Widespread use of generic drugs is considered to be indispensable if reductions in total health care costs are to be achieved, but the market share of such drugs remains low. In general, generic drugs have the same active ingredients as brand-name drugs, but this is not always the case. Thus, toxicity profiles may vary when brand-name and generic drugs are compared. We retrospectively investigated the incidence of hyponatremia in patients receiving brand-name cisplatin (CDDP) and a generic counterpart thereof.
We reviewed the medical records of patients treated with brand-name CDDP (n=53) and a generic formulation (n=26), and compared the incidences of hyponatremia and renal toxicity. Toxicities were graded using the Common Terminology Criteria for Adverse Events, version 4.0. Differences between groups were evaluated using the Student’s t-test, and the odds ratio for hyponatremia was estimated via logistic regression analysis.
Serum creatinine levels after chemotherapy increased significantly in both the brand-name and generic CDDP groups; no significant difference was evident between the two groups. Hyponatremia of grade 3 or above developed in 30.7% of the generic CDDP group compared to 15.1% of the brand-name CDDP group (P=0.011). Multivariate analysis showed that the use of generic CDDP increased the incidence of hyponatremia (odds ratio =5.661, 95% confidence interval =1.403–22.839; P=0.015).
Oncologists should be aware that use of a generic CDDP might be associated with more hyponatremia than would use of brand-name CDDP.
cisplatin; hyponatremia; brand-name; generic drug
Obstructive jaundice caused by metastases to the porta hepatis is often observed in patients with various advanced cancers; however, metastasis of lung cancer to the common bile duct with subsequent development of jaundice is rare. A 75-year-old female with lung adenocarcinoma harboring epidermal growth factor receptor (EGFR) mutation (15-bp in-frame deletion in exon 19 and T790M in exon 20) developed obstructive jaundice during therapy. Obstruction of the common bile duct caused by an intraductal tumor was identified by computed tomography, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography. Although primary cholangiocarcinoma was highly suspected according to the imaging findings, immunohistochemical evaluation of the intraductal tumor demonstrated thyroid transcription factor-1 positive adenocarcinoma. Furthermore, peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp analysis showed that the tumor contained the same EGFR mutation as that in the primary lung cancer. Thus, we confirmed intraductal metastasis from a lung adenocarcinoma. To our knowledge, this is the second report of obstructive jaundice caused by intraductal metastasis of lung cancer.
lung cancer; cholangiocarcinoma; EGFR
Docetaxel is a key antineoplastic drug for treatment of non-small cell lung cancer. Ocular adverse events of docetaxel include epiphora (excess tearing) and conjunctivitis. Epiphora has been reported to be associated with canalicular and nasolacrimal duct stenosis, but it is not necessarily caused by lacrimal duct obstruction.
We encountered three Japanese non-small cell lung cancer patients who developed epiphora after the administration of docetaxel-based chemotherapy. One patient with lacrimal puncta stenosis showed improvement with probing and irrigation. The other two patients resolved following cessation of docetaxel or administration of artificial tears.
As epiphora can interfere with activities of daily life and negatively affect quality of life, it is important for thoracic oncologists to be aware of this adverse event.
Non-small cell lung cancer; Docetaxel; Epiphora; Ocular adverse event
Non-small cell lung cancers (NSCLCs) are frequently heterogeneous and in approximately 70% of cases, NSCLCs are diagnosed and staged by small biopsies or cytology rather than by examination of surgically resected specimens. Thus, in most patients, the diagnosis is established based on examination of preoperative specimens alone. Recently, classification of NSCLC into pathologic subtypes has been shown to be important for selecting the appropriate systemic therapy, from both the point of view of treatment efficacy and prevention of toxicity.
We retrospectively reviewed the data of 225 patients to compare the preoperative classification of the NSCLC subtype on biopsy specimens with the postoperative classification based on examination of the resected specimens, in order to compare the accuracy of the two for the diagnosis of various histological subtypes of NSCLC.
In 169 of the 225 (75.1%) patients, the preoperative diagnosis was definite malignancy. Histologically, the final pathologic diagnosis made from the surgical specimens was adenocarcinoma (ADC) in 169 patients, and in 75.5% of these cases, the diagnosis was concordant with the preoperative diagnosis. Among the patients who had squamous cell carcinoma (SQC) in the preoperative specimens, the diagnosis was concordant with the preoperative diagnosis in 65.7% of cases. Misclassified preoperative biopsies included an even number of SQCs and ADCs, with all the misclassified biopsies being ADCs morphologically mimicking SQC due to solid growth. Significantly higher specificity, negative predictive value and accuracy were observed for the diagnosis of SQC.
Our study suggested that the concordance rates for diagnosis of the NSCLC subtypes, especially the "squamous" or "non-squamous" histologies, between preoperative and surgical specimens were satisfactory, as compared with previous reports. Therefore, pretreatment diagnosis of lung cancer using small samples is reasonable for selecting the optimal treatment. However, in order not to lose the opportunity for selecting an effective treatment, we should be aware that the diagnosis in preoperative small samples might be different from that based on examination of the surgical specimens.
The virtual slide(s) for this article can be found here:
Persistent phosphorylation of signal transducer and activator of transcription 3 (STAT3) has been demonstrated in 22%~65% of non-small cell lung cancers (NSCLC). STAT3 activation is mediated by receptor tyrosine kinases, such as epidermal growth factor receptor (EGFR) and MET, cytokine receptors, such as IL-6, and non-receptor kinases, such as Src. Overexpression of total or phosphorylated STAT3 in resected NSCLC leads to poor prognosis. In a preclinical study, overexpression of STAT3 was correlated with chemoresistance and radioresistance in NSCLC cells. Here, we review the role of STAT3 and the mechanisms of treatment resistance in malignant diseases, especially NSCLC. As STAT3 is a critical mediator of the oncogenic effects of EGFR mutations, we discuss STAT3 pathways in EGFR-mutated NSCLC, referring to mechanisms of EGFR tyrosine kinase inhibitor resistance.
signal transducer and activator of transcription 3; Janus kinase 2; epidermal growth factor receptor; non-small cell lung cancer; drug resistance
Rapid on-site evaluation (ROSE) is used widely during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). BIOEVALUATOR® is a device used for determining whether the tissues obtained by EBUS-TBNA are appropriate for a pathological diagnosis. This study describes our experience with ROSE using BIOEVALUATOR® during EBUS-TBNA for diagnosing pulmonary and mediastinal diseases.
MATERIALS AND METHODS:
We retrospectively evaluated the results of 35 patients who underwent EBUS-TBNA with BIOEVALUATOR® between December 2011 and February 2013. For the diagnosis, the tissue areas were appearing white and red through BIOEVALUATOR® are considered to be appropriate and inappropriate, respectively. We examined their medical records to obtain information concerning the examination of BIOEVALUATOR® results of the patient's materials (white/red), the diagnosis yield, site and size of lymph nodes and number of needle passes.
The median longest diameter of 40 lymph nodes (21 #7, 13 #4R, 4 #4L and 2 #11) from 35 patients was 27.9 (range 12.4-50.6) mm and the median number of needle passes was 2 (range 1-5). The definitive diagnosis was made by EBUS-TBNA in 28 of 35 patients, by thoracotomy in one patient and BIOEVALUATOR® results were white and lymphocytes were seen in the rest six patients. The BIOEVALUATOR® results of other patients without accurate diagnosis were left indefinitive. Finally, the six patients were judged as having benign lymphadenopathy because the lymph node size on computed tomography decreased or remained stable after for at least 8 months.
Checking aspirated samples using BIOEVALUATOR® appears useful for determining their adequacy for pathological diagnosis.
BIOEVALUATOR®; endobronchial ultrasound-guided transbronchial needle aspiration; rapid on-site evaluation
We encountered a family of Japanese descent in which multiple members developed lung cancer. Using whole-exome sequencing, we identified a novel germline mutation in the transmembrane domain of the human epidermal growth factor receptor 2 (HER2) gene (G660D). A novel somatic mutation (V659E) was also detected in the transmembrane domain of HER2 in one of 253 sporadic lung adenocarcinomas. Because the transmembrane domain of HER2 is considered to be responsible for the dimerization and subsequent activation of the HER family and downstream signaling pathways, we performed functional analyses of these HER2 mutants. Mutant HER2 G660D and V659E proteins were more stable than wild-type protein. Both the G660D and V659E mutants activated Akt. In addition, they activated p38, which is thought to promote cell proliferation in lung adenocarcinoma. Our findings strongly suggest that mutations in the transmembrane domain of HER2 may be oncogenic, causing hereditary and sporadic lung adenocarcinomas.
Midkine (MDK) is a heparin-binding growth factor that is highly expressed in many malignant tumors, including lung cancers. MDK activates the PI3K pathway and induces anti-apoptotic activity, in turn enhancing the survival of tumors. Therefore, the inhibition of MDK is considered a potential strategy for cancer therapy. In the present study, we demonstrate a novel small molecule compound (iMDK) that targets MDK. iMDK inhibited the cell growth of MDK-positive H441 lung adenocarcinoma cells that harbor an oncogenic KRAS mutation and H520 squamous cell lung cancer cells, both of which are types of untreatable lung cancer. However, iMDK did not reduce the cell viability of MDK-negative A549 lung adenocarcinoma cells or normal human lung fibroblast (NHLF) cells indicating its specificity. iMDK suppressed the endogenous expression of MDK but not that of other growth factors such as PTN or VEGF. iMDK suppressed the growth of H441 cells by inhibiting the PI3K pathway and inducing apoptosis. Systemic administration of iMDK significantly inhibited tumor growth in a xenograft mouse model in vivo. Inhibition of MDK with iMDK provides a potential therapeutic approach for the treatment of lung cancers that are driven by MDK.
The purpose of this study was to show the long-term outcome of induction chemoradiotherapy, using docetaxel and cisplatin with concurrent radiotherapy followed by surgery for non-small-cell lung cancer (NSCLC) with mediastinal nodal metastasis. Between January 2000 and July 2006, 22 consecutive NSCLC patients with pathologically proven mediastinal nodal metastasis were treated with tri-modality therapy. The regimen consisted of docetaxel and cisplatin plus concurrent radiation at a dose of 40–46 Gy. The induction therapy was followed by surgery 4–6 weeks later. The pulmonary resections were composed of a lobectomy in 19 patients, including 3 with a sleeve lobectomy, a bilobectomy in 2 patients and a left pneumonectomy in 1 patient. With a median follow-up duration of 8.7 years, the 3-year and 7-year overall survival (OS) rates for the entire population were 72.7 and 63.6%, respectively. Our results suggest that tri-modality therapy is promising for NSCLC patients with mediastinal nodal metastasis.
Non-small-cell lung cancer; Induction chemoradiotherapy; N2
A 72-year-old woman was referred to our hospital with Stage IV non-small-cell lung cancer (NSCLC). Chest computed tomography revealed a mass in the upper lobe of the right lung, with pleural effusion. Cytologic examination identified adenocarcinoma cells in the right pleural effusion. Furthermore, both a deletion mutation in exon 19 and a threonine–methionine substitution mutation at position 790 in exon 20 (T790M) were detected in the epidermal growth factor receptors (EGFR) in the malignant cells. As systemic chemotherapy consisting of carboplatin and pemetrexed or erlotinib proved ineffective, docetaxel monotherapy was initiated as a third-line treatment. Following salvage chemotherapy, her Eastern Cooperative Oncology Group performance status improved from 3 to 1, with tumor regression over 5 months. To the best of our knowledge, this is the first report of successful docetaxel treatment for a patient with NSCLC harboring the T790M EGFR-activating mutation identified before treatment with EGFR tyrosine kinase inhibitors.
non-small-cell lung cancer; EGFR mutation; pretreatment mutation; T790M; docetaxel
Treatment-related death (TRD) remains a serious problem in small-cell lung cancer (SCLC), despite recent improvements in supportive care. However, few studies have formally assessed time trends in the proportion of TRD over the past two decades. The aim of this study was to determine the frequency and pattern of TRD over time.
We examined phase 3 trials conducted between 1990 and 2010 to address the role of systemic treatment for SCLC. The time trend was assessed using linear regression analysis.
In total, 97 trials including nearly 25,000 enrolled patients were analyzed. The overall TRD proportion was 2.95%. Regarding the time trend, while it was not statistically significant, it tended to decrease, with a 0.138% decrease per year and 2.76% decrease per two decades. The most common cause of death was febrile neutropenia without any significant time trend in its incidence over the years examined (p = 0.139). However, deaths due to febrile neutropenia as well as all causes in patients treated with non-platinum chemotherapy increased significantly (p = 0.033).
The overall TRD rate has been low, but not negligible, in phase III trials for SCLC over the past two decades.
In advanced non-small-cell lung cancer (NSCLC), with the increasing number of active compounds available in salvage settings, survival after progression to first-line chemotherapy seems to have improved. A literature survey was conducted to examine whether survival post-progression (SPP) has improved over the years and to what degree SPP correlates with overall survival (OS).
Methods and Findings
Median progression-free survival (MPFS) time and median survival time (MST) were extracted in phase III trials of first-line chemotherapy for advanced NSCLC. SPP was pragmatically defined as the time interval of MST minus MPFS. The relationship between MPFS and MST was modeled in a linear function. We used the coefficient of determination (r2) to assess the correlation between them. Seventy trials with 145 chemotherapy arms were identified. Overall, median SPP was 4.7 months, and a steady improvement in SPP was observed over the 20 years (9.414-day increase per year; p<0.001) in parallel to the increase in MST (11.253-day increase per year; p<0.001); MPFS improved little (1.863-day increase per year). Overall, a stronger association was observed between MST and SPP (r2 = 0.8917) than MST and MPFS time (r2 = 0.2563), suggesting SPP and MPFS could account for 89% and 25% of the variation in MST, respectively. The association between MST and SPP became closer over the years (r2 = 0.4428, 0.7242, and 0.9081 in 1988–1994, 1995–2001, and 2002–2007, respectively).
SPP has become more closely associated with OS, potentially because of intensive post-study treatments. Even in advanced NSCLC, a PFS advantage is unlikely to be associated with an OS advantage any longer due to this increasing impact of SPP on OS, and that the prolongation of SPP might limit the original role of OS for assessing true efficacy derived from early-line chemotherapy in future clinical trials.
The patient was a 71-year-old man who underwent a right hemicolectomy for ascending colon cancer (pT3, pN1, pM0) and who opted not to receive adjuvant chemotherapy. Eight months later, multiple liver metastases occurred. He therefore received FOLFOX4 (5-fluorouracil/leucovorin and 85 mg/m2 oxaliplatin) therapy, up to a total of 5 courses, and showed a partial response. While receiving the sixth course of FOLFOX4, he complained of chest pain and systemic itching approximately 15 min after the start of chemotherapy. An electrocardiogram revealed typical signs of ischemia. Coronary arteriography showed that the coronary arteries were intact. Believing the chest pain to be merely coincidental, we continued with the same therapy. However, he again developed the same chest pain during the seventh cycle of FOLFOX4 and treatment was stopped. We concluded that the patient’s symptoms were due to acute coronary syndrome (ACS) associated with the FOLFOX4 regimen. Variant angina as a type of ACS is a rare adverse effect of FOLFOX4. Clinicians should be aware of this potential adverse effect when monitoring patients receiving FOLFOX4.
FOLFOX4; Acute coronary syndrome; Variant angina; Allergy
A 66-year-old Japanese man with pancreatic cancer received eleven courses of gemcitabine monotherapy. The tumor responded to gemcitabine until metastatic liver tumors progressed. Subsequently, he was treated with S-1, an oral fluoropyrimidine anticancer agent, as salvage chemotherapy. Forty-two days after initiating S-1, he presented with dyspnea and fever. Chest computed tomography showed diffuse interstitial lesions with thickening of the alveolar septa and ground glass opacity. Serum KL-6 level was elevated to 1,230 U/mL and he did not use any other drugs except insulin. Thus, the development of interstitial lung disease (ILD) was considered to be due to S-1. Arterial blood oxygen pressure was 49.6 Torr in spite of oxygen administration (5 L/min). Steroid therapy improved his symptoms and the interstitial shadows on chest radiograph. Although S-1-induced ILD has mostly been reported to be mild, clinicians should be aware that S-1 has the potential to cause fatal ILD.
Corticosteroid therapy; Interstitial lung disease; Pancreatic cancer; S-1
Obstructive jaundice sometimes may develop in association with advanced small-cell lung cancer (SCLC); however, SCLC initially presenting with obstructive jaundice is rare. This report presents the cases of two SCLC patients with obstructive jaundice at the initial diagnosis. A 64-year-old male presented with obstructive jaundice due to a tumor at the head of the pancreas. He was diagnosed with SCLC by transbronchial biopsy from a lung tumor in the left upper lobe. Another 74-year-old male was admitted with jaundice due to a tumor in the porta hepatis. He was also diagnosed with SCLC by a fine-needle aspiration biopsy of a lung tumor in the left lower lobe. Both cases were successfully treated with systemic chemotherapy after endoscopic retrograde biliary drainage.
small-cell lung carcinoma; jaundice; biliary obstruction; metastasis
Few studies have formally assessed whether treatment outcomes have improved substantially over the years for patients with extensive disease small-cell lung cancer (ED-SCLC) enrolled in phase III trials. The objective of the current investigation was to determine the time trends in outcomes for the patients in those trials.
Methods and Findings
We searched for trials that were reported between January 1981 and August 2008. Phase III randomized controlled trials were eligible if they compared first-line, systemic chemotherapy for ED-SCLC. Data were evaluated by using a linear regression analysis. Results: In total, 52 trials were identified that had been initiated between 1980 and 2006; these studies involved 10,262 patients with 110 chemotherapy arms. The number of randomized patients and the proportion of patients with good performance status (PS) increased over time. Cisplatin-based regimens, especially cisplatin and etoposide (PE) regimen, have increasingly been studied, whereas cyclophosphamide, doxorubicin, and vincristine–based regimens have been less investigated. Multiple regression analysis showed no significant improvement in survival over the years. Additionally, the use of a PE regimen did not affect survival, whereas the proportion of patients with good PS and the trial design of assigning prophylactic cranial irradiation were significantly associated with favorable outcome.
Conclusions and Significance
The survival of patients with ED-SCLC enrolled in phase III trials did not improve significantly over the years, suggesting the need for further development of novel targets, newer agents, and comprehensive patient care.
We analyzed MET protein and copy number in NSCLC with or without EGFR mutations untreated with EGFR tyrosine kinase inhibitors (TKIs). MET copy number was examined in 28 NSCLC and 4 human bronchial epithelial cell lines (HBEC) and 100 primary tumors using quantitative real-time PCR. Positive results were confirmed by array comparative genomic hybridization and fluorescence in-situ hybridization. Total and phospho-MET protein expression was determined in 24 NSCLC and 2 HBEC cell lines using Western blot. EGFR mutations were examined for exon 19 deletions, T790M, and L858R. Knockdown of EGFR with siRNA was performed to examine the relation between EGFR and MET activation. High-level MET amplification was observed in 3 of 28 NSCLC cell lines and in 2 of 100 primary lung tumors that had not been treated with EGFR-TKIs. MET protein was highly expressed and phosphorylated in all the 3 cell lines with high MET amplification. In contrast, 6 NSCLC cell lines showed phospho-MET among 21 NSCLC cell lines without MET amplification (p = 0.042). Furthermore, those 6 cell lines harboring phospho-MET expression without MET amplification were all EGFR mutant (p = 0.0039). siRNA-mediated knockdown of EGFR abolished phospho-MET expression in examined 3 EGFR mutant cell lines of which MET gene copy number was not amplified. By contrast, phospho-MET expression in 2 cell lines with amplified MET gene was not down-regulated by knockdown of EGFR. Our results indicated that MET amplification was present in untreated NSCLC and EGFR mutation or MET amplification activated MET protein in NSCLC.
MET; amplification; EGFR; gefitinib; lung cancer