INTRODUCTION:

Colorectal cancer is one of the most common causes of cancer death worldwide, and the prevalence is steadily increasing in developing countries.

According to GLOBOCAN 2020, colorectal cancer is the third most common cancer in both men and women (10.0% of total cases) and the second-highest number of deaths (9.4% of total deaths) in both sexes worldwide (http://cancer.org).

It remained one of the most common gastrointestinal cancer with tremendous morbidities, recurrences, and mortalities¹. Strategies and guidelines for colorectal cancer have been developed, including screening and identifying cancer pathology². Currently, conventional therapies available for colorectal cancer are surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, either in single therapy or combination therapy. Surgery is the most common modality to manage all stages of colorectal cancer³. Patients diagnosed with recurrent and metastatic colorectal cancer need a long-term application of those therapies, with the consequences of severe side effects and toxicities. Moreover, while various therapy has been applied, the prognosis remained poor⁴. They had to suffer from the disease and the aftermath of the therapy regimen. Patients with colorectal cancer, especially those in the end stage, need additional care to improve their quality of life. It has been known that patients might combine conventional care with complementary medicines. These treatments are mainly taken to improve wellness and pain management instead of cancer-specific reasons.

Currently, there are abundant choices of complementary medicines. Five categories of complementary therapies were available; biological, mind-body, body manipulation, energy, and alternative medical systems⁵. As the disease had physical and physiological consequences, research still seeks the effect of these complementary medicines on colon cancer patients. Patients commonly complained about uncomfortable feelings such as anxiety, pain, and fatigue. Nevertheless, evidence supports the effectiveness of different mind-body medicine in colorectal cancer patients⁶. Mindfulness was reported to be an effective therapy to relieve stress, while yoga and qigong could reduce anxiety and improve sleep quality ². Rational use of complementary medicines is also necessary under the supervision of qualified instructors. However, the most comprehensive therapy for maintaining the quality of life of end-stage colorectal cancer patients remains unclear. This systematic review aimed to sort out complementary medicines that could be advised to be used for colorectal cancer patients.

MATERIAL AND METHODS:

Search strategy:

A comprehensive systematic review was conducted on relevant studies about complementary therapeutic methods that have been given to colorectal cancer patients. The search was conducted on PubMed, Scopus, and ScienceDirect databases in February 2021. For the search strategy, the keywords used were: "Colorectal Cancer", "Palliative Care", and "Complementary Medicine".

Inclusion and exclusion criteria:

We made inclusion and exclusion criteria to limit the scientific sources searched from each database. A database search was conducted for the last six years, from 2015 to 2021. The articles chosen were original articles and review articles devoted to articles of Medical, Nursing and Health. The PICOS question (P = population; I = intervention; C = comparators; O = outcomes; S = study type) format was used for formulating the research questions (Table 1). The boundaries of the review question were deﬁned through the development of inclusion and exclusion criteria using the PICOS format. Studies were included for review if articles met the following inclusion criteria: (1) All types of study, whether experimental or non-experimental research conducted in colorectal cancer patients; (2) Intervention consisted of palliative and complementary therapy; (3) Outcomes related to the application of palliative complementary therapy in colorectal cancer patients.

The search results were limited to cross-sectional, intervention, and peer-reviewed studies published in English during 2015 – 2021. The time range was set to ensure the use of the most recent studies in developing theoretical models in colorectal cancer therapy.

Table 1. The PICOS Format of this study

Criteria	Inclusion	Exclusion
Population	Studies consisted of colorectal cancer patients with cimolementary palliative therapy	Colorectal cancer patients without complementary palliative therapy
Intervention	Complementary treatment and management of colorectal cancer	Conventional treatment of colorectal cancer
Comparators	None	No exclusion
Outcomes	Palliative complementary therapy analysis for colorectal cancer patients	Not described palliative complementary therapy analysis to colorectal cancer patients
Study Design and publication type	Systematic review, qualitative analysis	No exclusion
Publication years	2015 – 2021	Before 2015
Language	English	Language other than English

Study selection:

Five hundred and seventy-three studies were found from the database search (Figure 1), and we assessed and screened the title (n = 64). Exclusions were made because many data did not include colon cancer patients as subjects and did not describe complementary medicine. Abstract (n = 37) and full text (n = 9) were assessed in accordance with inclusion criteria (Table 2). We found six full-text articles eligible to conduct a systematic review.

Table 2. Summary of included articles

No.	Reference	Methods	Participant	Intervention	Outcome	Risk of bias
1.	Wong et al., 2021 ²	Cross-sectional	1,501,481 individuals with colorectal cancer, and 245,155,790 without	Complementary medicine	Complementary medicines were used both by individuals with colorectal cancer and without. 27.3% of cancer patients had used complementary medicine. The most common method used was mind-body medicine and chiropractic services. Mind-body modalities are safe. However, rational use under qualified experts is necessary.	The study did not examine the reason and satisfaction of complementary medicine use.
2.	Kong et al., 2020 ⁴	Review article	-	Chinese herbal medicines (CHMs)	Chinese herbal medicine has been widely used to find alternative therapies for colorectal cancer with high efficacy and few side effects. CHMs can modulate proliferation, apoptosis, cell cycle, adhesion and migration of cancer cells and tumor angiogenesis Several CHMs have the potential to reverse chemo-resistance in colorectal cancer treatment. Side effects of chemotherapy could also be minimized with CHMs.
3.	Li et al., 2016 ⁷	Review article		Traditional Chinese medicine, Chinese herbal medicine	Herbals with anti-inflammatory mechanisms could be used in the early stage of colorectal cancer to reduce inflammatory symptoms and tumor formation. Moreover, it had multiple target therapies compared to chemical therapies.
4.	Xu et al., 2017 ⁸	Prospective cohort	312 colorectal cancer patients	Traditional Chinese medicine	The longer duration of traditional Chinese medicine use was linked to better survival outcomes for patients who undergoing adjuvant chemotherapy after radical surgery. Recurrence and the metastatic rate were also lower.
5.	Wu, et al., ⁹	Retrospective cross-sectional	2,486 patients with colon cancer during 1998-2008	Chinese herbal product (CHP)	42.7% of colorectal cancer patients used CHP. The most common herbs used were Costusroot and Amomum Six Gentlemen Decoction. Ginseng radix dominates the prescribed CHP for colorectal cancer patients. These herbals could alleviate gastrointestinal symptoms as a side effect of chemical therapy.	There were no data regarding the severity of colorectal cancer and CHP utilization.
6.	Liu et al., 2018 ¹⁰	Systematic review and meta-analysis of randomized control trials (RCTs)	22 RCTs of acupuncture and related therapies	Acupuncture	Manual acupuncture was the most commonly used method to recover gastrointestinal function post-surgery. Acupuncture has shown a reduction in post-operative abdominal distention, reducing the time needed to recover gastrointestinal function. Different methods of acupuncture did not differ in effect sizes.	Methodological quality and associated risk of bias in included studies.
7.	Ayik and Özden, 2018 ¹¹	Randomized controlled trial	80 patients undergoing colorectal cancer surgery were divided into experimental group and control group	Aromatherapy massage	Aromatherapy massage with lavender oil before surgery could reduce anxiety level and increase the sleep quality of patients.
8.	Lu et al., 2019 ¹²	Randomized controlled trial	90 patients with colorectal cancer	Baduanjin qigong	Relieve chemotherapy-related fatigue in patients undergoing chemotherapy. Moreover, it could improve physical activity levels and sleep quality,	The intervention was only followed for 24 weeks.
9.	Black et al., 2017 ¹³	Randomized controlled study	57 colorectal cancer patients who undergo chemotherapy	Mindfulness-based stress reduction (MBSR)	More than twice as many patients in the mindfulness group showed cortisol rise from baseline in 20 minutes (69% vs 34%) compared to control, indicating a contradictory action to HPA axis blunting.

Complementary medicines in colorectal cancer management:

Numerous side effects and toxicities met the conventional treatment of colorectal cancer. The survivor could even have sequelae several months after therapy. 80–90% of cancer patients generally used complementary medicine as it alleviates some of the treatment’s symptoms, such as nausea, vomiting, and fatigue, both before and after surgery¹⁴. Popular ones include mind-body medicine, which includes yoga, meditation, mindfulness-based stress reduction, and art or music therapy. Other possible methods are biological-based therapies (dietary supplements, herbs, vitamins), body manipulation (massage, chiropractic, osteopathy), energy-based therapies (acupuncture, tai chi, qigong), and modalities based on alternative medical systems (naturopathy, traditional Chinese medicine, Ayurveda, homeopathy); which were classified by National Center for Complementary and Integrative Health (NICCIH)⁵. However, there was no firm conclusion regarding the effect of specific modalities on colorectal cancer patients.

Chinese herbal medicine:

A better prognosis for patients did not meet the advances in the diagnosis and treatment of colorectal cancer. Moreover, side effects and toxicities limit the usage of these therapies. The use of CHMs has increased due to their multiple mechanisms in modulating proliferation, apoptosis, cell cycle, adhesion and migration of tumor cells, and tumor angiogenesis. For example, Hedyotis diffusa, an infamous herbal medicine used in Chinese clinical practice to treat inflammation-associated diseases and tumors, could significantly inhibit signal transducer and activation of the transcription 3 (STAT3) pathway, promoting apoptosis and suppressing the proliferation of tumor cells⁴. Another proposed mechanism was via reactive oxygen species (ROS). Cancer cells showed higher levels of ROS than normal cells as ROS induced malignant transformation, sustained proliferation, angiogenesis, invasion, and metastasis. Antioxidant properties of CHMs could reduce intracellular ROS and antagonize ROS’ tumorigenic effect on normal cells. Moreover, CHMs can relieve chemotherapy’s toxic side effects by lowering ROS. Ginsenoside, an active ingredient in ginseng, was reported to be able to mitigate doxorubicin-induced cardiotoxicity by lowering ROS production. On the other hand, a controversial approach, the ROS-promotion strategy, showed a better anticancer effect¹⁵. The approach could either increase ROS production, reduce antioxidant activity, or both. Some CHMs active constituents could act as an anticancer effect with ROS-promoting mechanism¹⁵. However, an insufficient increase of ROS to the threshold level would promote tumorigenic activity, instead of inciting a cytotoxic effect, while the administration of antioxidants such as N-acetylcysteine could accelerate lung cancer and melanomas¹⁶. CHMs might also be combined to form a synergistic activity. In colon cancer patients, a mixture of multiple Chinese herbs could decrease the side effect induced by irinotecan, 5-fluorouracil, or leucovorin¹⁷.

In addition, CHMs had the potential to reverse chemo resistance with their bioactive compounds. Chemotherapy with multiple side effects such as nausea, vomiting, diarrhea, hepatotoxicity, myelosuppression and immunosuppression could be treated with CHMs combined with conventional treatment⁹. Therefore, herbal medicine could benefit patients by helping them adhere to chemotherapy programs. Moreover, it prevented tumor recurrence and metastatic tumor rate. Prolonged treatment with traditional Chinese medicine combined with chemotherapy after radical surgery resulted in better survival⁸. However, potential risks of the herb-herb and herb-drug interaction should be considered⁴. Furthermore, every individual needs tailored dosing and confirmed efficacy of CHMs for specific therapeutic regimen.

Acupuncture:

Acupuncture has been used as a complementary modality in cancer patients. Acupuncture technique includes needle insertion into the skin followed by manual or electrical manipulation. There were theories proposed concerning its mechanism of action. Endorphin theory, where acupuncture stimulated the release of particular neurotransmitters such as endorphin to modulate physiological responses, was the most widely studied¹⁸. The application of acupuncture could help manage chemotherapy-related-fatigue (CRF), chemotherapy-induced nausea vomiting (CINV), and leucopenia¹⁹. Surgery is often picked as the treatment of choice in colorectal cancer. However, post-operative ileus usually occurs and is typically resolved within five days in open abdominal surgery and three days after laparoscopic surgery. Acupuncture was found to significantly improved post-operative ileus compared to conventional care alone as it could shorten the hours to first flatus, first bowel movement²⁰, and lessen post-operative abdominal distension. The result of twenty-one RCTs showed that acupuncture could reduce the recovery time for gastrointestinal function after colorectal cancer surgery¹⁰. Another inconvenience experienced by cancer patients is pain and fatigue, in which acupuncture could significantly reduce pain with a quicker and longer analgesic effect than conventional medicine¹⁸. Few case reports had shown that acupuncture improved psychological complaints, e.g. anxiety, stress, and sleep quality²¹. Acupuncture has a relatively low side effect and could be suggested in patients experiencing cancer-related pain, especially when conventional care is unsatisfactory, post operatively, or in patients with anxiety, stress, and disturbed sleep quality.

Aromatherapy massage:

Few studies indicated that performing massage on patients in palliative care had several benefits^22–24. End-stage colorectal cancer patients often experience anxiety and depression. These problems could come from pain, concerns about leaving loved ones, and the perceived image of mortality²³. The massage was used to reduce stress, increase relaxation, treat anxiety and depression, relieve pain, and improve general wellness²⁵. Not only a body massage, but performing foot reflexology on cancer patients reduced pain intensity among them^26,27. Patients felt this kind of therapy relaxing, calming, and empowering. The therapy relieved them from the anxiety of present conditions, the future, and especially their disease. The feeling could last even after the session ended. However, the evidence of effectiveness had not shown significant benefit or harm in massage therapies ²³.

Studies showed that massage using aromatherapy could reduce a patient’s anxiety level. One commonly used oil was lavender oil, which could modulate neurons in the brain¹¹. Lavender oil has been reported to help increase sleep quality, notably in the elderly²⁸. Moreover, in another study, sleep depth, latency, awakenings, and quality were proved higher in the experimental group receiving massage prior to surgery¹¹. Aromatherapy could also affect mood through the connection between the olfactory and limbic systems²². It was thought to affect parasympathetic response to help relieve discomforts²⁹. However, personal expectation and perception of oil influenced the outcome, differentiating whether patients had experiences with a specific scent beforehand²⁴. The massage movement could increase vagal activity and decrease cortisol, stimulating an immune response and reducing stress. A Thailand study reported an increase of 11.4% in lymphocyte count in colorectal patients undergoing chemotherapy. Few other studies stated an increased number of lymphocyte count, WBC, and even CD4 and CD8 cells in other cancer patients²². Aromatherapy, massage, or a combination of both could be suggested as an additional treatment to improve the patient’s psychological well-being.

Baduanjin qigong:

Qigong, a range of Chinese energy exercises and therapies, has been developed and used in cancer treatment. It is divided into internal qigong, which is self-directed and involves movements, meditations, and breathing pattern to reach a flow of energy (qi) to improve well-being and external qigong, which require a trained practitioner to transmit the ‘qi’ to the body²⁰. Qigong integrates musculoskeletal and cognitive skills training and breath regulation conditioning³⁰. The Baduanjin is a form of qigong exercise. Its intensity and sequence were made in sync with kinematics and physiology. Research has found Baduanjin to be beneficial for the quality of life, sleep, and physical condition (e.g. blood pressure, heart rate, flexibility) ³¹. A clinically medium effect was observed for fatigue and sleep difficulty. A study found that Baduanjin exercise improves chemotherapy-related fatigue within 24 weeks of intervention¹². Rehabilitative therapy in adjunct to Baduanjin could be advised to improve the fatigue experienced. Despite its capability to reduce fatigue, qigong could modulate the immune system and inflammatory biomarkers. In general, the CRP value decreased after this intervention, and a few immune cells number were increased³¹. Due to the beneficial effects of improving immune response, the clinicians could advise qigong.

Mindfulness-based stress reduction (MBSR):

Mindfulness practice was focuses on the awareness of bodily sensations and experiences without engaging or reacting to them. It revolves around the Buddhist concept of non-judgmental awareness of the surrounding environment⁶. MBSR program was developed afterwards. It is an 8-week group-based program developed by Professor Jon Kabat-Zinn at the University of Massachusetts Medical Center ³². Early findings suggest mindfulness practice could influence cortisol profile in cancer survivors. It has been concluded that cancer patients experience severe physical and emotional events during and after treatments which elicit a stress response. Chronic stress activation could impair the hypothalamic-pituitary-adrenal (HPA) axis, blunting the diurnal cortisol rhythm. Mindfulness practice could counteract this, as proven by twice as many patients in the mindfulness group exhibiting cortisol rise from baseline to 20 minutes while undergoing chemotherapy compared to control group ¹³. A study in India found that MBSR in cancer patients could reduce stress as after-therapy resulted in none of the patients having a severe stress score ³³. Moreover, a meta-analysis found that MBSR also effectively reduces anxiety and depression. However, the persistence of this effect is still unknown ⁶.

In post-treatment cancer patients, sleep disturbances is the most common complaint. Polysomnographic data showed reduced sleep efficiency, prolonged latency to fall asleep, and increased awake time between sleep. Few studies had contradicting results on whether MBSR could improve sleep quality. However, it is a promising intervention to manage sleep disturbance in cancer patients ³⁴. Other than psychological pain, cancer patients also experience physical pain. Cancer pain could result from tissue inflammation that releases inflammatory mediators and damage sensory ending or when tumors disturb nerves. Evidence showed that cancer patients had low pain control, endurance, and a stigma of pain. Management of emotional response is necessary since the perceived idea of pain will influence pain severity. Mindfulness could help patients withdraw their attention away from unpleasant symptoms, hence less focused on their pain ⁶. Even though the exact physiology of such a process is unknown, using MBSR could benefit patient by reducing stress. However, even though it had many benefits, the persistence of the beneficial effect is unknown. Hence, more profound research may be necessary for the future.

CONCLUSION:

Multiple beneficial effects of complementary therapies have been found and could be advised by clinicians to increase the quality of life of cancer patients. Complementary modalities are generally safe; however, some therapies still warrant further investigation to confirm safety and beneficial consistency.

CONFLICT OF INTEREST:

No competing interests were declared.

FUNDING:

This study was supported by Riset Mitra Luar Negeri Tahun 2021, a grant from Universitas Airlangga, Surabaya, Indonesia

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Received on 07.03.2022 Modified on 01.07.2022

Research J. Pharm. and Tech 2023; 16(3):1540-1546.

DOI: 10.52711/0974-360X.2023.00252