EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases?

OBJECTIVES: Both bone and brain are frequent sites of metastasis in non-small cell lung cancer (NSCLC). Conflicting data exist whether EGFR mutant (+) patients are more prone to develop brain metastases or have a better outcome with brain metastases compared to EGFR/KRAS wildtype (WT) or KRAS+ patients. For bone metastases this has not been studied. METHODS: In this retrospective case-control study all EGFR+ (exons 19 and 21) patients diagnosed at two pathology departments were selected (2004/2008 to 2012). For every EGFR+ patient a consecutive KRAS+ and WT patient with metastatic NSCLC (mNSCLC) was identified. Patients with another malignancy within 2 years of mNSCLC diagnosis were excluded. Data regarding age, gender, performance score, histology, treatment, bone/brain metastases diagnosis, skeletal related events (SRE) and subsequent survival were collected. RESULTS: 189 patients were included: 62 EGFR+, 65 KRAS+, 62 WT. 32%, 35% and 40%, respectively, had brain metastases (p=0.645). Mean time to brain metastases was 20.8 [± 12.0], 10.8 [± 9.8], 16.4 [± 10.2] months (EGFR+-KRAS+, p = 0.020, EGFR+-WT, p = 0.321). Median post brain metastases survival was 12.1 [5.0-19.1], 7.6 [1.2-14.0], 10.7 [1.5-19.8] months (p = 0.674). 60%, 52% and 50% had metastatic bone disease (p=0.528). Mean time to development of metastatic bone disease was 13.4 [± 10.6], 23.3 [± 19.4], 16.4 [± 9.6] months (p = 0.201). Median post metastatic bone disease survival was 15.0 [10.6-20.3], 9.0 [5.2-12.9], 3.2 [0.0-6.9] months (p = 0.010). Time to 1st SRE was not significantly different. CONCLUSIONS: Incidence of brain and bone metastases was not different between EGFR+, KRAS+ and WT patients. Post brain metastases survival, time from mNSCLC diagnosis to metastatic bone disease and 1st SRE did not differ either. Post metastatic bone disease survival was significantly longer in EGFR+ patients. Although prevention of SRE's is important for all patients, the latter finding calls for a separate study for SRE preventing agents in EGFR+ patients.

Eligibility for concurrent chemotherapy and radiotherapy of locally advanced lung cancer patients: a prospective, population-based study.

BACKGROUND: Patients with stage III non-small-cell lung cancer (NSCLC) and limited disease small-cell lung cancer are excluded from concurrent chemoradiation mostly on the basis of comorbidity and age. The purpose of this prospective study was to get insight in what proportion of patients with locally advanced lung cancer would be suitable for concurrent chemoradiation. PATIENTS AND METHODS: From 2002 to 2005, all patients with a pathological diagnosis of lung cancer and with locally advanced disease in the Maastricht Cancer Registry, the Netherlands, comorbidity were prospectively assessed. Patients were regarded as noneligible for concurrent chemoradiation if they had one or more important comorbidity or were 75 years or older. RESULTS: In all, 711 patients were included, 577 with NSCLC and 134 with SCLC. Overall, 166 patients (23.3%) were 75 years or older. Of the 526 patients <75 years, comorbidities were as follows: 278 (52.9%) 0, 188 (35.7%) 1, and 56 (11.4%) 2 or more. In all, 408/686 (59%) of the whole patient group were considered as ineligible for concurrent chemoradiation. CONCLUSIONS: More than half of patients with stage III lung cancer were theoretically not eligible for concurrent chemoradiation. Less toxic alternatives are needed for these patients.

Maximal neutropenia during chemotherapy and radiotherapy is significantly associated with the development of acute radiation-induced dysphagia in lung cancer patients.

BACKGROUND: Acute dysphagia is a distressing dose-limiting toxicity after concurrent chemoradiation or high-dose radiotherapy for lung cancer. We therefore identified factors associated with the occurrence of acute dysphagia in lung cancer patients receiving radiotherapy alone or combined with chemotherapy. PATIENTS AND METHODS: Radiotherapy, chemotherapy and patient characteristics were analyzed using ordinal regression analysis as possible predictors for acute dysphagia (CTCAE 3.0) in 328 lung cancer patients treated with curative intent. RESULTS: The most significant association was seen between the maximal grade of neutropenia during chemoradiation and dysphagia, with an odds ratio increasing from 1.49 [95% confidence interval (CI) 0.63-3.54, P = 0.362] for grade 1-2 neutropenia to 19.7 (95% CI 4.66-83.52, P < 0.001) for patients with grade 4 neutropenia. Twice-daily schedule, mean esophageal dose and administration of chemotherapy were significant predictive factors. By combining these factors, a high-performance predictive model was made. On an individual patient level, 64% of patients were correctly classified and only 1.2% of patients were misclassified by more than one grade. CONCLUSIONS: The maximal neutrophil toxicity during concurrent chemotherapy and radiotherapy is strongly associated with the development of acute dysphagia. A multivariate predictive model was developed.

Fever as presenting symptom of multiple myeloma.

We describe a 68-year-old patient presenting with recurrent fever, who eventually turned out to suffer from multiple myeloma. He was treated with Vincristine, Doxorubicin and Dexamethasone combination chemotherapy and intermediate dose Melphalan (70 mg/m2), respectively. Apart from periods of fever due to sepsis following chemotherapy, the recurrent fever disappeared after response, but recurred synchronously with progression of the disease. Recurrent fever in this case should be considered as a symptom of active multiple myeloma. This form of presentation of multiple myeloma has been described in literature only a few times.

Results of resection of T3 non-small cell lung cancer invading the mediastinum or main bronchus.

BACKGROUND: T3 tumors can be divided into several subgroups. Surgical treatment of T3 tumors with chest wall invasion results in good survival. This study shows the results of resection of T3 non-small cell tumors located in the main bronchus or with invasion of mediastinal structures. METHODS: From 1977 through 1993, 108 patients underwent resection for primary non-small cell carcinomas located in the main bronchus or with invasion of mediastinal structures. A complete resection was performed in 70 patients (64.8%). Actuarial survival time was estimated and risk factors for late death were identified. RESULTS: Overall hospital mortality was 8.3%. All deaths followed pneumonectomy. Mean 5-year survival was 29% for all hospital survivors, 35% for patients with complete resection, and 18% for patients with incomplete resection (p = 0.03). In patients with complete resection, mean 5-year survival was 45% for N0 patients and 37% for N1 patients. There were no 5-year survivors in the group of N2 patients. The mean 5-year survival was greater (but not statistically significantly greater) in patients with tumors located in the main bronchus (40%) than in patients with tumors with invasion of mediastinal structures (25%) (p > 0.05). Histology, tumor spill, age, sex, and type of operative procedure were not significant prognostic factors. CONCLUSIONS: Patients with tumors located in the main bronchus have a better survival than patients with invasion of the mediastinal structures. Pneumonectomy increases hospital mortality. Incompleteness of resection and mediastinal lymph node involvement influence survival significantly.

Surgical treatment of 125 patients with non-small cell lung cancer and chest wall involvement.

BACKGROUND: The optimum operative procedure for lung cancer with chest wall invasion (T3) remains controversial. In this study results of en bloc resection and extrapleural dissection are reviewed to determine survival characteristics. METHODS: Between 1977 and 1993 125 patients underwent surgery for primary non-small cell lung cancer with chest wall invasion. Patients with superior sulcus tumours, metastatic carcinomas, synchronous tumours, or recurrences were excluded. Extrapleural dissection was performed in 73 patients and en bloc resection (range 1-4 ribs) in 52. Resection was regarded as complete in 86 and incomplete in 39 patients. Actuarial survival time was estimated and risk factors for late death were identified. RESULTS: Hospital mortality was 3.2%. (n = 4). Estimated mean five year survival was 24% for all hospital survivors (n = 121), 11% for patients with incomplete resection, and 29% for patients having a complete resection. In patients who underwent complete resection mediastinal lymph node involvement and intrapleural tumour spill worsened the prognosis. Patients with adenocarcinoma had a better chance of long term survival. No relationship was found between survival and age, type of operative procedure, depth of chest wall invasion, and postoperative radiotherapy. CONCLUSIONS: Both operative procedures show reasonable survival results. Incomplete resection, mediastinal lymph node involvement, and intrapleural tumour spill adversely influence survival.

Tetraplegia after a tracheal resection procedure.

We describe a 27-year-old patient who was admitted to our hospital for a tracheal stenosis caused by an adenocystic carcinoma. A tracheal resection procedure was performed and the head was fixed to the anterior chest wall by two sutures. Postoperatively he became tetraplegic, from which he completely recovered after the sutures were removed. We think that the decreased blood flow in the arterial spinal artery with flexion of the neck in combination with hypotension was the direct cause of this major complication.