Management of adverse events related to first-generation tyrosine receptor kinase inhibitors in adults: a narrative review.

OBJECTIVE: The aim of this article is to conduct a literature review on first-generation TRK inhibitors (TRKi), namely entrectinib and larotrectinib, to describe the most common adverse events (AEs) and their management in adults. METHODS: A search strategy was conducted in MEDLINE, EMBASE, and Google Scholar using a list of predetermined keywords. Peer-reviewed articles written in English and published through June 2021 were included. Articles covered included randomized clinical trials and expert recommendations, as well as patent and other types of reviews. RESULTS: The discussed AEs include weight gain and withdrawal pain, as well as neuromuscular, central nervous system (dysesthesias and peripheral sensory neuropathies, dizziness and ataxia, and dysgeusia), gastrointestinal (nausea, vomiting, and diarrhea), and respiratory symptoms. Additionally, several AEs encountered with entrectinib specifically (cognitive and vision disorders, congestive heart failure, QTc elongation, and skeletal fractures) are discussed. First, an overall mechanism of action explaining these AEs is presented. Then, for each AE, incidence and severity are stated and followed by practical management recommendations. While nearly all AEs were reversible upon TRKi suspension, the proposed managements are mainly constituted of pharmacological and non-pharmacological interventions. CONCLUSION: With the estimated growth of gene sequencing in the coming years, it is foreseeable that TRKi will take a larger position in the oncologic therapeutic arsenal. Therefore, adequate management of AEs associated with TRKi in adults should be a prime focus.

Effect of mannitol on acute kidney injury induced by cisplatin.

PURPOSE: Acute kidney injury (AKI) is a frequent dose-limiting toxicity induced by cisplatin. Mannitol has been used in hydration protocols to mitigate this adverse event but its role remains controversial. The aim of this study is to define the impact of mannitol on AKI in patients receiving cisplatin. METHODS: This retrospective observational study was conducted in cancer patients who received at least one dose of cisplatin between September 2010 and December 2016 at the Centre hospitalier de l'Université de Montréal. The primary outcome of this study was the comparison of all grade cisplatin-associated AKI between hydration protocols with or without mannitol. RESULTS: A total of 1821 patients were included of which 658 received mannitol whilst 1163 received hydration alone. The risk of all grade cisplatin-associated AKI was significantly lower for the mannitol group (Hazard Ratio (HR) = 0.62; 95% CI [0.42, 0.89]). This result was mainly driven by gynecologic (HR = 0.50), upper gastrointestinal (HR = 0.32), urinary tract malignancies (HR = 0.29) and lymphoma (HR = 0.33). No significant difference was seen for head and neck (HN), lung, germ cells and other cancers. However, HN cancers patients receiving mannitol had fewer grade 2 and 3 AKI. Significantly fewer AKI events were observed in HN, lung, upper gastrointestinal and urinary tract cancer when mannitol was added for cisplatin dose <75 mg/m2. CONCLUSION: Although the results were generally driven by a decrease of grade 1 AKI for most cancers, the greatest benefit of mannitol was seen with cisplatin doses lower than 75 mg/m2 and should probably be reinstated in this setting.

Single agent trabectedin in heavily pretreated patients with recurrent ovarian cancer.

PURPOSE: In 2012, due to a shortage of pegylated liposomal doxorubicin, single agent trabectedin was proposed as an alternative of treatment to our patients with recurrent ovarian cancer (ROC) at our center. The aim of this retrospective study was to evaluate efficacy and tolerability of trabectedin in this context. PATIENTS AND METHODS: This retrospective study included all patients who received intravenous trabectedin 1.3mg/m2 over 3h every 3weeks for ROC between January 2012 and December 2015 at the Centre hospitalier de l'Université de Montreal. The primary outcome was the progression-free survival (PFS) based on CA-125 levels, clinical exam and/or Response Evaluation Criteria in Solid Tumors criteria. We also evaluated overall survival (OS), response rate and toxicities. RESULTS: A total of 42 patients with a median age of 59years received trabectedin in 2nd or 3rd line (12% of patients), 4th or 5th line (43%), and ≥6 lines (45%) and 45% were platinum-resistant. The median number of cycles received was 6 (range 1-19cycles). Complete response (CR), partial response (PR), stable disease (SD) and progression occurred in 19%, 29%, 33% and 19% of patients, respectively. The median PFS and OS was 4.3months (95% CI, 3.4-5.1) and 16.2months (95% CI, 9.0-23.5), respectively. In patients with a clinical benefit (CR, PR, SD), the median PFS was 4.6months. Trabectedin was well tolerated with few adverse events. CONCLUSION: Our results demonstrate that trabectedin has an interesting efficacy as a single agent in heavily treated ROC patients.

Safe administration of docetaxel after weekly paclitaxel-induced acute pancreatitis.

Acute pancreatitis is an inflammatory process of the pancreas that can be mild to severe. It requires biochemical or radiologic evidence to establish the diagnosis. Only few chemotherapy agents are directly linked to acute pancreatitis. In this case report, we describe a patient who developed a mild acute pancreatitis on weekly paclitaxel with a positive dechallenge and rechallenge. A 57-year-old woman with advanced ovarian cancer started chemotherapy with carboplatin (AUC 5 every three weeks) and weekly paclitaxel (80 mg/m2 on days 1, 8, and 15). On day 13 of cycle 1, the patient presented with elevated lipase and mild epigastric pain with a suspicion of acute pancreatitis. Because the patient was asymptomatic and pancreatic enzymes decreased on day 16, the third paclitaxel dose was given on day 17 and was followed by another increase of these enzymes. She later received carboplatin and docetaxel without any perturbation of the amylase and lipase. Applying the Naranjo adverse drug reaction probability scale, a score of nine was obtained, indicating a definite association between the administration of paclitaxel and acute pancreatitis. This adverse event could be explained by paclitaxel itself or one of two diluents: cremophor or ethanol. Because paclitaxel is use in many chemotherapy protocols, pharmacists and physicians should be aware of this rare adverse event. Docetaxel administration proved to be safe in this patient without any appearance of pancreatitis signs or symptoms.

Analyzing temozolomide medication errors: potentially fatal.

The EORTC-NCIC regimen for glioblastoma requires different dosing of temozolomide (TMZ) during radiation and maintenance therapy. This complexity is exacerbated by the availability of multiple TMZ capsule strengths. TMZ is an alkylating agent and the major toxicity of this class is dose-related myelosuppression. Inadvertent overdose can be fatal. The websites of the Institute for Safe Medication Practices (ISMP), and the Food and Drug Administration (FDA) MedWatch database were reviewed. We searched the MedWatch database for adverse events associated with TMZ and obtained all reports including hematologic toxicity submitted from 1st November 1997 to 30th May 2012. The ISMP describes errors with TMZ resulting from the positioning of information on the label of the commercial product. The strength and quantity of capsules on the label were in close proximity to each other, and this has been changed by the manufacturer. MedWatch identified 45 medication errors. Patient errors were the most common, accounting for 21 or 47% of errors, followed by dispensing errors, which accounted for 13 or 29%. Seven reports or 16% were errors in the prescribing of TMZ. Reported outcomes ranged from reversible hematological adverse events (13%), to hospitalization for other adverse events (13%) or death (18%). Four error reports lacked detail and could not be categorized. Although the FDA issued a warning in 2003 regarding fatal medication errors and the product label warns of overdosing, errors in TMZ dosing occur for various reasons and involve both healthcare professionals and patients. Overdosing errors can be fatal.

Adjuvant treatment for endometrial cancer: literature review and recommendations by the Comité de l'évolution des pratiques en oncologie (CEPO).

OBJECTIVE: Despite the very good prognosis of endometrial cancer, a number of patients with localized disease relapse following surgery. Therefore, various adjuvant therapeutic approaches have been studied. The objective of this review is to evaluate the efficacy and safety of neoadjuvant and adjuvant therapies in patients with resectable endometrial cancer and to develop evidence-based recommendations. METHODS: A review of the scientific literature published between January 1990 and June 2012 was performed. The search was limited to published phase III clinical trials and meta-analyses evaluating the efficacy of neoadjuvant or adjuvant therapies in patients with endometrial carcinoma or carcinosarcoma. A total of 23 studies and five meta-analyses were identified. RESULTS: The selected literature showed that in patients with a low risk of recurrence, post-surgical observation is safe and recommended in most cases. There are several therapeutic modalities available for treatment of endometrial cancers with higher risk of recurrence, including vaginal brachytherapy, external beam radiotherapy, chemotherapy, or a combination of these. CONCLUSIONS: Considering the evidence available to date, the CEPO recommends the following: (1)post-surgical observation for most patients with a low recurrence risk; (2)adjuvant vaginal brachytherapy for patients with an intermediate recurrence risk; (3)adjuvant pelvic radiotherapy with or without vaginal brachytherapy for patients with a high recurrence risk; addition of adjuvant chemotherapy may be considered as an option for selected patients (excellent functional status, no significant co-morbidities, poor prognostic factors); (4)adjuvant chemotherapy and pelvic radiotherapy with or without brachytherapy and para-aortic irradiation for patients with advanced disease;

Impact of Pharmacist-Provided Education Using New Information Sheets on Activation in Patients Treated with Oral Antineoplastic Drugs (IMPACT-OAD Project).

Background: Oral antineoplastic drugs (OADs) play an increasing role in the treatment of cancer. Patients must have a high degree of understanding and autonomy to manage the numerous adverse effects at home. In Quebec, recommendations have been made for oncology pharmacists to systematically counsel all patients who are starting an OAD. Objective: To measure the impact of education provided by oncology pharmacists on patient activation. Methods: In this prospective, single-centre, observational cohort study, patients starting an OAD received education from oncology pharmacists, who used the 2020 updated version of information sheets from the Groupe d'étude en oncologie du Québec (GEOQ, www.geoq.info). The Patient Activation Measure (PAM-13) questionnaire was used to measure patients' activation before and after the intervention. Results: Of the 43 patients recruited in the intention-to-treat analysis, 41 were included in the modified intention-to-treat analysis. The mean difference between PAM-13 scores before and after the intervention was 2.30 (standard deviation [SD] 11.85) (p = 0.22) in the intention-to-treat analysis and 3.63 (SD 10.33) (p = 0.032) in the modified intention-to-treat analysis; these differences were less than the 5 points required for a result to be considered clinically meaningful. None of the effect-modifying variables for which data were collected had a significant impact on the degree of activation; however, a weak negative correlation was observed between the level of health literacy and the change in PAM-13 score. Conclusions: The study did not show a clinically meaningful change in patient activation following pharmacist-provided education, according to the updated GEOQ information sheets. Further studies are needed to evaluate these data in a larger population and to determine whether the impact of education persists beyond the first treatment cycle.

Contexte: Les médicaments antinéoplasiques par voie orale (MAVO) occupent une place grandissante dans le traitement du cancer. Les patients doivent avoir un degré élevé de compréhension et d'autonomie pour gérer les nombreux effets indésirables à domicile. Au Québec, des recommandations ont été émises pour que les pharmaciens en oncologie conseillent systématiquement tous les patients qui débutent des MAVO. Objectif: Mesurer l'impact des enseignements effectués par les pharmaciens en oncologie sur l'activation du patient. Méthodes: Dans cette étude de cohorte prospective, monocentrique et observationnelle, les patients qui commençaient à prendre des MAVO ont reçu un enseignement effectué par un pharmacien en oncologie. Ceux-ci utilisaient les feuillets d'information pour les patients du Groupe d'étude en oncologie du Québec (GEOQ, www.geoq.info) mis à jour en 2020. Le questionnaire de Mesure d'activation du patient (MAP-13) a été utilisé pour mesurer l'activation des participants avant et après l'intervention. Résultats: Sur les 43 participants recrutés dans l'analyse en intention de traiter, 41 ont été inclus dans l'analyse en intention de traiter modifiée (mITT). La différence moyenne entre les scores MAP-13 avant et après était de 2,30 (écart type [SD] 11,85) (p = 0,22) dans l'analyse en intention de traiter et de 3,63 (SD 10,33) (p = 0,032) dans l'analyse mITT; ces différences étaient inférieures aux 5 points requis pour qu'un résultat soit considéré comme cliniquement significatif. Aucune des variables modificatrices d'effet pour lesquelles des données ont été recueillies n'a eu d'effet significatif sur le degré d'activation; cependant, une faible corrélation négative a été observée entre le niveau de littératie en santé et la variation du score MAP-13. Conclusions: L'étude n'a pas démontré de changement cliniquement significatif dans l'activation des patients à la suite de l'enseignement effectué par le pharmacien en oncologie sur la base des feuillets d'information actualisés du GEOQ. D'autres études sont nécessaires pour évaluer ces données chez une plus grande population et pour déterminer si l'impact de l'enseignement perdure au-delà du premier cycle de traitement.

Opinion, experience and educational preferences concerning pharmacogenomics: an exploratory study of Quebec pharmacists.

Aim: To evaluate the current opinion, experience and educational preferences of pharmacists in Quebec concerning pharmacogenomics. Method: A web-based survey containing 25 questions was sent to all Quebec pharmacists. Results: Most pharmacists were willing to advise patients (81%) and physicians (84%) on treatment choices based on pharmacogenomic test results after proper training. Only 31% had been previously exposed to pharmacogenomic test results, and 91% were favorable to pharmacogenomics training, with e-learning through interactive video sessions (69%). The preferred training session length was between 1 and 3 h (59%). Hospital pharmacists were more often exposed to pharmacogenomic tests (p < 0.0001) and more frequently advised patients on treatment choices (p < 0.001) than community pharmacists. Conclusion: Pharmacists remain favorable toward pharmacogenomics, but its use in clinical practice stays limited. Identifying the educational preferences of pharmacists may help in the development of educational programs to help them integrate pharmacogenomics in their clinical practice.

Antibiotics are associated with decreased progression-free survival of advanced melanoma patients treated with immune checkpoint inhibitors.

Background: The gut microbiota has been shown to be an important determinant of the efficacy of immune checkpoint inhibitions (ICI) in cancer. Several lines of evidence suggest that antibiotic (ATB) usage prior to or within the first month of ICI initiation negatively impacts clinical outcomes. Methods: We examined patients with advanced melanoma treated with an anti-PD-1 monoclonal antibody (mAb) or an anti-CTLA-4 mAb alone or in combination with chemotherapy. Those receiving ATB within 30 days of beginning ICI were compared with those who did not receive ATB. Response rates as determined by RECIST 1.1, progression-free survival (PFS), overall survival (OS) and immune-related toxicities were assessed. Results: Of these 74 patients analyzed, a total of 10 patients received ATB (13.5%) within 30 days of initiation of ICI. Patients who received ATB 30 days prior to the administration of ICI experienced more primary resistance (progressive disease) (0% of the objective response rate compared to 34%), and progression-free survival (PFS) was significantly shorter (2.4 vs 7.3 months, HR 0.28, 95% CI (0.10-0.76) p = 0.01). Overall survival (OS) was also shorter; however, this was not statistically significant (10.7 vs 18.3 months, HR:0.52, 95% CI (0.21-1.32) p = 0.17). The multivariate analysis further supported that ATB administration was associated with worse PFS (HR 0.32 (0.13-0.83) 95% CI, p = 0.02). Conclusion: These findings suggest that ATB use within 30 days prior to ICI initiation in patients with advanced melanoma may adversely affect patient outcomes.

Use of Intermediate Endpoints in the Economic Evaluation of New Treatments for Advanced Cancer and Methods Adopted When Suitable Overall Survival Data are Not Available.

OBJECTIVES: This study assessed the use of intermediate endpoints in the economic evaluation of new treatments for advanced cancer and the methodological approaches adopted when overall survival (OS) data are unavailable or of limited use. METHODS: A systematic literature review was conducted to identify economic evaluations of treatments for advanced cancer published between 2003 and 2013. Cost-effectiveness and cost-utility analyses expressed in cost per life-year gained and cost per quality-adjusted life-year using an intermediate endpoint as an outcome measure were eligible. Characteristics of selected studies were extracted and comprised population, treatment of interest, comparator, line of treatment, study perspective, and time horizon. Use of intermediate endpoints and methods adopted when OS data were lacking were analyzed. RESULTS: In total, 7219 studies were identified and 100 fulfilled the eligibility criteria. Intermediate endpoints mostly used were progression-free survival and time to progression, accounting for 92 % of included studies. OS data were unavailable for analysis in nearly 25 % of economic evaluations. In the absence of OS data, studies most commonly assumed an equal risk of death for all treatment groups. Other methods included use of indirect comparison based on numerous assumptions, use of a proxy for OS, consultation with clinical experts, and use of published external information from different treatment settings. CONCLUSION: Intermediate endpoints are widely used in the economic evaluation of new treatments for advanced cancer in order to estimate OS. Currently, different methods are used in the absence of suitable OS data and the choice of an appropriate method depends on many factors including the data availability.

Bevacizumab and central nervous system (CNS) hemorrhage.

BACKGROUND: Bevacizumab is widely used and may cause life-threatening bleeding. We attempted to identify clinical characteristics associated with central nervous system (CNS) hemorrhage in a broad population. METHODS: We performed a retrospective review of the FDA MedWatch database of adverse events reported with bevacizumab from 11/1997 to 5/2009. Our search used keywords: bleeding, hemorrhage, cerebral, intracranial, subarachnoid, cerebellar, hemorrhagic stroke and brain. RESULTS: A total of 17,466 reports were included in the database: 154 described CNS hemorrhage in 99 patients, and 1,041 reports described non-CNS bleeds. Median age was 62 years, and the primary cancers were consistent with indications for bevacizumab. Patients received a median of three (1-36) doses of bevacizumab prior to the bleed. Thirty percent had documented history of hypertension. Sixteen patients with CNS hemorrhage were reported to have CNS metastases. Death was reported as a complication of hemorrhage in 48 %. The most common predisposing factor for CNS bleeds was use of medications associated with bleeding, followed by thrombocytopenia. CONCLUSION: In this database, 154 of 1,195 reports of bleeding associated with bevacizumab described a CNS bleed. Although CNS bleeds were not common, they were the reported cause of death in two-thirds of cases.

An evaluation of pharmacists' expectations towards pharmacogenomics.

BACKGROUND: Given their expertise in pharmacotherapy, pharmacists are well positioned to play a leading role in the implementation of pharmacogenomics in clinical practice. However, little is known about the opinions of pharmacists towards pharmacogenomics or their willingness to integrate this new field in their practice. METHODS: We conducted a survey of 284 pharmacists practicing in the province of Québec (Canada) to describe the opinions, expectations and concerns of pharmacists toward pharmacogenomics. RESULTS: Pharmacists were very hopeful regarding the potential role of pharmacogenomics. Moreover, more than 95% of responders would be willing to recommend pharmacogenomic testing. Nevertheless, only 7.7% of pharmacists currently felt comfortable advising patients based on pharmacogenomic test results. Accordingly, the majority of responders (96.6%) indicated that they would like to undertake continuing education related to pharmacogenomics. CONCLUSION: Pharmacists are extremely hopeful towards pharmacogenomic testing. Furthermore, a vast majority is willing to integrate these tests as part of their clinical practice. Proper education will be required if the integration of pharmacogenomics in patient care is to be optimal.

Going past the data for temozolomide.

The benefit of six cycles of adjuvant temozolomide was documented in a randomized phase III (EORTC-NCIC CE.3) trial, and this therapy, following combined temozolomide and radiation, is the standard of care for patients with newly diagnosed glioblastoma. We comment on the differences in the length of adjuvant therapy in both clinical practice and national studies (e.g. RTOG 0825), usually doubling the length in the EORTC/NCIC study, and relate to historic adjuvant trials for solid tumors.

Hematologic adverse events associated with temozolomide.

PURPOSE: Temozolomide (TMZ) is a widely used oral alkylating agent that has been associated with the development of severe hematologic adverse events (HAEs). Limited clinical information about HAEs is available. METHODS: We searched the FDA MedWatch database for TMZ and obtained all MedWatch reports on TMZ submitted to the FDA from November 1, 1997 to September 3, 2008. We defined major HAEs, namely agranulocytosis, aplasia, aplastic anemia (AA), leukemia (various), myelodysplastic syndrome (MDS), and lymphoma, and several minor HAEs. RESULTS: A total of 5,127 reports on 3,490 patients were submitted to MedWatch. Among these, we identified 112 cases of major HAEs. Of the 44 reported deaths, the major HAE was considered the cause in 32 cases. The median duration of TMZ treatment was 6 weeks [0.5-108 weeks]. Seventy-six cases of AA or aplasia and 17 cases of leukemia represented the most common major HAE. Important minor HAEs were bone marrow failure and pancytopenia/pancytopenia-like with 325 combined cases; these reports are clinically similar to aplastic anemia. CONCLUSION: The hematologic toxicity profile of TMZ differs from that of other alkylating agents. TMZ HAEs are emerging as significant concerns. Among alkylating agents, AA appears unique to TMZ, and the high rate warrants disclosure of patients. The duration of TMZ exposure prior to the development of AA may be quite short. The risk of AML/MDS is low, but the length of follow-up is insufficient to assess the true risk.