, there are not enough conventional CIPN treatments available, and the
most prescribed medication is Duloxetine, even though its effect size has been reported
to be moderate [9,10]. With the help of a systematic review, Hou et al. 2018 [1] identified
26 other treatment options in 35 included studies that were also on laser therapy and
acupuncture. The results, however, need to be considered with caution, as most studies
had small sample sizes and a variety of outcome measures. Hence, there is a need for
pointing out further treatment options to alleviate CIPN symptoms in order to relieve the
suffering of those affected. This is also shown in the fact that research indicates that up
to 80% of patients with cancer have an interest in so-called natural, non-pharmacological,
complementary interventions for self-managing their symptoms and actively take control
in their own symptom management [11,12]. Surveys have also identified an increase
of cancer patients’ use of complementary therapies from the timepoint before to after a
cancer diagnosis [13]. In this course of time, for example, the use of biologic products for
general symptom management and for coping with the new life situation has tripled to
52% [13]. Thus, healthcare teams should know how to consult patients suffering from
CIPN on complementary treatment options when conventional drugs like Duloxetine or
Gabapentine [14] are not effective enough or when patients’ preference is oriented towards
complementary and integrative health care (CIH).
Previous literature reviews have examined key complementary treatments that can
be applied to relieve general cancer pain [15] or neuropathic pain resulting from drug-
based tumor therapy [16]. The latter systematic review, however, has not included nursing
interventions, like external applications, which are relevant to consider when aiming to
relieve patients’ symptoms and treat them in a holistic and natural way. Even though
Med. Sci. 2023, 11, 15 3 of 34
Brami et al. [16] did suggest applying complementary therapies to prevent or treat CIPN—
for example, Vitamin E, L-Glutamine, Goshajinkigan, and Omega-3—the authors think
that the oral intake of such natural products is not the only option available. In the last
years, there have been other studies published reporting that henna applications [17] or
cryocompression [18,19] are also beneficial, to name just a few more options, and they can
be applied for CIPN symptom management.
Therefore, the purpose of this article is to provide interprofessional healthcare teams
with a comprehensive literature review and clinical recommendations of the best available
evidence on complementary treatments for the prevention of CIPN and for the supportive
management of CIPN during or after conventional treatment.
2. Materials and Methods

The methodology for outlining the clinical recommendations of evidence-based com-
plementary prevention and treatment options followed a two-phase guideline [20,21]. In
Phase 1, a scoping review to find external evidence by published studies was conducted,
and in Phase 2, a structured expert consensus process on complementary interventions for
CIPN was performed. This was followed by a synthetization of both phases in terms of
their non-pharmacological treatment options.
According to Sackett’s approach of evidence-based medicine, individual clinical deci-
sions should be made by considering the best available scientific evidence, the personal ex-
pertise of the health professionals, and the needs and values of the persons to be treated [22].
Ideally, the highest level of evidence is available for the specific clinical decision question
from randomized controlled trials (RCTs), systematic reviews, or meta-analyses. For some
questions, however, only evidence from lower levels is available, so that the next possible
evidence must be sought and considered [22]. In the hierarchy of evidence, assessments by
experts are assigned to the lowest level of evidence [23].
Based on clinical experience with naturopathic medicine, especially in German-
speaking hospitals, we experienced that many different symptom management methods
are used as supportive care for CIPN. Furthermore, due to the different levels of evidence
and standardization of these methods, the authors wanted to first clarify these commonly
used methods in a consensus meeting and then compare those results with the systematic
literature search. The authors also see that approaches based on consensus and literature
reviews make a significant contribution to the prevention and treatment of various symp-
toms in patients with cancer in the field of nursing and integrative care practice [21,24].
Therefore, the authors think that this study will contribute to the literature, especially in
terms of comparing the consensus-based results of the practices used in German-speaking
countries by an expert consensus team with the results of a systematic literature search.
2.1. Phase 1: Scoping Review

2.1.1. Literature Search
A review of the literature was performed following the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) Checklist
(Supplementary S1) [25]. As recommended, the frameworks by Arksey and O’Malley [26]
and Levac et al. [27] were used as a guidance, as presented in the synthesis and enhancement
of the Joanna Briggs Institute (JBI) [28]. A primary search on CIPN (or the risk of developing
CIPN) as the main outcome was performed using the terms “(cancer) AND (neuropathies or
peripheral neuropathy or CIPN) AND (complementary therapies or non-pharmacological
therapies)”. An additional search was conducted on general pain as the main outcome and
also including other chronically ill patients, to get further insights for transferability of the
results to CIPN. In line with the definition by the National Center for Complementary and
Integrative Health (NCCIH) [29] and by Witt et al. 2017 [30], the authors understand non-
pharmacological interventions in the field of integrative oncology to be evidence-based and
complementary to conventional therapy, which can help alleviate patients’ symptoms and
enhance their quality of life and resilience. A primary search was performed using the terms
Med. Sci. 2023, 11, 15 4 of 34
“(cancer) AND (neuropathies or peripheral neuropathy or CIPN) AND (complementary

therapies)”. Search strategies were adapted for the databases of Pubmed/MEDLINE,
PsycINFO, PEDro, Cochrane Central, and CINAHL, ending on 31 July 2021. The full
search strategy can be found in Supplementary S2 and was reported in the review protocol
registered at PROSPERO 2020 (CRD 42020165851) [31].
2.1.2. Study Screening and Selection Criteria

The inclusion criteria were designed to include all possible study types (e.g., RCTs,
controlled studies, cohort studies, case studies, pilot studies, expert opinions, reviews,
qualitative studies, clinical guidelines). Articles were included in this review if adult
patients with cancer (search one) or chronically ill patients were the focus of interest of the
research (extended search two). There were no restrictions by population characteristics
(e.g., type of cancer, stage of cancer, adults, gender, comorbidities, country, geographic
location, ethnicities, cultural groups). Only studies published in English, French, or German
language were included. Study protocols and pre-clinical studies were excluded. Studies
with children were also excluded as such patients require special pediatric treatment.
2.1.3. Data Extraction and Reporting

Titles and abstracts were retrieved by two review authors (NK, RS) working indepen-
dently, and then imported to EndNote X9 © (Clarivate Analytics, PA, USA) and dedupli-
cated. Selected records were then uploaded to Rayyan (Qatar Computing Research Institute,
Doha, Qatar) [32] and screened for eligibility. Then, a core team of four researchers (RS, BK,
JB, NK) screened titles and abstracts, with relevant articles selected for full-text review. This
was conducted in duplicate, so that there was a mutual review and further coordination if
necessary. Disagreements on inclusion or exclusion were resolved by regularly discussing
and solving the “conflicts” displayed in Rayyan. In Figure 1, the search and screening and
selection process of the articles are documented according to PRISMA-ScR. A data charting
form was developed to capture relevant data from studies (see Tables S1 and S2 in the
Supplementary S3 and S4).
2.1.4. Risk of Bias Assessment

All included studies were assessed using the Critical Appraisal Skills Program (CASP) [33],
which consists of a set of criteria to proof, and is available for different study types. For
instance, the CASP Randomized Controlled Trials Checklist (2017) entails 11 questions regard-
ing the quality of the study (Supplementary S5, Table S3: Critical appraisal of the included
studies). Microsoft Excel and FreeHand were used for graphical display, data cleaning,
formatting, and analysis.
2.2. Phase 2: Structured Expert Consensus Process

The methodology is based on the systematic and structured process of expert con-
sensus used by the AWMF (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen
Fachgesellschaften e.V. = Association of the Scientific Medical Societies) to develop scientific
clinical guidelines [34]. For this second phase, a two-day workshop was planned under
the theme “Supportive management for CIPN in patients with cancer” and took place in
September 2018 at the Evang. Kliniken Essen-Mitte in Essen, North Rhine-Westphalia,
Germany. Sixteen experts with a naturopathic background and experience in cancer
treatment and care from nine different clinical settings in Germany and Switzerland dis-
cussed non-pharmacological treatment options for CIPN. The expert panel consisted of
11 nurses, 4 physicians, and 1 psychologist. The aim of the symposium was to share
experiences and also to develop clinical and research recommendations for the support-
ive treatment of CIPN. As there is no professional society for naturopathic care in Ger-
many, renowned experts from clinics with many years of experience in naturopathy were
invited to the symposium. In the meantime, the expert group has become a working
group of the German Society for Nursing Science section of oncological nursing (https:
Med. Sci. 2023, 11, 15 5 of 34
Med. Sci. 2023, 11, x FOR PEER REVIEW 5 of 36
//dg-pflegewissenschaft.de/sektionen/klinische-pflege/onkologische-pflegeforschung-2/, ac-
cessed on 1 December 2022).
Figure 1. Flowchart of article selection process.

Figure 1. Flowchart of article selection process.
Criteria for Consensus Finding
On the 2.1.4. Risk all
first day, of Bias Assessment
supportive adjunct therapies for CIPN were discussed under the
question “What All measures
included dostudies
you use to prevent
were assessed or treatthe
using CIPN in clinical
Critical practice?”
Appraisal in
Skills Program
the expert panel.
(CASP)Since all measures
[33], which consists have already
of a set been
of criteria applied
to proof, andinisclinical
availableuse
forfor manystudy
different
types.
years, only safe For instance,
measures were the CASP Randomized
mentioned. In total, 17Controlled Trials Checklist
complementary (2017) were
treatments entails 11
summarizedquestions regarding
on a collecting the On
board. quality of the day,
the second studyall(Supplementary
the complementary S5, Table S3: Critical
treatments
were furtherappraisal of theFor
consented. included studies).
arranging andMicrosoft Excelthe
classifying and nursing
FreeHandinterventions,
were used for graphical
the
display,
following criteria dataconsidered
were cleaning, formatting,
as highlyand analysis.
relevant: safety, clinical experience, effort of
training, and practical feasibility. It was consented to rate all complementary treatments on
these criteria as follows:
Med. Sci. 2023, 11, 15 6 of 34
• S = safe;
• CE = clinical experience (rated on a numerical scale 0 to 5, with 0 = no effect and
5 = maximum effect);
• ET = effort of training (education requirements in addition to a nursing grade; 0 = no
additional instructions or education needed, 1 = instructions needed, 2 = application under
guidance, 3 = repeated practice needed, 4 = basic training of rhythmical embrocation (200 h)
recommended but partial skills can be acquired with less than 200 h, and 5 = basic training
of rhythmical embrocation (200 h) needed);
• PF = practical feasibility (PFt = feasibility limited due to time requirements; PFtt = feasibility
strongly limited due to time requirements; PFc = feasibility limited due to high costs
(>30 EUR per month)).
The consensus process is based on the AWMF’s systematic and structured process for
the development of scientific clinical guidelines [34]. It was moderated by two physicians
(DS, PV) and each intervention was evaluated on the above-mentioned criteria. Each
clinic had one vote, and when a clinic was represented by more than one participant, the
participants had to coordinate their vote with each other.
3. Results
3.1. Search Results
A total of 264 potentially relevant articles were identified and screened, wherein
145 articles were assessed in detail, of which 75 studies (41 quantitative studies, 3 mixed-
methods studies, 26 reviews, 5 clinical guidelines) were included in the scoping review
(Figure 1). Most studies were conducted in North America (n = 27), Europe (n = 18), Asia
(n = 16), the Middle East (n = 8), UK (n = 4), and Australia (n = 2).
3.2. Consensus from the Expert Panel

During the two-day expert symposium (08/18), consensus was found for 17 non-pharmacological
interventions (see Table 1, and detailed version in Table S4 in Supplementary S6), and some
could also/only be applied for preventive use. The experts rated all nursing interventions as
safe, and practical feasibility was given for 15 of them. Only for the therapeutic application
of rhythmical embrocations (RE) practical feasibility was assessed as limited because RE
are more time-consuming and require a high level of qualification. All other interventions
can be performed by the patients themselves after instruction.
3.3. Preventative Options for CIPN

The review included 14 studies focused on CIPN (Table 1) that dealt with preven-
tive interventions. Those were phytotherapy (Phy) (henna application) on hands and
feet [17], Phy in Traditional Chinese Medicine [35], and Phy for hand and foot baths or
fumigation [36]; sensorimotor training (SM), e.g., been bath [37], physical activity [38],
cryotherapy (CT) [19,39,40], massage (M) [41], and cryocompression (CC) [18]; some nutri-
tional interventions [16,42]; and acupuncture/acupressure [42]. Additionally, compression
was recommended by one study [43] as well as by the expert panel. This recommended in
total six interventions that can be used for prevention, but without an assessment of their
effectiveness (Table 1).
3.4. Complementary Treatment Options for CIPN

Key findings of the included studies are presented in Table 1 including a condensed
result presentation of the review and the consensus process. The classification of classical
natural therapies according to Kneipp and non-classical natural therapies [44] was applied
to further categorize and analyze the complementary therapies that were reported in the
studies. In total, 13 distinct categories were identified (Figure 2).
Details of the interventions examined in the included studies can be found in Tables S1–S3;
Table S1 (“Characteristics of selected studies included in the scoping review (nursing
interventions for CIPN)”) and S2 (“Characteristics of other relevant studies for treat-
Med. Sci. 2023, 11, 15 7 of 34
ing pain with complementary therapies in cancer patients of other patient populations”)
can be found in Appendices 3 and 4). Overall, the study quality ranged from excellent
(n = 29) [15,17,35,37,41,42,45–66] to satisfactory (n = 8) [19,67–73] and poor (n = 1) [74],
while most studies had good study quality (n = 37) [16,18,38–40,43,75–105] (see Table S3 in
Supplementary S5).
Figure 2 illustrates the evidence (Tables S1, S2 and S5) by referring to the number
of studies/expert recommendations that the authors included for the 13 categories of
non-pharmacological treatment options, which can be administered by doctors, oncology
nurses, psycho-oncologists, physiotherapists, and all other members of interprofessional
healthcare teams. Figure 3 visualizes how the different treatment options relate to the
different health professionals. In 38 out of 75 of the studies, statements were made on the
conceptual therapeutic approach. In the following, the evidence for the top seven most
frequently identified complementary procedures are described.
Figure 2. Overview of number of evidence sources for CIPN and general pain.
Figure 2. Overview of number of evidence sources for CIPN and general pain. Legend of Figure 2.
Legend of Figure 2.
− 1 incl. aromatherapy, topical therapy, no oral phytotherapeutics, and flaxseed bath;
−2 incl. physical therapy, sensorimotor training, exercise, closed kinematic chain exer-
− 1 incl. aromatherapy, cise,
topical therapy,
resistance nocardiovascular
training, oral phytotherapeutics, and
exercises, walking, flaxseed
cycling, bath;
whole-body-vi-
− 2 incl. physical therapy,
bration,sensorimotor training,
passive mobilization, exercise,
coordination training,closed kinematic
and tactile stimulation; chain
exercise, resistance− training,
3 incl. relaxation, PMR, yoga, meditation,
cardiovascular exercises,hypnosis,
walking, guided imagery,
cycling, cognitive ther-
whole-body-
apies, and distraction therapy, as well asQi Gong and Tai Chi;
vibration, passive−mobilization, coordination training, and tactile stimulation;
4 incl. vitamin and mineral supplements and dietary modification;
− 3 incl. relaxation, −PMR, yoga,
5 incl. meditation,
alcaline bath and coldhypnosis,
knee and/or guided imagery, cognitive thera-
arm showers;
− therapy,
pies, and distraction 6 incl. Tai Chi, Qi Gong,
as well andGong
as Qi massageandacc. to
TaiTCM;
Chi;
− 7 incl. cryocompression, cold applications, and hypothermia;
− 4 incl. vitamin and −
mineral supplements and dietary modification;
8 incl. hyperthermia;
− 5 incl. alcaline bath
− and cold kneereflexology,
9 incl. massage, and/or arm showers;
and foot reflexology;
− 6 incl. Tai Chi, Qi −Gong, and
10 incl. massage
healing touch, acc.
Reiki,to
andTCM;
therapeutic touch;
− 11 incl. compression, cupping (draining procedures), hydroelectric bath, music ther-
− 7 incl. cryocompression, cold applications, and hypothermia;
apy, support groups, patient education, and nurse-led follow-up.
− 8 incl. hyperthermia;
− Note. Study quality of the included studies varied—see Table S3 (Supplementary S5)
− 9 incl. massage, reflexology,
for criticaland foot reflexology;
appraisal.
− 10 incl. healing touch, Reiki, and therapeutic touch;
− 11 incl. compression, cupping (draining procedures), hydroelectric bath, music ther-
apy, support groups, patient education, and nurse-led follow-up.
− Note. Study quality of the included studies varied—see Table S3 (Supplementary S5)
for critical appraisal.
Med. Sci. 2023, 11, 15 8 of 34
Table 1. Summary of studies and results of consensus process regarding the options (O) for prevention (p) or/and treatment (t) of CIPN.
O for p or t Author 1 Study Design 2 p3 t3 Intervention Outcome Measures Result/Clinical Experience (CE) 4
√ Significant beneficial effect. Low cost,

Arslan et al. 2020 [17] RCT (n = 60) - Henna application CIPN assessment tool safe intervention, and well tolerated
by patients.
Fallon et al. 2015 in S3 √ Brief Pain Inventory (BPI), Significant reduction in
clinical guideline Proof of concept study - Application of menthol crème 1%
Quantitative Sensory Testing pain symptoms.
Supportive therapy [37]
√ Neuropathic symptoms, numeric Significant lower severity of pain
Izgu et al. 2019 [101] Pilot RCT (n = 46) - Aroma hand and foot massage.
rating scale based on NRS.
√ √ Improvement of sensory nerve

All types of Chinese herbal medicine
Li et al. 2019 [35] Meta-analysis CIPN grade, Levi’s grade conduction velocity and motor nerve
in TCM
conduction velocity.
Syst. Review of RCTs √ √ All types of Phy used Clinical improvement, nerve Potentially preventive and/or
Noh et al. 2018 [36]
(n = 28) for medicinal purposes conduction study (NCS) therapeutic effects for CIPN
Phytotherapy
√ Statistically significant
Noh and Park 2019 [50] RCT (n = 31) - Aroma foot reflexology CIPN assessment tool
reduction of symptoms.
√ Functional Assessment of Cancer Failed to improve the symptoms of
Rostami et al. 2019 [75] RCT (n = 34) - Topical c. colocynthis oil
Therapy (FACT), Neurotoxicity score CIPN compared with placebo.
√ √
Consensus process N/A Aconit oil application Clinical improvement CE 3
√
Consensus process N/A Solum oil application Clinical improvement CE 1
√ √
Consensus process N/A Flaxseed bath Clinical improvement CE 4
√ √
Consensus process N/A Arnica comp/Formica oil application Clinical improvement CE 3
√ Arnica comp/Formica ointment (for
Consensus process N/A - Clinical improvement CE 3–4
stronger effect of Aconit)
√
Consensus process N/A - Rosemary ointment Clinical improvement CE 3–4
√ Peppermint oil application for heat
Consensus process N/A - Clinical improvement CE2
sensations and paraesthesia
√ Eucalyptus oil application for heat
Consensus process N/A - Clinical improvement CE 2
sensations and paraesthesia
Med. Sci. 2023, 11, 15 9 of 34
Table 1. Cont.
Improvement of CIPN pain for
Single-blind ex-ploratory √ √ Patient questionnaires, quantitative patients with breast cancer.
Andersen et al. 2020 [38] Physical therapy
RCT (n = 48) sensory testing Correlation to preservation of
sensory function.
Evidence was reported for
interventions consisting of physical
√ Nerve conduction velocity, (NCV), activity components; for strength and
Systematic review of
Brami et al. 2016 [16] - Physical activity Neurological Symptom Score, Total endurance training; and for
RCTs (n = 13)
Neuropathy Score, QoL multimodal self-help strategies
including physical activity, yoga,
and mindfulness.
Single-group pre-post √
Fernandes and Kumar Modified Total Neuropathy Score Significant change in values before
prospective study - Closed kinematic chain exercise
2016 [69] (mTNS), Berg Balance Score (BBS) and after the exercise.
(n = 25)
Comprehensive
inte-grative √ Empirical evidence is insufficient to
Kanzawa-Lee et al. 2020 Exercise with Aerobic, strength
review(7 RCTs, - CIPN, balance, and fitness definitively conclude that exercise
Movement therapies
[54] training, and balance training

6 quasi-experimental interventions ameliorate CIPN.
studies)
EXCAP©® a standardized,
√ individualized, moderate-intensity, Reduction of CIPN symptoms
Secondary analysis of a
Kleckner et al. 2018 [48] - home-based, six-week progressive Patient-reported CIPN symptoms (hot/coldness in hands/feet,
phase III RCT (n = 355)
walking and resistance numbness, and tingling).
exercise program
Prospective pilot Total Neuropathy Score—clinical Reduction of CIPN symptoms and
√ 8-week multimodal exercises
intervention study, single version (TNSc), EORTC CIPN-20, related functional and quality of life
McCrary et al. 2019 [84] - (resistance, balance,
group pre-post design functional assessment tools, disability, deficits. No changes in sensory or
cardiovascular training)
(n = 35) and QoL motor neurophysiologic parameters.
Functional Assessment of Cancer
√ Whole-body vibration including Therapy/Gynecologic Oncology Significantly and clinically relevant
Schönsteiner et al. 2017 Randomized exploratory
- massage, passive mobilization, and Group neurotoxicity subscale beneficial impact on symptom relief,
[89] phase 2 study (n = 131)
physical exercise. (FACT/GOG-NTX), EORTC QLQ-C30 physical fitness, and sensory function.
Quantitative sensory testing (QST)
VPT score, numeric rating scale for Significant reductions in postural
pain (NRS), neuropathy-related sway parameters in challenging
Single blinded, √ Interactive motor adaptation balance numbness in feet (NRS score), semi-tandem position.
Schwenk et al. 2016 [90] randomized controlled -
training program Short-Form Health Survey (SF-12), No significant changes were noted for
pilot study (n = 22)
Falls, Efficacy Scale-International balance with “eyes closed”, gait speed,
(FES-I) and fear of falling.
Med. Sci. 2023, 11, 15 10 of 34
Table 1. Cont.
Steinmann et al. 2011 in
√ √ 81% of patients consider tactile
S3 clinical guidelineS3
Overview article Tactile Stimulation (e.g., been bath) Clinical improvement stimulation to be very effective
Guideline Supportive
or effective.
therapy 2020 [37]
Streckmann, Kneis et al.
√ QOL; coordination, Due to the highly significant
2014 in Exercise (sensorimotor training,
RCT (n = 62) - endurance, strength, therapy-induced physiological parameters, the study
S3 Guideline Supportive endurance, strength)
side-effects. was terminated prematurely.
therapy 2020 [37]
Systematic review of √ Number of patients with reduced
Streckmann, Zopf et al.
RCTs (n = 10), CCT - Exercise interventions Side effects of Polyneuropathy deep sensitivity could be diminished.
2014 [60]
(n = 8) Only one RCT related to CIPN.
Sensorimotor training and
Movement therapies
whole-body vibration represent new

options for CIPN treatment.
√ Clear evidence of improvement of
S3 Guideline Supportive
S3 Guideline - Non-drug methods Not described functional limitation through
therapy 2020 [37]
non-medicinal procedures such as
sports therapy, occupational therapy,
physiotherapy, and physical therapy
including electrotherapy.
Review of RCTs (n = 10), Recommendation of physical therapy
single-arm study (n = 1), √ as a treatment option, but no studies
Neuropathy symptoms,
Tofthagen et al. 2012 [96] cross-over-study (n = 1), - Strength training and balance training were identified that evaluate strength
strength, balance
quasi-experimental study training and balance training for
(n = 1) treatment of CIPN.
√ Multimodal exercise program, Regarding CIPN (TOI), there were

Trial Outcome Index
Zimmer et al. 2018 [94] RCT (n = 30) - (endurance, resistance, significant differences between groups
(TOI),NCI-CTC/FACT/GOG-NTX
balance, coordination) in the main analysis.
√
Consensus process N/A - Sugar oil peeling Clinical improvement CE 3
√ √
Consensus process N/A Tactile stimulation Clinical improvement CE 2–3
√ Evidence was reported for

Systematic review of NCV, Neurological Symptom Score,
Brami et al. 2016 [16] - Mind-Body modalities self-management strategies including
Mind-body
RCTs (n = 13) Total Neuropathy Score, QoL

therapies
yoga and mindfulness.

Functional Reach, Timed Up and Go,
Open-label, single-arm, √ Patient Neurotoxicity Questionnaire Significant improvements were found
Galantino et al. 2019 [80] - Yoga, Meditation
feasibility trial (PNQ), in flexibility, balance, and fall risk.
(FACT-GOG-NTX)
Med. Sci. 2023, 11, 15 11 of 34
Table 1. Cont.
Comprehensive
Mind-body
therapies
inte-grative √ Empirical evidence is insufficient to

Kanzawa-Lee et al. 2020
review(7 RCTs, 6 - Yoga, exercises CIPN, balance, and fitness definitively conclude that exercise
[54]
quasi-experimental interventions ameliorate CIPN.
studies)
Vitamin E, Glutamine, Goshajinkigan,
√ √ Glutamine, Goshajinkigan, vitamin E,
Systematic review of NCV, Neurological Symptom Score, and Omega-3 may prevent CIPN.
Brami et al. 2016 [16] Omega 3, Acetyl-l-carnitine,
RCTs (n = 13) Total Neuropathy Score, QoL Acetyl-l-carnitine may worsen CIPN;
Alpha-lipoic-acid
Alpha-lipoic-acid activity is unknown.
Nutritional
therapy
Clinical practice Acetyl-l carnitine is not recommended

guideline based on a √ √ Omega-3, fatty acids, vitamin E, to prevent CIPN. Insufficient evidence
Greenlee et al. 2017 [42] -
systematic literature alpha-lipoic acid, dietary modification that Omega-3, fatty acids, and vitamin
review of RCTs. E help to reduce neuropathy.
√ Positive effects. No statistically
Rostock et al. 2013 [88] Four arm RCT (n = 60) - Vitamin B complex Detailed questionnaire, NRS
significant results.
Hydrotherapy
√ Alkaline bath for hand/foot, then

Aconit oil application
√
Consensus process N/A - Cold knee and/or arm showers Clinical improvement CE 3
Systematic review of √ NCV, Neurological Symptom Score,

Brami et al. 2016 [16] - Electroacupuncture Not superior to placebo.
RCTs (n = 13) Total Neuropathy Score, QoL
Acupuncture/Acupressure
meta-analyses (n = 4), √ Some improvement regarding VAS

Deng et al. 2013 [53] - Acupuncture VAS, neuropathy symptoms, QoL.
syst. Reviews (n = 14), and neuropathy symptoms.
RCT (n = 16)
Retrospective √ 82% (n = 14) reported improvement of
Donald et al. 2011 [68] - Acupuncture CIPN symptoms.
Evaluation (n = 18) neuropathy symptoms.
Clinical practice
√ √ Insufficient evidence that
guideline based on a
Greenlee et al. 2017 [42] Acupuncture, electroacupuncture - electroacupuncture help to
systematic literature
reduce neuropathy.
review of RCTs.
Rostock et al. 2013 [88] Four arm RCT (n = 60) - Electroacupuncture Detailed questionnaire, NRS Scale
Med. Sci. 2023, 11, 15 12 of 34
Table 1. Cont.
Acupuncture/Acupressure
S3 guideline
complementary √ Data are available from a
BPI, Total Neuropathy Score, NCS,
medicine in the S3 guideline - Acupuncture, electroacupuncture meta-analysis and two RCTs on the
Functional Assessment, QoL.
treatment of oncology efficacy of A- for CIPN.
patients [57]
Prospective phase 2 √ Numbness score, mTNS, Edmonton Statistically significant difference at 6

Wong et al. 2016 [93] - Acupuncture like TENS
study (n = 40) Symptoms Assessment Scale (ESAS) months from the baseline pain score.
Proof-of-concept study √ Potentially improve efficacy of

Bandla et al. 2020 [18] - Cryocompression Total neuropathy score (TNS), NCS
(n = 26) preventing CIPN. Safe and tolerable.
√ Significant reduction of CIPN symptoms.
Beijers et al. 2020 [39] RCT (n = 180) - Frozen glove and sock CIPN20
Dropout of one-third of patients.
Cryotherapy
√ No significant differences in
Neuropathic Pain Symptom
Griffiths et al. 2018 [19] RCT (n = 29) - Frozen glove and sock neuropathy or pain. Drop-out rate,
Inventory, BPI.
more than 50 %.
Prospective pilot study √ Visual analog scale (VAS), No significant difference in NCS. Well
Sundar et al. 2017 [40] - Continuous-flow limb hypothermia.
(n = 20) subjective tolerance scale, NCS, tolerated by all patients.
√
Consensus process N/A - Frozen gloves and socks Clinical improvement Cannot be assessed.
√ Greatly reduced CIPN symptoms

Brami et al. 2016 [16] - Massage, touch therapy MD Anderson Symptom Inventory from grade 2 to 1 and significantly
RCTs (n = 13))
improved quality of life.
√ Greatly reduced CIPN symptoms

Cunningham et al. 2011
Case report - Massage MD Anderson Symptom Inventory from grade 2 to 1 and significantly
[74]
Manipulative therapies
improved quality of life.

Self-Leeds Assessment of
√ Massage successfully prevented CIPN,
Neuropathic Symptoms and Sign
Izgu et al. 2019 [41] RCT (n = 40) Massage improved the QoL, and showed
(S-LANSS), EORCT QLQ CIPN20,
beneficial effects on the NCS findings.
NCS.
VAS, Doleur
√ Neuropatique/Neuropatic pain
Sarisoy, et al. 2020 [76] RCT (n = 40) - Foot-massage Positive effect on CIPN pain.
(DN4), Pittsburg Sleep Quality Index
(PSQI)
√ Whole-body vibration including (FACT/GOG-NTX), Significantly and clinically relevant

Schönsteiner et al. 2017 Randomized exploratory
- massage, passive mobilization, and EORTC QLQ-C30 beneficial impact on symptoms relieve,
[89] phase 2 study (n = 131)
physical exercise. Quantitative sensory testing (QST) physical fitness, and sensory function.
Med. Sci. 2023, 11, 15 13 of 34
Table 1. Cont.
√
Consensus process N/A - Aconit oil—rhythmical embrocation Clinical improvement CE 4
embrocations
Rhytmical
√ Arnica comp/Formica
oil—rhythmical embrocation
√ NRS, BPI, European Organization for Clinically important and statistically

Expanded trial, single
TENS/Scrambler
Coyne et al. 2013 [67] - Scrambler therapy Treatment and Cancer CIPN20 significant improvements were seen in
arm trial (n = 39)
(EORTCCIPN20) average, least, and worst pain.
therapy
Gewandter et al. 2019 √ EORTC-CIPN20, Utah Early Significant improvements were

Single-arm study (n = 29) - TENS
[65] Neuropathy Score observed with the EORTC-CIPN20.
RCT, two arm phase II √ EORTC CIPN20, NAS questionnaire Scrambler therapy improves CIPN
Loprinzi et al. 2020 [71] - Scrambler therapy, TENS
pilot trial (n = 50). regarding CIPN-associated pain symptoms more than TENS.
Double-blind phase 2 √ No significant reduction of
Kotani et al. 2021 [43] - Compression Incidence of Grade ≥ 2 CIPN.
interventions
trial (n = 56) CIPN incidence.

supportive
Other

Rostock et al. 2013 [88] Four arm RCT (n = 60) - Hydroelectric bath Detailed questionnaire, NRS
√
Consensus process N/A - Compression Clinical improvement Cannot be assessed.
√
Consensus process N/A - Copper ointment (0.4%) Clinical improvement E2
1 2 3 √ 4
Legend. The number in brackets refer to the comprehensive reference list (see full article). N/A: not applicable. : meets criteria; -: does not meet criteria, CE = Clinical experience
(rated on a numerical scale 0 to 5 with 0 = no effect and 5 = maximum effect.
Med. Sci. 2023, 11, 15 14 of 34
Figure 3. Interprofessional
Figure CIPNCIPN
3. Interprofessional symptom management.
symptom Legend.
management. Number
Legend. in brackets
Number refer torefer
in brackets ex- to
ternal study evidence and results of the consensus process (Tables S1, S2 and S5).
external study evidence and results of the consensus process (Tables S1, S2 and S5).
3.5. 3.5. Manipulative

Manipulative Therapies
Therapies
ThisThis section
section reports the
reports the results
resultsononnon-classical naturopathic
non-classical treatments
naturopathic of manipulative
treatments therapies,
of manipu-
which
lative include which
therapies, massage (M), reflexology
include massage (R),
(M),and R of the feet.
reflexology (R),The
andmedical literature
R of the on M
feet. The therapy
medi-
cal yielded
literature 25 results, of whichyielded
on M therapy 5 studies25were especially
results, related
of which 5 to the therapy
studies were of CIPN [16,41,74,76,89]
especially related
to and
the 19 studies focused
therapy of CIPNon cancer pain [15,45,46,49,51,56,58,63,64,66,77,78,83,87,99,100,102,103,105]
[16,41,74,76,89] and 19 studies focused on cancer painand
1 [72] on any medical condition, which may result from the
[15,45,46,49,51,56,58,63,64,66,77,78,83,87,99,100,102,103,105] andpresence
1 [72] on of CIPN. Within the
any medical
condition, which may result from the presence of CIPN. Within the 25 studies, theresystem-
25 studies, there are 10 RCTs [41,45,46,49,76–78,83,87,89], 11 reviews (including are
atic reviews/meta-analysis)
10 RCTs [41,45,46,49,76–78,83,87,89], [15,16,51,56,58,64,72,99,100,102,103],
11 reviews (including systematic1reviews/meta-anal-
case report [74], 1 quasi-
ysis)experimental study [105] and 2 recommendations
[15,16,51,56,58,64,72,99,100,102,103], from guidelines
1 case report [63,66]. The quality
[74], 1 quasi-experimental of most
study
studies,
[105] and 2including the two guidelines,
recommendations were rated
from guidelines excellent
[63,66]. (nquality
The = 11) [15,41,45,46,49,51,56,58,63,64,66]
of most studies, includ-
ing according to the CASP
the two guidelines, scheme
were rated[106] or good
excellent (n (n = 12)
= 11) [16,76–78,83,87,89,99,100,102,103,105].
[15,41,45,46,49,51,56,58,63,64,66] ac-
One study was rated satisfactory (n = 1) [72] and the case report [74] was rated as poor in
cording to the CASP scheme [106] or good (n = 12) [16,76–78,83,87,89,99,100,102,103,105].
Oneterms
studyofwas quality.
ratedMore details on
satisfactory (n the
= 1)assessment
[72] and theofcase
study quality
report [74]according
was ratedtoas CASP
poorcanin be
found in the Supplementary S5 (Table S3).
terms of quality. More details on the assessment of study quality according to CASP can
be found in the Supplementary S5 (Table S3).
Massage, Reflexology, and Foot Reflexology
Massage,During M, mechanical
Reflexology, and Foottouch techniques are used to act on the muscles and connective
Reflexology
tissues. The main purpose of classical M is said to be the treatment and prevention tension;
During M, mechanical touch techniques are used to act on the muscles and connec-
the stimulation of blood and lymphatic circulation and metabolism; and the influence on
tive tissues. The main purpose of classical M is said to be the treatment and prevention
circulation, blood pressure, respiration, and psyche. R is a form of M in which pressure
tension; the stimulation of blood and lymphatic circulation and metabolism; and the in-
is applied to the hands and feet [49,107]. Pain reduction through M is explained by
fluence on circulation, blood pressure, respiration, and psyche. R is a form of M in which
desensitization of nociceptors [83].
Med. Sci. 2023, 11, 15 15 of 34
Of the five studies with focus on CIPN, three assessed classical M. Classical M signifi-
cantly prevented CIPN and neuropathic pain as well as improved nerve conduction and
QoL when compared to usual care at week 12 (n = 1 study; n = 40 participants receiving ad-
juvant paclitaxel for breast cancer; intervention duration: 12 weeks) [41]. In one case report,
which is also reported in a systematic review [16], classical M is associated with greatly
reduced CIPN symptoms from grade 2 to 1 and markedly improved quality of life [74]. In
one RCT, foot M was shown to reduce patients’ pain scores and have a positive effect on
sleep quality, compared to clinical routine (n = 40 patients with non-Hodgkin’s lymphoma;
intervention duration: four weeks) [76]. A program including M and mobilization as well
as physical E and WBV had a significantly and clinically relevant beneficial impact on
symptom relief, physical fitness, and sensory function (n = 1 study; n = 131 participants;
intervention duration: 15 weeks) [89].
Of the four RCTs that assessed classical M for cancer pain [49,83,87,105], two found
no statistically or clinically improvement in pain (n = 2 studies; n = 610 participants with
cancer pain; intervention duration: two and four weeks) [49,87] and one found significantly
higher reduction of physical discomfort in IG compared to routine health care (n = 1 study;
n = 86 participant; intervention duration: five weeks) [83]. Foot massage showed positive
effects on pain (n = 1 study; n = 87; intervention duration: three consecutive days) [105].
The four RCTs that assessed R in cancer patients [45,46,77,78] reported heterogeneous
effects regarding pain. R was found to have positive effect on pain and overall well-being
compared to aromatherapy-M (n = 1 study, 115 participants, intervention duration: four
treatments) [46]. Reflexology complemented by PMR exercises was found to decrease
pain and fatigue and increase quality of life (n = 1 study; n = 80 participants, intervention
duration: eight weeks) [45]). No statistically significant effect could be shown for pain in
cancer patients treated with foot R (n = 1 study; n = 36 participants; intervention duration:
two times, 24 h apart) [77]. In contrast, an immediate positive effect of foot R for patients
with metastatic cancer who reported pain was found (n = 1 study; n = 256 participants;
intervention duration: four weeks) [78]. Evidence for R as a treatment for any medical
condition could not be demonstrated convincingly in a systematic review (n = 18 RCTs;
n = 949 participants) [72].
In the nine reviews and meta-analyses that assessed M or R in cancer patients [15,
51,56,58,64,99,100,102,103], studies with different types of massage and reflexology were
included. The results were heterogeneous. Improvement of pain through M was reported
(n = 2 studies; n = 30 RCTs; n = 4448 participants) [56,58] as well as through foot reflexology
(n = 1 study; n = 12 RCTs; n = 559 participants) [56]. Weak recommendations are suggested
for M, compared to an active comparator, for the treatment of pain, fatigue, and anxiety.
No recommendations were suggested for M therapy compared to no treatment or sham
control (n = 1 study; n = 16 RCTs) [51]. Beneficial effects of classical M for pain of any origin
are reported in a nursing guideline [66]. Due to the heterogeneous data from RCTs on the
effectiveness of classical M in reducing pain in oncology patients, no recommendation can
be made for or against the use of classical M to reduce pain in another guideline [63].
3.6. Rhythmical Embrocations (Including Healing Touch, Therapeutic Touch, Reiki)

RE are a gentle, gliding touch along archetypal forms of the body [108]. It is believed
that RE strengthen life forces, enhance warmth, and harmonize rhythmic processes in the
body. For application, RE utilizes massage oils and plant or metal ointments. Therapeutic
touch (TT) describes a method of laying hands on a person by a therapist. Thereby it is
assumed that there are human energy fields, which are in constant interactions with each
other and with their environment. The therapist’s goal is to bring these energy fields back
into balance [63,81,104].
The medical literature yielded six results of which five were related to cancer-related
symptoms [15,63,81,87,104] and one to low back pain [86]. Among the studies, there was
one systematic review [15], three RCTs [81,87,104], one guideline [63], and one observational
Med. Sci. 2023, 11, 15 16 of 34
study [86]. The quality of two studies [15,63] was rated excellent according to the CASP
scheme, and four studies were rated good [81,86,87,104].
According to expert consensus, RE increases the effectiveness of two nursing inter-
ventions for CIPN (Aconit oil, Arnica comp. Formica oil) by one point on the five-point
Likert scale from three to four (Table S4, Supplementary S6). Three RCTs assessed TT or
healing touch (HeTo) in cancer patients. HeTo as well as classical M are more effective
than presence alone or standard care in reducing pain, mood disturbance, and fatigue in
patients receiving cancer chemotherapy (n = 1 study, n = 230 participants, intervention
duration: 4 weeks) [87]. TT led to significantly higher well-being compared to rest period
(n = 1 study; n = 20 participants, intervention duration: 4 consecutive days) [81]. TT
significantly decreased pain and fatigue more than usual care, while the placebo group
indicated a decreasing trend in pain and fatigue scores compared with the usual care group
(n = 1 study; n = 90 participants; intervention duration: 5 days) [104]. One guideline states
that the quality of the included studies [109–111] on TT is too low to provide meaningful
results [63].
HeTo for cancer patients was assessed in one systematic review. HeTo seems promising,
particularly in the short term, but cannot be recommended because of a paucity of rigorous
trials. Future research should focus on methodologically strong RCTs to determine potential
efficacy of these CAM interventions [15]. RE with Solum oil was shown in an observational
study to be a promising and useful complementary method for the treatment of chronic
low back pain [86].
3.7. Phytotherapy (including Herbal Medicines)

Phy is one of the oldest medical therapies and is indigenous to all continents and
cultures. While Western medicine and traditional Persian medicine tend to use single medic-
inal plants, in Traditional Chinese Medicine (TCM), for example, combinations or mixtures
of more than three herbal drugs are common [112]. This category includes most types of
external applications (EAP). These are applications from aromatherapy (AT) (e.g., Aconit
oil application), topical therapy (ToT) (e.g., Citrullus colocynthis), phytotherapy (Phy),
or herbal medicine (e.g., flaxseed bath, astragalus, henna). Eleven nursing interventions
recommended by the expert panel can be assigned to this category (see Table S4, Sup-
plementary S6). Some nursing interventions combine the types of EAP, such as RE and
AT (Aconit oil—therapeutic application) or hydrotherapy (HTK) and phytotherapy (Phy)
(flaxseed bath).
Eight nursing interventions were recommended by the expert panel based on Phy (Solum oil ap-
plication; flaxseed bath; Arnica comp/Formica oil application; Arnica comp/Formica oil—therapeutic
application; Arnica comp/Formica ointment; Aconit oil application; Aconit oil—therapeutic
application; alkaline bath for hand/foot, then Aconit oil application). In anthroposophic
medicine and nursing, Aconite oil is considered a substance that can compensate for over-
stimulation of nerves and senses in neuropathic pain by its warming and relaxing agents.
Solum oil forms a protective thermal mantle that prevents overstimulation of nerves and
senses. Except for Solum oil, all interventions are rated 3 or 4 on the five-point Likert scale.
Aconit oil application is used most frequently (five out of six institutions).
The literature search yielded seven results related to CIPN [17,35–37,50,75,101] and
five results related to other types of pain [15,46,47,56,86]. Among the studies, there were
two meta-analyses [35,56], two systematic reviews [15,36], five RCTs [17,46,47,50,75], one
pilot CCT [101], one observational study [86] and a S3 guideline [37], which reports a
non-randomized pilot study. The quality of nine studies was rated excellent according to
the CASP scheme [15,35–37,46,47,50,56,75], and three studies were rated good [17,86,101].
More details on the assessment of study quality according to CASP can be found in the
Supplementary S5 (Table S3).
Henna application (HA) on hands and feet for women under Oxaliplatin treatment
showed significant beneficial effect on CIPN. The procedure is considered inexpensive and
well tolerated (n = 1 study; n = 60 participants; intervention duration: three 15-day treatment
Med. Sci. 2023, 11, 15 17 of 34
courses) [17]. All types of Phy (e.g., hand/foot bath, compress) used in TCM for reducing
CIPN were assessed in the meta-analysis. Herbs that activate blood, improve micro-
circulation, and dilate collaterals (e.g., astragalus, ginger) were found to have potential
healing effects as well as improvement in sensory nerve conduction velocity (SNCV) and
motor nerve conduction velocity (MNCV). This was found for all grades of CIPN for
preventive and curative treatment, even though more research is needed (n = 20 stud-
ies; n = 1481 participants) [35]. In another review, some types of Phy were found to have
potentially preventive and/or therapeutic effects for CIPN. Due to the characteristics of
CIPN, the direct application would be considered an effective dosage form (n = 28 studies;
The safety and efficacy of topical Citrullus colocynthis (bitter apple) oil in the manage-
ment of CIPN was evaluated in a RCT. No significant improvement could be shown. The
intervention failed to improve the symptoms of CIPN compared with placebo (n = 1 study;
n = 18 participants, intervention duration: two months) [75]. Solum oil administered as RE
was shown in an observational study to be a promising and useful complementary method
for the treatment of chronic low back pain [86].
Aromatherapy, Aromatherapy Massage, and Aromatherapy Reflexology

Aromatherapy (AT) is a part of Phy and deals with the application of essential oils
with physical, psychosomatic, psychological, and physiological effects [113], which are
processed in the limbic system [47,114,115].
Aromatherapy massage (AT-M) or reflexology (AT-R) combines two therapeutic ap-
proaches. The systematic, controlled application of essential oils through AT with the
application of specific physical manipulations to the soft tissues of the body through M or
stimulation of specific trigger points through reflexology (R). Three nursing interventions
recommended by the expert panel focused on AT (rosemary ointment, peppermint oil for
heat sensations and paresthesia, and eucalyptus oil application for heat sensations and
paresthesia). These are used in one of the six institutions. Rosemary oil was rated between
three and four on the five-point Likert scale, while peppermint oil and eucalyptus oil were
rated two.
Compared to standard medical care, aromatherapy hand and foot massage (AT-M)
significantly reduced incidence of neuropathic pain at week six; severity of neuropathic
pain at weeks two, four, and six; and fatigue at week eight (n = 1 study; n = 46 participants
with CIPN and fatigue receiving Oxaliplatin; intervention: 18 sessions of 40 min over six
weeks) [101]. AT-R conducted by patients themselves resulted in statistically significant
reduction of PNP symptoms in a RCT with pre-post design (n = 1 study, n = 63 participants,
intervention duration: six weeks) [50].
One proof of concept pilot study (Fallon et al. 2015), discussed in the S3 guideline
supportive therapy [37], showed significant reduction in CIPN pain symptoms plus an
improvement in functionality and sensitivity by application of Menthol crème 1%. AT-M
was shown to significantly decrease neuropathic pain severity and quality of life (QoL) in
diabetic patients (n = 1 study; n = 46 participants; intervention duration: four weeks) [47].
Various types of massage were assessed in a meta-analysis [56]. AT-M had significant effects
on cancer pain in two studies, but pain relief was short-lived (two weeks) (n = 12 RCTs;
n = 559 participants) [56]. The beneficial effects of AT-M on self-selected problems mea-
sured by MYCaW score have been confirmed by a non-blinded, randomized study for
patients with cancer (n = 1 study; n = 115 participants; intervention duration: four treat-
ments) [46]. Bardia et al. investigated in their systematic review on complementary
treatments (CTs) for cancer-related pain. One study with high quality based on the Jadad
score added lavender AT to M and found no difference in effect on pain (n = 18 RCTs;
Med. Sci. 2023, 11, 15 18 of 34
3.8. Movement Therapies

Movement therapy (MT) applies body movement that can help persons to cope with
physical or mental illnesses, disabilities, or life challenges. The aim of MT, which can
include various physical activities, is to enhance the person’s cognitive, physical, mental,
social, and emotional well-being. There have been multiple studies investigating the effect
of different forms of physical activity and MT on CIPN. They are thought to attenuate CIPN
through its influence on blood circulation, inflammation, pain-inhibiting neurotransmitters,
endogenous opioids, and coping and symptom interaction mechanisms [48,54].
In total, evidence was found for 18 studies with different study designs and differ-
ent forms of exercises (Es), i.e., cardiovascular E, coordination training, cycling, closed
kinematic chain Es, passive mobilization, resistance training, sensorimotor training, whole-
body-vibration, and walking. Most studies were reviews (n = 8) [54,57,60,64,96,97,100,102]
or were conducted with controlled designs (n = 6) [38,48,69,84,89,94], and clinical guidelines
were also considered (n = 3) [37,66,98]. Study quality ranged from satisfactory (n = 1) [69]
to good (n = 11) [38,84,89,90,94,96–98,100,102] to excellent (n = 7) [37,48,54,57,60,64,66].
Most of the included E studies focused on examining CIPN for patients with cancer
(n = 12) [37,38,48,54,64,66,69,89,94,96,98,102], while some studies exclusively examined pa-
tients with breast cancer (n = 3) [38,48,64], patients with colorectal cancer (n = 1) [94],
or patients with lymphoma (n = 1) [60], and two studies specifically focused on cancer
survivors [84,98]. Some of the included studies (n = 3) focused on improving general pain
in patients with cancer [57,66,100], while some studies (n = 3) mainly included diabetic
patients with neuropathies only [60,96,97].
Closed kinematic chain exercises (CKC-Es) are based on the concept of moving specific
joints and segments, creating a chain of events that affects the movement of neighboring
joints of segments. By performing CKC-Es, the hand or foot is in contact with the surface on
which one practices (e.g., squats, lunges, deadlifts, power cleans, leg presses, push-ups and
derivates; pull-ups or chin-ups; and dips). CKC-Es significantly decreased the modified
total neuropathy score (mTNS) and significantly increased the Berg Balance Score (BBS)
in a single-group pre-post prospective study (n = 1 study; n = 25 individuals with CIPN;
intervention duration: 15 sessions over 3 weeks) [69]. Future research might investigate on
long-term clinically significant effects and consider larger sample sizes.
An interactive sensor-based balance training (BT) significantly reduced a sway of
hip, ankle, and center of mass when compared to a CG (n = 1 study; n = 22 participants;
intervention duration: two sessions per week (45 min) for four weeks) [90]. The challenges
of postural performance, by coordinating the ankles as well as the dynamic weight shifting,
may have contributed to those effects and can be further assessed in larger trials. The
beneficial effects of BT have been confirmed in a systematic review on exercise intervention
studies for neuropathic patients [60]. The results indicate that BT have a stronger effect on
peripheral neuropathies than exercise intervention focusing on strength or endurance or
both. Only one included study (Streckmann, Kneis et al. 2014) in the review by Streckmann,
Zopf et al. [60] and referred to in one clinical guideline [37] focused specifically on CIPN
and indicated that BT and in particular sensorimotor training (SMT) may have the most
beneficial effect for supporting patients with cancer during therapy for improving quality
of life outcomes and also for improving their peripheral deep sensitivity.
Physical therapy significantly decreased CIPN when compared to a CG after chemother-
apy and three months post-chemotherapy (n = 1 study; n = 48 breast cancer patients (stage
I-III); intervention duration: four visits by a physical therapist to develop a home E and
education program at the beginning of chemotherapy) [38]. Nerve gliding Es (for elon-
gating the nerve) were completed three times daily for five to ten minutes and not only
significantly reduced CIPN, but also significantly improved pain pressure threshold and
grip dynamometry.
The beneficial effects of exercises have been confirmed by another study assessing a
multimodal exercise intervention consisting of resistance training (RT), balance training
(BT), and cardiovascular exercises (CardEs) (n = 1 study; n = 29 cancer survivors; interven-
Med. Sci. 2023, 11, 15 19 of 34
tion duration: three times per week for a duration of eight weeks) [84]. CIPN symptoms
improved significantly from pre-E to post-E. Such findings are encouraging and could
be confirmed by a larger trial. Current clinical guidelines for the supportive therapy for
patients with cancer [37] and survivors [98] recommend E therapies as well.
An exercise program including progressive walking (W) and resistance training (RT)
has an effect on patients’ CIPN symptoms [48] (n = 1 study; n = 355 individuals affected with
cancer; intervention duration: six weeks). Compared to the CG, symptoms of hot/coldness
in hands/feet and numbness and tingling were significantly reduced in the IG. This effect
may have developed as exercises can reduce chronic inflammation, and inflammatory pro-
cesses appear to play a role in the etiology and treatment of CIPN. Thus, the authors clearly
call on interprofessional healthcare teams to prescribe exercise therapies for their patients.
A multimodal exercise program including endurance (EN), resistance (RT), and
balance training (BT) on CIPN helped patients to keep their CIPN symptoms stable
(n = 1 study; n = 24 metastasized colorectal cancer patients; intervention duration: two
times per week for 60 min) [94]. Compared to the CG, patients in the IG did not experience
a worsening of their symptoms. Another integrated exercise program including massage
(M), passive mobilization (PM), and physical exercise (E) evaluated whole-body vibration
(WBV) (by applying the vibration platform Galileo-Fitness) (n = 1 study; n = 131 patients
with CIPN; intervention duration: 15 training sessions within 15 weeks) [89]. Patients in
the WBV condition plus the integrated E program performed better with regard to the
primary outcome, the chair-rising test (CRT) (a test where patients are asked to stand up
from a chair and then cross their arms in front of the chest for five times as fast as possible).
All patients completing the study experienced less symptoms and pain and improved their
CRT over time. The authors conclude that this program could be well integrated into daily
clinical practice, but a standardized assessment of CIPN is needed as well as adequate
education of nursing staff. One review assessed WBV [97]. Of the five included studies,
four studies were on diabetic peripheral neuropathy, and one study was on HIV-associated
distal symmetrical polyneuropathy. Three of the five studies found a beneficial effect of
WBV on neuropathic pain as well as for improvements in strength and balance; however,
this was not confirmed by two others of the included studies. As the methodology for all
included studies was reported to be low, and none was focused on patients with cancer
or survivors, the authors conclude that there is a high need to further explore the effect of
WBV in high-quality trials in cancer populations.
Those encouraging results and recommendations, however, have been dimmed by
some reviews including a range of studies investigating if MT contribute to CIPN and
pain relief. One current review synthesized evidence for the effects of exercise on CIPN
symptoms [54], and only clinical trials and meta-analyses have been searched, so that the
results yielded in 13 included studies investigating four different types of exercise (E): Yoga
(Y), aerobic (Ae) E, strength training (STr), and balance training (BT). It was concluded
that none of the studies met 100% of the CONSORT checklist criteria, and only two of the
studies were considered as moderate-quality evidence. Even though all the seven studies
demonstrated that AeE led to significant CIPN benefits, the authors recommended inter-
preting the results with caution and suggested that more evidence is needed to conclude
that E interventions influence CIPN symptoms. Nevertheless, healthcare professionals
including oncologists, oncology nurses, psycho-oncologists, nutritional therapists, physio-
therapist, and pharmacists can inform and encourage patients and survivors of practicing
physical E to improve their balance, fitness, and better manage their symptomatic burden.
The authors of a Cochrane review [57], which already dates back several years, came to
a similar conclusion, and due to a large heterogeneity of included E programs (40 trials
on STr, resistance training (RT), walking (W), cycling (Cy), Y, QG, and TC), it was difficult
to draw concrete conclusion and recommendations. In a systematic review of systematic
reviews [64], effects of multiple rehabilitation interventions, including E and physical
activity (PhA), complementary and alternative medicine, Y, lymphoedema treatment, and
psychosocial interventions, could be demonstrated for general pain and other symptom
Med. Sci. 2023, 11, 15 20 of 34
outcomes. Here again, the effect concepts have not been differentiated. All 37 included
studies were evaluated with the AMSTAR 2 tool, with 21 were having low, 14 having mod-
erate, and 2 having high methodological quality. In other reviews, however, the general
benefits of non-pharmacological interventions including physical therapy (PT) to reduce
CIPN [102] and general pain [100] have been pointed out and are more comprehensible
due to the applied categorization system.
One review assessed strength- and balance-training (STr and BT) programs in pa-
tients at high risk of falls [96]. Overall, 3 out of 13 studies found that Str and BT were
safe and effective at reducing falls and improving strength and balance in adult patients
with diabetes-related peripheral neuropathy. Future research could use this as a basis to
conduct further studies with these safe and effective interventions for cancer patients with
CIPN. One clinical guideline assessed preventative options for CIPN [37]. Regular MT, in
particular for training the fingers and toes, as well as sensorimotor training (SMT) with
bean baths, or electrotherapy with two- or four-cell baths (here one or two extremities—
feet/lower legs or hands/forearms—are immersed in a water bath and a larger plate
electrode—200 to 300 cm2 —is placed lumbar or cervical, respectively) have been presented
as non-pharmacological options for preventing CIPN. Tactile stimulation by application
of special naturopathic procedures, such as beeswax kneading, hedgehog ball massage,
and quartz sand baths, has also been recommended by the expert panel based on yearlong
experience as options for early prevention and/or treatment of CIPN.
3.9. Mind–Body Therapies

According to the National Center of Complementary and Integrative Health (NCCIH),
mind–body therapies (MBT) or modalities (MBM) are “practices that focus on the interac-
tions among the brain, mind, body and behavior with the intent to use the mind to affect
physical functioning and promote health” [116]. MBT focus on training the mind–body
connection and include modalities as relaxation techniques, meditation, mindfulness-based
therapies, body scanning, yoga, progressive muscle relaxation, guided imagery, autogenic
training, hypnosis, biofeedback, and cognitive therapies. Existing evidence shows that
mind–body therapies are frequently used in oncology and that they have an effect [117].
Patients use them to improve the quality of life, to strengthen their immune system, to
reduce stress, and to stimulate hope. Smaller numbers of patients use these therapies to
treat specific symptoms such as pain and fatigue [118].
The medical literature on MBT yielded 16 studies, of which 3 studies were on CIPN [16,54,80].
The other studies (n = 13) were focused on other pain treatment. The most frequently
described MBM of the studies included was related to yoga (Y) [52,54,57,64,73,80,92], fol-
lowed by distraction therapies (DT) [66,70,100,102] and relaxation (Rel) [15,66,70,95,100].
Further studies focused on progressive muscle relaxation (PMR) [45], cognitive behavioral
interventions such as problem-solving therapies [79], meditation [80], self-management
therapies [70], Qi Gong [70], Tai Chi [70], hypnosis [15], imagery [100], and mind–body prac-
tices [16]. Within the 21 results, there are 10 systematic reviews [15,16,52,54,57,64,73,95,100,102],
4 RCTs [45,70,79,92], 1 study with an open-label, single-arm, mixed-methods design [80],
and 1 expert standard for pain management in nursing [66]. The quality of most studies was
rated either excellent [15,45,52,54,57,64,66] or good [16,79,80,92,95,100,102]. The quality of
two studies was assessed with satisfactory [70,73]. More details on the assessment of study
quality according to CASP can be found in the Supplementary S5 (Table S3).
3.9.1. Yoga
Yoga (Y) is an ancient Indian system focusing on the physical, mental, and spiritual
practices with the aim to calm one’s thoughts and belief concepts. Thus, Y has a strong
meditative component that also includes pranayamas, or breathing techniques.
An intervention consisting of somatic Yoga (Y) and meditation (Me) improved QoL,
flexibility, and balance (n = 1 study; n = 10 participants with cancer survivors suffering of
CIPN; intervention duration: twice a week for eight weeks for 1.5 h) [80]. Two systematic
Med. Sci. 2023, 11, 15 21 of 34
reviews assessed MBT. Furthermore, 1 of 13 RCTs in one systematic review [16] found MBT
including self-management strategies like Y and Me to reduce CIPN symptoms. Another
systematic review including seven RCTs and six quasi-experiments [54] recommended
balance training including Y as promising preventive interventions and treatments for
CIPN. Additionally, 16 studies assessed MBT for other pain and patient-reported outcomes.
Y sessions improved psychological distress as well as fatigue, nausea and vomiting, pain,
shortness of breath, insomnia, loss of appetite, and constipation compared to a CG at week
6 (n = 1 study; n = 40 breast cancer patients receiving adjuvant radiotherapy; intervention
duration: three Y per week for six weeks) [92]. Two systematic reviews focused on Y
practices. In nine RCTs, Y was compared with a CG and was found to significantly reduce
distress, anxiety, depression, and moderately reduce fatigue, as well as moderately increase
general HRQoL, emotional function, and social function in patients with breast cancer [52].
However, studies lacked long intervention durations; only two studies lasted 12 weeks
or longer, all others were shorter and ranged from 6 to 10 weeks. Another systematic
review of systematic reviews [64] recommended Y for treating anxiety during active cancer
treatment and for improving fatigue, sleep disturbances, gastrointestinal symptoms, and
depression. The practice of Y was recommended for at least 3 months. Another Cochrane
review assessed exercise interventions including Y on HRQoL and associated outcomes
in cancer survivors [57]. The totality of the movement interventions had an effect on
HRQoL at 12 weeks and 6 months follow-up compared to a CG. Exercise interventions also
reduced anxiety at 12 weeks follow-up, fatigue at 12 weeks and between 12 weeks and 6
months follow-up, and pain at 12 weeks follow-up compared to a CG. In another review
educational article, Y was also recommended for patients with spinal cord injury (SCI)
suffering of neuropathic pain (NP) [73]. Even though the pathogenesis of SCI induced NP
is different compared to CIPN, the evidence shows that Y has also the potential to alleviate
other pain types.
3.9.2. Distraction Therapies and Relaxation

By applying distraction therapy (DT) it is possible to divert one’s attention from
an unpleasant experience and focus on a positive sensory or cognitive stimulus instead.
Computational tasks, music, images of nature, and inhaling of aromas can reduce the
pain experience by distracting and relaxing oneself [16]. Distraction therapy (DT) has
been assessed (n = 4 studies) with mixed results. Pain scores decreased significantly in a
single pre-test and post-test group (n = 1 study; n = 34 female cancer patients with breast
or gynecologic cancer; intervention duration: participants were free to use it as often as
needed) after the end of a 48-hour period [70,100]. Another educational review article [102]
recommended to apply DT as a non-drug therapy for peripheral neuropathy; however,
a reference specifically relating to CIPN was missing; thus, no concrete conclusion can
be drawn. DT and relaxation (Rel) have also been recommended by a German expert
standard for pain management in nursing with reference to one systematic review on
non-pharmacological and non-invasive chronic pain interventions (Skelly et al. 2018) [66].
3.9.3. Additional MBMs

Progressive Muscle Relaxation and Relaxation
Progressive muscle relaxation (PMR) and reflexology (R) significantly decreased
pain intensity and fatigue and improved QoL compared with PMR alone (n = 1 study;
n = 80 women with gynecologic cancer, intervention duration: two sessions totaling 60 min
were conducted at each of the 16 home visits over 8 weeks) [45]. Two systematic reviews
assessed non-pharmacological treatments for pain [15,95]. Overall, 3 of 18 RCTs in one
systematic review found relaxation/imagery and hypnosis to have significant benefits on
cancer pain management [15,95].
Med. Sci. 2023, 11, 15 22 of 34
Problem-Solving Therapies
Problem-solving therapy (PST) significantly reduced symptom limitations including
pain when compared to a CG (n = 1 study; n = 237 individuals affected with cancer;
intervention duration: 18-week cognitive behavioral intervention with 10 contacts) from
week 10 onwards [79].
3.10. Acupuncture/Acupressure (TCM)

Acupuncture (A) has been used in all forms of medicinal healing in Chinese medicine.
A is based on the essential theory of harmonizing imbalances in the body [53]. It is assumed
that A triggers pain-inhibiting and regulation-promoting mechanisms at the neuronal,
vegetative, and hormonal levels via local and systemic points of action [42,53,63]. The
concept of A from Traditional Chinese Medicine (TCM) is the regulation of the energy flow
of the pathways by the insertion of needles into defined body parts. These are supposed to
positively influence disturbances of the organism. Electric current between two A points is
used in electro-A. Acupressure (AP) is a variation of A in which the A points are stimulated
by finger pressure and is suitable for self-treatment [63].
The literature search yielded seven results related to CIPN [16,42,53,63,68,88,93] and five
results related to cancer pain [64,95,98,100,102]. Among the studies were six [16,53,64,95,100,102]
reviews, one four-arm RCT [88], one retrospective service evaluation [68], one prospec-
tive Phase 2 study [93], and three guidelines [42,63,98]. The quality of four studies was
rated excellent [42,53,63,64] according to the CASP scheme, seven studies were rated
good [16,88,93,95,98,100,102], and one was rated satisfactory [68]. Further details on the as-
sessment of study quality according to CASP can be found in Supplementary S5 (Table S3).
In the studies described in one review, significant effects could be described in the
application of EA in different outcomes. Regarding CIPN, EA was not superior to placebo
(n = 13 RCTs; n = 1370 participants) [16]. In another review, it was confirmed that A has
been frequently studied for cancer-related pain, but the data regarding alleviation of CIPN
have not yet been convincing (n = 4 meta-analyses, 14 systematic reviews, 16 RCTs) [53].
One RCT investigated the use of electro-A for CIPN, but because the sample was small, no
final results could indicate a clear improvement for CIPN (n = 1 study; n = 60 participants;
intervention duration: three weeks) [88]. Improvement of CIPN symptoms was reported
for EA (n = 1 study; n = 27; intervention duration: six to eight weeks) [93] and for A
(n = 1 study; n = 18 participants; intervention duration: six weeks) [68]. According to one
guideline, A can be considered for CIPN [63]. According to another guideline, there is
insufficient evidence that EA help to reduce neuropathy in breast cancer patients [42].
Positive effects for A for joint pain in cancer survivors were described in one guideline [98].
Another review referred to a study on acupuncture by Lim et al. 2011; here, A was
tolerated, but little to no effects could be found in terms of pain reduction (n = 11 studies;
Two further studies have described A for general pain, thus not differentiating in
neuropathic pain [42,70,98]. AP can be used for nausea or tumor pain [63,64] but has not
been described for CIPN. Two further reviews related to A state that little data exist [102],
and evidence on A is sparse on CIPN [95]. In one review, A was found to be beneficial to
reduce chemotherapy-induced nausea and vomiting (n = 37 systematic reviews) [64].
3.11. TENS/Scrambler Therapy

Transcutaneous electrical nerve stimulation (TENS) reduces the enhanced central
excitability of nociceptive neurons and decreases release of the excitatory neurotransmitter
glutamate in the spinal cord [65]. TENS is usually applied at the site of pain, stimulating
large-diameter (A-β) afferent fibers, resulting in decreased transmission cell activity and
subsequently decreased pain perception, according to the gate-control theory [119]. Scram-
bler therapy (ST) is an electro-analgesia therapy for the non-invasive treatment of chronic
neuropathic and cancer pain.
Med. Sci. 2023, 11, 15 23 of 34
The literature search yielded three results related to CIPN [65,67,71] and four to cancer
pain [66,98,100,102]. Within these studies, two systematic reviews [100,102], three four-arm
RCTs [65,67,71] and two guidelines [66,98] were included. The quality of two studies was
rated as excellent according to the CASP scheme [65,66], three studies as good [98,100,102],
and two as satisfactory [67,71]. Further details on the assessment of study quality according
to the CASP scheme can be found in Supplementary S5 (Table S3).
3.11.1. TENS
A wireless, patient-controlled TENS unit significantly improved CIPN and associ-
ated outcomes (numeric rating scale of pain, tingling, numbness, and cramping) after
patients’ completion of chemotherapy (n = 1 study; n = 26 patients with CIPN symptoms;
intervention duration: 2–6 h per day stimulation for 6 weeks).
Two systematic reviews assessed TENS. One of the included studies in an educational
review on CIPN describes the physical effects resulting of TENS: increase of endorphin
release and block noxious sensory impulses trough distraction, strongly supporting that
physical therapists may administer TENS [102]. One of eleven studies in one systematic
review [100] found TENS to have the potential to reduce cancer bone pain. One expert
standard discussed TENS for pain management with the conclusion that there is currently
not enough evidence of TENS efficacy for adults with neuropathic pain [66]. One clinical
guideline on cancer survivorship recommended TENS as well as ST as non-pharmacological
treatment options for general cancer pain, pointing out that oncologists might refer to such
therapy options when addressing patients’ needs in consultations [98].
3.11.2. Scrambler Therapy

Positive effects with regard to ST have been reported (n = 2 studies). Standardized ST
significantly and clinically importantly reduced pain resulting of CIPN at 14 days as well
as 1, 2, and 3 months (n = 1 study; n = 39 oncology patients; intervention duration: 45-min
daily treatment for 10 consecutive days) [67]. Scrambler-treated patients experienced
significantly greater improvement in pain, numbness, and tingling compared to TENS-
treated patients (n = 1 study; n = 50 patients with CIPN; intervention duration: 30 min per
day for 10–14 days) [71].
3.12. Conceptual Therapeutic Approach

In 6 out of the 75 studies, statements were made on the conceptual therapeutic ap-
proach [17,35,37,41,50,75]. These were as follows: use of analgesic, anti-inflammatory
effects [17,75]; regulation of muscles, joints, tendons, and ligaments in the body [41]; pro-
mote blood circulation [35]; influence the energy of life [35,50]; improve or normalize nerve
activity through mechanical stimuli [37]; and activation of TRP (transient receptor potential)
ion channels [37].
3.13. Side Effects and/or Interactions

All reported therapies have been described as well tolerated if administered by trained
healthcare staff; however, it should be noted that sporadically some side effects may occur.
Patients receiving TENS have reported contact dermatitis, worsening or new paresthesia,
or pain and cramping or tightness in the lower limps [65,71,100]. Contraindications to the
use of TENS include gestational adherence and sensitive skin. In addition, the electrodes
should not be placed near or over a pacemaker or implanted defibrillator, on the front
of the neck and on the front of the chest [66]. Scrambler therapy has been reviewed
as a safe and analgesic intervention for CIPN, and its use can be considered in clinical
care [120–122]. Few adverse events have been reported for massage (M): for example,
cerebrovascular accidents, hematoma, nerve damage, and various pain syndromes [53,69].
One study also reported respiratory infection and gastrointestinal bleed [51]. Additionally,
acupuncture (A) is not entirely risk free, as rare cases of pneumothorax and infections
have been reported [53,123]. Regarding Yoga (Y), only one study has reported adverse
Med. Sci. 2023, 11, 15 24 of 34
events in patients with back pain [52]. Otherwise, Y can be considered as a safe mind–body
intervention and can in particular be recommended to patients for improving their quality
of life as well as their mental health status [124]. Adverse events for cupping (C) are rare as
well, but there have been three cases of fainting (vaso-vagal syncope) reported with wet
C [55]. No recommendation can be made for Acetyl-l-carnitine (AlC), as this supplement
may worsen CIPN [16,42,63,125].
4. Discussion
This two-phase approach with a systematic scoping review and a structured consensus
process aimed to provide interprofessional healthcare teams with a comprehensive review
and recommendations for clinical practice of the best available evidence on complementary
treatments for the supportive management of CIPN. In total, 13 non-pharmacological
interventions were identified. The evidence of the scoping review showed that patients with
cancer may benefit from treatments that healthcare providers practice or recommend for
patients like massage (M), reflexology (R), therapeutic touch (TT), rhythmical embrocations
(REH), or aromatherapy (AT) or AT-M. One advantage of complementary treatments is
that patients may practice, after a short briefing and education session, those therapies by
themselves, like movement therapies (MT) ranging from cardiovascular exercises (CardE)
to walking (W), as well as mind–body therapies (MBT) like meditation (Me), Yoga (Y), or
relaxation (Rel) techniques. Interprofessional healthcare teams, however, should be aware
that each potential intervention should be carefully considered regarding its external study
evidence and its study quality, as well as the individual patients’ needs and preferences
and their possibly prior experiences with complementary therapies.
The recommendations by the integrative oncology expert panel (Tables 1, S1 and S5)
demonstrated a highly consistent benefit in preventing or relieving CIPN symptoms pa-
tients with cancer can experience when using complementary treatments by nursing in-
terventions in the form of phytotherapeutic (Phy) interventions, cryotherapy (CT), hy-
drotherapy (HTK), and tactile stimulation (TS). Additional supportive interventions are
presented in Table S2 of the scoping review. Here, the authors aimed to match the expert
recommendations from practice with external study evidence and wanted to highlight
even more treatment possibilities. In total, we could include 16 studies with different study
designs to demonstrate that there is incipient nascent evidence for different nursing inter-
ventions in the context of CIPN symptom management. The effects for henna application
(HA), cryocompression (CC), frozen gloves (FG), cryotherapy (CT), classical massage (M),
foot massage (FM), foot reflexology (FR), reflexology (R), and herbal medicines (Phy) and
sensorimotor training (SM) are encouraging and have been presented as possible further
complementary treatment options. Previous reviews [15,18] or clinical guidelines [42,63]
have not been able to clearly point out such recommendations, probably due to their publi-
cation date or because they only considered RCTs, and non-RCTs were left out for a reason
due to quality/risk of bias concerns. Thus, the authors think that the above mentioned
non-pharmacological interventions are priority areas for future rigorous RCTs to confirm
efficacy prior to being routinely recommended to patients.
With the help of a scoping review methodology, the authors were able to also include
studies with a non-RCT study design and pilot studies, as well as studies with a quasi-
experimental design, case reports, or controlled studies, to point out a comprehensive
map of treatments that are available and might help in individual patients. Of course, the
presented therapy options cannot be applied with a “watering can principle” or a “one-size-
fits-all” approach. According to the EbM approach, the choice of intervention is selected
in consideration of the patient’s perspective and the individual clinical expertise of the
health professionals [22]. For all presented complementary treatments, appropriate training
is necessary, and a precise understanding of the interventions as well as the indications
and contraindications is an important precondition before applying those interventions
in everyday care. As a first step into the field of complementary therapies, interested
healthcare professionals can find an overview of effective therapies here, but the second
Med. Sci. 2023, 11, 15 25 of 34
step needs to be a comprehensive training in such therapies to precisely get to know which
patients can benefit from which complementary therapies in which situations.
4.1. Interprofessional Teamwork

Cancer treatment and care involves interprofessional and interdisciplinary teamwork
and collaboration around and with the cancer patient (see Figure 3). Within comprehen-
sive cancer care, it is even more important that healthcare professionals collaborate with
each other to find together the most effective and best treatment strategy for the cancer
patient and his/her family. Thus, with Table S2, the authors aimed to demonstrate other
advances in complementary treatment options that can be conducted by other healthcare
professionals like doctors, psychologists, nutrition therapists, midwives, pharmacists, or
physiotherapists. If nurses get to know that their patients are interested in other comple-
mentary therapies—for instance, acupuncture (A), mind–body therapies (MBT), movement
therapies (MT), TENS/scrambler therapy (ST), and nutritional therapy (NT)—to better
cope with the CIPN symptoms, they might refer their patients to their healthcare pro-
fessionals’ colleagues and vice versa. In total, Table S2 has 59 entries with references to
external study evidence. All included studies involved different healthcare professionals
(except nurses as they are considered in Table S1) and primarily focused on improving
the outcome CIPN. In some cases, however, the authors also included studies if they
focused on pain only [15,67,86], or included study participants other than patients with
cancer [47,86,97]. The authors did this additional effort and described the concept of effect
to demonstrate which complementary therapies were examined in similar clinical contexts
with the according outcomes, so that those results could be used as basis in future research
on CIPN.
4.2. Challenges of Categorizing Non-Pharmacological Therapies

In the thriving field of complementary therapies, it is highly relevant to differentiate
between therapies that indeed have been studied in research and have demonstrated
clinical effects compared to those therapies that have not been studied in research. The
authors of the present study wanted to report proven treatment options, which might be
considered in some patient cases, so that patient safety and well-being can be guaranteed.
In addition, the framework of Kneipp has been in use for many years, especially in German-
speaking countries, and has also become an established system in academic teaching of
complementary therapies [126,127]. For collating and assembling the results from the
expert symposium and the many study references, the authors found this classification
system very useful, as every expert recommendation or study reference could be assigned
to one of the 13 categories. Sometimes, there were overlaps of categories, for example in the
case of Qi Gong (QG) or Tai Chi (TC), as those therapies originate of a Traditional Chinese
Medicine (TCM) context. As these also can be applied detached from TCM, they were
considered in two categories: “mind–body therapies (MBTs)” (classical natural therapies)
AND “other TCM categories” (non-classical natural therapies). The authors would have
done the same with Yoga (Y), and would have made a frequency count in two categories:
“mind–body therapies (MBT)” AND “Ayurvedic medicine”, as this technique is a holistic
practice system of its own (hence, it would count in the category “MBT”), but is also closely
connected with Ayurvedic medicine and can be applied in Ayurvedic contexts too (hence,
it would further count in the category “Ayurvedic medicine”). At this time point, however,
there have been no further studies or recommendations published for CIPN management
from Ayurvedic medicine, so these are just explanations in the subjunctive and a call to do
further research in this field, as it is highly requested by patients [128,129].
In the current review, the systematic categorization of classical natural therapies
according to Kneipp and the non-classical natural therapies were applied to better point
out the effect concept of the categorized interventions. According to this established
categorization, for instance, the authors of the current review would not have categorized
Y, QG, or TC exclusively to MT, but rather to MBT (or non-classical natural therapies and
Med. Sci. 2023, 11, 15 26 of 34
Ayurvedic medicine in the case of Y or TCM in the case of QG and TC), as the effect concept
is different compared to classical MT like AeT or RT. Future research on CIPN interventions
might focus more on patient-reported outcomes measures (PROMs) and validated grading
systems for neuropathy in the first instance, so that patient-oriented outcomes (PROs) can
be measured and compared within and between the studies. Such data are also relevant for
clinical consultations in which healthcare professionals can then better address the current
needs and demands of their patients.
4.3. Further Integration of Non-Pharmacological Therapies in the Healthcare System

There is a high demand and interest in complementing conventional care by pa-
tients [13,130] and by providers [131,132]. It is urgent that the structures in the healthcare
systems be adjusted and enhanced to meet patients’ needs and to guarantee patient safety.
If patients are not informed and counselled by their healthcare team in the clinics or by
their GPs, they consult other external providers who often do not have adequate educa-
tion and take a lot of money out of the patient’s pocket [133]. Studies indicate that the
majority of nurses have a positive attitude towards complementary therapies, but most
of them feel unsure about how to talk about those therapies with their patients [134]. The
topic of indication-based application of complementary therapies has not been anchored
enough in medical and healthcare education, but this is highly needed, so that healthcare
professionals are educated at an early stage on evidence-based complementary therapy
options and can communicate this with their patients in an open, self-confident, and com-
petent dialogue. Within this clinical practice guideline, the authors aim to inform and
educate interested healthcare providers on the treatment possibilities for CIPN symptom
management. We have presented the evidence for the seven most frequently mentioned
complementary therapies: (1) manipulative therapies (2) phytotherapy, (3) movement ther-
apies, (4) mind–body therapies, (5) acupuncture/acupressure, (6) rhythmical embrocations,
and (7) TENS/scrambler therapy. Three of the five Kneipp’s pillars have been presented
as the top treatment options, as there has been much evidence identified for those pillars.
Interested healthcare professionals might start by engaging themselves with a basic training
in the five pillars of classical natural therapies on which the naturopathic health concept
according to Kneipp is based [126,127].
4.4. Directions for Future Research

The review does not only aim to inform and extend clinical practice, but also identifies
important areas for future research. This includes in particular the important question
if CIPN can be prevented. Currently, the majority of research focuses on treating CIPN,
and some researchers are of the opinion that there are no effective preventive applications
available for CIPN [76,132]. The current results, however, show recommendations for
20 prophylactic interventions (see Table 1) that can be investigated further in systematic
research. There have also been some studies reported on Phy for preventive use [29,44];
however, such reports need to be considered with caution, as in non-Western countries,
there is often a mixture of substances usually tested in studies and, thus, transferability is
difficult [105]. More research on preventive measures is therefore highly recommended,
mainly because the conventional therapies are not sufficiently satisfactory.
The consensus results (the preventive and complementary treatment options for CIPN)
of the expert panel can be used in clinical practice and can also be used as a basis for
designing future research in this area. The applied classification system of classical and
non-classical natural therapies clearly illustrates that, in the context of CIPN management,
there is much experiential evidence for nursing interventions (around EAP/AT/ToT/Phy)
and much external evidence for MT or/and MBT. The latter therapy options have been
broadly considered in research studies, and it is expected that future research of nursing
interventions will follow a similar line, and that suitable research designs and contexts will
be encouraged by appropriate requests for research proposals promoted by healthcare orga-
nizations and institutes. As long as there is not much external evidence of nursing studies
Med. Sci. 2023, 11, 15 27 of 34
nor clinical guidelines focusing on recommendations for action in this field, it is even more
important to make the practical experience of the many years of experiential knowledge of
oncology nurses visible and applicable to other clinics and nurses. Stolz et al. [20] reported
on a systematic methodology combining both evidence types with which it is possible
to generate clinical recommendations. Following this approach, the authors were able to
comprehensively overview all possible complementary therapy options for CIPN manage-
ment, thereby considering the field from an interprofessional perspective; thus, the authors
could present in detail which therapies can be conducted by which healthcare professionals
(Figure 3). Future research may be especially recommended for cryotherapy interventions,
however, only for cryocompression and continuous-flow hypothermia [18,40]. In contrast
to the high drop-out rates up to 50% for cryotherapy with frozen gloves [19], cryocompres-
sion and continuous-flow hypothermia [18,40] were safe and well-tolerated interventions
to prevent CIPN and should be investigated in a larger trial.
For future intervention research, the authors strongly recommend including a qualitative–
quantitative process analysis running parallel to the main outcome study, so that it is
possible to (1) include the perspective of the patients and the health professionals and
(2) consider context and individual aspects that cannot be measured with quantitative
data [135]. Another important aspect for future supportive care research, especially in
the area of CIPN, is to include more patient-reported outcomes measures (PROMs, which
are experienced by patients in everyday life) and patient-reported experience measures
(PREMs, like patient satisfaction with conventional and complementary treatment), so that
patient care interventions can be assessed in a validated and reliable way.
4.5. Strengths and Limitations

The present study has some limitations. First, this review mainly considered published
English, French, and German language literature about adult patients with cancer. The
results could have been even more comprehensive if we included opinions and expertise
from professionals in the languages and databases of other interesting cultures like Asia,
the Middle East, South America, and Africa, with a great tradition in naturopathic tradition.
However, this review did include studies conducted in non-English- and non-German-
speaking countries, such as China, Finland, France, Iran, Italy, Netherlands, Singapore,
Republic of Korea, Sweden, Taiwan, and Turkey. Second, even though the authors oriented
on the guidelines for conducting a scoping review to be able to include a wider range and
consider a variability of different studies, the review did not include a search of the many
written and electronic sources of information for patients or for health professionals. In
total, the authors included 17 expert recommendations, 70 studies, and 5 clinical guidelines
relevant for the treatment of polyneuropathies resulting from chemotherapy treatment,
which is a considerable data pool, but it could have been more extensive if the authors were
able to consider other contexts and sources too. With the help of a scoping review study
design [26,27,136], the authors aimed to also include studies with a non-randomized study
design, pilot studies, and qualitative studies focusing on the patient perspective and their
experiences. However, as the results show, the authors included 42 quantitative studies with
different designs, but the search only yielded 3 mixed-methods studies (controlled studies
with a qualitative component). The authors would have expected more qualitative results,
especially in studies reporting about innovative complementary medicine interventions.
Furthermore, even though the core research team has many years of experience in academic
work as well as in patient care in Western countries, it could have been affected by reporting
bias [137], with the tendency of researchers to submit positive, but not negative results
for publication.
Despite these limitations, this is, to the best of the authors’ knowledge, the first com-
prehensive review with clinical recommendations that reports about supportive treatment
options for patients with cancer affected by polyneuropathies. In addition, by examin-
ing not only the nursing interventions, but also the interventions conducted by medical
doctors, psychologists, physiotherapists, and nutritional therapists, a stronger invocation
Med. Sci. 2023, 11, 15 28 of 34
for considering applying such complementary therapies in routine care and treatment is
provided. The authors decided to appraise the quality of the studies, as it is common with
systematic reviews and increasingly with scoping reviews, by applying CASP [33] to have
a better insight into the quality of the included studies and to know if some studies need to
be excluded. The CASP appraisal form was, however, not always suitable for the different
studies considered. As there were no appraisal forms available, for example for case reports
or retrospective studies, those were appraised with the CASP-RCT form, even though not
all questions (in particular questions 4–7) were applicable. The rating would therefore have
been different with other appraisal tools.
5. Conclusions
The best available evidence of non-pharmacological treatments for CIPN management
in patients with cancer are summarized herein. Based on the literature and the long-
term practical experience of the involved experts, the interventions shown here have
high potential to be widely implemented into routine care. For complementary methods
for CIPN to be implemented into safe and evidence-based practice, healthcare providers
would need to expand clinical practice with additional training. Patients would need
more information that empowers them to actively ask their healthcare team for these
treatments more often. To support this, future research in symptom care and treatment
would be useful to make the expert knowledge “tangible”. Future prospective trials are
also needed to validate the efficacy and safety of the here presented non-pharmacological
interventions in individuals affected with cancer, so targeted interventions can be developed
and implemented to treat and prevent the symptoms of complex CIPN.
Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

.3390/medsci11010015/s1, Supplementary S1: “PRISMA-ScR checklist”, Supplementary S2: “Search
strategy”, Supplementary S3: “Table S1. Characteristics of selected studies included in the scoping
review (nursing interventions for CIPN)”, Supplementary S4: “Table S2. “Characteristics of other
relevant studies for treating pain with complementary therapies in cancer patients of other patient
populations”, Supplementary S5: “Table S3. Critical appraisal”, Supplementary S6: “Table S4. Expert
judgements of nursing procedures for treating CIPN based on consensus process”.
Author Contributions: Conceptualization and methodology, N.K., R.S., P.V., D.S., M.L., and C.M.W.;
writing—original draft preparation, N.K.; writing—review and editing, J.B., R.S., M.W., C.I., E.K.,
C.M., C.M.W., D.S., B.B.-S., P.V., and R.H., formal analysis and investigation, N.K. and R.S.; visualiza-
tion, project administration, and resources, N.K.; data curation, N.K., J.B., B.K., and R.S.; supervision,
R.S. All authors, including P.N., U.H., H.J., T.Z., B.S., S.J., I.M., S.K. All authors have read and agreed
to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Acknowledgments: The authors would like to acknowledge and thank the interprofessional working
group “Integrative Care in Oncology: Healthcare Experts” (German Society for Nursing Science) and
the academic working group “Healthcare Services Research and Implementation Science” (Depart-
ment of General Practice and Health Services Research, University Hospital Heidelberg, Germany)
for their feedback and advice of this study. A big thank you also goes to K. Stolz and to M. Klafke for
the final formatting and for the professional help with the graphics.
Conflicts of Interest: The authors declare no conflict of interest.
Med. Sci. 2023, 11, 15 29 of 34
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Med. Sci. 2023, 11, 15. https://doi.org/10.3390/medsci11010015 https://www.mdpi.com/journal/medsci

Keywords: chemotherapy-induced peripheral neuropathy (CIPN); complementary therapies; sup-

2. Materials and Methods

2.1. Phase 1: Scoping Review

“(cancer) AND (neuropathies or peripheral neuropathy or CIPN) AND (complementary

2.1.2. Study Screening and Selection Criteria

2.1.3. Data Extraction and Reporting

2.1.4. Risk of Bias Assessment

2.2. Phase 2: Structured Expert Consensus Process

Med. Sci. 2023, 11, x FOR PEER REVIEW 5 of 36

Figure 1. Flowchart of article selection process.

3.2. Consensus from the Expert Panel

3.3. Preventative Options for CIPN

3.4. Complementary Treatment Options for CIPN

√ Significant beneficial effect. Low cost,

√ √ Improvement of sensory nerve

[54] training, and balance training

whole-body vibration represent new

√ Multimodal exercise program, Regarding CIPN (TOI), there were

√ Evidence was reported for

RCTs (n = 13) Total Neuropathy Score, QoL

yoga and mindfulness.

inte-grative √ Empirical evidence is insufficient to

Clinical practice Acetyl-l carnitine is not recommended

√ Alkaline bath for hand/foot, then

Systematic review of √ NCV, Neurological Symptom Score,

meta-analyses (n = 4), √ Some improvement regarding VAS

Prospective phase 2 √ Numbness score, mTNS, Edmonton Statistically significant difference at 6

Proof-of-concept study √ Potentially improve efficacy of

√ Greatly reduced CIPN symptoms

√ Greatly reduced CIPN symptoms

improved quality of life.

√ Whole-body vibration including (FACT/GOG-NTX), Significantly and clinically relevant

√ NRS, BPI, European Organization for Clinically important and statistically

Gewandter et al. 2019 √ EORTC-CIPN20, Utah Early Significant improvements were

trial (n = 56) CIPN incidence.

√ Positive effects. No statistically

3.5. 3.5. Manipulative

3.6. Rhythmical Embrocations (Including Healing Touch, Therapeutic Touch, Reiki)

3.7. Phytotherapy (including Herbal Medicines)

Aromatherapy, Aromatherapy Massage, and Aromatherapy Reflexology

3.8. Movement Therapies

3.9. Mind–Body Therapies

3.9.2. Distraction Therapies and Relaxation

3.9.3. Additional MBMs

3.10. Acupuncture/Acupressure (TCM)

3.11. TENS/Scrambler Therapy

3.11.2. Scrambler Therapy

3.12. Conceptual Therapeutic Approach

3.13. Side Effects and/or Interactions

4.1. Interprofessional Teamwork

4.2. Challenges of Categorizing Non-Pharmacological Therapies

4.3. Further Integration of Non-Pharmacological Therapies in the Healthcare System

4.4. Directions for Future Research

4.5. Strengths and Limitations

Supplementary Materials: The following are available online at https://www.mdpi.com/article/10

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