Rostock et al. (2013): Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture

Reference ↗
Title	Chemotherapy-Induced Peripheral Neuropathy in Cancer Patients: A Four-Arm Randomized Trial on the Effectiveness of Electroacupuncture
Topic	Vitamin B1, Vitamin B6, Electroacupuncture
Author	Rostock, M, Jaroslawski, K, Guethlin, C, Ludtke, R, Schröder, S, Bartsch, HH
Year	2013
Journal	Evidence-based Complementary and Alternative Medicine
DOI	http://dx.doi.org/10.1155/2013/349653

Brief summary

In the study by Rostock and colleagues, 59 patients who were currently undergoing a rehabilitation program after chemotherapy were examined. They were randomly divided into four arms and examined over three weeks. The arms received either electroacupuncture, hydroelectric baths, a vitamin combination of vitamin B1 and B6 or placebo capsules. The symptoms of peripheral neuropathy, a disorder of one or more nerves, were assessed by the patients themselves. The neuropathy scores, the intensity of the symptoms (assessed by a neurologist) and the quality of life were also recorded. The results showed that the arms did not differ with regard to the factors examined. They all improved in their symptoms, the neuropathy value decreased, the intensity of the symptoms decreased and the quality of life tended to increase. However, the different treatment measures did not appear to have any significant reinforcing or inhibiting influence on this. The main criticism of this study is the small sample size and the fact that the patients' complaints were already low at the beginning. It is possible that this made it difficult to achieve an improvement in general and that differences could not be detected for this reason. In addition, the patients were treated in parallel with medication and therapies such as psychotherapy or sports therapy, so it remains unclear what effect these had on the results and the well-being of the patients. For this reason, the results should only be viewed critically and the effect of the combination of vitamin B1 and B6 should not be generalized.

In der Studie von Rostock und Kollegen wurden 59 Patienten untersucht, die sich gerade in einem Rehabilitationsprogramm nach einer Chemotherapie befanden. Sie wurden zufällig in vier Gruppen aufgeteilt und über drei Wochen untersucht. Die Gruppen bekamen entweder Elektroakupunktur, Hydroelektrische Bäder, eine Vitaminkombination aus Vitamin B1 und B6 oder Placebo-Kapseln. Untersucht wurden die Symptome peripherer Neuropathie, einer Störung einer oder mehrerer Nerven, die durch die Patienten selbst beurteilt wurden. Außerdem wurden die Werte der Neuropathie, die Intensität der Beschwerden (eingeschätzt durch einen Neurologen) und die Lebensqualität erhoben. Die Ergebnisse zeigten, dass sich die Gruppen hinsichtlich der untersuchten Faktoren nicht unterschieden. Sie verbesserten sich alle in ihren Symptomen, der Neuropathie-Wert sank, die Intensität der Beschwerden ließen nach und die Lebensqualität stieg tendenziell an. Die unterschiedlichen Behandlungsmaßnahmen hatten darauf aber scheinbar keinen bedeutsamen verstärkenden oder hemmenden Einfluss. Hauptkritikpunkt dieser Studie ist die geringe Stichprobengröße und die schon von zu Beginn geringen Beschwerden der Patienten. Dies kann dafür gesorgt haben, dass eine Verbesserung generell nur noch schwer möglich war und Unterschiede aus diesem Grund nicht entdeckt werden konnten. Außerdem wurden die Patienten parallel medikamentös und durch Therapien, wie bspw. Psycho- oder Sporttherapie betreut, sodass hier unklar bleibt, welchen Effekt diese auf die Ergebnisse und das Wohlbefinden der Patienten hatten. Man sollte die Ergebnisse aus diesem Grund nur kritisch betrachten und die Wirkung der Kombination von Vitamin B1 und B6 nicht verallgemeinern.

Study Design

Blinding: double-blind for vitamin B and placebo, open for electroacupuncture and hydroelectric baths

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Monocentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	Double
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	4

Study characteristics

Inclusion criteria	Patients in remission after chemotherapy with taxanes, platinumderivatives, or vinca alkaloids and who presented with symptoms of CIPN
Exclusion criteria	?
N randomized	60
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	mITT Analysis
Specifications on analyses	n (Analysis) = 59, 1 drop-out in hydroelectric bath arm (no treatment received); "all randomized patients who received at least one study treatment were included in all (effectiveness or safety) analyses"
Countries of data collection	Germany
LoE Level of evidence	2b Oxford 2009
Outcome timeline Data collection times	T0: Baseline, Day 0 of therapy T1: Day 21, i.e. directly after treatment T2: Follow-up, day 84 after treatment

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	No therapy setting
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Breast Cancer, Gynecologic Cancers - Ovarian Cancer, Hematologic Cancers - Lymphoma (Hodgkin and Non-Hodgkin), Other Cancers
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	NI
Specifications on cancer stages	NI
Comorbidities	Four patients (3 in hydroelectric bath arm, 1 in placebo arm) presented with additional neurological problems other than CIPN: - 2 patients: facial paresis - 1 patient: double vision - 1 patient: one had diminished strength in the right hand
Current cancer therapies	No therapy
Specifications on cancer therapies	Mean times from the last chemotherapy, last surgery, or last radiotherapy were comparable between groups (all 𝑃 values >0.25)
Previous cancer therapies	Surgery, Chemotherapy, Radiation therapy
Gender	Female
Gender specifications	Overall 78% female; male/female per arm: - electroacupuncture arm: 4/10 - hydroelectric bath arm: 1/12 - vit. B arm: 5/10 - placebo arm: 3/14
Age groups	Adults (18+)
Age groups specification	Overall mean (SD): 52.7 (10.0) years; per arm: - electroacupuncture arm: 49.9 (9.6) - hydroelectric bath arm: 52.3 (11.3) - vit. B arm: 56.3 (11.1) - placebo arm: 52.0 (8.1)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	14
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	3
Drop-out reasons	- Anxious of being needled (day 1): n=1 - Lost to follow-up (day 21): n=1 - Lost to follow-up (day 84): n=1
Intervention	Electroacupuncture
Dosage and regime	8x ± 1 sessions for 15min Point combinations for ... - patients with CIPN symptoms in the lower extremities: LV3 (Taichong), SP9 (Xiongxiang), GB41 (Zulingqi),GB34 (Yanglingquan) - patients with CIPN symptoms in the upper extremities: LI4 (Hegu), LI11 (Quchi), SI3 (Houxi), and HT3 (Shaohai) - patients with CIPN symptoms in the upper and lower extremities: treated with complete point combination Acupuncture needles were deeply inserted bilaterally until the deqi phenomenon was triggered; each session included 15 minutes of electrostimulation (50Hz) consisting of a combination of rectangular currents and high amplitude waves
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	21
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	13
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	0
Drop-out reasons	NA
Intervention	Hydroelectric baths
Dosage and regime	8x ± 1 sessions for 15min - patients dipped their arms up to a hand’s width above the elbow and their feet up to a hand’s width above the ankle into a special water basin with water at a temperature of about 35∘ - cross-galvanisation of each individual extremity by low-frequency (50Hz) faradic current (direct current impulses) up to the individual’s sensitive threshold (i.e., the point where the tingling feeling is considered to be just acceptable)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	21
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	15
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8
Drop-out reasons	- Study was too strenuous (day 1): n=1 - Tumor progession (day 13): n=1 - Lost to follow-up (day 21): n=2 - Lost to follow-up (day 84): n=4
Intervention	Vitamin B Complex (vitamin B1/B6)
Dosage and regime	100mg thiamine nitrate + 100mg pyridoxine hydrochloride, oral, 3 capsules daily
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	21
Side effects / Interactions	NI

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Placebo
Number of participants (arm) N randomized	17
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	5
Drop-out reasons	- Withdrawal of consent (day 1): n=1 - Lost to follow-up (day 21): n=1 - Lost to follow-up (day 84): n=3
Intervention	Placebo
Dosage and regime	Same form and frequency as in Vit. B arm (oral, 3 lactose capsules daily)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	21
Side effects / Interactions	NI

Outcomes

Peripheral neuropathy

Outcome type As specificed by the authors	Primary
Outcome specification	- Extension and intensity (non, mild, moderate,or severe) of CIPN complaints (numbness, swelling, tingling, pain, and subjective impairment in everyday life and at work) - Heaviness of suffering due to CIPN complaints - Severity of neuropathic symptoms -> Outcome change from day 0 of treatment until day 21 (after treatment)
Type of measurement	NRS (Numeric Rating Scale), Interview
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Improvement of symptoms in all arms, no significant group difference at day 21 (directly after treatment): d = -0.3; CI: -1.4, 0.8; p = 0.705)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Peripheral neuropathy

Outcome type As specificed by the authors	Secondary
Outcome specification	Neuropathy score (assessed by an independent neurologist)
Type of measurement	Neurologic examination
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Neuropathy score decreased in all arms during treatment (from day 0 until day 21); no significant differences between any two arms (no p-values reported)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Peripheral neuropathy

Outcome type As specificed by the authors	Secondary
Outcome specification	Electroneurographical tests/sensible nerve conduction studies of the median (upper extremities) and the sural nerve (lower extremities)
Type of measurement	Neurologic examination
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	No significant differences between the treatment arms (from day 0 until day 21); no p-value reported
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Peripheral neuropathy

Outcome type As specificed by the authors	Secondary
Outcome specification	Intensity of the CIPN complaints
Type of measurement	NCI-CTC v.2 (National Cancer Institute-Common Toxic Criteria), Neurologic examination
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Similar improvement in all four arms during treatment (from day 0 until day 21); no significant differences in the four arms (no p-value reported)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Quality of life

Outcome type As specificed by the authors	Secondary
Outcome specification	NI
Type of measurement	EORTC QLQ (European Organisation for Research and Treatment of Cancer Core/ Quality of Life questionnaire)
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Moderate increase in all four arms during treatment (from day 0 until day 21); no significant differences in the four arms (no p-value reported)
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NI

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Study was supported by the Fördergesellschaft Forschung Tumorbiologie, Freiburg, Germany, and the Karl and Veronica Carstens Foundation, Essen, Germany.
Conflicts of Interest	According to authors no conflict of interest

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Ethics vote available
• Calculation of power analyses
• Intention-to-treat analyses
• Double-blinded if possible

CONTRA:

• Small sample size
• Low intensity of complaints, which left little room for improvement (floor effect)
• Possibility of confounding variables exists (medication and other concurrent therapies, inequality of cancer treatment medication use between arms caused by unequal distribution of cancer types (n.s.), also descriptive inequality of symptoms (n.s))
• Little detailed description of the follow-up results (overall concise results section)