Each and every one of us is affected by cancer in some way, shape or form. Whether it’s a close friend or family member or even the Terry Fox Run that happens every year, each one of our lives are related to this massive disease. Unfortunately, despite all the new research that happens every year, cancer treatment is still inherently toxic to a person and many cancer patients are not able to fully complete their perscribed treatment. In order to combat the negative effects of cancer treatment, such as toxicity and decreased quality of life, as well as possibly increase the long-term survival of cancer patients, oncologists have started implementing adjuvant interventions, interventions that are used after chemoradiation therapy. So many people with a cancer diagnoses are also facing financial hardships encured by the costs of their treatment so it is vital that interventions that are proposed for these people are not only effective but accessible both physically and financially. Lung cancer is one of the most fatal cancers with one of the highest mortality rates globally so it is imperative that we seek to utilize what available medicine there is to us today to better the lives of millions.

This study was conducted via a literature review that intended to identify possible interventions for non-small cell lung cancer (NSCLC) at stages IIIB and IIIC.  Papers that were published between January 2009 and December 2024 on the use of complementary and alternative medicine (CAMs) in lung cancer were pulled from the National Center for Complementary and Integrative Health, Natural Medicines, MEDLINE (Ovid), PubMed, Cochrane Library, Cumulated Index to Nursing and Allied Health Literature, MEDLINE (Ebsco), AHS Insite, OAISter, ClinicalTrials.gov, American Society of Clinical Oncology, European Society of Medical Oncology, Google, and Google Scholar. Key terms of the search included terms related to complementary medicine, alternative medicine, lung cancer, stage III cancer, and a list of CAMs compiled by Psychosocial Oncology Professor Dr. Linda Carlson in the Department of Oncology, Cumming School of Medicine at the University of Calgary.

These papers were then vetted through a spreadsheet organizer made in Microsoft Excel^TM (Excel 2024), where they were then categorized by author, treatment stage, manipulated variable, and paper type. For papers on interventions, it was also noted whether the intervention was intended to be used in a complementary or adjuvant fashion.

The aim of this study was to identify an intervention that could be used as an adjuvant therapy or treatment after chemoradiation therapy and before immunotherapy. To satisfy these criteria, papers that proposed interventions as a preventative measure to lung cancer, interventions implemented before or after surgery, treatments administered prior to chemoradiation therapy, or for those used after immunotherapy were excluded. This ensured that the interventions being considered were related to the specific time in the treatment cycle that was being considered and that the interventions were intended to be used for stage IIIB and IIIC NSCLC.

Papers remaining from the initial search were then categorized based on their proposed intervention. Types of interventions included traditional Chinese medicines (TCMs), activities such as yoga or breathing exercises, dietary regulation or supplementation, medication, as well as others with significantly fewer results. The most prevalent types of interventions studied were TCMs, activity-based interventions, and dietary alterations. However, despite the abundance of papers on TCMs, the extreme diversity in TCMs made it difficult to properly evaluate them for the review. Due to this and unfamiliarity with the subject, papers related to TCMs were not considered in the review.

Papers that were classified as reviews, systematic reviews, non-peer-reviewed papers, non-English papers, and commentaries were also excluded from this study to ensure the integrity of the review process.

The application of these three criteria resulted in paring down the 315 initially pulled abstracts to 13 papers. These papers were then sorted into three categories based on the type of intervention: dietary, exercise/activity, and breathing exercises. From these, each paper was then scored according to a scoring system that evaluated efficacy, cost-effectiveness, and feasibility. In order to maintain the maximum amount of integrity in the scoring of the interventions, any pulled paper was considered regardless of any contradictory claims. 

The effectiveness scoring of the intervention was weighed the heaviest of the three due to the importance of an intervention being most closely linked to its ability to be impactful on patients after chemoradiation therapy. Scoring of the effectiveness of each intervention was based on a scale from one to five, with five demonstrating positive trends based on collected data, two representing interventions that did not display any positive trends, and one representing interventions that were possibly harmful to patients based on current data. Cost-effectiveness, which was the second most important factor in the scoring of the interventions, was evaluated based on how expensive the intervention was to be implemented. This primarily looked at the cost for patients and was also scored on a one to five scale, with five being without additional costs and one being significantly above average costs of interventions in Canada as per currently available data. Finally, the feasibility of the interventions was measured based on the accessibility of the interventions, including but not limited to accessibility related to time or distance needing to be traveled. This metric was also scored on a scale of one to five, with five being relatively easy for someone to do without committing multiple hours or needing to travel far and one being inaccessible through metrics such as time commitment, distance, or difficulty in completing the activity. Feasibility also took into consideration the amount of support that would be needed to complete the activity, with activities that required constant aid or were overly strenuous being scored lower compared to less strenuous or more independent activities.

The intervention with the highest overall score according to this system was identified as being the most potentially impactful if implemented into patient care. From there, a hypothesis was established that summarized the findings of the review, weighing the benefits of each intervention against its drawbacks. The hypothesis was then used to set up further investigations on the identified intervention, aiding in improving future outcomes in quality of life, treatment effectiveness, and patient survival in patients with stage IIIB/C NSCLC.

Lung cancer is one of the most common types of cancer world-wide, accounting for the greatest number of cancer-related deaths per year.¹ In men, it is the most common type of cancer and the second most common in women.² The global mortality rate of lung cancer in 2022 was roughly 73%, one of the highest globally.² An elevated risk of lung cancer has been associated with practices such as smoking tobacco and cigarettes.³ This risk increases with both the duration and quantity of smoking.⁴

Non-small-cell lung cancer (NSCLC) is a type of lung cancer that originates in the epithelial cells^5,6 and accounts for 85% of all lung cancer cases.⁷ Epithelial cells are specialized cells that make up primary tissue throughout the body, lining organ surfaces, body cavities, and blood vessels.⁸ The two predominant types of NSCLC are adenocarcinomas and squamous cell carcinoma (SQCC).¹ Adenocarcinomas, which specifically impact the glandular tissue of the lungs,⁹ may be treated by targeting specific mutations surrounding the epidermal growth factor receptor and the anaplastic lymphoma kinase, when these mutations are expressed.¹ These treatments have not been as effective when combatting SQCC where these mutations are not present.¹

Cancer is staged on a system that evaluates the size of the tumor (T), the lymph nodal involvement (N), and the movement of the cancer (M).¹⁰ This system is referred to as the TNM system.¹⁰ Each of the letters carry a number from 1 to 4 based on the local extent of the primary tumor, lymph nodal involvement, and the distant spread of the tumor to other organs or locations.¹⁰ Stage 3 lung cancer refers to lung cancer that has spread to the lymph nodes of the lungs.⁷ Stage 3 lung cancer can be divided into three stages, progressing from smaller tumors that are easier to treat to more severe tumors that are more difficult to treat.¹¹ These stages; 3A, 3B, and 3C, have increasing involvement in the lymph nodes of the lungs and tend to increase in the size of the tumor.¹¹ In reference to the TMN system, stages 3A-3C would range from T1a-4, N0-3, M0.¹¹ Stage 3 non-small cell lung cancer (S3 NSCLC) has impacted the lymph nodes of the lungs in addition to the epithelial cells.⁷

There are multiple treatment options for S3 NSCLC, including surgery (for stage 3A and selective cases of 3B),⁷ chemoradiotherapy, and targeted cancer medication.⁷ The cornerstone of cancer treatment is generally surgery when possible, typically with removal of the impacted lobe(s) of the lung and involved nodes.^7,12 In instances where surgery is not possible, such as in stage 3C, other treatments are offered.^7,12 Despite technological advances, chemoradiation is sometimes not sufficient in treating NSCLC and in order to combat this, recent studies have found that, in addition to initial treatments, immunotherapy is effective in achieving remission of the cancer.⁷ In cases where surgery is not recommended, the standard of care would be a regimen of chemoradiation therapy followed by immunotherapy.⁷

Immunotherapy involves modulating the immune system to better recognize and therefore attack cancerous cells.¹³ It can be divided into two categories, active and passive.¹³ Active immunotherapy uses the immune system to directly target tumor-associated antigens that are present on the surfaces of tumors.¹³ Types of active immunotherapy include adoptive cell therapy, chimeric antigen receptor T-cell therapy, and engineered T-cell receptor therapy.¹³ Passive immunotherapy amplifies the immune system’s inherent anticancer responses with the use of monoclonal antibodies, cytokines, and lymphocytes.¹³

Despite the advances that immunotherapy has made in cancer treatment, it still presents challenges.¹⁴ Common issues surrounding immunotherapy after the initial treatment of the cancer are the toxicity inherent to chemoradiation therapies and immunotherapy and the side effects that are associated with them.¹⁵ To address these challenges, oncologists have introduced changes to diet, physical activity, or medication as interventions during and after initial cancer treatments (complementary or adjuvant treatments) to minimize harmful side effects associated with chemoradiation therapy and immunotherapy and to improve outcomes.¹⁵ Interventions range from changes in activity or habits, such as changes in a patient’s diet,¹⁶ to medications such as Durvalumab which saw a 55.9% progression-free survival rate in this lung cancer populatuion.¹⁷ There are a plethora of interventions being considered for the general treatment of lung cancer, however, many novel interventions for cancer have not yet been studied or their effectiveness on NSCLC has not been identified.¹⁵

Due to the abundance of cases of NSCLC⁷ and the number of lung cancer interventions that have not yet been applied to NSCLC specifically, this project aims to determine the  potential interventions that have yet to be implemented in NSCLC treatment to further improve patient survival, ability of patients to complete prescribed treatments, or to improve quality of life beyond existing standards of care. A review current literature for positive trends in adjuvant treatments of lung cancer was conducted and these trends were characterized and scored based on their potential to be impactful on patient survival, ability to complete treatment, minimized negative side effects, or patient comfort when applied to NSCLC treatment while also considering the cost effectiveness, feasibility, and practicality of the intervention. The ultimate goal is to hypothesize on the most impactful adjuvant therapy. In the long-term, the identified interventions will be proposed to be the subject of a clinical trials, and the conduction of these trials will allow for the analysis of results that identifies the most impactful intervention.

From the 315 papers pulled in the initial data search, 7 papers were found to be relevant to the project after utilizing the references list of various meta-analyses. The four primary interventions identified were mind-body (aerobic) exercises, breathing exercises, dietary advice, and fatty acid supplements. These interventions varied in the number of papers available, with dietary advice and breathing exercises only having one paper respectively, fatty acid supplements having two papers, and mind-body exercises with three. 

This table breaks down the scores given to each paper (efficacy, cost effectiveness, and feasibility) as well as gives the overall score. 

Scores were determined based on the conclusions of the clinical trials, for example with Baldwin’s study on dietary advice, results demonstrated no actual effects hence the score of 1 in efficacy. The overall scores in the table were averaged to 14 for breathing exercises, 14.17 for mind-body exercises, 9 for dietary advice, and 13 for fatty acid supplements. 

This graph shows a direct comparison between the average scores of the interventions. 

As seen in the graph, there is a very small difference between the averages of breathing exercises and mind-body exercises and this is likely due to the lack of studies on breathing exercises not being able to have a proper average when compared to mind-body exercises. This highlights one of the primary sources of error in the project, the lack of current material on adjuvant interventions for non-small-cell lung cancer. 

These two interventions, breathing exercises and mind-body exercises, demonstrated efficacy for both mental and physical health. Primarily tested through a six minute walking distance test and a sit-to-stand test, these interventions demonstrated increases in patient’s abilities to perform various physical activities. For mental health, mind-body exercises were more effective based on current data and saw decreases in anxiety and depression in post-chemoradiation cancer patients. 

Dietary interventions, although fatty acid supplements were fairly effective, scored lower compared to activity-based interventions. One thing to note, the clinical trial on dietary advice mentioned how many patients did not adequately complete logs of when they took the recommended advice and when they did not. This likely caused error in this study as there was nothing researchers could do to ensure that their protocols were being followed. For fatty acid supplements, they were extremely effective in improving mental health as well as indicating possibilities of decreasing the expression of some cancer proteins. However, these studies focused on fatty acid supplements that were fairly expensive to access in Canada due to how they are not part of the typical Western diet. Taking this into consideration, fatty acid supplements, although effective, could not receive a full score in cost effectiveness due to price and feasibility due to difficulty of access and patient reluctance to take them

Based on the available data on Stage IIIB/C non-small-cell lung cancer interventions, we were able to conclude that mind-body exercises were most likely to be effective if implemented into standard non-small-cell lung cancer care (NSCLC). This is because they were seen to be the most effective for decreasing anxiety and depression, increasing six minute walking distance, and overall improving patient quality of life. Closely followed was breathing exercises which also saw improvements in physical health but lacked improvements in mental health or other aspects of quality of life. The large differences between dietary and activity based interventions allow us to draw the conclusion that activity based interventions are better for improving patient quality of life both physically and mentally. This was seen through the stronger trends of decreased anxiety and depression in activity based interventions when compared to dietary ones and the trend of increased physical ability with activity based interventions, specifically mind-body exercises. However, there is a large risk of bias or error in these results because of our extremely limited data after the application of all the exclusion criteria. As two of the interventions we scored only had one available study, there is not any way for us to validate these results as of right now. In the future, when more papers on this topic are published, we can revisit it to validate our findings. 

In order to improve this project in the future, we are hoping to increase our range of available papers or decrease the specificity of our search. The majority of papers on Stage III lung cancer applied to only Stage IIIA which was not included in this study. To allow for more diverse data, this study could be re-run to include IIIA and our analysis refined to categorize findings based on intervention as well as stage of cancer. It is highly possible that an intervention that is applicable to Stage IIIA lung cancer is going to be at least marginally effective towards stages IIIB and C considering the similarities between these substages. 

Another way in which this project could be improved would be through diversifying the initial data search or including traditional Chinese medicines (TCMs) into our study. TCMs were initially excluded due to time pressures and the extreme diversity in the studies on them. Future directions of this project could include them to further evaluate novel interventions. Our initial data search could also be expanded to include other key search terms that would ideally expand the number of studies pulled which would in turn increase the number of papers applicable to this study. 

There are many possible future directions for this project however the primary one is the application of our scoring system into more diverse fields or further refinement of our scoring system. For example, expanding the use of scoring criteria beyond NSCLC to other kinds of lung cancer or even an entirely different kind of lung cancer. Our scoring system could also be refined to better suit specifically NSCLC. This would include adding criteria that evaluated symptoms specific to lung cancer, for example how an intervention targets shortness of breath in lung cancer patients. 

Ideally, this project will lead to further research on mind-body exercises in the near future. With sufficient research on this intervention, the end goal is to propose a clinical trial where we can actually evaluate the efficacy of this intervention and our scoring system in identifying interventions with high potential.

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Thank you to Dr. Kerba from the department of Oncology at the University of Calgary, Marcus Vaska from the University of Calgary, and Dr. Garcia from Webber Academy for their guidance and help with the research process