Osimertinib in poor performance status patients with T790M-positive advanced non-small-cell lung cancer after progression of first- and second-generation EGFR-TKI treatments (NEJ032B).

BACKGROUND: Osimertinib is effective in patients with T790M mutation-positive advanced non-small-cell lung cancer (NSCLC) resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, its effectiveness and safety in patients with poor performance status (PS) are unknown. METHODS: Enrolled patients showed disease progression after treatment with gefitinib, erlotinib, or afatinib; T790M mutation; stage IIIB, IV, or recurrent disease; and PS of 2-4. Osimertinib was orally administered at a dose of 80 mg/day. The primary endpoint of this phase II study (registration, jRCTs061180018) was response rate and the secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate, and safety. RESULTS: Thirty-three patients were enrolled, of which 69.7% and 24.2% had PS of 2 and 3, respectively. One patient was excluded due to protocol violation; in the remaining 32 patients, the response rate was 53.1%; disease control rate was 75.0%; PFS was 5.1 months; and OS was 10.0 months. The most frequent adverse event of grade 3 or higher severity was lymphopenia (12.1%). Interstitial lung disease (ILD) was observed at all grades and at grades 3-5 in 15.2% (5/33) and 6.1% (2/33) of patients, respectively. Treatment-related death due to ILD occurred in one patient. Patients negative for activating EGFR mutations after osimertinib administration had longer median PFS than those positive for these mutations. CONCLUSION: Osimertinib was sufficiently effective in EGFR-TKI-resistant, poor PS patients with T790M mutation-positive advanced NSCLC. Plasma EGFR mutation clearance after TKI treatment could predict the response to EGFR-TKIs.

Long-term follow-up of unresectable adenoid cystic carcinoma of the trachea and bronchus treated with high-dose proton beam therapy: A report of two cases.

Adenoid cystic carcinoma (ACC) of the trachea is a rare disease that is slow growing and has a risk of distant metastasis. The standard treatment for ACC of the trachea is surgery, but this tumor is often unresectable. In definitive radiotherapy using photons for unresectable ACC of the trachea, it is sometimes difficult to deliver a sufficient dose to the target without exceeding the tolerable dose to the surrounding normal tissues. Here, we report two cases of ACC of the trachea that received a high dose (74 Gy [relative biological effectiveness]) of proton beam therapy and achieved long-term survival.

Effects of lymphopenia on survival in proton therapy with chemotherapy for non-small cell lung cancer.

Lymphocytes play an important role in the cancer immune system. In the present study, we aimed to evaluate the associations of lymphopenia during proton beam therapy (PBT) and concurrent chemotherapy with clinical outcomes and to determine whether lung or bone is more influential on lymphopenia during PBT. Data from 41 patients with stage III non-small cell lung cancer (NSCLC) who received PBT of 74 GyE with concurrent chemotherapy between 2007 and 2017 were reviewed retrospectively. The correlation between dosimetry parameters obtained from dose-volume histograms of the bone and lung and lymphopenia during PBT were analyzed. Minimum absolute lymphocyte count (ALCmin) and maximum neutrophil/lymphocyte ratio (NLRmax) were used as indicators of lymphopenia. Bone V5-20 and lung V5-50 were significantly correlated with the ALCmin and NLRmax during PBT. Multivariable analysis showed that the NLRmax, but not the ALCmin, was associated with overall survival (OS), progression-free survival (PFS) and distant metastasis-free survival (DMFS). The 3-year rates of OS, PFS and DMFS of patients with a low (≤ 6.3) versus high (> 6.3) NLRmax were 73.9% vs 44.4% (P = 0.042), 26.1% vs 5.6% (P = 0.022) and 39.1% vs 5.6% (P < 0.001), respectively. Lung V20 was significantly associated with DMFS on multivariable analyses (hazard ratio: 1.094, P = 0.008), whereas bone V5 had no impact on survival outcomes. We concluded that the NLRmax was a better prognostic indicator than the ALCmin, and the lung dose had more influence than the bone dose on the main survival outcomes in stage III NSCLC patients treated with PBT combined with concurrent chemotherapy.

[Syndrome of inappropriate secretion of ADH following chemoradiation therapy].

We report a 69-year-old female patient with pulmonary adenocarcinoma complicated by the syndrome of inappropriate secretion of antidiuretic hormone(SIADH)following systemic chemotherapy with cisplatin(CDDP)and vinorelbine(VNR). She was admitted to our hospital for chemo-radiotherapy for advanced lung cancer, and became restless 4 hours after the administration of CDDP and VNR. Symptoms such as restlessness and incontinence were worsening despite the massive infusion that was completed. Laboratory examinations on day 6 after chemotherapy showed severe hyponatremia(107mEq/L)with decreased serum osmolarity(227mOsm/L)and increased urine osmolarity(452mOsm/L). The serum anti-diuretic hormone(ADH)level was elevated to 16. 7 pg/mL despite severe hyponatremia. She was diagnosed with SIADH and was treated with hypertonic saline infusion and fluid restriction. Her restlessness and other psychiatric symptoms were improved. The use of carboplatin and VNR in the subsequent course did not develop SIADH, indicating that the SIADH was induced by CDDP. Although SIADH following CDDP administration is rare, the electrolyte balance should be carefully monitored throughout the clinical course of chemo-radiation therapy, when psychiatric symptoms are found in patients with lung cancer.

Real-world outcomes of chemotherapy for lung cancer patients undergoing hemodialysis: A multicenter retrospective cohort study (NEJ-042).

INTRODUCTION: Malignant tumors are the major cause of death in hemodialysis patients. Management of these patients remains challenging as there is no evidence that chemotherapy is beneficial, and a lack of information about actual clinical practice. METHODS: This multicenter retrospective study included hemodialysis patients who were diagnosed with lung cancer from January 2002 to June 2018. We reviewed their clinical information including patient characteristics associated with lung cancer and end-stage renal disease, regimen, efficacy and safety of chemotherapy, and outcomes. RESULTS: A total of 162 patients from 22 institutions in Japan were registered. Of 158 eligible patients, 91 received chemotherapy (80 as palliative chemotherapy and 11 as chemoradiotherapy) and 67 received best supportive care only regardless of cancer stage. In small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) patients who received cytotoxic chemotherapy, the objective response rates (ORR) and median overall survival (OS) were 68.1 %, 12.3 months and 37.0 %, 8.5 months, respectively. The ORR and median OS in patients with EGFR-mutant NSCLC treated with EGFR-tyrosine kinase inhibitors (TKI) were 44.4 % and 38.6 months. The treatment-related adverse events (Grade 3 or higher) induced by cytotoxic chemotherapy were myelosuppression and febrile neutropenia; treatment-related death (TRD) was observed in one patient. TRD occurred in 3 of 18 patients who received EGFR-TKI. CONCLUSION: Chemotherapy should be considered for hemodialysis patients with EGFR-mutant NSCLC and SCLC. However, the survival benefits of chemotherapy for NSCLC patients with EGFR-wild type are unclear; physicians should carefully consider whether to offer chemotherapy to this patient subset.

Real-World Data Analysis of Pembrolizumab Monotherapy for NSCLC Using Japanese Postmarketing All-Case Surveillance Data.

Introduction: Pembrolizumab is a programmed death-ligand 1 inhibitor that was initially indicated for monotherapy in patients with advanced lung cancer. The Japanese Lung Cancer Society conducted an observational study on pembrolizumab using confirmative data obtained through postmarketing all-case surveillance (PMACS), which was performed by a pharmaceutical company under the Japanese law in 2017. Methods: This multicenter observational study was conducted by the Japanese Lung Cancer Society using PMACS data with the newly created central registration system regarding patients with NSCLC who received pembrolizumab monotherapy between February 1, 2017 and June 30, 2017; a new database was created by adding the clinical information regarding prognosis for 3 years after therapy to the existing data collected by PMACS. Results: A total of 300 patients from 43 facilities were enrolled in this study. The median overall survival and progression-free survival after pembrolizumab initiation were 558 and 188 days, respectively. Moreover, the 1- and 3-year survival rates were 58.9% and 33.7%, respectively. Results of multivariate analysis revealed performance status (p < 0.0001), histology (p = 0.0118), previous chemotherapy (p = 0.0007), programmed death-ligand 1 expression status (p = 0.0195), and previous steroid use (p = 0.0460) as significant factors that affected overall survival. The toxicity profile was similar to that previously reported. Conclusions: In this first attempt to use PMACS data, we successfully collected clinical information and found the real-world efficacy and safety of pembrolizumab.

Long-term outcomes of high-dose (74 GyE) proton beam therapy with concurrent chemotherapy for stage III nonsmall-cell lung cancer.

BACKGROUND: To evaluate the long-term outcomes of high-dose (74 GyE) proton beam therapy (PBT) with concurrent chemotherapy for stage III non-small cell lung cancer (NSCLC). METHODS: Between July 2007 and March 2018, 45 patients with stage III NSCLC were treated with passive-scattering PBT of 74 GyE and concurrent chemotherapy. Among the 45 patients, the median age was 62 years (range 39-79 years) and 32 patients were men. The clinical stages were stage IIIA in 14 patients and stage IIIB in 31 patients. Thirty-six patients received chemotherapy consisting of cisplatin and vinorelbine. RESULTS: The median follow-up time was 42.1 months (range 6.4-127.0 months) for all patients and 63.5 months (range 9.4-127.0 months) for the 12 survivors. The 3- and 5-year overall survival rates were 63.7% and 38.8%, respectively, and the median overall survival was 49.1 months. Over the follow-up period, disease recurrence was observed in 32 (71%) patients. The 3- and 5-year progression-free survival rates were 22.2% and 17.7%, respectively, with a median progression-free survival of 13.1 months. In-field control improved survival and the in-field control rate was better in patients with T0-3 tumors (p = 0.023) and stage IIIA/IIIB-N3 disease (p = 0.030). Dosimetric parameters of the heart and lung were not associated with survival. No grade 4 or 5 acute or late non-hematologic toxicities were observed. CONCLUSIONS: Passive-scattering PBT of 74 GyE with chemotherapy showed favorable survival and a low incidence of severe adverse events in patients with stage III NSCLC.

[Diffuse cerebral atrophy and reversible polyneuropathy in a patient with chronic Bromvalerylurea intoxication: a case report].

A 37-year-old man who had been on bromvalerylurea (BU) medication for 11 years at a maximum dose of 2,400 mg per day for headache therapy was admitted to our hospital due to gait disturbance. He had weight loss and exanthema all over his body. Cognitive dysfunction, intellectual deterioration, attention disturbance, decreased muscle strength, and decreased vibratory sense in the lower limbs were observed. Brain MRI showed diffuse brain atrophy, and a peripheral nerve conduction examination revealed decreased nerve conduction velocity and action potential amplitude in the extremities. We diagnosed him with chronic BU intoxication based on pseudohyperchloremia, BU detected in the blood, and bromide elevation. By discontinuing BU and performing intravenous infusion, neurological symptoms and exanthema were improved, and peripheral nerve conduction examination findings also improved. There are few reports of peripheral neuropathy cases of chronic BU intoxication; herein we report one such case along with previously reported cases.

Salvage Photon or Proton Radiotherapy for Oligo-recurrence in Regional Lymph Nodes After Surgery for Non-small Cell Lung Cancer.

BACKGROUND/AIM: To evaluate the outcome of definitive salvage radiotherapy (RT) in non-small cell lung cancer (NSCLC) patients with oligo-recurrence in regional lymph nodes after surgery. PATIENTS AND METHODS: Between January 2003 and December 2016, 33 patients with NSCLC were reviewed from radiotherapy database at our hospital. All patients received photon or proton salvage RT for metastases in the regional lymph nodes. RESULTS: The median follow-up from salvage RT was 35.2 (range=5.9-89.6) months. Recurrences occurred in 18 (55%) patients, and the 3-year overall and progression-free survival rates were 63.8% and 45.1%, respectively. Regional and local control improved patients' survival and these control rates were increased by use of concurrent chemotherapy (p=0.039) and proton RT (p=0.084). No grade 4 acute or late non-hematologic toxicities were observed. CONCLUSION: Salvage RT is an effective treatment for NSCLC patients with oligo-recurrence at regional lymph nodes.

Small-Cell Lung Cancer Treatment of Newly Diagnosed Patients with Poor Performance Status.

Small-cell lung cancer (SCLC) is highly sensitive to platinum-based chemotherapy. However, its indication in patients with a poor performance status (PS) at initial diagnosis is controversial. We retrospectively reviewed all clinical courses of pathologically diagnosed SCLC patients with poor PS, Eastern Cooperative Oncology Group PS 3 and 4. Among 18 patients, 12 were treated with chemotherapy and 6 with supportive care alone. During the chemotherapy courses, PS improved in 7 (58.3%, including the PS 4 cases), remained stable in 2 (16.7%), and deteriorated in 3 (25%) patients. Moreover, 5 patients showed partial responses to chemotherapy (response rate of 41.7%). Grade 3-4 neutropenia developed in 10 (83.3%) patients and grade 3 febrile neutropenia occurred in 5 (41.7%) patients, but no grade 4 non-hematological toxicity was noted. Mortality associated with lung toxicity (grade 5) due to treatment occurred in a 77-year-old-male patient with PS 3. No substantial difference in survival was observed between patients with PS 3 and 4, even when including those treated with supportive care alone. Treatment had a positive effect on survival: after chemotherapy, the 6-month survival rate of PS 3 and 4 patients was 66.7%. In contrast, all patients treated with supportive care alone died within 5 months. These findings suggest that chemotherapy is indicated in selected SCLC patients not only with PS 3, but also with PS 4.

Rechallenge with First-Line Platinum Chemotherapy for Sensitive-Relapsed Small-Cell Lung Cancer.

BACKGROUND: Sensitive-relapsed small-cell lung cancer (SCLC) is thought to be sensitive to chemotherapy; therefore, second-line chemotherapy is recommended. Although platinum rechallenge is performed in the second-line chemotherapy for sensitive-relapsed SCLC, it remains unclear whether such a strategy is effective. METHODS: We retrospectively analyzed the outcome of rechallenge chemotherapy for sensitive-relapsed SCLC. The endpoints of this study were progression-free survival from the time of relapse (PFS-Re) and overall survival from the time of relapse (OS-Re). We also compared the toxicity profile of rechallenge chemotherapy to that of first-line chemotherapy. RESULTS: Of the 133 SCLC patients who received first-line treatment, 20 patients satisfied the definition of sensitive relapse and received rechallenge chemotherapy. Combined carboplatin and etoposide was the most commonly used rechallenge regimen, and 17 (85%) received it at a reduced dose due to hematological toxicity during the first-line treatment. Median PFS-Re and OS-Re were 4.5 months (95% CI: 3.5-5.4) and 10.5 months (95% CI: 7.9-13.0), respectively. There was no association between dose adjustment and survival. The frequency of hematologic toxicity tended to be lower with rechallenge than first-line treatment. The incidence of grade 3 febrile neutropenia decreased from 40% in first-line treatment to 15% in rechallenge. CONCLUSION: Platinum rechallenge could be a useful second-line option for sensitive-relapsed SCLC, having favorable efficacy and safety. Dose adjustment at rechallenge based on the toxicity profile during the first-line chemotherapy could reduce toxicity without weakening efficacy.

Chronic expanding hematoma in the chest: A case report.

Chronic expanding hematoma (CEH) is a rare disease that is usually present as a large solitary pulmonary nodule. CEHs are slow growing, but processes underlying their development remain unknown. The present study herein reports the case of a 76-year-old male patient with CEH and discusses a number of CEH cases published in the literature. The majority of these previously described patients were Asians. The CEH in the present case was not a successfully resected one, but the patient's clinical course provided information concerning the natural history of the disease. During the clinical course, the patient underwent several chest computed tomography scans. For the present case report, the doubling time and volume change of the mass was calculated, which revealed that the lesion had an inconstant growth rate and that its onset was between 8.2-11.0 years before the patient succumbed to this disease. Accumulation of knowledge about this rare disease will help to elucidate it further.

Late fatal recurrence in gefitinib-treated NSCLC patients.

Gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. Long-term survival in patients with metastatic non-small-cell lung carcinoma (NSCLC) treated with gefitinib has recently been reported. We showed herein two cases of fatal rapid recurrence after a long-term disease control by gefitinib. The biology of fatal aggressive recurrence of gefitinib-treated NSCLC is not well characterized. Regardless of the mechanism, however, physicians treating patients with gefitinib should be alert to the possibility of fatal rapid recurrence after a long-term disease control by this drug.

[A case of limited form of Wegener's granulomatosis showing repeated occurrence and disappearance of nodules in chest X ray with no medication].

A 69-year-old woman was admitted to because of bloody sputum. Chest CT showed some nodules. The patient was seronegative for PR3-ANCA. One month after the admission, these shadows vanished with no medication. She was asymptomatic for one and a half years, and then she complained of cough again. Multiple nodules were seen on chest CT again. She was admitted, and surgical biopsy by video-assisted thoracoscopic surgery was performed. She was diagnosed to have a limited form of Wegener's granulomatosis. Multiple shadows vanished without medication, again. Administration of sulfamethoxazole-trimethoprim was started and there has been no relapse.

Paraneoplastic limbic encephalitis with late-onset magnetic resonance imaging findings: A case report.

Paraneoplastic limbic encephalitis (PLE), a paraneoplastic neurological syndrome (PNS), is a rare nervous system disorder that results from the indirect effects of tumors and is commonly associated with small-cell lung cancer (SCLC). Previous studies have reported that magnetic resonance imaging (MRI) may be useful for diagnosing LE. Temporal lobe abnormalities are observed using T2-weighted and fluid-attenuated inversion recovery sequences; however, such abnormalities are detected in only 60% of patients with PLE. The present study describes a case of PLE associated with SCLC, in which LE was observed using MRI 26 days after the first convulsive seizure. Although the serum and cerebrospinal fluid analyses for onconeural antibodies were negative, the findings of this case indicate that PLE should be considered in the differential diagnosis, and that repeated brain MRI may be more helpful for diagnosis, as the brain MRI findings may be normal during the early stages of PLE.

Acute multifocal bacterial nephritis complicated with acute renal failure and thrombocytopenia.

A 50-year-old woman was transferred to our hospital because of acute renal failure and thrombocytopenia. Due to rapid enlargement of the kidney, we first suspected that she had diffuse renal invasion of anaplastic carcinoma or lymphoma of the kidney. Anti-bacterial treatment for complicated urinary tract infection and hemodialysis treatment resulted in recovery of both renal function and thrombocytopenia. Serial CT study demonstrated disappearance of kidney swelling and multiple masses within the kidney. We finally made a diagnosis of acute multifocal bacterial nephritis. Timely initiation of dialysis therapy and appropriate anti-bacterial treatment was essential to rescue this case.

Similar survival benefits of a good response and stable disease to platinum-based chemotherapy in non-small cell lung cancer.

The present study aimed to evaluate the similar survival benefits of a good response [complete response or partial response (CR/PR)] and stable disease (SD) to chemotherapy in non-small cell lung cancer (NSCLC) patients in clinical practice. All 322 patients who were treated between 1999 and 2012 with first-line platinum-based chemotherapy were retrospectively analyzed. Tumor responses were classified according to the response evaluation criteria for solid tumors. A total of 67 (20.8%) patients experienced CR/PR and 165 (51.2%) achieved SD. There was no difference in progression-free survival between the patients with CR/PR and those with SD (P=0.347). There was also no difference between the two groups with regard to overall survival time (P=0.878). In multivariate analysis, disease-control (more than SD) was one of the favorable prognostic factors. In clinical practice, a survival benefit would be provided not only for the patients who have good response, but also for those with SD.

Specific organ metastases and survival in metastatic non-small-cell lung cancer.

The present retrospective study was performed to evaluate the clinicopathological characteristics associated with distant metastasis from non-small-cell lung cancer (NSCLC). The records of NSCLC patients with metastasis at the time of diagnosis between 1999 and 2012 were reviewed. Of the consecutive 1,542 NSCLC patients diagnosed during the study period, 729 (47.3%) patients presented with distant metastasis. Among those 729 metastatic NSCLC patients, 250 (34.3%), 234 (32.1%), 207 (28.4%), 122 (16.7%), 98 (13.4%) and 69 (9.5%) had bone, lung, brain, adrenal gland, liver and extrathoracic lymph node metastasis, respectively. In a multivariate analysis using the Cox proportional hazards model, liver and adrenal gland metastases were unfavorable prognostic factors. However, brain and bone metastases were not statistically significant prognostic factors. Using a logistic regression analysis, metastasis to the adrenal glands and the presence of pleural and/or pericardial fluid effusion were correlated with a poor performance status. Therefore, when planning the treatment of NSCLC patients, particularly those with liver and adrenal gland metastases, we should take into consideration information regarding these unfavorable organ metastases.