Martin R. Chasen

Rehabilitation following cancer treatment.

Abstract Purpose: Cancer survivorship is increasing. However, life-saving treatments often leave people with physical, cognitive and emotional sequelae that contribute to activity and participation limitations. The purpose of this review is to summarize current evidence regarding rehabilitation interventions to address problems during survivorship. Method: Best evidence synthesis. The review took as its starting point a systematic review of patient needs and supportive care interventions following cancer treatment. The study team identified the needs which could be addressed by rehabilitation and suggested others not originally included. Then they built on the earlier review’s conclusions regarding effective intervention through extraction of results from subsequent systematic reviews and randomized controlled trials. Results: Evidence regarding the effectiveness of potential rehabilitation interventions was reviewed for physical functioning, fatigue, pain, sexual functioning, cognitive functioning, depression, employment, nutrition and participation. With the exception of physical rehabilitation interventions following breast cancer, this literature tends to focus on psychoeducational interventions, which have demonstrated limited effectiveness for rehabilitation outcomes. Conclusions: Most of the knowledge available regarding potential rehabilitation interventions comes from psychosocial oncology literature. While there are limitations, this literature provides an excellent starting point to examine the potential effectiveness of rehabilitation interventions within cancer survivorship programs. Implications for Rehabilitation Good evidence exists for the use of exercise/physical rehabilitation in reducing fatigue after treatment for most cancers, and improving upper extremity functioning following treatment for breast cancer. Preliminary evidence exists in a number of areas that may be improved by rehabilitation interventions, such as pain, sexual functioning, cognitive functioning and return to work, but further research is needed. No intervention studies addressing participation limitations were identified. Rehabilitation professionals are encouraged to take the lead in exploring participation limitations among cancer survivors and developing suitable interventions.

Phase II Study of the Novel Peptide-Nucleic Acid OHR118 in the Management of Cancer-Related Anorexia/Cachexia

BACKGROUND AND OBJECTIVE OHR118 represents a new class of immunomodulatory and cytoprotective drugs in managing anorexia cachexia. Previously in patients with advanced HIV-AIDS, increases in appetite, strength, and alertness were noted. The objective was to determine the effect of OHR118 on appetite, early satiety, and nutritional intake in patients with advanced cancer. Secondary end points included changes in performance status, lean muscle mass, and quality of life (QOL). METHODS Eligible patients received 4.0 mL of OHR118 in subcutaneous daily injections. Patients underwent bi-monthly evaluations during the 28-day initial treatment (phase A). Evaluations included Karnofsky performance status, Edmonton Symptoms Assessment Scale (ESAS), Patient-Generated Subjective Global Assessment (PG-SGA), Simmonds Functional Assessment (SFA), Dyspepsia Symptom Severity Index (DSSI), weight, lean body mass, skin fold thickness, and grip strength. Patients who benefited from phase A could elect to continue with therapy (phase B). RESULTS Of 21 enrolled patients, 11 completed phase A. Eight patients chose to continue with OHR118 treatment (phase B). Weight stabilization or gain was observed in 7 of 11 patients. Total PG-SGA scores improved significantly (P ≤ .01). Appetite (P ≤ .01) and depression (P = .05) scores improved on ESAS. Frequent burping/belching (P = .02), feeling full (P = .04), and stomach distention (P = .03) improved on the DSSI. A deterioration in the timed sit to stand was noted (P = .01). OHR118 was well tolerated with no serious side effects reported. CONCLUSIONS OHR118 again mediated statistically significant improvements in anorexia, dyspepsia, strength, and depression in this trial, consonant with the previous AIDS trial results.

An interprofessional palliative care oncology rehabilitation program: effects on function and predictors of program completion

BACKGROUND After treatment, patients with active cancer face a considerable burden from the effects of both the disease and its treatment. The Palliative Rehabilitation Program (prp) is designed to ameliorate disease effects and to improve the patients functioning. The present study evaluated predictors of program completion and changes in functioning, symptoms, and well-being after the program. METHODS The program received referrals for 173 patients who had finished anticancer therapy. Of those 173 patients, 116 with advanced cancer were eligible and enrolled in the 8-week interprofessional prp; 67 completed it. Measures of physical, nutritional, social, and psychological functioning were evaluated at entry to the program and at completion. RESULTS Participants experienced significant improvements in physical performance (p < 0.000), nutrition (p = 0.001), symptom severity (p = 0.005 to 0.001), symptom interference with functioning (p = 0.003 to 0.001), fatigue (p = 0.001), and physical endurance, mobility, and balance or function (p = 0.001 to 0.001). Reasons that participants did not complete the prp were disease progression, geographic inaccessibility, being too well (program not challenging enough), death, and personal or unknown reasons. A normal level of C-reactive protein (<10 mg/L, p = 0.029) was a predictor of program completion. CONCLUSIONS Patients living with advanced cancers who underwent the interprofessional prp experienced significant improvement in functioning across several domains. Program completion can be predicted by a normal level of C-reactive protein.

Pedometer-facilitated walking intervention shows promising effectiveness for reducing cancer fatigue: a pilot randomized trial:

Objective: Mechanisms for cancer related fatigue suggest that exercise but “not too much and not too little” could be effective. This study aimed to investigate feasibility and estimate the potential effects of a walking exercise program in people with advanced cancer and fatigue. Design: A pilot randomized trial. Setting: McGill University Health Centre (MUHC), Montreal, Canada. Subjects: People with advanced cancer undergoing interdisciplinary assessment and rehabilitation with a fatigue level of 4 to 10 on a visual analogue scale. Interventions: An 8-week fatigue-adapted, walking intervention, facilitated using a pedometer (STEPS), and offered at the same time as or after rehabilitation. Measures: Measures of fatigue, physical function and well-being were administered at entry, and 8, 16 and 24 weeks. Generalized estimating equations (GEE) estimated the odds of response for people receiving the STEPS program in comparison to the odds of response in the controls (odds ratio, OR). Results: Twenty-six persons were randomized to three groups: during rehabilitation, after rehabilitation, and usual care. For the fatigue measures the OR for STEPS offered at any time using an intention-to-treat approach was 3.68 (95%CI: 1.05-12.88); for the physical function measures, the OR was 1.40 (95%CI: 0.41- 4.79) and 2.36 (95%CI: 0.66-8.51) for the well-being measures. Conclusion: Fifty percent of eligible people were able to participate. This small trial suggests that a personalized exercise program reduces fatigue and that 100 people are needed in a full strength trial.

Rehabilitation in Cancer

Cancer rehabilitation is a process that assists the individual with a cancer diagnosis to obtain optimal physical, social, psychological, and vocational functioning within the limits created by the disease and its treatment.

Erratum: Tumour inflammatory response: adding fuel to the fire?

[This corrects the article on p. 7 in vol. 22, PMID: 25684982.].

Tumour inflammatory response: adding fuel to the fire?

The immune system appears to play a key role in the carcinogenic process, but whether that role is a protective or harmful one is not clear. There is evidence that primary immunodeficiency is associated with an increased risk of specific neoplastic conditions, and the inability of the immune system to control certain viral infections (such as hiv-1, hepatitis B virus, and human papillomavirus) results in the well-known development of specific cancer types1. The converse scenario of an inappropriately active immune response having an effect on the outcome of cancer brings us to a conundrum. The natural mechanisms that suppress cancer development are both cell-autonomous (autophagy, senescence, apoptosis) and non-cell-autonomous (chemo-attraction or “find-me signals,” tumour senescence, tumour killing and clearance), with the latter involving interactions of cells with their microenvironment and especially with the immune system2. It therefore seems apparent that inflammation is the host’s defense against any foreign protein, antigen, or cell. However, it is becoming increasingly apparent that, in most cancers, cancer-associated inflammation is a key determinant of disease progression and survival3,4. Numerous molecules that play a critical role in inflammation have been directly or indirectly related with parameters such as tumour necrosis factor, interleukins 1 and 6, chemokines, cyclooxygenase 2, 5-lipoxygenase, matrix metalloproteases, vascular endothelial growth factor, twist-related protein 1, and cell surface adhesion molecules. Each of the latter molecules has also individually been found to have prognostic value in at least one type of cancer. What is common to all the molecules is that they are regulated by the transcription factor nuclear factor κB. Nuclear factor κB is now known to be ubiquitous to all cell types and present in the cytoplasm during a cell’s resting stage5. It is unclear whether the association between aggressive patterns of immunologic markers and poor overall survival in multiple cancer types is attributable to the effects of an intense immune response paradoxically working against the host or to the fact that the more hostile cancers are able to evade even an intense response from the immune system. Immunotherapy has revolutionized cancer treatment. In 1975, Georges Kohler and Cesar Milstein of the Medical Research Council Laboratory of Molecular Biology in Cambridge, United Kingdom, described a method of obtaining antigen-specific antibodies in large quantity6. In 1997, with the approval of rituximab for targeting CD20 in patients with low-grade non-Hodgkin lymphoma7, monoclonal antibody technology opened the door to the development of targeted cancer therapy. Rituximab was followed by trastuzumab for the treatment of breast cancer positive for human epidermal growth factor receptor 2 and by other agents for various cancer types. Interferon and interleukins have also been used as anticancer agents. More recently, potentiation of the naturally occurring immune response by blockade of the immune checkpoint inhibitors ctla-4, pd-1, and pdl-1 has proved to be very successful in melanoma and seems promising for other cancers8,9. Inflammatory cytokines such as tumour necrosis factor α, interleukins 1 and 6, and interferon γ are implicated in maintaining the inflammatory response that leads to the wasting of structures constituting lean body mass. They are believed to be responsible for the cancer anorexia–cachexia syndrome (cacs). The proven role of immune-modulatory agents—for example, corticosteroids, thalidomide and eicosapentaenoic acid, nonsteroidal anti-inflammatory drugs, and statins—in the treatment of cacs supports that theory10. The association of the aforementioned cytokines with cacs and the improvement of cacs with administration of immunomodulatory agents has brought about the notion of the immune response being ultimately harmful in cancer patients. More recently, growth differentiation factor 15, a protein that belongs to the transforming growth factor β superfamily, was found to have a role in regulating inflammatory and apoptotic pathways in injured tissues and during disease processes. It is being investigated as a drug target for delaying the progression of cacs, and it has been found to be a predictor of benefit (overall survival, disease-free survival, locoregional recurrence-free survival, and distant metastasis-free survival) from paclitaxel– platinum–5-flurouracil chemotherapy in oral squamous cell carcinoma11,12. Multiple immunologic parameters have proved to have useful prognostic and assessment significance in cancer: for example, pretreatment serum albumin13, C-reactive protein (crp), and neutrophil-to-lymphocyte ratio14,15. Clinical trials have suggested using various combinations of clinical and laboratory parameters to predict recurrence or mortality, given the fact that the inflammatory response per se is associated with trends toward higher mortality in large population cohorts16. The modified Glasgow Prognostic Score has been studied as mortality predictor in many cancers17–19, and recently, its prognostic value was found to be improved with the addition of neutrophil and platelet counts and of high-sensitivity crp20. Another score involving crp and a white cell count was recently published by Kasymjanova et al. in Current Oncology. Those authors prospectively assessed the association of baseline systemic inflammation with freedom from progression in response to chemotherapy and with survival in 134 patients having stage iv non-small-cell lung cancer. The proposed scoring system was the only significant factor prognostic for survival, even after adjustment for performance status, smoking, and weight loss21. In this edition of Current Oncology, Zeng et al.22 report a retrospective analysis suggesting that crp at a cut-off 8 mg/L can have prognostic value for cancer-specific survival in patients with nasopharyngeal carcinoma. They also suggest that normalization of crp levels after chemoradiation could similarly be a prognostic factor in such patients. Should their data be duplicated in a prospective and well-powered analysis, a new set of questions could arise, including whether further interventions to normalize crp after chemoradiation might have further benefit, whether crp or other markers could be used to monitor disease response in a subset of patients, and whether crp as a marker could be applicable for other cancer sites. However, an important variable that has a proven strong prognostic value—human papillomavirus status—has not yet been considered in statistical models that address inflammatory markers. The oncogenicity of human papillomavirus is relevant and intriguing from an immunologic standpoint, because that virus is associated with cervical cancer and with a type of squamous cell carcinoma of the head and neck that has a much better prognosis than its non-associated head-and-neck counterparts. The mechanisms of oncogenicity related to human papillomavirus and the role of the immune system in that respect remain unknown. Although it is evident that the immune system has an ongoing interaction with the neoplastic process that starts with the very origins of that process, the factors that turn the response into a protective or harmful one is unclear. Although inflammatory biomarkers have proven prognostic value in various cancers, their usefulness in stratifying patients for therapeutic purposes is a field that has to be further studied.

The growing pains of cancer survivors: a call for a paradigm of interdisciplinary care

As improved cancer surveillance, more accurate diagnosis, and more efficacious treatment begin to extend life expectancy for numerous patients, the number of cancer survivors will predictably continue to grow into the future1. And as the survivor population increases, new and unique challenges become more apparent. For example, more than 40% of cancer survivors experience pain after their initial diagnosis2. For those survivors, physical pain is not the only hardship to be faced. They also encounter numerous psychological, social, spiritual, and financial challenges after diagnosis and treatment3. The entire spectrum of pain is now recognized to be more prevalent than earlier thought and unique to each person who has undergone cancer treatment. Particular factors acting in conjunction with the physical causes of pain and contributing to total pain include loss of appetite, loneliness, fatigue, social isolation, existential distress, and family disharmony. Communication is a vital ingredient for the adequate assessment and treatment of patients and their pain. The level of communication about pain can vary for team members, both with each other and with their patients. Patients may also feel lost within an oncologic setting because of the vast variety of professionals they encounter, each speaking different jargon and rarely communicating with one another. As a result, patients and their families are often left to decipher the overall message and to try to make sense of what is being relayed to them. Thus, many patients might not recognize—or might even understate—the degree of their pain. The interdisciplinary team approach implies integration of several disciplines to develop solutions open-mindedly. The team focuses on common goals and shared development of treatment processes4. This approach allows aspects of care that might remain unaddressed by some medical professionals to be picked up and addressed by others. In addition, increased communication within the team can further the ability of various team members to be more effective within their own treatment processes. The patient can also take advantage of a much larger toolbox to describe pain symptoms and to mitigate mal-communication5. Interdisciplinary teams allow for a continuing dialogue between physicians; nurses; physical, occupational, and vocational therapists; dieticians; social workers; psychologists; and the patient. The philosophies of cancer treatment have been transformed in recent years, and health care professionals have reached a point at which integration of pharmacologic and nonpharmacologic treatment for the relief of pain is the order of the day. With this transformation in mind, the ultimate goals of oncologic health care include eradication or control of the disease, minimization of treatment side effects, optimization of function and overall quality of life, and for survivors, empowerment. Even given this knowledge, management of chronic pain for cancer survivors is still not optimal. For the patient, pain management is achieved through a variety of measures: revision of the pain source, alteration of pain perception, and inhibition of the transmission of pain messages to the central nervous system. Among pharmacologic treatments, agents such as opioids have been used as the foundation of analgesic therapy. Morphine is currently the most widely used opioid, but little research has been conducted to attempt to distinguish whether some opioids might be more effective than others. Tricyclic antidepressants promise to play a role in future for the treatment of neurologic pain. Anti-inflammatory agents—more commonly known as nsaids (nonsteroidal anti-inflammatory drugs)—and steroids are used in combination with opioids to treat several pain symptom types for cancer survivors. The next step is to provide patients with nonpharmacologic approaches that offer holistic treatment. These sorts of approaches allow for the patient’s other pain symptoms to be addressed through roundtable discussion with the interdisciplinary team and with spiritual or religious counsel; through training to encourage the stamina and endurance needed to counter the effects of treatment; and through a powerful ability to recognize stressful situations and to apply effective and learned coping skills. Already, use of a team approach has shown great efficacy in the treatment of chronic pain in the general population. One third of individuals so managed are able to return to work, and a decrease in pain intensity of 70% and an improvement in mood of 90% have been noted6. Those results show much promise for application within the treatment of cancer survivors. As the lives of cancer survivors continue to be prolonged, every type of pain that they might experience must be cared for. The interdisciplinary team reaches far beyond the basic paradigms of clinical treatment to both understand and manage pain. Cancer survivors will continue to experience chronic pain, but once this holistic form of treatment is fully realized, the team will be able to provide the patient with one of the most powerful tools of all: a return to a sense of meaning in life, as Victor Frankl so aptly described it7.