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F1000Research

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10.12688/f1000research.134167.1

Study Protocol

Articles

Effect of proprioceptive neuromuscular facilitation technique and TENS on improving lower limb sensorimotor function, balance and quality of life in chemotherapy induced peripheral neuropathy in gynecological cancer: A randomized controlled trial protocol

[version 1; peer review: 1 approved]

Seth

Nikita H.

Conceptualization Data Curation Formal Analysis Investigation Methodology Project Administration Resources Writing – Original Draft Preparation Writing – Review & Editing https://orcid.org/0000-0003-4103-9895 a 1 Quershi

Irshad

Conceptualization Resources Supervision Validation Visualization 2 1Neuro Physiotherapy, Datta Meghe Institute of Higher Education and Research, Wardha, Maharashtra, 442001, India 2Neuro Physiotherapy, Datta Meghe Institute of Higher Education and Research, Wardha, Maharashtra, 442001, India

a sc2022rn00090@dmimsu.edu.in

No competing interests were disclosed.

22 5 2023

2023

527

9 5 2023

2023

This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gynecological cancers are the most prevalent cancers in women, making it a significant public health concern. Chemotherapy drugs are an extremely effective approach for reducing cancer progression since they have various targets and mechanism of action focused at killing quickly multiplying cancer cells. Unfortunately, these drugs also affect normal cells and structures of the body, resulting in a variety of deleterious effects. Most common among them is chemotherapy induced peripheral neuropathy (CIPN). Taxanes, platinum medicines, vinca alkaloids and thalidomide are examples of popular pharmaceuticals that are prone to cause CIPN. When CIPN develops during active chemotherapy phase, it may result in the discontinuation or reduction of chemotherapy dose, which may render the dosage ineffective in cancer management. As a result, it is essential that physiotherapists investigate novel approaches to successfully manage the side effects that survivors must deal with. Here’s the idea we suggest by conducting a study which aim to assess the effectiveness of Proprioceptive Neuromuscular Facilitation Technique (PNF) with Transcutaneous Electrical Nerve Stimulation (TENS) and closed kinetic chain exercises with TENS on subjects with CIPN in Gynecological Cancer in two arm parallel superiority randomized control trial (RCT) on improving lower limb sensorimotor function, balance & quality of life. The total participants in the study will be divided into two equal groups and then the intervention will be given for 8 weeks to both the groups with 5 days in a week with 50 minute session each day. The results will be evaluated after 8 weeks of treatment and 3 weeks after completion of intervention for follow up. If the hypothesis of our study proves to be effective, this physiotherapy intervention could be included in management of CIPN. Along with it, it will help in reducing the rate of discontinuation of chemotherapy dose due to neuropathy.

Gynecological cancer Chemotherapy Induced Peripheral Neuropathy Physiotherapy Intervention Balance Quality of Life.

The author(s) declared that no grants were involved in supporting this work.

Introduction

The fact that gynecological cancers are among the most prevalent cancers in women makes them a serious public health concern. Due to heterogeneous pathology, a lack of effective screening facilities in developing nations like India, and the fact that most women report at advanced stages, prognosis and clinical outcomes are affected. With rates of occurrence rising over time, ovarian cancer has emerged as one of the most prevalent malignancies affecting women in India. Even though it has decreased, cervical cancer is still the second most common cancer in women, only after breast cancer. ¹

Every year, 122,844 women in India are diagnosed with cervical cancer, with 67,477 dying from the illness. Chemotherapy for ovarian cancer is typically a combination of two distinct types of medications. Using a combination of medications rather than just one drug as a first-line treatment for ovarian cancer appears to be more successful. Typically, the combination includes a platinum component (typically Cisplastin or Carboplatin) and another type of chemotherapy medication known as a taxanes, such as paclitaxel or docetaxel; these are the drugs most likely to induce peripheral neuropathy. Taxanes, platinum medicines, vinca alkaloids, thalidomide, and bortezomib are examples of popular pharmaceuticals with a high risk of causing CIPN. Clinically, CIPN manifests as varying degrees of sensory, muscular, and/or autonomic dysfunction. ²

When CIPN happens during active chemotherapy, the chemotherapy dose may be terminated or reduced, rendering the dosage ineffective in cancer management. As a result, it is essential that physiotherapists research novel methods to treating cancer survivors and managing the side effects that survivors must deal with. The most common side effects of chemotherapy is CIPN, and there has been little study into non-pharmacological treatments to manage its symptoms. There is a paucity of research on the use of PNF in the therapy of CIPN symptoms. There is paucity of research into improving equilibrium in chemotherapy-induced peripheral neuropathy caused by gynecological cancer. There is a scarcity of data concerning physical therapy intervention and outcomes in CIPN. ³

Transcutaneous Electrical Nerve Stimulation (TENS) and closed kinetic chain exercises are the usual methods for improving sensorimotor function and balance. TENS is the application of a low-level electrical current to neurons via electrodes. TENS has been shown to alleviate pain and is safe to use in chemotherapy patients. The TENS device modulates the frequency, width, length, and intensity of the pulse. TENS is defined as having a high frequency > 50 Hz and a low intensity, implying that it causes paraesthesia without causing discomfort or motor contraction. Exercise has been shown to help several aspects of CIPN following treatment. However, the potential for prevention has gotten less attention, and the results are sometimes contradictory. ⁴

Since it has been discovered that exercise regimens aimed at improving balance in the elderly should include coordination and Proprioception activities as well as strength exercises, the Proprioceptive neuromuscular facilitation (PNF) method is presented as an intriguing option. During PNF movement execution, muscles are temporarily stretched before contracting, stimulating neuromuscular terminals that generate higher levels of force. ⁵ PNF motions are also performed in a diagonal pattern parallel to muscular topography, replicating physiological movements such as gait. It has also been suggested that PNF training results in a better balance of agonistic and antagonistic muscle activation, with less co activation. There is no written evidence that Proprioceptive Neuromuscular Facilitation can be used to treat CIPN symptoms. ⁶

The aim of this study is to test the effectiveness of Proprioceptive Neuromuscular Facilitation Technique with Transcutaneous Electrical Nerve Stimulation (TENS) and closed kinetic chain exercises with TENS on subjects with chemotherapy Induced Peripheral Neuropathy in Gynecological Cancer in two arm parallel superiority/equivalence randomized control trial (RCT) on improving lower limb sensorimotor function, balance & quality of life in end point results on marginal difference.

Aims and objectives

To study the subjects with lower limb peripheral Neuropathy (Modified Total Peripheral Neuropathy Scoring Criteria), balance (Berg Balance Scale) & Quality of life (Fact/GOG Ntx) due to Chemotherapy Induced Peripheral Neuropathy in Gynaecological cancers treated with Proprioceptive Neuromuscular Facilitation Technique (PNF) and Transcutaneous Electrical Nerve Stimulation (TENS) on its effect on improving the sensorimotor Function, balance and Quality of life in the overall population.

To study the subjects with chemotherapy Induced Peripheral Neuropathy in Gynaecological Cancer for the change in pain (measured on VAS), Sensory function (Semmes Weinstein Monofilament Test) treated with Proprioceptive Neuromuscular Facilitation Technique (PNF) and TENS, if it can reduce pain and improve sensory function in overall population.

To study the efficacy over the treatment of Proprioceptive Neuromuscular Facilitation Technique along with Transcutaneous Electrical Nerve Stimulation (TENS) and Closed kinetic chain exercises along with TENS on mTNS for change in lower limb sensorimotor Function,balance & quality of life for the population with chemotherapy Induced Peripheral Neuropathy in Gynaecological Cancer.

Trial Design - Single Centric, two arm parallel open label equivalence randomized controlled trial.

Protocol

This is hospital-based study where participants consent will be received in written format and will be recruited from Siddharth Gupta Memorial Cancer Hospital constituent branch of Acharya Vinobha Bhave Hospital Sawangi, Meghe, Wardha, Maharashtra, after receiving approval from the institutional ethics committee of Datta Meghe institute of higher education & research the population over the region with inclusion exclusion criteria for the study. Study participant will be distributed in to two arms. Arm-A (PNF and TENS) & Arm-B (Closed kinetic chain Exercises and TENS) by randomization for 1:1 allocation with intent to treat purpose. Subjects will be invited & screened for inclusion process of this study. Randomization process will be run for subject allocation using randomization process with computer generated list. Study will be carried out as open label with cut-off values at baseline parameters will be used for the inviting the participants considering inclusion & exclusion criteria for selection. For more participants in the study if required second source of recruitment will be done throughout the period of recruitment of six months. Active group will receive Proprioceptive Neuromuscular Facilitation Technique (PNF) plus TENS therapy control group will receive Closed Kinetic Chain Exercises (CCK) plus TENS therapy to assess improvement of lower limb sensorimotor Function, balance & quality of life at end point results on marginal difference. Participants will be included and will be assessed over different time scheduled mentioned as -visit 1 for subject enrolment, visit 2 for participants screening, at baseline, 8 weeks and 3 weeks post treatment for follow up at which primary & secondary parameters will be measured. The study design is visualized in Figure 1.

Figure 1. Flowchart of procedure.

TENS - Transcutaneous Electrical Nerve Stimulation.

Inclusion criteria

A newly diagnosed patient with stage I to III gynaecologic cancers, including ovarian, uterine, and cervical cancer, who intends to undergo a fixed amount of platinum-based compounds chemotherapy.

Patients who are administered Taxanes and Platinum-based compounds - Cisplastin, Carboplatin, and Oxaliplatin.

Patients with Grade I or II peripheral neuropathy according to the National Cancer Institute’s standard toxicity criteria.

Planned to undergo a minimum of four cycles of chemotherapy treatment utilizing one of the chemotherapy agents (Platinum based compound).

Women aged 50 to 70 years.

Exclusion criteria

The Male Patient.

Patients with a history of peripheral nerve damage.

Type 2 Diabetes Mellitus Patient with Autoimmune and Inflammatory Disorders.

Patients with Grade III, IV, or V peripheral neuropathy, as defined by the National Cancer Institute’s common toxicity guidelines, are excluded from the study.

Previous exposure to any of the involved chemotherapy agents within the previous 5 years, which may have caused peripheral neuropathy.

Cancer in the fourth stage.

Patients with metal devices.

Patients who have an artificial pacemaker.

Any traumatic injury to the lower leg of the patient.

Interventions

Experimental group

After identifying the area with pain the TENS will be applied along the distribution of the nerve for the duration of 15 minutes, High Frequency (50 to 100 Hz) with intensity such that it causes paraesthesia without pain or motor contraction followed by Proprioceptive Neuromuscular Facilitation Techniques which include hold – relax, contract- relax, slow reversal and rhythmic stabilization along with diagonal patterns of the lower limb. Each technique was repeated for 10 minutes with adequate pacing between each repetition. Total duration of treatment is approximately 50 min. ⁷

Control group

After identifying the area with pain the TENS will be applied along the distribution of the nerve for the duration of 15 minutes, High Frequency (50 to 100 Hz) will be used with intensity such that it causes paraesthesia without pain or motor contraction. ⁸ Along with the closed kinetic chain exercises will be given which will be as follows ( Table 1).

Table 1. Closed kinetic exercises regimen.

Sr no	Exercise	Description	Dosage
1	Ball – Terminal Knee Extension Exercise	Patient will be in standing position, a ball placed behind the knee and against the wall with knee partially flexed then patient is asked to press the knee against the wall while trying to straighten the knee.	5 Repetitions with 10 second hold and 2 set
2	Lateral Step ups	Patient will be standing next to the box and patient will be asked to laterally raise the foot on the stool and bring back down from the same side	10 Repetitions with 2 sets
3	Wall Squats	Patient will be standing with wall support with crossed around the chest and then patient is asked to slide the body downward and return back to upright position. The knee should not pass the front of foot while squatting	5 Repetitions with 20 second hold with 1 set
4	Side Stepping	Patient is asked to stand in partial squat position with feet together and asked to move laterally and then bringing back to normal position.	10 Repetitions with 2 set
5	Standing Heel Raise - single leg	Standing on one leg and raising up on toes until the heel is raised and the opposite knee flexed to 90 degree	10 Repetitions with 2 set

Criteria for discontinuing or modifying allocated interventions for a given trial participant is drug dose change in response to harms, participant request, or worsening of disease.

Relevant concomitant care include considering the fatigue there will be adequate pacing between the exercises, care of skin at the site of TENS application.

Outcomes

Primary outcome 1.

Change in modified total peripheral Neuropathy Score

The modified Total Neuropathy Score incorporates data from scoring signs, symptoms, and quantified sensory tests to provide one indicator of neuropathy. The TNS has high inter- and intrarater dependability. (0.966 & 0.986 respectively). The mTNS is scored from 0 to 24, with every neuropathy item graded 0-4. A higher overall prevalence indicates that the neuropathy is more severe. When the first iteration of the TNS (a 0-21 scoring system) was developed in 1994, the results scores were divided into three levels: 0-7, 8-14, and 15-21 for mild, intermediate, and severe neuropathy, respectively. ⁹

Change in Berg Balance Score

The measure was designed specifically to assess balance in the elderly. It has a dependability grade of 0.97. It earned a total of 56 points. It comprises of 14 items, each with a maximum score ranging from 4.0 to 20: A individual with this score will almost certainly need the assistance of a wheelchair to move around safely. A person with a score of 21 to 40 will need some type of walking assistance, such as a cane or walker. 41-56: A individual with a score in this range is considered independent and ought to be able to move around safely without a cane or walker. ¹⁰

Change in FACT - GOG (Quality of life) Scoring

It is a reliable and valid instrument to evaluate the impact of neuropathy on health-related aspects of life. The Ntx the subscale demonstrated sensitivity to therapeutic distinction and alterations over time. The FACT/GOG-NTX measures peripheral neuropathy symptoms such as sensory, motor, and auditory difficulties, as well as cold sensitivity. This instrument has been shown to be reliable, with internal consistency, content validity, and concurrent validity, as well as sensitivity to change over time, in various samples of cancer patients getting chemotherapy. ¹¹

<bold>Secondary outcome</bold> <list list-type="order"> <list-item> <label>1.</label> Reduction in VAS Score The visual analogue scale (VAS) is a subjective, verified measure of acute and chronic pain. Scores are recorded by drawing a handwritten mark on a 10-cm line representing a pain scale ranging from “no pain” to “worst pain”. <xref ref-type="bibr" rid="ref12">12</xref> </list-item> <list-item> <label>2.</label> Change in Semmes Weinstein Monofilament Grading The greater the labelled number, the thicker the filament becomes and the more force is required to stretch the filament. The strands are graded from 1 to 5 based on their thickness: 1.65-2.83 equal’s grade 5, 3.22-3.61 equals grade 4, 3.84-4.31 equals grade 3, 4.56-6.45 equals grade 2, and 6.65 equals grade. It is a clinical test that uses a numerical quantity to assess the reaction of the monofilament to a touching sensation. It has a sensitivity of 98% and a specificity of roughly 99%. <xref ref-type="bibr" rid="ref13">13</xref> </list-item> </list> <sec id="sec9"> <title>Sample size calculation

We perform the sample size calculation through Power analysis at 80% power and 5% Type 1 error calculated for the primary variable – modified total peripheral neuropathy score in comparison with the difference between PNF and TENS & Closed kinetic chain exercises and TENS treatment groups from baseline to end visits in frequency (%) We used prior estimated effect size difference in % from the RCT for study in, [Citation],.We expected 30% of margin improvement in comparison to control group considerable for clinically relevant margin for superiority at 30% through expertise opinion.

To calculate sample size

N = Z 1 − α + Z 2 ( P 11 − P1 + P 21 − P2 / P 2 − P 1 2

Z alpha = 1. = 1.965 Type I error at 5%

Z beta = 0.84 = Type II error at 20%

Primary Variable: - Modified Total Neuropathy score (mTNS)

P1 - Effect of Closed Kinetic chain exercises on sensorimotor function - 52% change (Reference)

P1 - Effect of Proprioceptive Neuromuscular facilitation Technique on sensorimotor function = 82% (Expected as discussed with expertise opinion)

Clinically relevant Difference (P2-P1) = 30%

Minimum sample size N = 2 * (1.965 + 0.84) ² ((0.52) (1-0.52) + (0.82) (1-0.82)/(0.30)) ² = 36 each in 2 groups.

Considering 10% drop out = 40 samples each group.

Reference Article – Effect of lower limb closed kinetic chain exercises on balance in patients with chemotherapy induced peripheral neuropathy-pilot study, International Journal of Rehabilitation Research, Jorida Fernandes et al (Pg -368). ⁸

Analysis - Results over the outcome variables will be tabulated & described using descriptive statistics; data over the outcome variables will be tested for normal distribution for the mean and standard deviation (SD) median statistics will positioned for finding skewed distributions and interquartile range (IQR). Frequency and percentages for binary and categorical variables will be tabulated for descriptive statistics. R-software free version will be used for all statistical analysis. The inferential statistics will be analyzed as per the description given below.

Primary outcome: - Inferential statistics will be used for comparing the two groups for measurement score resulted (active treatment versus control treatment) for their mean change in primary variable (mTNS, BBS, FACT - GOG) between baseline and 8 weeks applying the linear mixed model. Participants will be tested for the results considering difference in primary variable from baseline to timeline measured during the study (visit1 and after the end of 8 weeks and follow up after 3 weeks of completion of intervention). Random effects will be generalized for study subjects, fixed effects will be analyzed by considering treatment group and visit number. Effect size over mean change difference on primary variable from baseline to end line visit at 8 week and 3 weeks follow up will be measured with corresponding 95 % confidence interval (CI) will be presented.

Primary End Point (Description): Secondary outcomes (Simmens monofilament test, VAS) will be analyzed as per the above linear mixed model effect for predicting effect size difference between active and control group. T test (Unpaired) will be used to measure the significant difference between the means in comparison between the two groups if the data follows the normal distribution. For non normal distribution Mathematical algorithms will be used for conversion of the data to normal distribution.If Data over primary variable still follows the non normal distribution then we will use alternate non parametric test (Chi square, Mann Whitney, Wilcoxon test.

Dissemination

Planning to publish in indexed journal and present the study in National Conference Proceedings.

Study status

The Recruitment of participants is yet to be started.

Ethical considerations

Institutional Ethical Clearance has been obtained on 4/2/2023

IEC No – DMIHER (DU)/IEC/2023/48

CTRI Registration was obtained 13/3/2023

Data availability

No data are associated with this article.

Acknowledgements

I would like to acknowledge Mr Laxmikant Umate who has helped me in sample size calculation and data analysis planning.

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Reviewer response for version 1

Kovela

Rakesh Krishna

1 Referee https://orcid.org/0000-0002-3744-4778 1Nitte Institute of Physiotherapy, Nitte (deemed to be) University, Mangalore, Karnataka, India

Competing interests: No competing interests were disclosed.

16 8 2023

2023

This is an open access peer review report distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

recommendation

approve

As its a protocol, the methodology is clear except for the objectives as they are lengthy; the authors can cut short the length of the objectives. Permissions from scale developers need to be mentioned. Permission from onco HOD to take the samples from oncology unit need to be mentioned. Overall the protocol is quite acceptable to be indexed.

Is the study design appropriate for the research question?

Yes

Is the rationale for, and objectives of, the study clearly described?

Yes

Are sufficient details of the methods provided to allow replication by others?

Yes

Are the datasets clearly presented in a useable and accessible format?

Yes

Reviewer Expertise:

Physiotherapy in Paediatrics, Physiotherapy in adult neurological conditions, physiotherapy in developmental disorders

I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.