Long-term Treatment-related Side Effects Research Articles

Vestibular Neurostimulation for Parkinson's Disease: A Novel Device-Aided Non-Invasive Therapeutic Option.

Dopaminergic replacement therapy remains the mainstay of symptomatic treatment for Parkinson's disease (PD), but many unmet needs and gaps remain. Device-based treatments or device-aided non-oral therapies are typically used in the advanced stages of PD, ranging from stereotactic deep brain stimulation to levodopa or apomorphine infusion therapies. But there are concerns associated with these late-stage therapies due to a number of procedural, hardware, or long-term treatment-related side effects of these treatments, and their limited nonmotor benefit in PD. Therefore, there is an urgent unmet need for low-risk adjuvants or standalone therapies which can address the range of burdensome motor and nonmotor symptoms that occur in PD. Recent studies suggest that non-invasive neurostimulation of the vestibular system may be able to address these gaps through the stimulation of the vestibular brainstem sensory network which extensively innervates brain regions, regulating both motor and a range of nonmotor functions. Therapeutic non-invasive vestibular stimulation is a relatively modern concept that may potentially improve a broad range of motor and nonmotor symptoms of PD, even at early stages of the disease. Here, we review previous studies supporting the therapeutic potential of vestibular stimulation for the treatment of PD and discuss ongoing clinical trials and potential areas for future investigations.

Radiation-Induced Pericardial Disease: Mechanisms, Diagnosis, and Treatment.

We aim to give a concise overview of the different clinical manifestations of both acute and long-term radiotherapy-related pericardial diseases, the underlying pathophysiology as well as the diagnosis and treatment options. Radiotherapy-related pericardial disease is common, but despite radiotherapy being a cornerstone of many cancer treatments, this disease entity is relatively underrepresented in clinical trials, resulting in a paucity of research data on pathophysiology and management. Since the development of innovative cancer treatments, survival has significantly improved. Therefore, the importance of long-term treatment-related side effects increases, most notably cancer treatment-related cardiovascular toxicity. In patients undergoing radiotherapy as a part of their cancer treatment, radiotherapy-related pericardial disease can manifest early (during or shortly after radiotherapy administration) or very late (several years to decades after treatment). This exceptionally long latency period confronts physicians with treatment-related side effects of radiotherapy regimens that may have been abandoned already.

Promising drugs and treatment options for pediatric and adolescent patients with Hodgkin lymphoma.

Currently-available therapies for newly-diagnosed pediatric and adolescent patients with Hodgkin lymphoma result in >95% survival at 5years. Long-term survivors may suffer from long-term treatment-related side effects, however, so the past 20years have seen clinical trials for children and adolescents with HL gradually abandon the regimens used in adults in an effort to improve this situation. Narrower-field radiotherapy can reduce long-term toxicity while maintaining good tumor control. Various risk-adapted chemo-radiotherapy strategies have been used. Early assessment of tumor response with interim positron emission tomography and/or measuring metabolic tumor volume has been used both to limit RT in patients with favorable characteristics and to adopt more aggressive therapies in patients with a poor response. Most classical Hodgkin's lymphoma relapses occur within 3years of initial treatment, while relapses occurring 5years or more after diagnosis are rare. As the outcome for patients with relapsed/refractory classical Hodgkin lymphoma remains unsatisfactory, new drugs have been proposed for its prevention or treatment. This review summarizes the important advances made in recent years in the management of pediatric and adolescent with classical Hodgkin lymphoma, and the novel targeted treatments for relapsed and refractory classical Hodgkin lymphoma.

Clinical outcomes of medical treatments for progressive desmoid tumors following active surveillance: a systematic review.

Approximately 80% of desmoid tumors (DTs) show spontaneous regression or disease stabilization during first-line active surveillance. Medical treatment can be considered in cases of disease progression. This systematic review aimed to evaluate the effectiveness and toxicity of each medical treatment by reviewing only the studies that included progressive disease as the inclusion criterion. We searched the EMBASE, PubMed, and CENTRAL databases to identify published studies for progressive DTs. The disease control rates of the medical treatments, such as low-dose chemotherapy with methotrexate plus vinblastine or vinorelbine, imatinib, sorafenib, pazopanib, nilotinib, anlotinib, doxorubicin-based agents, liposomal doxorubicin, hydroxyurea, and oral vinorelbine for progressive DTs were 71-100%, 78-92%, 67-96%, 84%, 88%, 86%, 89-100%, 90-100%, 75%, and 64%, respectively. Low-dose chemotherapy, sorafenib, pazopanib, nilotinib, anlotinib, and liposomal doxorubicin had similar toxicities. Sorafenib and pazopanib were less toxic than imatinib. Doxorubicin-based chemotherapy was associated with the highest toxicity. Hydroxyurea and oral vinorelbine exhibited the lowest toxicity. Stepwise therapy escalation from an initial, less toxic treatment to more toxic agents is recommended for progressive DTs. Sorafenib and pazopanib had limited on-treatment side effects but had the possibility to induce long-term treatment-related side effects. In contrast, low-dose chemotherapy has some on-treatment side effects and is known to have very low long-term toxicity. Thus, for progressive DTs following active surveillance, low-dose chemotherapy is recommended in young patients as long-term side effects are minor, whereas therapies such as sorafenib and pazopanib is recommended for older patients as early side effects are minor.

Long-term Castration-related Outcomes in Patients With High-risk Localized Prostate Cancer Treated With Androgen Deprivation Therapy With or Without Docetaxel and Estramustine in the UNICANCER GETUG-12 Trial.

Neoadjuvant chemotherapy with docetaxel and estramustine (DE) significantly improved relapse-free survival in patients with high-risk localized prostate cancer treated with androgen deprivation therapy (ADT) for 3 years and a local treatment in the GETUG-12 phase III trial. We sought to explore whether the addition of DE impacts long-term treatment-related side effects. Patients randomized within the UNICANCER GETUG-12 trial at Gustave Roussy who were alive when ADT was discontinued were followed-up prospectively. Serum testosterone levels and clinical data regarding body weight, libido, erection, and cardio-vascular events were collected. Seventy-eight patients were included: 36 patients had been treated with ADT plus a local treatment and 42 with ADT+DE plus a local treatment. With a median follow-up of 5.9 years after ADT discontinuation, serum testosterone levels returned to normal values (> 200 ng/mL) for 57 (78%) of 72 evaluable patients, and 29 (43%) of 68 evaluable patients reported erections allowing intercourse without medical assistance. No impact of DE on testosterone level recovery, libido, quality of erections, and changes in body weight after ADT discontinuation was detected. The incidence of cardiovascular events was low and similar in both treatment arms. Treatment with DE was not associated with excess long-term castration-related toxicity in men with high-risk localized prostate cancer. The relapse-free survival improvement seen with DE in GETUG-12 is likely not related to differed testosterone recovery.

Cutaneous lupus erythematosus: A review of the literature.

Knowledge with regard to the pathogenesis of lupus erythematosus has progressed rapidly over the past decade, and with it has come promising new agents for the treatment of cutaneous lupus erythematous (CLE). Classification of CLE is performed using clinical features and histopathologic findings, and is crucial for determining prognosis and choosing therapeutic options. Preventative therapy is critical in achieving optimal disease control, and patients should be counseled on sun-safe behavior and smoking cessation. First-line therapy includes topical corticosteroids and calcineurin inhibitors, with antimalarial therapy. Traditionally, refractory disease was treated with oral retinoids, dapsone, and other oral immunosuppressive drugs, but new therapies are emerging with improved side effect profiles and efficacy. Biologic agents, such as belimumab and ustekinumab, have been promising in case studies but will require larger trials to establish their role in routine therapy. Other novel therapies that have been trialed successfully include spleen tyrosine kinase inhibitors and fumaric acid esters. Finally, new evidence has been published recently that describes safer dosing regimens in thalidomide and lenalidomide, both effective medications for CLE. Given the chronic disease course of CLE, long-term treatment-related side effects must be minimized, and the introduction of new steroid-sparing agents is encouraging in this regard.

Thirty Year Experience with Rosai Dorfman Disease treated with Radiation, Chemotherapy, and/or Surgery.

Rosai-Dorfman Disease (RDD) is a rare disorder with histiocytosis and massive painless lymphadenopathy. It usually develops from the accumulation of non-Langerhans type histiocytic cells inside lymph nodes. Because the etiology of RDD is not well understood, the treatment is still nonspecific and controversial. Current data on the optimal management of RDD is limited to small case reviews/series. Herein we aim to describe treatment and outcomes, including the use of and response to radiation, in a large cohort of patients with RDD. We report on 27 patients diagnosed with Rosai-Dorfman Disease, who were evaluated at a single institution. Patients were diagnosed with RDD between 1980 and 2016. All patients had pathologic confirmation of RDD. We included patients who had a minimum of 3 months of follow up after diagnosis of RDD. We included patients of any age, with unifocal or multifocal disease, lymphatic and/or extranodal disease, and patients with previous treatment for RDD at outside institutions. We report descriptive outcomes for these patients. Median length of diagnosis was 73 months (IQR: 23- 138). Median age at diagnosis was 43 (range: 3 – 81). Fifty-two percent of patients were female. Three patients (11%) had nodal involvement alone, 17 patients (63%) had extranodal disease alone, and 7 patients (26%) had nodal disease and extranodal involvement at presentation. The most common site of disease involved the head and neck in 13 patients (48%). The most common therapeutic approaches included local or systemic steroids (n=11, 41%), chemotherapy (n=11, 41%), radiotherapy (n=9, 33%), and surgery (n=15, 55%). Eighteen patients were treated with 2 or more modalities (67%). Four of nine (44%) patients treated with radiation experienced a sustained response in the irradiated field. Median dose of RT was 36 Gy (range: 20 – 50 Gy). Intensity modulated radiation therapy (IMRT) was used for 5 patients. Various chemotherapy regimens were employed over the years, Clofarabine and Cladrabine were the most common systemic treatments. Seven (out of 11) patients receiving chemotherapy had stabilization, improvement, or resolution of disease after chemotherapy. At time of last follow up, 13 patients (48%) were with no evidence of disease, 11 patients had short interval stable disease (41%), and 3 patients (11%) had progressive disease. The optimal management of RDD remains elusive. Based on our review it seems that multiple treatment options may benefit patients. Radiation could be useful as an alternative option to avoid systemic therapy. Keeping in mind that avoiding long-term treatment related side effects is paramount, clinical factors such as age, location of the lesion(s), and symptoms, must be considered when recommending therapy for this benign condition.

Risks of Major Long‐Term Side Effects Associated with Androgen‐Deprivation Therapy in Men with Prostate Cancer

To examine the risks and compare the occurrences of major long-term side effects (sexual dysfunction, bone fractures, diabetes, cardiovascular morbidity, acute myocardial infarction [MI], and dementia) in patients with prostate cancer who received androgen-deprivation therapy (ADT) with those who did not. Propensity score-matched retrospective cohort study using Medicare claims data. National Cancer Institute's Surveillance, Epidemiology, and End Results Program-Medicare linked database. A total of 201,797 patients 66 years or older who were diagnosed with any stage of prostate cancer between 1992 and 2009; of these, 94,528 patients received ADT; 107,269 patients did not. We identified receipt of ADT and number of claims for ADT, and ascertained the long-term treatment-related side effects that occurred during 19 years of follow-up, from 1992-2010, from Medicare claims data. Cox proportional hazards models were used to estimate the incidences and hazard ratios (HRs) of newly developed side effects. Among all potential long-term side effects, the risk of bone fractures was highest (HR 1.39, 95% confidence interval [CI] 1.35-1.43), followed by diabetes (HR 1.21, 95% CI 1.18-1.24), dementia (HR 1.16, 95% CI 1.13-1.20), coronary heart disease (HR 1.12, 95% CI 1.09-1.14), and acute MI (HR 1.11, 95% CI 1.08-1.15) in those who received ADT compared with those who did not. The HRs for bone fractures and diabetes increased steadily as the number of ADT doses increased, indicating a linear trend in the dose-response relationship. Compared with patients who received active surveillance, ADT was associated with a 12% increased risk of sexual dysfunction (HR 1.12, 95% CI 1.05-1.20). The HR for sexual dysfunction increased to 1.68 (95% CI 1.59-1.77) when ADT was combined with radiation therapy and to 3.54 (95% CI 3.26-3.85) when ADT was combined with radiation and surgery. The results of this study demonstrated that in men with prostate cancer, receipt of ADT was associated with higher risks of bone fractures, diabetes, dementia, coronary heart disease, acute MI, and sexual dysfunction than in those who did not receive ADT.

Physical activity and breast cancer survivors: Importance of adherence, motivational interviewing and psychological health

Behavioral change theories have been used to support interventions that increase both motivation for and adherence to physical activity programs for breast cancer survivors. Most of the programs can improve psychological health-related quality of life. Depressive and anxious symptoms seem to be associated with some stressors, such as the perception of breast cancer, prognosis, long-term treatment-related side-effects and fear of cancer recurrence. Beyond physical fitness, several physical activity programs for breast cancer survivors have been reported to improve psychosocial wellness and life satisfaction. However, many physical activity programs have failed to motivate breast cancer survivors due to barriers such as general health issues and lack of time. More specifically, women may have little confidence in the benefits of physical activity and breast cancer outcomes. Therefore, engaging breast cancer survivors in physical activity is challenging for health care professionals. Herein, we identify cancer-related mental distress, coping style and behavioral theories applied to physical activity programs in breast cancer survivors. More specifically, we discuss the effectiveness and limitations of 3 psychological theories and 2 concepts related to behavioral change, including the theory of planned behavior, social cognitive theory, self-determination theory, transtheoretical model and motivational interviewing for physical activity adherence in breast cancer survivors.

The Association of Long-term Treatment-related Side Effects With Cancer-specific and General Quality of Life Among Prostate Cancer Survivors

To examine the association between treatment-related side effects and cancer-specific and general quality of life (QOL) among long-term prostate cancer survivors. Within the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial, we conducted telephone interviews with prostate cancer survivors (N = 518) who were 5-10 years after diagnosis. We assessed demographic and clinical information, sexual, urinary, and bowel treatment-related side effects (Expanded Prostate Cancer Index Composite), cancer-specific QOL (Functional Assessment of Cancer Therapy--total score), and general QOL (the Medical Outcomes Study Short Form 12's physical and mental subscales). Participants were aged 74.6 years on average, primarily White (88.4%), and married (81.7%). Pearson correlation coefficients between the 3 treatment-related side effect domains (urinary, sexual, and bowel) and QOL ranged between 0.14 and 0.42 (P <.0001). Multivariable linear regression analyses revealed that poorer urinary and sexual functioning and greater bowel side effects were independently associated with poorer cancer-specific QOL (P <.0001). Bowel and urinary functions were also associated with poorer general QOL on the Medical Outcomes Study Short Form 12's physical component summary and mental component summary (P <.05). Bowel side effects demonstrated the strongest association with all QOL outcomes. Treatment-related side effects persisted for up to 10 years after diagnosis and continued to be associated with men's QOL. These results suggest that each of the treatment-related side effects was independently associated with cancer-specific QOL. Compared with the other Expanded Prostate Cancer Index Composite domains, bowel side effects had the strongest association with cancer-specific and general QOL. These associations emphasize the tremendous impact that bowel side effects continue to have for men many years after their initial diagnosis.

Randomised clinical trial: the safety and tolerability ofTrichuris suisova in patients with Crohn's disease

Recent evidence suggests that embryonated eggs of the porcine whipworm Trichuris suis ova (TSO) may be an effective treatment for inflammatory bowel disease (IBD). To assess the safety and tolerability of TSO following a single dose in patients with Crohn's disease. This was a sequential dose-escalation (500, 2500 and 7500 viable embryonated TSO), randomised, double-blind, placebo-controlled study to evaluate the safety of a single dose of oral suspension TSO in patients with Crohn's disease. Twelve patients were randomised into each of three cohorts. Patients were assessed 1, 3, 5, 7, 9, 11 and 14days following dosing (via a telephone call and diary symptom collection through 14days postdose) for adverse events, changes to concomitant medications and gastrointestinal (GI) signs and symptoms. Patients were again assessed at Months 1, 2 and 6. Eighteen males and 18 females were enrolled, ages 20 to 54years. All patients were dosed and completed the initial 2-month follow-up period (five patients did not attend their 6-month study visit). GI disorders were reported with the highest frequency; 7 (25.9%) TSO-treated patients and 3 (33.3%) placebo-treated patients. No dose-dependent relationship was observed, with 3 (33.3%) placebo, 4 (44.4%) TSO 500, 0 (0.0%) TSO 2500 and 3 (33.3%) TSO 7500 patients experiencing at least one GI event, and no clinically meaningful changes in GI signs and symptoms. A single dose of Trichuris suis ova up to 7500 ova was well tolerated and did not result in short- or long-term treatment-related side effects. Clinicaltrials.gov NCT01576461.

Association of social network and social support with health-related quality of life and fatigue in long-term survivors of Hodgkin lymphoma

As the number of survivors of Hodgkin's lymphoma (HL) increases, there has been a growing interest in long-term treatment-related side effects and their impact on the quality of life (QoL). The aim of this study was to assess the association of social network and social support with the QoL and fatigue among long-term HL survivors. A total of 200 HL survivors were included. The generic Short Form-12 (SF-12) questionnaire, the QoL cancer survivor's questionnaire (QOL-CS), and the Multidimensional Fatigue Inventory were used to assess QoL and fatigue. Social network and social support were evaluated with the Social Support Survey. Social network and all social support measures were favorably associated with two or more SF-12 scales, mainly with physical functioning and the mental health scales. Social network and social support dimensions were also associated with better QOL-CS scores. Affective support, informational support, positive interaction, and emotional support were associated with less fatigue. Both social network and social support are associated with better QoL and lower levels of fatigue in HL survivors. This information may be useful to health professionals and community organizations in implementing effective interventions to improve these patients' quality of life.

Follow-up strategies in head and neck cancer other than upper aerodigestive tract squamous cell carcinoma

Post-therapy follow-up for patients with head and neck cancer other than upper aerodigestive tract squamous cell carcinoma should meet several objectives: to detect both local, regional or distant recurrences, to evaluate acute and long-term treatment-related side effects, to guide the rehabilitation process, and to provide psychosocial support when needed. To our knowledge, there are no published reports in the literature dedicated to the follow-up of patients with these tumours. A comprehensive literature search for post-treatment follow-up strategies spanning from 1980 to 2012 was performed on several databases. This review focuses on malignant salivary gland tumors, soft tissue sarcomas, cutaneous squamous cell carcinomas, and sinonasal adenocarcinomas. Given the varying biological behavior and treatment-related factors and based on the literature, different recommendations are made on the follow-up of patients with the above-mentioned tumors.

ACR Appropriateness Criteria® on Hodgkin's Lymphoma—Favorable Prognosis Stage I and II

The treatment for favorable-prognosis stage I and II Hodgkin's lymphoma has evolved over the past several years. Studies have attempted to reduce long-term treatment-related side effects, such as second malignancies and cardiac toxicity, through reduced chemotherapy or reduced radiotherapy. Randomized trials have compared radiation therapy alone with combined-modality therapy (chemotherapy followed by involved-field radiotherapy). Recent and ongoing trials have evaluated the optimal regimen and number of cycles of chemotherapy and the optimal radiotherapy dose and field size as part of combined-modality therapy, as well as the elimination of radiation therapy. Combined-modality therapy represents the current standard of care for most patients with favorable-prognosis early-stage Hodgkin's lymphoma. Chemotherapy alone could also be an option for selected patients who are at low risk for relapse and high risk for late effects from radiotherapy. This article reviews recent and ongoing studies on treatment for favorable-prognosis early stage Hodgkin's lymphoma. Representative clinical cases are presented, with treatment recommendations from an expert panel of radiation oncologists and medical oncologists.

Minimal toxicity during protein a immunoadsorption treatment of malignant disease: An outpatient therapy

Extracorporeal removal or modulation of circulating immune complexes (CIC) from plasma of animals and humans with malignant disease may be associated with induction of immune-mediated anti-tumor responses. Immunoadsorption columns containing heat-killed and formalin-fixed Staphylococcus aureus or staphylococcal protein A have been used for this purpose but treatments have often been associated with cardiopulmonary toxicity. Recently, an immunoadsorption device containing highly purified protein A covalently attached to a silica matrix (PROSORBA column) was used to treat 142 patients with refractory malignancies and 22 of 104 patients evaluated for anti-tumor response had objectively measurable reduction in tumor burden. In contrast to earlier experience with other devices, the procedures used in this trial were well tolerated and could be performed on an outpatient basis. The most common side effects observed among 1,306 treatments were chills (28% of treatments), low grade fever (28%), and musculoskeletal pain (16%). Side effects were mild to moderate and required no treatment or only symptomatic treatment. Treatment schedules were interrupted due to side effects for only six patients and there were no treatment-related deaths. Of 64 patients available for long-term follow-up evaluation (mean of 11 months), none exhibited evidence of long-term treatment-related side effects. None of the patient deaths in that period were associated with short or long-term treatment-related side effects. Protein A-silica (PROSORBA columns) can be used safely for development of further experimental treatments of malignant disease.