Reactions Weekly | 2021
Multiple drugs
Abstract
Various toxicities, lack of efficacy and off label use: 5 case reports In a case series, a 69-year-old man (case A), a 62-year-old woman (case B), a 60-year-old man (case C), an adult woman (case D) and a 32-year-old woman (case E) were described, who exhibited lack of efficacy during treatment with folinic-acid, fluorouracil, oxaliplatin, irinotecan, carboplatin, paclitaxel, letrozole or gemcitabine for cholangiocarcinoma, pancreatic neuroendocrine tumour, endometrial cancer or craniopharyngioma. All the patients received off label treatment with dabrafenib and trametinib, of whom 2 patients during treatment developed intermittent shivers (case A), fever and rash [case E; duration of treatments to reactions onsets not stated; not all routes and dosages stated]. Case A: The man had a history of hypertension, psoriasis, smoking and daily alcohol consumption. He presented with a few months of nausea in November 2017. After several investigations, he was diagnosed with cholangiocarcinoma with multiple hepatic, solitary pulmonary metastasis. Subsequently, in-house Next Generation Sequencing (NGS) gene panel revealed BRAF V600E mutation with a Variant Allele Fraction (VAF) of 13%. He received first line therapy with cisplatin and gemcitabine. After 3 cycles, he achieved partial response. However, at end of the 6 cycle lung biopsy revealed metastatic cholangiocarcinoma, followed by radiofrequency ablation of lung and liver lesions. After 2 months, metabolic progression of one pre-existing liver lesion was seen. Therefore, he started receiving off label treatment with oral dabrafenib 150mg twice daily and oral trametinib 2mg daily. The treatment was well tolerated except an intermittent episodes of shivers. He achieved significant metabolic response with stability of the right hepatic lesion. Subsequently, he underwent extended right hepatectomy with resection of the right hemi-diaphragm. Following 12 months of treatment, imaging revealed no evidence of disease recurrence. Case B: The woman with a history of endometriosis and hypertension underwent diagnostic workup for gallstones in early 2018. Subsequently, she was diagnosed with intrahepatic cholangiocarcinoma. she received first line treatment with cisplatin and gemcitabine. After 4 cycles, she showed mixed tumour response with interval growth of satellite liver lesions, stable main liver lesion, reduction in the size of portacaval lymph nodes and development of right-sided pleural effusion. Subsequently, she started receiving second line chemotherapy with folinic acid, fluorouracil [5-Flourouracil] and oxaliplatin. However, the treatment was refractory. Molecular profiling revealed V600E BRAF mutation. Therefore, she started receiving off label treatment with oral dabrafenib 150mg twice daily and oral trametinib 2mg daily in May 2018. The treatment was well tolerated without evidence of toxicity. Eventually, she had improvement in the lung and liver lesions. The response was maintained till disease progression. Therefore, the treatment was stopped and she was referred back to local oncology team. Case C: The man was examined for loin pain in December 2016. Several investigations revealed carcinoma with neuroendocrine features. Subsequently, he was confirmed with pancreatic acinar cell carcinoma (pancreatic neuroendocrine tumour). He started receiving first line treatment with folinic acid, flourouracil, irinotecan and oxaliplatin. After 7 cycles, he had disease progression. An in-house NGS revealed BRAF V600E mutation. Therefore, he started receiving off label treatment with dabrafenib and trametinib in January 2018. The treatment was well tolerated without toxicity. After 8 weeks of the treatment, a response was noted. He had received 32 months of treatment with excellent maintained clinical and radiological response. Case D: The woman at the age of 49 years, underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy in 2001. Histopathological review demonstrated stage 1b well-differentiated endometrial adenocarcinoma (endometrial cancer) with oestrogen receptor expression 30% and early myometrial invasion. After 11 years of the diagnosis, she had a disease recurrence in the left pelvic sidewall. She was managed with carboplatin and paclitaxel followed by radical radiotherapy. She achieved good response with remaining of a small residual soft tissue lesion. After 2 years, she had progression with interval growth of pelvic soft tissue mass. She was started on letrozole, but after 2 months of treatment, she had further progression. Subsequently, she started receiving second-line treatment with gemcitabine and carboplatin. However, after 6 cycles, she had disease progression with development of new bilateral lung metastases. Pyrosequencing of archival tumour tissue revealed BRAF V600E mutation. She was enrolled in a clinical trial and received paclitaxel and unspecified a fatty-acid synthase inhibitor. However, after 5 cycles, progression in the left pelvic sidewall mass and the lung metastases was noted. Subsequently, she was enrolled in another clinical trial and started receiving off label dabrafenib 150mg twice daily with rifampincin [rifampin] and rabeprazole for only the first cycle in December 2015. After 3 months of treatment, CT scan revealed reduction in size of all the lung metastases and the left pelvic soft tissue mass. At 6 months of dabrafenib monotherapy, CT scan revealed continued response of the lung metastases but slight increase of the size of the pelvic mass. Therefore, off label trametinib 2mg was added. After 3 months of the combination therapy, imaging revealed stable size of the previously documented pelvic mass and maintained radiographic response in the lung metastases. However, at the end of the 12 months of the combination treatment, radiologic disease progression of the pelvic mass was noted. Therefore, the treatment was stopped and she was referred back to her local oncology team. Case E: The woman had a history of cutaneous basal cell carcinoma. She presented with visual deterioration and was diagnosed with craniopharyngioma. After transcranial debulking, craniopharyngioma was resolved. Until February 2018, her examinations were unremarkable. MRI scan revealed disease progression within the residual capsule located in the pre-chiasmatic location, which was managed with stereotactic radiosurgery and a good radiographic response was achived. After 2 months, she experienced recurrence with displacement of the suprasellar structures, which was successfully treated with decompressive surgery. Genomic sequencing of archival tissue revealed a BRAF V600E mutation. Therefore, she started receiving oral dabrafenib 150mg twice daily and oral trametinib 2mg daily. The treatment was initially well tolerated, however, a dose reduction was required due to grade 2 fever and grade 2 rash. After 3 months of treatment, an MRI scan revealed stable disease.