Immediate severe hypersensitivity reaction to etoposide phosphate: Case report and review of the literature.

INTRODUCTION: Hypersensitivity reactions from intravenous (IV) etoposide have been rarely reported, with these being seen more commonly with etoposide than with etoposide phosphate. This is generally explained by the need for polysorbate 80, a known cause of hypersensitivity, as a solubiliser, in the etoposide formulation. CASE REPORT: We report a 22-year-old male, being treated with adjuvant BEP (bleomycin/etoposide phosphate/cisplatin) for a testicular germ cell tumour. Bleomycin and cisplatin were administered without incident. Within one minute of etoposide phosphate commencement he experienced a severe hypersensitivity reaction, consisting of widespread erythematous rash, facial swelling, and nausea. Observations included unrecordable blood pressure, tachycardia, hypoxia, and loss of consciousness, confirming a diagnosis of anaphylactic shock. MANAGEMENT AND OUTCOME: Etoposide phosphate was ceased immediately. He was successfully managed with IV hydrocortisone, IV promethazine, intramuscular adrenaline, IV fluids and oxygen. Following admission for observation, significant improvement occurred over 48 h. DISCUSSION: Hypersensitivity reactions to etoposide were first reported in the 1980s. Following reactions to etoposide, substituting etoposide phosphate into chemotherapy regimens has commonly allowed treatment to continue without incidence. Anaphylactic reactions to etoposide phosphate were first documented in 2012, with further cases reported subsequently. Unlike etoposide, etoposide phosphate is highly soluble in aqueous solutions and doesn't require adjuvants in the formulation. Hypersensitivity reactions to etoposide phosphate are therefore likely related to the etoposide drug molecule itself. Clinicians should be aware of this rare, but potentially life-threatening, toxicity when using etoposide-based treatments and have procedures in place to urgently manage any hypersensitivity reactions that may occur.

Acquired Hemophilia A following Pfizer-BioNTech SARS CoV-2 mRNA vaccine, successfully treated with prednisolone and rituximab.

INTRODUCTION: Acquired haemophilia A (AHA) is a rare bleeding disorder, characterised by the presence of autoantibodies to clotting factor VIII (FVIII). AHA can be idiopathic or occur in the context of malignancy, autoimmune disease, drugs, or pregnancy. Recently, cases of AHA following both COVID-19 infection and vaccination have been reported. CASE REPORT: We report the case of a 95-year-old female who was immunised with the Pfizer-BioNTech SARS CoV-2 mRNA vaccine, with doses given three weeks apart. Spontaneous bruising over her extremities appeared one week after the initial dose, with hospital admission occurring three weeks after the second. Examination revealed a large haematoma on the dorsum of the right hand with resultant bleeding and widespread ecchymoses. Investigations confirmed a diagnosis of AHA. MANAGEMENT AND OUTCOME: Initial management included high dose prednisolone, recombinant Factor VIII and tranexamic acid. There was no significant clinical improvement after three days, so intravenous rituximab 100 mg weekly for four weeks was commenced. The activated partial thromboplastin time (aPTT) normalised after two doses and Factor VIII level reached 0.68U/ml on day + 22. The patient was successfully discharged from hospital after 37 days. DISCUSSION: Four cases of AHA following administration of COVID mRNA vaccines (Pfizer and Moderna) have been documented. AHA should be a differential in patients presenting with bleeding following COVID-19 vaccination, in the presence of a normal platelet count. Rapid recognition, prompt initiation of immunosuppressive treatment and rigorous supportive cares are required to minimise morbidity and mortality.

Retrospective analysis of mortality within 30 days of systemic anticancer therapy and comparison with a previous audit at an Australian Regional Cancer Centre.

PURPOSE: To retrospectively determine the rate of death occurring within 14 and 30 days of systemic anticancer therapy (SACT), compare this against a previous audit and benchmark results against other cancer centres. Secondly, to determine if the introduction of immune checkpoint inhibitors (ICI), not available at the time of the initial audit, impacted mortality rates. METHOD: All adult solid tumour and haematology patients receiving SACT at an Australian Regional Cancer Centre (RCC) between January 2016 and July 2020 were included. RESULTS: Over a 55-month period, 1709 patients received SACT. Patients dying within 14 and 30 days of SACT were 3.3% and 7.0% respectively and is slightly higher than our previous study which was 1.89% and 5.6%. Mean time to death was 15.5 days. Males accounted for 63.9% of patients and the mean age was 66.8 years. 46.2% of the 119 patients dying in the 30 days post SACT started a new line of treatment during that time. Of 98 patients receiving ICI, 22.5% died within 30 days of commencement. Disease progression was the most common cause of death (79%). The most common place of death was the RCC (38.7%). CONCLUSION: The rate of death observed in our re-audit compares favourably with our previous audit and is still at the lower end of that seen in published studies in Australia and internationally. Cases of patients dying within 30 days of SACT should be regularly reviewed to maintain awareness of this benchmark of quality assurance and provide a feedback process for clinicians.

Severe cisplatin-induced renal toxicity in a patient with xeroderma pigmentosum.

INTRODUCTION: Xeroderma pigmentosum is a rare genetic disorder of DNA repair, defined by extreme sensitivity to sunlight, leading to sunburn, skin pigmentation and increased incidence of skin cancers. Cisplatin acts by interfering with DNA repair mechanisms to cause DNA damage and apoptosis. It has indications in many malignancies including bladder, head and neck and lung cancers. Acute kidney injury is a well-known complication of cisplatin. CASE REPORT: We report a 42-year-old male with a long history of Xeroderma pigmentosum treated with adjuvant cisplatin (40 mg/m2) in combination with radiotherapy for cutaneous squamous cell carcinoma of the neck. He presented to clinic prior to his second weekly dose of cisplatin with a severe acute kidney injury and a creatine level of 813 mmol/L and eGFR of 7 mL/min. No myelosuppression was present. MANAGEMENT AND OUTCOME: Treatment consisted of aggressive electrolyte and fluid management. Creatinine levels slowly improved with conservative management without the need for dialysis. Radiation was completed without further cisplatin. DISCUSSION: Three cases of severe adverse effects from cisplatin administration in patients with Xeroderma pigmentosum have been reported, with all fatal. Xeroderma pigmentosum complementation group C plays an important role in the DNA repair process with the recognition and repair of damage to normal cells following cisplatin. Patients with Xeroderma pigmentosum can be carriers of defective Xeroderma pigmentosum complementation group C and if the degree of Xeroderma pigmentosum complementation group C inactivity is significant, fatalities could occur. Physicians should be aware of this rare but potentially lethal toxicity when considering systemic therapy for squamous cell carcinoma in patients diagnosed with Xeroderma pigmentosum.

Preventing drug vial wastage and reducing expenditure associated with injectable cancer drugs: International oncology pharmacy survey.

PURPOSE: Our objective was to determine what vial sharing techniques and other strategies were being used globally to reduce wastage from partially used single-use drug vials, what barriers are preventing these strategies being employed, and what savings are being achieved. METHODS: A survey, comprising 19 questions, was distributed to the membership of the International Society of Oncology Pharmacy Practitioners and British Oncology Pharmacy Association. Questions asked included how parenteral cancer drugs are obtained and prepared, what vial sharing strategies are used, what means are employed to extend stability, how prepared products are reused and what cost savings are achieved. RESULTS: In all, 74 responses were received from 20 countries, most from the United Kingdom. Some manufacturing is done by 60.8% of institution, with 41.9% making all products. Vial sharing strategies, for frequently used drugs, were employed in 53% of cases. Barriers preventing vial sharing being used included government legislation, USP 797 guidelines, and health insurance companies. Extension of stability was possible for 70.2% of centres. Most respondents reported reduction in cytotoxic and biological waste, and alleviation of drug shortages from vial sharing utilisation. Cost savings were achieved in 74% of cases and was significant in one third. CONCLUSIONS: The survey has determined that drug vial wastage and expenditure can be reduced, and vial sharing facilitates this. International collaboration plus the assistance of governments and the pharmaceutical industry is vital in achieving this aim. These findings can hopefully guide oncology pharmacy in establishing appropriate strategies to reduce wastage internationally.

Systematic review and meta-analysis of febrile neutropenia risk with TCH(P) in HER2-positive breast cancer.

BACKGROUND: Docetaxel, carboplatin and trastuzumab, with or without pertuzumab (TCH(P)), has become the preferred (neo)adjuvant regimen for HER2-positive breast cancer. However, its associated febrile neutropenia (FN) risk is unclear: pivotal studies reported FN risks < 10%, but in clinical practice, a high FN rate (> 20%) was observed. This systematic review and meta-analysis determine the FN risk associated with TCH(P) and the indication for primary prophylactic granulocyte colony-stimulating factor (PP G-CSF). METHODS: The MEDLINE, Embase, Web of Science and Cochrane databases were searched for full-text English articles reporting the FN incidence in early breast cancer patients receiving (neo)adjuvant TCH(P). The primary endpoint was the pooled crude FN incidence in patients treated without PP G-CSF using the random effects method. Secondary endpoints were the FN risk with PP G-CSF support, age-related differences in FN and differences in risk with TCH versus TCHP. RESULTS: Seventeen studies were included in the systematic review. The pooled estimates of FN incidences were 27.6% (95% CI 18.6 to 37.1) in patients who did not receive PP G-CSF (primary meta-analysis, 9 studies, n = 889) versus 5.0% (95% CI 2.6 to 8.0) in patients administered PP G-CSF (secondary meta-analysis, 7 studies, n = 445). Two studies reported non-significant age-related differences in FN. The risk comparison between TCH and TCHP was inconclusive. CONCLUSIONS: The crude FN risk associated with (neo)adjuvant TCH(P) is over 20%, the upper limit above which the international guidelines unanimously advise PP G-CSF administration. G-CSF prophylaxis effectively reduces FN risk and should become the standard of care with (neo)adjuvant TCH(P).

Temozolomide-induced aplastic anaemia: Case report and review of the literature.

INTRODUCTION: Temozolomide (TMZ) is an oral alkylating agent principally indicated for neurological malignancies including glioblastoma (GBM) and astrocytoma. Most common side effects are mild to moderate, and include fatigue, nausea, vomiting, thrombocytopenia and neutropenia. Severe or prolonged myelosuppression, causing delayed treatment or discontinuation, is uncommon. Major haematological adverse effects such as myelodysplastic syndrome or aplastic anaemia (AA) have rarely been reported. CASE REPORT: We report a 68-year old female with GBM treated at a tertiary hospital with short-course radiotherapy and concurrent temozolomide following craniotomy. On treatment completion she was transferred to our hospital for rehabilitation. She was thrombocytopenic on admission. Platelets continued falling with significant pancytopenia developing over the next two weeks. Blood parameters and a markedly hypocellular bone marrow confirmed the diagnosis of very severe AA, probably due to TMZ. MANAGEMENT AND OUTCOME: Treatment consisted of repeated platelet transfusions, intravenous antibiotics, antiviral and antifungal prophylaxis, and G-CSF 300 mcg daily. Platelet and neutrophil counts had returned to normal at 38 days following the completion of TMZ treatment. DISCUSSION: Whilst most cases of AA are idiopathic, a careful drug, occupational exposure and family history should be obtained, as acquired AA may result from viruses, chemical exposure, radiation and medications. Temozolomide-induced AA is well documented, though only 12 cases have been described in detail. Other potential causes were eliminated in our patient. Physicians should be aware of this rare and potentially fatal toxicity when prescribing. Frequent blood tests should be performed, during and following TMZ treatment, to enable early detection.

Elevated beta human chorionic gonadotropin in a non-pregnant female diagnosed with anal squamous cell carcinoma.

INTRODUCTION: Elevated serum beta human chorionic gonadotrophin (ß-hCG) in a female normally indicates pregnancy or possibly, gestational trophoblastic disease or ovarian germ cell tumours. Expression of ß-hCG has been demonstrated in cervical and endometrial carcinoma and other non-germ cell tumours of the ovary, vulva, breast, prostate, lung, colon, oral/facial tissue and stomach. CASE REPORT: We report a 43-year-old premenopausal woman with p16 positive squamous cell anal cancer. Pre-treatment urinary screening was positive for ß-hCG (218 IU/L), which was confirmed on serum and expressed in the tumour. Pelvic ultrasound ruled out pregnancy. Cervical cytology detected human papilloma virus p16 infection and a potential squamous intraepithelial lesion. Management and outcome: She received definitive chemoradiation (Mitomycin/5-fluorouracil) for six weeks. ß-hCG, taken four weeks post completion, had returned to normal levels (<2 IU/L). DISCUSSION: Cases of elevated serum ß-hCG are documented in different cancers including breast, gastric, lung, ovarian and renal cell. In our case, the elevated ß-hCG is probably ectopic excretion by the squamous cell carcinoma tumour in the anus. While this has never been reported previously in the anus, it is likely due to the documented risk of development of precancerous as well as cancerous anal and cervical lesions through human papilloma virus infection. Raised levels of ß-hCG have been reported in cervical cancers. Other possible causes of ß-hCG elevation were excluded. Following treatment, her ß-hCG level returned to normal strengthening the hypothesis that ß-hCG elevation was due to the anal carcinoma. In conclusion, unexplained ectopic secretion of ß-hCG may be the first sign of a primary malignancy.

Optic neuritis induced by 5-fluorouracil chemotherapy: Case report and review of the literature.

Introduction: For over 50 years, 5-Fluorouracil has played a critical role in the treatment of numerous malignancies, including colorectal cancer. Ocular side effects are uncommon and include blurred vision, conjunctivitis, excessive lacrimation and keratitis. Case report: We report a 57-year-old male with metastatic colorectal cancer who had received extensive chemotherapy with 5-Fluorouracil-based regimens for over 12 months. Following his seventh cycle of cetuximab/FOLFIRI, he developed acute onset global headache, nausea and loss of vision in the right eye. After detailed investigations, including ophthalmologic and neurologic consultations, a diagnosis of optic neuritis was made. Management and outcome: Chemotherapy was ceased immediately, and intravenous methylprednisolone (1 g) daily for five days was commenced. His headache resolved and vision started to improve within 24 h. Three weeks after completion of corticosteroids, constriction of the right visual field had fully resolved. Discussion: Atypical optic neuritis is an inflammatory optic neuropathy that can be caused by ischaemia, mechanical compression, nutritional deficiency, toxins and drugs. Drug-induced optic neuritis, while rare, is associated with cytotoxic medications including methotrexate, cisplatin, carboplatin, vincristine and paclitaxel. There have only been five previous case reports implicating 5-Fluorouracil in the development of optic neuropathy. The likelihood of the adverse drug reaction due to 5-Fluorouracil was assessed using the Naranjo algorithm. A score of +7 indicates probable causality. Clinicians should be alert to this potential ocular toxicity in order to initiate prompt cessation of treatment and early ophthalmology referral to prevent visual loss and damage to ocular structures.

Pembrolizumab-induced thrombotic thrombocytopenic purpura.

INTRODUCTION: Pembrolizumab is a humanised monoclonal antibody targeting the receptor programmed cell death protein-1 (PD-1), with anti-tumour activity demonstrated for many malignancies. Such immune checkpoint inhibitors are associated with many immune-related adverse events including rash, colitis, hepatitis, pneumonitis, endocrinopathy and, rarely, haematological adverse events, including immune-related thrombocytopenia. CASE REPORT: We report a 60-year-old female with metastatic non-small cell lung cancer treated with pembrolizumab every three weeks. Following her fifth cycle, she presented to our hospital with community-acquired pneumonia. Thrombocytopenia developed the next day and, after detailed investigations, thrombotic thrombocytopenic purpura was diagnosed. MANAGEMENT AND OUTCOME: Pembrolizumab was immediately ceased and plasma exchange commenced along with IV methylprednisolone 250 mg daily for three days followed by oral prednisolone. After five days of plasma exchange, platelet counts normalised and haemolytic anaemia resolved. DISCUSSION: Acquired thrombotic thrombocytopenic purpura is an autoimmune disorder caused by an inhibitory autoantibody against ADAMTS-13. While most cases of acquired thrombotic thrombocytopenic purpura are idiopathic, certain conditions (e.g. bacterial infection, autoimmune disorders, malignancies) and medications are associated with thrombotic thrombocytopenic purpura. Other potential causes were eliminated in our patient. As acquired thrombotic thrombocytopenic purpura is an autoimmune disorder, pembrolizumab, given its unique mechanism of action and association with immune-related adverse events, is believed to be implicated in the development of thrombotic thrombocytopenic purpura. This case is one of only two linking anti-PD-1 therapy to thrombotic thrombocytopenic purpura development (the other occurring in a patient on nivolumab plus ipilimumab). Thrombotic thrombocytopenic purpura is life-threatening and clinicians are advised to be aware of its possible occurrence in immune checkpoint inhibitor-treated patients.

Systemic anticancer therapy in the last 30 days of life: Retrospective audit from an Australian Regional Cancer Centre.

BACKGROUND: Cessation of chemotherapy at an appropriate time is an important component of good quality palliative care. Published studies looking at administration of chemotherapy at the end of life vary widely. OBJECTIVE: To retrospectively determine the rate of death occurring within 14 and 30 days of chemotherapy and use this to benchmark against other cancer centres as a quality of care measure. METHOD: All adult patients who received systemic anticancer therapy for solid tumours and haematological malignancies at an Australian Regional Cancer Centre between 2011 and 2015 were included. RESULTS: Over a five-year period, 1215 patients received systemic anticancer therapy. Of these, 23 (1.89%) died within 14 days following systemic anticancer therapy and 68 (5.60%) within 30 days. All patients who died had been treated with palliative intent. Mean time to death was 17.7 days. The majority were female (61.8%) and the mean age was 62.3 years. The most common cause of death was disease progression (80.9%). Nearly half died at the Regional Cancer Centre, including 30.9% who lived in rural or remote localities. CONCLUSION: The rate of death observed in this study is at the lower end of the range seen in published studies for both the last 14 and 30 days post-systemic anticancer therapy. It is important to routinely collect data to enable benchmarking against other institutions, determine factors potentially associated with higher risks of mortality at the end of life and improve clinical decision making.

[A Survey to Compare the Specifications and Stability of Anticancer Drugs in Japan, the United States, Canada, and Australia].

Recently, expensive anticancer drugs such as molecularly targeted drugs have been reportedly ineffective. The use of drug vial optimization(DVO)has been proposed to overcome this problem. The specifications and stability of anticancer drugs in Japan were compared to those in other countries that used DVO, based on the results of the survey reported at the 2016 International Society of Oncology Pharmacy Practitioners meeting that compared the international specifications and stability of anticancer drugs. Our survey investigated expensive and frequently used anticancer drugs: 14 anticancer monoclonal anti- bodies(MABs)and 26 cytotoxic agents. About 29%(4/14)of the MABs and 54%(14/26)of the cytotoxic agents mar- keted in other countries were sold in larger vials than those marketed in Japan. About 67%(2/3)of theMABs and 38%(8/ 21)of the cytotoxic agents marketed in other countries had stability data of reconstitution obtained across longer test periods than those in Japan. About 29%(4/14)of theMABs and 50%(13/26)of the cytotoxic agents marketed in other countries had stability data of final dilution obtained across longer test periods than those in Japan. The stability data obtained in Japan were comparable to those obtained in 3 other countries that used DVO. However, some differences were noted in the specifications of anticancer drugs between Japan and other countries.

Opportunities to significantly reduce expenditure associated with cancer drugs.

AIM: To identify cancer drugs amenable to strategies for reducing expenditure and avoiding drug wastage. METHODS: Information was sourced from product information in 20 countries on parenteral cytotoxic agents, and cancer and noncancer monoclonal antibodies. Data were collected on vial sizes, overage, stability and presentation forms. RESULTS: Vial size availability varied significantly between countries, with often only single vial sizes for numerous medications. Overage was poorly reported. Stability data were inconsistent and variable between countries, with most drugs only having a 24 h expiry. Three cancer-indicated monoclonal antibodies, thought suitable for prefilled syringe administration, were only available as vials. CONCLUSION: Many expensive cancer drugs are suitable for global cost-reduction strategies. Collaboration is vital to affecting change and reducing expenditure.