Article Text

Getting the MOST out of follow-up: a randomized controlled trial comparing 3 monthly nurse led follow-up via telehealth, including monitoring CA125 and patient reported outcomes using the MOST (Measure of Ovarian Symptoms and Treatment concerns) with routine clinic based or telehealth follow-up, after completion of first line chemotherapy in patients with epithelial ovarian cancer
  1. Paul A Cohen1,2,3,
  2. Penelope M Webb4,
  3. Madeleine King5,
  4. Andreas Obermair6,
  5. Val Gebski7,
  6. Phyllis Butow8,9,
  7. Rachael Morton7,
  8. Wanda Lawson10,
  9. Patsy Yates11,
  10. Rachel Campbell5,
  11. Tarek Meniawy12,
  12. Michelle McMullen12,
  13. Andrew Dean13,
  14. Jeffrey Goh14,15,
  15. Orla McNally16,17,
  16. Linda Mileshkin18,19,
  17. Philip Beale20,
  18. Rhonda Beach10,
  19. Jane Hill21,
  20. Cyril Dixon21,
  21. Sue Hegarty21,
  22. Jim Codde3,
  23. Angela Ives22,
  24. Yeh Chen Lee23,24,
  25. Alison Brand25,26,
  26. Anne Mellon27,
  27. Sanela Bilic1,
  28. Isobel Black1,
  29. Stephanie Jeffares1 and
  30. Michael Friedlander23,28
  1. 1 Department of Gynaecological Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia
  2. 2 Division of Obstetrics and Gynaecology, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
  3. 3 Institute for Health Research, The University of Notre Dame Australia, Fremantle, Western Australia, Australia
  4. 4 Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  5. 5 Faculty of Science, School of Psychology, University of Sydney, Faculty of Science, Sydney, New South Wales, Australia
  6. 6 Gynaecological Cancer Research, The University of Queensland, Brisbane, Queensland, Australia
  7. 7 NHMRC Clinical Trials Centre, The University of Sydney, Sydney, New South Wales, Australia
  8. 8 Psycho-oncology Co-operative Research Group (PoCoG), School of Psychology, University of Sydney, Sydney, New South Wales, Australia
  9. 9 Centre for Medical Psychology and Evidence-based Decision-making (CeMPED), School of Psychology, The University of Sydney, Sydney, New South Wales, Australia
  10. 10 Australia and New Zealand Gynaecological Oncology Group, Sydney, New South Wales, Australia
  11. 11 Faculty of Health, Centre for Healthcare Transformation, Queensland University of Technology, Brisbane, Queensland, Australia
  12. 12 Department of Medical Oncology, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia
  13. 13 Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia
  14. 14 Department of Oncology, Royal Brisbane & Women’s Hospital, Herston, Queensland, Australia
  15. 15 Faculty of Medicine, University of Queensland, St Lucia, Queensland, Australia
  16. 16 Oncology and Dysplasia Unit, The Royal Women's Hospital, Melbourne, Victoria, Australia
  17. 17 Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia
  18. 18 Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
  19. 19 The Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  20. 20 Cancer Services, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia
  21. 21 Ovarian Cancer Australia, Melbourne, Victoria, Australia
  22. 22 Division of Surgery, The University of Western Australia Faculty of Health and Medical Sciences, Perth, Western Australia, Australia
  23. 23 Prince of Wales Clinical School, University of New South Wales, Randwick, New South Wales, Australia
  24. 24 Medical Oncology, Prince of Wales and Royal Hospital for Women, Randwick, New South Wales, Australia
  25. 25 Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia
  26. 26 Westmead Clinical School, University of Sydney, Sydney, New South Wales, Australia
  27. 27 Hunter New England Centre for Gynaecological Cancer, John Hunter Hospital, New Lambton Heights, New South Wales, Australia
  28. 28 Medical Oncology, Prince of Wales Hospital, Sydney, New South Wales, Australia
  1. Correspondence to Dr Paul A Cohen, Department of Gynaecological Oncology, St John of God Subiaco Hospital, Subiaco, Western Australia, Australia; paul.cohen{at}uwa.edu.au

Abstract

Background Physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common in women after treatment for ovarian cancer. Most patients would like and need help dealing with these symptoms. The traditional model of follow-up care is unstructured and largely focused on diagnosing recurrent disease, and most oncologists lack skills to identify and manage psychosocial issues. No high quality prospective clinical trials have been conducted to determine the optimal follow-up regimen or the cost effectiveness of ovarian cancer surveillance strategies.

Primary Objective(s) To assess emotional wellbeing, acceptability, safety, and cost effectiveness of nurse led follow-up via telehealth for women with ovarian cancer following completion of primary treatment.

Study Hypothesis We hypothesize that compared with routine clinic based follow-up, nurse led follow-up via telehealth, including serum CA125 monitoring and completion of a patient reported outcome instrument, the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26), will improve emotional wellbeing in women with ovarian cancer; be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease; will result in greater patient satisfaction; will identify more patients with psychological distress, lead to better care, and improved psychological outcomes; and be cost-effective.

Trial Design Phase II multicenter randomized trial comparing 3 monthly nurse led telehealth consultations that include serum CA125 monitoring and completion of the MOST-S26, with routine clinic based follow-up. The allocation ratio will be 1:1.

Major Inclusion/Exclusion Criteria Eligible patients will be women with high grade epithelial ovarian cancer who have normalized serum CA125 (to <35 kU/L) at completion of first line chemotherapy.

Primary Endpoint(s) Emotional wellbeing at 12 months.

Sample Size 150 patients.

Estimated Dates for Completing Accrual and Presenting Results July 2023. Results expected in 2025, 24 months after the last participant is enrolled.

Trial Registration ACTRN12620000332921

  • ovarian cancer
  • quality of life (PRO)/palliative care

Data availability statement

There are no data in this work.

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Introduction

Background and Rationale

Most women with epithelial ovarian cancer are diagnosed with advanced disease, and most cancers will recur within 24 months after completion of first line treatment.1 The aims of ovarian cancer follow-up include detecting symptoms and signs of recurrence, identifying and managing late side effects of surgery and chemotherapy, and providing psychological support to patients with high levels of psychological distress and fear of recurrence.2 Routine follow-up comprises regular clinic visits, measurement of serum CA125, and a history and physical examination by a doctor.3 A patient may see different doctors at each follow-up visit, which can lead to a lack of continuity of care and patient dissatisfaction. For many rural patients, traveling to tertiary centers for follow-up involves considerable cost in terms of time, transport, and accommodation. In Australia, more than 4000 women are living with ovarian cancer, 29% of whom live in regional and remote locations.4

Serial CA125 measurement is sensitive and specific for detecting recurrence in the asymptomatic phase. CA125 doubling criteria have a sensitivity and specificity of 86% and 91%, respectively, and its elevation precedes clinical findings by 4–6 months on average.5 However, in a prospective randomized trial, treatment with chemotherapy at early asymptomatic relapse compared with treatment at symptomatic relapse had a negative impact on quality of life without prolonging survival.6 While acknowledging these findings, the European Society for Medical Oncology recommends that clinicians continue to conduct follow-up with serum CA125 and, while agreeing that routine use of CA125 does not provide benefit in terms of survival or quality of life, the society recommends its use for all ovarian cancer patients who currently are or who will be participating in a study, who will not have frequent clinical follow-up, or for whom secondary surgery will be considered on recurrence.7

Physical examination to detect ovarian cancer recurrence has low sensitivity. In a retrospective study of 80 patients with recurrence following completion of first line treatment, 41 patients (51%) had abnormal physical findings, but only 3 patients (3.8%) first presented with physical findings, and none had abnormal physical findings alone.8 In an Australian cohort study, 452 of 742 patients (61%) recurred but only 2 (0.5%) had abnormal physical findings in the absence of symptoms and/or an elevation in CA125.9

Nurse led follow-up has proven effective in breast cancer, improving continuity of care, psychological support, and meeting patient information needs.10 Nurse led telephone follow-up may be a promising alternative for ovarian cancer, particularly in Australia where many patients are geographically distant from centralized oncology services. A pilot study among 52 ovarian cancer patients in the UK who received nurse led telephone follow-up over a 10 month period found that 73% of women preferred nurse led telephone follow-up compared with clinic based follow-up.11 In a subsequent study of women in this cohort, three core themes emerged regarding the positive impact of nurse led telephone follow-up: perception of increased psychosocial support; deep trust in the expertise of the nurse and the reassurance of the continued blood tests; and perception of relaxed follow-up appointments with time to talk and the perceived practical benefits of this approach. Telehealth is acceptable, and is associated with improved and more equitable access to specialist care, and cost savings to the health system and to patients.12

An ovarian cancer diagnosis and its treatment may have a wide range of sequelae for patients; as well as physical symptoms, anxiety, depression, fear of recurrence, sexual dysfunction, and social withdrawal are common. In a prospective cohort study, more than 40% of patients experienced clinical levels of anxiety or depression during treatment or during the first 3 years of follow-up. For 42% of those affected, this was their first experience of distress and >50% did not receive appropriate medication or psychological support.13 In a recent systematic review, fear of recurrence was identified as a moderate to high level unmet need following first line treatment.14 Most patients would like and require help dealing with these symptoms. However, the traditional model of follow-up care does not facilitate this because it is largely focused on diagnosing recurrent disease, most gynecologic and medical oncologists lack skills to identify and manage psychosocial issues, and referrals to psychologists, counselors, and social workers are haphazard. In the UK pilot study, specialist nurses sought evidence of both relapse (with rapid referral to the oncologist if suspected) and psychosocial concerns, with 60% of patients raising such psychological concerns.11

The current model of ovarian cancer follow-up is not evidence based. No high quality prospective clinical trials have ever been conducted to determine the optimal follow-up regimen or the cost effectiveness of surveillance protocols. A 2014 Cochrane review of ovarian cancer follow-up highlighted a lack of randomized studies on most aspects of follow-up care after treatment15 and concluded that randomized controlled trials are needed to compare different follow-up models on the outcomes of survival, quality of life, cost, and psychological effects. To our knowledge, no such trials have been conducted in the intervening years.

Hypotheses

We hypothesize that compared with routine follow-up, nurse led follow-up via telehealth, including monitoring CA125 and standardized symptom assessment with the Measure of Ovarian Symptoms and Treatment concerns-Surveillance (MOST-S26) will:

  • improve emotional wellbeing in women with ovarian cancer;

  • be feasible, safe, acceptable, and not delay the time to diagnosis of recurrent disease;

  • result in greater patient satisfaction;

  • identify more patients with psychological distress and will result in a greater proportion of referrals to clinical psychologists for counseling, and greater use of online support tools to manage anxiety/depression and insomnia;

  • be cost-effective.

Methods

Trial Design

This study is a non-comparative phase IIb multicenter randomized clinical trial (Figure 1).

Figure 1

Study schema. MOST, Measure of Ovarian Symptoms and Treatment; PARPi, poly (ADP-ribose) polymerase inhibitors.

Funding Sources

The Western Australian Health Translation Network and the Australian Government’s Medical Research Future Fund; the Ladybird Foundation and Australia and New Zealand Gynaecological Oncology Group Fund for New Research Grant.

Participants

Inclusion and exclusion criteria, and study endpoints are shown in Boxes 1 and 2, respectively.

Box 1

Inclusion and exclusion criteria

Inclusion criteria

  • Patients diagnosed with epithelial carcinoma arising from the ovary, fallopian tube, or peritoneum

  • International Federation of Gynecology and Obstetrics (FIGO) stages I–IV

  • High grade serous, grade 3 endometrioid, clear cell, and mucinous histotypes

  • Eastern Cooperative Oncology Group score 0–2

  • Normalization of serum CA125 (to <35 kU/L) and other relevant tumor markers at completion of first line chemotherapy

  • No disease progression on imaging performed after the final chemotherapy cycle and before signing of the study consent form, in centers where post-treatment imaging is performed

  • Age ≥18 years

  • Proficient in English

Exclusion criteria

  • Patients who did not undergo cytoreductive surgery

  • Patients who did not receive chemotherapy

  • An individual assessed as mentally incapable of providing informed consent

  • Patients not proficient in English

Box 2

Study endpoints

Primary endpoint

  • Emotional wellbeing at 12 months, assessed by the emotional wellbeing subscale of the Functional Assessment of Cancer Therapy-Ovarian Subscale (40)

Secondary endpoints

  • Feasibility: assessed by recruitment, retention, and crossover

  • Safety: assessed by adverse events and time to diagnose recurrence

  • Healthcare resource use, costs, and cost effectiveness of the intervention

  • Proportion of patients in the intervention arm (nurse led follow-up group) who completed the MOST-S26 prior to their follow-up consultation

  • Proportion of patients in the intervention arm who crossed over to the standard care arm

  • The duration of the 3 monthly nurse led follow-up consultations and the number and duration of any additional calls

  • The number of referrals for symptom management generated in both arms

  • The outcomes of these referrals: whether the patient attended, what treatment was recommended, and whether the patient adhered to the recommended treatment

  • Patient satisfaction: CANHELP Lite at baseline, 6 months, 12 months, and 24 months

  • Health related quality of life: European Organization for Research and Treatment of Cancer core quality of life questionnaire (EORTC QLQ-C3041)

  • Fear of recurrence: Fear of Cancer Recurrence Inventory Severity subscale 8

  • Acceptability: assessed by a qualitative sub-study

  • Preference based health related quality of life utility scores derived from QLQ-C30 responses using Australian utility weights for the EORTC multi-attribute utility instrument QLU-C10D

  • Recurrence detection rates in each arm

  • Time to first recurrence

  • Test–retest reliability of MOST

Women ≥18 years of age who demonstrate normalization of serum CA125 (to <35 kU/L) at completion of first line therapy for epithelial ovarian cancer will be recruited from outpatient clinics and consulting rooms at 10 sites in Australia (Table 1). A 24 month period of enrollment, with a participation of 24 months, allows for a maximum of 48 months of active study time.

Table 1

Participating sites

Randomization

Once consented, participants will be randomized to the intervention or control group, stratified by prescription of maintenance therapy and timing of surgery. Patients who are not prescribed maintenance therapy after completion of first line treatment and are randomized to the intervention will receive a nurse led telehealth consultation every 3 months and will undergo standardized symptom assessment via the MOST-S26 (Online supplemental file). Patients who are prescribed maintenance therapy after completion of first line treatment and are randomized to the intervention will receive a nurse led telehealth consultation and undergo standardized symptom assessment via the MOST-S26 every 3 months in addition to attending their regular specialist clinic for consultation with their treating physician. All patients randomized to the standard care group will attend their regular clinic or have telehealth appointments every 3 months for consultation with their treating physician without nurse-led telehealth consultations.

Supplemental material

Nurse Led Follow-up

The first nurse led follow-up consultation will be held 3 months after completion of first line chemotherapy. Subsequently, they will be held every 3 months for up to 2 years. The nurse led follow-up consultation will be delivered by experienced gynecologic oncology nurses employed specifically for this study, in each of the four participating states: Western Australia, Queensland, New South Wales, and Victoria. The nurse follow-up consultation will be scheduled in the lead site database and the nurse at each site will send reminders by email or SMS to patients 1 week before and 48 hours before the scheduled follow-up consultation. Reminders will include a prompt to patients to have a blood test at their local pathology provider (eight blood request forms for CA125 and other relevant tumor markers will be provided to patients at enrollment), 1–4 days prior to the consultation. The blood results will be obtained by the nurse from the pathology laboratories, collated, and recorded in the case report form. Patients will also be prompted to complete the MOST-S26 via an online survey platform available for mobile devices and personal computers, or paper based if needed, 1–4 days prior to the consultation. If a patient has not completed the MOST-S26 by the time of the consultation, then the nurse will complete it with the patient during the consultation.

The study nurse will contact patients for the video consultation via Healthdirect Video Call. The video call service was developed and is delivered by Healthdirect Australia through the support of Commonwealth and state health departments to make it easy for healthcare providers to offer their services via video consultation in a secure and confidential manner. Patients will be able to connect with the study nurses via smartphone, tablet, or desktop computer from wherever is most convenient for them. Patients without, or with slow, internet access, who do not own or are unable to use personal devices, will have the option of completing a paper version of the MOST-S26 and additional study questionnaires, and communicating with the study nurses via landline telephone.

During the consultation, the nurse will conduct a semi-structured interview, reviewing patients’ MOST-S26 responses. The nurse will ask the patient questions about symptoms (fatigue, appetite, abdominal pain/swelling, nausea, vomiting, constipation, shortness of breath, leg swelling, sleep, paresthesia, and peripheral neuropathy), problems with sleep and concentration, and emotional, psychological, and overall wellbeing. The patient’s responses to the MOST-S26 will provide a framework for discussion during the consultation with the nurse focusing on symptoms that have been bothersome (indicated by a score of 4 or more) in the last 7 days and/or where there has been a deterioration in any MOST symptom score since the previous follow-up consultation (indicated by a worsening of score of 4 or more points). The nurse will advise patients of their CA125 and other relevant tumor marker results.

If appropriate, the nurse will make relevant referrals to address problems identified during the consultation. Physical symptoms such as pain and fatigue may require discussion with the patient’s oncologist, or trigger referral to a physiotherapist or dietitian. Practical problems such as financial or work related issues may trigger referral to a social worker. Spiritual issues such as those related to death and meaning, or purpose of life, may trigger referral to a pastoral care service. Psychological/emotional issues such as those related to anxiety or depression may trigger referral to a support group, the patient’s family practitioner, clinical psychologist, or psychiatrist, depending on the degree of severity. The study nurses will screen and assess patients for anxiety and depression using the scores of the MOST-S26 and a stepped care approach shown on page 36 of the Online Supplemental File.

Outcome Assessment

The primary outcome measure is emotional wellbeing at 12 months, assessed by the emotional wellbeing subscale of the Functional Assessment of Cancer Therapy-Ovarian Subscale. Secondary outcome measures are described in the full protocol (Online supplemental file). Study outcome measures will be completed by all patients at enrollment, and at 6, 12, and 24 month visits, as shown in the patient timeline (see full protocol in the Online supplemental file). A subset of patients (n=30) and nurses (n=4) will be interviewed about their experiences of the nurse led telephone follow-up to explore the acceptability of the intervention.

Sample Size

Previous studies have demonstrated that 40% of women following primary treatment for epithelial ovarian cancer have persistent low emotional wellbeing with standard follow-up care. A sample size of 75 patients will have at least 85% power with 95% confidence to exclude a persistent 40% rate of low emotional wellbeing in favor of a lower rate of 25%. The randomization will allow for contemporary control and exploratory comparisons to identify sub-populations which show a larger benefit, yielding a total sample size of 150 patients.

Randomization and Blinding

Treatment allocation will be implemented by a telephone interactive voice response system using the method of minimization, stratified by primary debulking surgery/neoadjuvant chemotherapy (level1, level2), maintenance therapy/no maintenance therapy (level1, level2), and site. Research nurses at each site will assign patients to the intervention group or the control group, as provided by the interactive voice response system allocation. As this is an open label study, patients, treating specialists, investigators, and study personnel will not be blinded to treatment allocation.

Statistical Methods

For this signal finding non-comparative design, the percentage of patients experiencing low emotional wellbeing in the MOST-S26 guided group will be obtained, together with the 95% confidence interval. The degree of benefit will be ascertained by (i) examining the consistency of this proportion with the historical level (40%) and (ii) with that of the contemporary control group. Exploratory analyses will also be performed and, where appropriate, according to the principle of intention to treat. The significance level of any exploratory comparisons will be 5% with no adjustment made for multiple comparisons. Categorical variables will be described using frequency and per cent, and continuous scale variables will be described using mean, standard deviation, and minimum and maximum. Group differences will be examined using the χ2 tests (and, if necessary, appropriate exact tests) for categorical and binary outcomes, and the t or z tests (normal distribution) for continuous variables. Where departure from symmetry is suspected, the outcomes may be transformed as appropriate. Multivariate analyses exploring the effects of baseline patient/disease characteristics will be performed using appropriate regression models (for outcomes that are continuous, linear regression; binary logistic regression and time to event, proportional hazards). Similar statistical methods will be used to assess the different health related quality of life scales, as well as describing the health related quality of life profiles over time for different health related quality of life domains.

Test–retest reliability of MOST items will be determined by calculating intraclass correlations between baseline and week 1 item scores. Intraclass correlation values >70 will be considered as evidence of good test–retest reliability. The semi-structured interviews conducted with patients and nurses to explore the acceptability of the intervention will be audio recorded, transcribed, and thematically analyzed. Coding of interviews will be conducted by a single researcher; a second researcher will conduct an independent audit to confirm that the analysis was systematic and transparent, and that the resulting themes are credible. NVivo qualitative data management software will facilitate the analysis.

A cost consequence analysis will be undertaken that tabulates the healthcare resource use and costs from a health system and patient perspective, and the health benefits of nurse led follow-up compared with standard care to ascertain incremental costs and benefits of nurse led telehealth follow-up.

Discussion

This study will assess a novel approach to ovarian cancer follow-up that utilizes nurse led follow-up via telehealth, serum CA125 monitoring, and standardized patient reported symptom assessment, the MOST-S26. The hypotheses are that the intervention will improve emotional wellbeing and satisfaction; be feasible, safe, acceptable, cost effective, and not reduce time to diagnosis of recurrent disease; identify more patients with psychological distress compared with routine follow-up; result in a greater proportion of referrals to psychologists for counseling and use of online support tools to manage anxiety/depression and insomnia; and lead to improved care and psychological outcomes.

Data availability statement

There are no data in this work.

Ethics statements

Patient consent for publication

Ethics approval

The trial was approved by the Sir Charles Gairdner and Osborne Park Health Care Group Human Research Ethics Committee (RGS00000038).

Acknowledgments

We thank patients for their participation in this study. We would also like to acknowledge Letitia Lancaster, Estefania Vicario, Kate Campbell, Trudi Cattley, and Dr Janine Lombard.

References

Footnotes

  • Contributors Substantial contributions to the conception or design: all authors. PAC is the principal investigator of the trial and drafted the manuscript. Drafting the work and revising it critically for important intellectual content: all authors. Final approval of the version published: all authors. Agreement to be accountable for all aspects of the work: all authors.

  • Funding The study is funded by the Western Australia Health Translation Network’s Health Service Translational Research Project Grant, the Australian Government’s Medical Research Future Fund, the Australia and New Zealand Gynaecological Oncology Group (ANZGOG), and the Ladybird Foundation.

  • Competing interests PAC reports honoraria from Seqirus and Astra Zeneca unrelated to the submitted work. AO reports grants, personal fees, and other funding from SurgicalPerformance PTY Ltd, and grants from Medtronic, not directly related to the subject of this manuscript; consultancy fees from Baxter Healthcare Australia and New Zealand and Astra Zeneca Australia, not directly related to the subject of this manuscript; and a trademark licensed to SurgicalPerformance Pty Ltd. PB reports honoraria from GSK. MF reports grants from Astra Zeneca, Novartis, and Beigene; consulting fees from Astra Zeneca, Novartis, GSK, MSF, Takeda, and Lilly; honoraria from Astra Zeneca, GSK, and ACT Genomics; and support for travel from Astra Zeneca, unrelated to the submitted work. MK, MF, PMW, RC, and PAC developed the MOST-S26.

  • Provenance and peer review Commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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