Youxin Ji

Sorafenib in liver function impaired advanced hepatocellular carcinoma.

OBJECTIVE To explore the efficacy and safty of sorafenib in Child-Pugh class B to class C hepatocellular carcinoma (HCC). METHODS In this three-center open-label study from November 2011 to May 2013, we randomly assigned 189 patients with advanced Child-Pugh class B or C HCC patients into two groups, one group with 95 patient to receive sorafenib (400 mg a time, twice a day) and the other group with 94 patients to receive best supportive care. The primary end points were progression-free survival and overall survival. RESULTS The median progression-free survival was 2.2 months and 1.9 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.55; 95% confidence interval, 0.40-0.75; P=0.002). The median overall survival was 4.0 months and 3.5 months in the sorafenib group and best supportive care group respectively (Hazard ratio in the sorafenib group, 0.48; 95% confidence interval, 0.35-0.68; P<0.001). The main adverse effect of sorafenib was rash and acne of the skin (in 51.7% patients). The incidences of severe rash, diarrhea, and dry skin were 5.6%, 5.6%, and 2.2% in the sorafenib group. One patient reached partial response in the sorafenib group. CONCLUSIONS Sorafenib is safe in patients with liver function impaired advanced HCC. It is effective in terms of progression-free survival and overall survival compared with best supportive care. Liver functions are the important predictive factors.

AZD9291-induced Acute Interstitial Lung Disease

To the Editor: A 32-year-old Chinese male patient with 1 week cough and dyspnea on exertion was presented to hospital. He was a metastatic lung adenocarcinoma patient with 3 years treatment history. In October 2012, the patient complained cough, short of breath, and thoracic computerized axial tomography scan (CAT-scan) revealed left lung hilum mass with the right lung multismall patches or opacities. Core needle biopsy on supraclavicular lymph nodes was performed and diagnosis of Stage IV (T3N3M1a) lung adenocarcinoma was made by radiologist, pathologist, and oncologist. Chemotherapy with cisplatin and pemetrexed was initiated and a partial response (PR) was reached. After 6 cycles of double-bullet chemotherapy, maintenance therapy with pemetrexed was used. In January 2014, positron emission tomography-computed tomography scan showed the right lung disease progression and bone metastasis. Fine needle aspiration (FNA) was performed on right lung node and genetic sequencing study showed epidermal growth factor receptor (EGFR) 19 del erlotinib (Tarceva, Roche, Switzerland) was administrated orally and both lung lesions became shrunk and a good PR was achieved after 1 month of erlotinib treatment. This result maintained 9.5 months until patients lung disease progression and liver metastasis which were confirmed by CAT-scan and FNA. The 3rd line treatment with docetaxel (Qilu Pharmaceutical Co., China) and bevacizumab (Avastin, Roche, Switzerland) was administered, PR was reached. Patients symptoms got severe and CAT-scan showed disease progression on both lungs after 4 months of above treatment. FNA was performed on the right lung lesion and gene panels were tested, it showed EGFR T790M, 19 del, and TP53 mutation. AZD9291 (Tagrisso, Osimertinib, AstraZeneca, UK) was used at a dose of 80 mg oral daily. The patient performed well and CAT-scan showed PR at 1 month follow-up, and the lesions continued remission on the last follow-up at 5.5 months therapy. The patient complained light cough and short of breath on exertion at 4.5 months of AZD9291 therapy. Physical examination was unremarkable; there were no rales or wheezes on chest auscultation. Oxygen saturation was 98%, blood works results were all within normal range. CAT-scan revealed interstitial lung fibrosis change on both lungs and obvious ground-glass opacities on the right upper lung [Figure 1a]. After carefully reviewed patients history and series CAT-scans, drug-induced acute interstitial lung disease (ILD) was confirmed by pathologist, radiologist, and oncologist. Figure 1 CAT-scan revealed interstitial lung fibrosis change on both lungs. (a) 4.5 months after AZD9291 treatment, right upper lung interstitial fibrosis. (b) One month after AZD9291 dose reduction and dexamethasone treatment. Because AZD9291 was the 4th line therapy of this patient, stop taking it to avoid worsening ILD was quite dangerous for him. The aggressive treatment plan was immediately initiated with dose reduction to 80 mg every other day, low-dose continued oxygen inhalation, and high-dose corticosteroid (10 mg dexamethasone infusion once a day for 10 days). Patients symptoms got improved, ground-glass opacities on the right lung were remarkable attenuated, and both lung fields got clearer on CAT-scan at 1 month follow-up [Figure 1b]. AZD9291 is an oral, potent, irreversible 3rd generation EGFR tyrosine kinase inhibitor (TKI), inhibits kinase activity. In vitro and in vivo studies, it showed strong inhibition lung cancer cells with EGFR sensitizing mutation or with T790M resistance mutation, but less activity on wild-type compare to the 1st generation gefitinib or erlotinib.[1] In patients with relapsed or metastasized disease after 1st generation TKI, its overall response rate (ORR) was around 50%; and patients with EGFR T790M mutation positive or negative had a 60% ORR and PFS 9.6 months or 21% ORR and PFS 2.8, respectively.[2] ILD is a rare complication during EGFR-TKI therapy, about 1–3% patients will acquire it. The mechanism of TKI-induced ILD is not very clear, TKI interrupting type II pneumocytes and alveolar wall repair may play an important role.[3] There is no standard guideline for the treatment of TKI-induced ILD; current management includes oxygen inhalation, drug discontinuation, and high-dose and prolongs corticosteroids or immunosuppressive. High-dose N-acetylcysteine alleviates pulmonary fibrosis in rats but needs further study in human.[4] The patient had been treated with multiline therapies, maintenance 3rd generation EGFR-TKI is the most reliable method to sustain patients survival. We reduced 50% dosage of the drug administration according to the half-life and metabolic characters of it,[1] to maintain effective blood drug concentration and maximally reduce its side effects. Drug-induced ILD is a severe and a fatal complication if not intervened promptly. This case showed that early diagnosis and early intervention of this complication is critical important during TKI treatment of advanced nonsmall cell lung cancer. AZD9291 dose reduction and aggressive corticosteroid treatment could be a promising treatment option for patient who required 3rd generation TKI to maintain disease remission. Clinical physicians must cautiously weigh the benefits and risks of targeted therapies causing ILD in order to provide optimal treatments and favorable outcomes. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

A Live Splenic Ectopic Pregnancy

Splenic ectopic pregnancy is very rare, it is easy to be negligence by doctors and the outcome is ominous if not treated promptly. Here we reported an extremely rare case happened in a young Chinese woman. She was admitted in to hospital by hypovolemic shock. A live splenic ectopic pregnancy was diagnosed by ultrasound. Laparotomy with splenectomy was performed and histology confirmed the diagnosis. Early diagnosis of live splenic ectopic pregnancy is critical important for save patients life, doctors should aware this disease.

Osimertinib compared docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated non-small-cell lung cancer

OBJECTIVE To compare the efficacy and toxicity of osimertinib versus docetaxel-bevacizumab as third-line treatment in EGFR T790M mutated NSCLC. METHODS In this phase 3, open-label, three-center study, we randomly assigned (1:1) previously treated with TKI-chemotherapy or chemotherapy-TKI recurrent or metastatic advanced non-squamous lung cancer patients into two groups. These patients had acquired EGFR T790M resistance mutation confirmed by tumor tissues or serum. One group received oral osimertinib (80 mg/day) and the other group received intravenous infusion docetaxel (75 mg/m2) and bevacizumab (7.5 mg/kg) every 21 days until disease progression, unacceptable toxic effects or patient death. The primary endpoint of this study was progression-free survival (PFS) and the secondary endpoints were response rates, toxicities and overall survival (OS). This trial was registered with ClinicalTrials.gov, number NCT02959749. RESULTS A total of 147 patients were treated. Among them, 74 were enrolled in the osimertinib group and 73 were in the docetaxel-bevacizumab group. The median progression-free survival was 10.20 months in the osimertinib group versus 2.95 months in the docetaxel-bevacizumab group (hazard ratio 0.23; 95% confidence interval [CI], 0.12-0.38; P < 0.001). The overall response rate in the osimertinib group was significantly better than in the docetaxel-bevacizumab group (61.6%; 95% CI, 55.5-67.7 versus 8.3%; 95% CI, 1.3-15.3; p < 0.001). Because all the progressed patients in the docetaxel-bevacizumab group crossed over to the osimertinib group, there was no significant difference in the median OS between two groups at the time of last follow-up (hazard ratio 0.79; 95% CI, 0.38-1.61; P = .551). The main grade 3 or 4 toxic effects were diarrhea (2.7%) and interstitial lung disease (1.4%) in the osimertinib group and alopecia (15.3%), anorexia (12.5%), neutropenia (9.7%) and nausea (8.3%) in the docetaxel-bevacizumab group. CONCLUSIONS Osimertinib had higher response rate, longer PFS and milder side effects than docetaxel-bevacizumab in third-line therapy in patients with EGFR T790 M positive advanced NSCLC.

Treatment of skin reaction induced by nivolumab combined with radiotherapy in non-smallcell lung cancer: a casereport

Skin reaction or dermatological toxicities induced by immunotherapy is common. It usually manifests skin rash or erythema and can be cured by skin lotion or steroid. Nivolumab, a human IgG4 programmed cell death protein 1 (PD-1) inhibitor, blocks T cells activation preventing signal and allows the immune system to clear cancer cells. Nivolumab was approved in the second-line therapy in squamous cell lung cancer by FDA, with less than 10% unusual skin reaction, like sensory neuropathy, peeling skin, erythema multiforme, vitiligo, and psoriasis. Radiotherapy could aggravate this skin reaction through inflammatory response and promotion of immunity. The combined treatment of anti-PD-1 and radiotherapy represented a new promising therapeutic approach in many studies, but the risk of side effects may be high. We reported a patient with advanced squamous cell lung cancer who suffered from serious skin immune-related adverse events when he was treated with nivolumab and radiotherapy. The immune overreaction of the treatment of anti-PD-1 treatment and radiotherapy might cause these serious skin adverse events. Our report warranted careful workup to reduce the risk of side effects by combinative therapy with anti-PD-1 and radiotherapy.

Successful Treatment of Erlotinib on Metastatic Adenoid Cystic Carcinoma of the Lacrimal Gland

To the Editor: A 32‐year‐old Chinese woman, complained diplopia, exophthalmos, and upper‐right orbital pain and was admitted into the hospital in July 2009. Computerized tomography (CT) scan showed an upper‐right orbital mass, measured 25 mm × 14 mm [Figure 1a]. Extensive surgical resection of the tumor was done on January 14, 2010. The histology confirmed the tumor was lacrimal gland adenoid cystic carcinoma (LGACC) [Figure 1b]; tumor cells infiltrated into the orbital soft tissue but were free of the orbital bone. Three‐dimensional conformal external beam irradiation on the upper‐right orbital area was implemented at 2 weeks after surgery with the total dose of 66GY/33F. The patient was scheduled to follow‐up periodically after irradiation.

Primary resistance to crizotinib treatment in a non-small cell lung cancer patient with an EML4-ALK rearrangement: a case report

Crizotinib, a small molecular tyrosine kinase inhibitor, manifests dramatic responses in patients with non-small cell lung cancer with echinoderm microtubule associated protein like 4-anaplastic lymphoma kinase (EML4-ALK) rearrangements. ALK gene point mutation is the primary mechanism of acquired crizotinib resistance; however, the intrinsic mechanism is not fully understood. Here, we report a patient with a low mutant allele fraction (MAF) of EML4-ALK rearrangement, who experienced primary resistance to crizotinib treatment. The patient was a 66-year-old Chinese man, who had a history of metastatic lung cancer and was treated with first- and third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs). After 14 months of osimertinib treatment, his disease progressed, and next-generation sequencing was performed from a liquid biopsy of the patient’s blood. An EML4-ALK rearrangement was found and crizotinib was administered. The patient’s lung lesions continued to progress after one month of crizotinib treatment, and pemetrexed-bevacizumab was initiated. After two cycles of chemotherapy, the metastatic cancers shrunk, and the patient maintained stable disease at his last follow-up. EML4-ALK rearrangements can happen in patients with EGFR-positive NSCLC, after acquired resistance to EGFR TKI treatment. The EGFR T790M and C797G mutations occur in cis is a critical mechanism of resistance to osimertinib therapy. The MAF of EML4-ALK rearrangements in cancer cells might be a predictive factor for crizotinib treatment.

Clinical Observation of Bevacizumab Combined with S-1 in the Treatment of Pretreated Advanced Esophageal Carcinoma.

Objective To investigate the clinical effects and safety of bevacizumab combined with S-1 as the second-line treatment of recurrent and/or metastatic esophageal cancer after chemoradiation. Methods Patients with recurrent or metastatic esophageal cancer after chemoradiation were treated with bevacizumab and S-1. Bevacizumab was used by intravenous infusion, 7.5mg/kg body weight on day 1; S-1 was used by oral at 80mg/m2·d on day 1-14, 21 days as a cycle of treatment and repeated until either pro- gressive disease or intolerable toxicity occurred. Chest CT were performed and RECIST 1.1 was used for response evaluation. Kaplan-Meier method was used for survival analysis. Side effects were recorded and analyzed. Results Totally 78 patients were enrolled in the study, including 67 squamous cell carcinoma and 11 adenocarcinoma histologically. The overall response (CR+PR) rate was 22.4% (17/76) and disease control (CR+PR+SD) rate was 61.8% (47/76) respectively. The median follow-up time was 20 months (range from 9 to 44 months). The median progression-free survival (PFS) was 4.9 months (95% CI 4.4-5.5) and the median overall survival (OS) was 8.1 months (95% CI 7.6-9.2). The median PFS and OS of patients with metastasis diseases were 6.2 months (95% CI 3.3 to 6.3) and 8.5 months (95% CI 5.8 to 11.2), where PFS was longer than that of patients with local regional recurrence (median 5.0 months, 95% CI 3.0 to 5.5, P=0.017) and OS was longer than that of patients with regional disease and metastasis (median 8.0 months, 95% CI 4.6 to 9.5, P=0.010). The common adverse effects were mild to moderate neutropenia (84.2%), grade I-II hand and foot syndrome (51.3%), grade I-II nausea (48.7%), mild epistaxis (30.1%) and mild vomiting (14.5%). Esophageal bleeding occurred in 7.9% of patients. One patient (1.3%) died from massive bleeding which was caused by esophageal perforation. Conclusion Bevacizumab combined with S-1 was effective and safe for esophageal cancer patients who had recurrent or metastatic diseases after chemoradiation.