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Randomized study comparing mannitol with furosemide for the prevention of cisplatin-induced renal toxicity in non-small cell lung cancer: The OLCSG1406 trial.
Makimoto, G, Hotta, K, Oze, I, Ninomiya, K, Nakanishi, M, Hara, N, Kano, H, Watanabe, H, Hata, Y, Nishii, K, et al
Asia-Pacific journal of clinical oncology. 2021;(1):101-108
Abstract
AIM: Evidence is lacking on the best standard method for forced diuresis to prevent cisplatin-induced nephrotoxicity. We compared the cisplatin-induced nephrotoxicity prevention effect of furosemide or mannitol in patients with advanced non-small cell lung cancer. METHODS Patients with advanced non-small cell lung cancer suitable to receive cisplatin-containing regimen were randomly assigned to receive furosemide or mannitol with appropriate hydration. The primary endpoint was the proportion of ≥ grade 1 serum creatinine elevation in the first cycle. RESULTS The trial was terminated early with 44 (22 per arm) of the planned 66 patients because of slow accrual. Patients' characteristics were well balanced with median baseline creatinine clearance of 98.0 and 95.1 mL/min in the furosemide and mannitol arms, respectively. In the first cycle, two (9%) and four (18%) patients developed grade 1 creatinine elevation (P = .66), respectively, despite no ≥ grade 2 toxicity. The median times to develop the worst creatinine score were 10 and 8 days, respectively. For all cycles, median times to recover to grade 0 were 56 and 20 days, respectively. The furosemide arm was characterized by relatively high urine output after cisplatin administration (900 vs 550 mL/h), low frequency of unplanned additional hydration (14% vs 32%), and high incidence of hyponatremia (18% and 5%) compared with the mannitol arm. Both arms showed similar progression-free survival and overall survival. CONCLUSION The preventive effect of the two forced diuretics on cisplatin-induced nephrotoxicity was not significantly different. However, the two diuretics have some distinct types of clinical presentations.
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Difference in decline in renal function due to cisplatin after a short or long hydration scheme in non-small-cell lung cancer: A retrospective cohort study (HYCIS-XL).
Niggebrugge-Mentink, KL, Beex-Oosterhuis, MM, Ter Horst, PGJ, van de Poll, MEC, Dieleman, HG, van Kesteren, C
Journal of clinical pharmacy and therapeutics. 2020;(5):1153-1158
Abstract
WHAT IS KNOWN AND OBJECTIVE Nephrotoxicity is a frequently occurring side effect of cisplatin, which may be reduced by applying ample hydration. The aim of this study was to determine whether there is a difference in decline in renal function due to cisplatin between a short hydration (SH) and long hydration scheme (LH). METHODS A retrospective, observational, cohort study was conducted in two hospitals. Patients in one hospital received an SH scheme (SH group), whereas patients in the other hospital received an LH scheme (LH group). Other aspects of treatment and hydration were comparable between both patient groups. Consecutive patients (≥18 years) treated for non-small-cell lung cancer with cisplatin-pemetrexed with ≥1 cisplatin dose were included. Patients were excluded when serum creatinine at baseline was <40 μmol/L. Primary outcome was the difference in estimated glomerular filtration rate (eGFR) between baseline and after the last cisplatin cycle for the SH and LH patients, regardless of the number of administered cisplatin courses. RESULTS Fifty patients were included in the SH and LH group. There were no significant differences in baseline characteristics between the two groups. None of the patients had renal failure at baseline. After two cisplatin cycles, the median differences between the baseline eGFR and the eGFR after the last cisplatin dose were 1 (-6 to 5) and -9 (-22 to -2) mL/min/1.73 m2 (interquartile range) for the SH and LH group, respectively (P = .000). Less patients completed the four cycles in the LH group (16%) compared to the SH group (64%), mainly because more LH patients were switched to another treatment and due to nephrotoxicity. However, the difference in eGFR remained statistically significant (P = .027). WHAT IS NEW AND CONCLUSION In this retrospective study, the SH scheme resulted in less decrease in renal function compared with the LH scheme, with a significant and clinically relevant difference. Additionally, more LH patients had to stop this effective treatment prematurely due to nephrotoxicity. Therefore, a short hydration scheme provides adequate and safe hydration, with a lower risk of nephrotoxic side effects and therefore better outcomes for patients and a reduction of healthcare costs.
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Are segmentectomy and lobectomy comparable in terms of curative intent for early stage non-small cell lung cancer?
Mimae, T, Okada, M
General thoracic and cardiovascular surgery. 2020;(7):703-706
Abstract
In 1995, Ginsberg et al. compared lobectomy with limited resection including segmentectomy and wide-wedge resection for stage I lung cancer in a randomized controlled trial and found that limited resection should not be applied to otherwise healthy patients with clinical stage IA lung cancer who can tolerate lobectomy. However, recent advances in diagnostic technology have improved the precision of detecting early-stage and small lung cancers. Therefore, whether radical segmentectomy, anatomical segmentectomy with hilar and mediastinal lymph node dissection (that is more valuable than wedge resection in terms of oncological aspects) and lobectomy are comparable in terms of curative intent for patients with early-stage non-small cell lung cancer (NSCLC) remains controversial. The role of segmentectomy differs according to tumor or patient characteristics. High resolution computed tomography findings of tumor size, location, and the presence or ratio of a ground glass opacity (GGO) component and the maximum of standardized uptake value on fluorine-18-2-deoxy-D-glucose positron emission tomography are important for selecting surgical procedures because the malignant potential of even early-stage NSCLC is variable. The ongoing JCOG0802/WJOG4607L, JCOG1211, and CALGB140503 trials will disclose the influence of segmentectomy for patients with early-staged NSCLCs that are small peripheral tumors based on preoperative high-resolution computed tomography findings about preserved pulmonary function and long-term prognosis. Segmentectomy is a key surgical procedure that general thoracic surgeons will need to master considering that it can be converted to lobectomy if the surgical margin is insufficient or lymph node metastasis is intraoperatively confirmed.
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Comparison of First-Line Treatments for Patients With Extensive-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-analysis.
Zhou, T, Zhang, Z, Luo, F, Zhao, Y, Hou, X, Liu, T, Wang, K, Zhao, H, Huang, Y, Zhang, L
JAMA network open. 2020;(10):e2015748
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Abstract
IMPORTANCE Combinations of chemotherapy with immunotherapy or bevacizumab in first-line treatments of extensive-stage small cell lung cancer (ES-SCLC) have been evaluated in various clinical trials. However, it remains unclear what the optimal combination regimen is. OBJECTIVE To clarify which first-line combination regimen is associated with the best tumor response among patients with ES-SCLC. DATA SOURCES Electronic databases (PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were systematically searched to extract eligible literature from database inception to December 2019. STUDY SELECTION Head-to-head randomized clinical trials on first-line treatments for patients with ES-SCLC were included with outcomes and toxic effects reported, including objective response rate (ORR, involving complete response and partial response), disease control rate (DCR, involving complete response, partial response, and stable disease), progression-free survival (PFS), overall survival (OS), and treatment related adverse events (TRAEs) of grades 3 to 5. Of 199 eligible articles, 14 were included. DATA EXTRACTION AND SYNTHESIS Data were independently extracted and collected by 2 reviewers based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES Main outcomes were OS, PFS, DCR, ORR, and TRAEs of grades 3 to 5. RESULTS A total of 3 phase 2 and 11 phase 3 randomized clinical trials involving 4838 patients were included. Programmed cell death ligand 1 (PD-L1) inhibitor (durvalumab and atezolizumab) plus etoposide-based chemotherapy, compared with etoposide-based chemotherapy alone, showed the most favorable OS (hazard ratio, 1.40; 95% CI, 1.09-1.80) and the best DCR (odds ratio [OR], 0.42; 95% CI, 0.21-0.81). Bevacizumab plus etoposide-based chemotherapy provided the best PFS compared with etoposide-based chemotherapy alone (hazard ratio, 1.54; 95% CI, 1.09-2.27), although this was not translated into OS benefit. The addition of PD-L1 inhibitors to etoposide-platinum chemotherapy caused no more toxic effects in general (compared with etoposide-based chemotherapy alone: OR, 1.14; 95% CI, 0.36-2.31), while bevacizumab plus etoposide-platinum regimen induced the most TRAEs grades 3 to 5 among all first-line treatments (eg, compared with irinotecan-platinum regimen: OR, 4.24; 95% CI, 1.26-14.57). Based on the surface under the cumulative ranking curve value, PD-L1 inhibitor plus etoposide-platinum had the highest probability of being ranked first for OS (0.87) and DCR (0.97). CONCLUSIONS AND RELEVANCE The findings of this systematic review and network meta-analysis suggest that the combination of a PD-L1 inhibitor (durvalumab and atezolizumab) and etoposide-based chemotherapy may be an optimal first-line treatment option for patients with ES-SCLC patients.
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Randomized Phase II Study Comparing Mannitol with Furosemide for the Prevention of Renal Toxicity Induced by Cisplatin-based Chemotherapy with Short-term Low-volume Hydration in Advanced Non-small Cell Lung Cancer: The OLCSG1406 Study Protocol.
Makimoto, G, Ichihara, E, Hotta, K, Ninomiya, K, Oze, I, Minami, D, Ninomiya, T, Kubo, T, Ohashi, K, Tabata, M, et al
Acta medica Okayama. 2018;(3):319-323
Abstract
Although cisplatin-based chemotherapy shows a survival advantage compared to carboplatin for treating advanced non-small cell lung cancer, high-volume hydration and a long infusion time are necessary to avoid nephrotoxicity, and cisplatin-based chemotherapy has been difficult to administer in outpatient settings. A low-volume hydration method using mannitol or furosemide as forced diuresis was recently introduced, but there are no clear conclusions regarding which agent should be used. We describe our ongoing randomized phase II trial (the OLCSG1406 Study) evaluating the efficacy of forced diuresis. This study will clarify whether mannitol or furosemide is more suitable in cisplatin-based chemotherapy with low-volume hydration.
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Randomized phase II study comparing weekly docetaxel-cisplatin vs. gemcitabine-cisplatin in elderly or poor performance status patients with advanced non-small cell lung cancer.
Jang, J, Kim, HK, Cho, BC, Lee, KH, Yun, HJ, Woo, IS, Song, HS, Ryoo, HM, Kim, CH, Sun, DS, et al
Cancer chemotherapy and pharmacology. 2017;(5):873-880
Abstract
BACKGROUND Docetaxel/cisplatin (DP) and gemcitabine/cisplatin (GP) are standard treatment regimens for advanced non-small cell lung cancer (NSCLC). In spite of potent efficacy, the conventional 1-day DP is regarded as having more toxicity as compared with GP. There is increasing interest in a biweekly split administration of DP to reduce its toxicity. Hypothesis was that first-line biweekly DP is as safe as GP in the elderly or poor performance status (PS) patients. METHODS Chemotherapy-naïve patients with advanced NSCLC (IIIB/IV) who were elderly (65<) or PS (ECOG 2) were randomized to DP or GP arm by balancing for ECOG (0-1 vs. 2) and stage (IIIB vs. IV). DP comprised docetaxel (35 mg/m2)/cisplatin (30 mg/m2) iv on days 1 and 8, every 3 weeks. GP comprised gemcitabine (1000 mg/m2)/cisplatin (30 mg/m2) iv on days 1 and 8, every 3 weeks. Chemotherapy lasted up to 4-6 cycles or until progression. Primary endpoint was safety (proportion of grade 3/4 toxicities). Planned sample size was 49 patients in each arm. RESULTS From November 2009 to August 2012, a total of 99 patients were randomized (DP 50/GP 49) from nine institutions. Adenocarcinoma and squamous cell carcinoma were observed in 62% and 33% of patients, respectively. Toxicity profiles were comparable for both arms and the differences were not statistically significant except for anemia and leucocytopenia. Any grade of anemia (86 vs. 98%) and of leucocytopenia (18 vs. 43%) was more common in the GP arm with statistical significance. Oral mucositis tended to be predominant in the DP arm. Patients in the DP arm (51%) suffered grade 3 or higher toxicities as did 47% in the GP arm (47%). The most common grade 3 or higher toxicities were as follows: In the DP arm, neutropenia (8%), leucopenia (8%), anemia (4%), pneumonia with normal ANC (4%) and febrile neutropenia (2%) were observed. In the GP arm, anemia (15%), neutropenia (15%), pneumonia with normal ANC (4%), thrombocytopenia (4%) and leucopenia (2%) were observed. The best overall response rates (CR + PR) for the DP and GP arms were 20.0 and 21% with no CR, respectively, and disease control rates (CR + PR + SD) were 70.0 and 76%, respectively. Median progression-free survival and median overall survival were 3.7 and 14.9 months in the DP arm and 5.6 and 20.8 months in the GP arm, respectively. CONCLUSION This study showed that DP is similar to GP in terms of efficacy and toxicity in treatment of elderly or poor performance patients. Both regimens showed similar grade 3/4 toxicities with different profiles.
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Comparison of continuous epidural block and continuous paravertebral block in postoperative analgaesia after video-assisted thoracoscopic surgery lobectomy: a randomised, non-inferiority trial.
Kosiński, S, Fryźlewicz, E, Wiłkojć, M, Ćmiel, A, Zieliński, M
Anaesthesiology intensive therapy. 2016;(5):280-287
Abstract
BACKGROUND Video-assisted (VATS) lung lobectomy can be associated with stronger postoperative pain than is commonly believed. It is generally accepted to introduce multimodal analgaesic strategies based on regional blockade, opioids and non-steroidal anti-inflammatory drugs. However, there is still no consensus regarding the optimal regional technique. The aim of this study was to compare the analgaesic efficacy of continuous thoracic epidural block (TEA) and percutaneous continuous paravertebral block (PVB) in patients undergoing video-assisted lung lobectomy. METHODS Fifty-one patients undergoing VATS lobectomy were enrolled in the present prospective, randomised clinical trial. The same analgaesic regimen in both groups included continuous infusion of 0.25% bupivacaine with epinephrine, intravenous ketoprofen and paracetamol. The doses of local anaesthetics were determined to achieve the spread of at least 4 segments in both groups. Postoperative static and dynamic visual analogue pain scores, as well as patient-controlled morphine usage, were used to compare the efficacy of analgaesia. Side effects and failure rates of both blocks were analysed. RESULTS Static and dynamic pain scores at 24 postoperative hours were significantly lower in the paravertebral group, as were the static pain score at 36 and 48 postoperative hours (P < 0.05). No difference between the treatment groups was identified regarding postoperative morphine usage. The failure rate was higher in the epidural group than in the paravertebral group. No complications were noted in either group, but side effects (urinary retention, hypotension) were more frequent in the epidural group (P < 0.05). CONCLUSIONS Postoperative pain following VATS lung resection procedures is significant and requires the application of complex analgaesic techniques. Percutaneous paravertebral block is equally effective as thoracic epidural block in providing analgaesia in patients undergoing VATS lobectomy. Paravertebral block has a better safety profile than thoracic epidural block.
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A randomised phase II study of pemetrexed versus pemetrexed+erlotinib as second-line treatment for locally advanced or metastatic non-squamous non-small cell lung cancer.
Dittrich, C, Papai-Szekely, Z, Vinolas, N, Sederholm, C, Hartmann, JT, Behringer, D, Kazeem, G, Desaiah, D, Leschinger, MI, von Pawel, J
European journal of cancer (Oxford, England : 1990). 2014;(9):1571-80
Abstract
INTRODUCTION Pemetrexed and erlotinib have been approved as second-line monotherapy for locally advanced or metastatic non-small cell lung cancer (NSCLC). This multicentre, randomised, open-label, parallel phase II study assessed efficacy and safety of pemetrexed versus pemetrexed+erlotinib in patients with advanced non-squamous NSCLC. METHODS NSCLC stage III-IV patients who failed one prior platinum-based chemotherapy regimen, ≥ 1 measurable lesion by Response Evaluation Criteria in Solid Tumors, and Eastern Cooperative Oncology Group performance status ≤ 2 were eligible. Patients received pemetrexed 500 mg/m(2) with vitamin B12 and folic acid q3w alone or combined with erlotinib 150 mg daily. The primary end-point was progression-free survival (PFS). Secondary end-points were overall survival (OS), time-to-treatment failure (TTTF), response and toxicity. RESULTS Of 165 randomised non-squamous patients, 159 were treated (pemetrexed: 83; pemetrexed+erlotinib: 76). The median PFS (months; 95% CI) was 2.89 (1.94, 3.38) for pemetrexed versus 3.19 (2.86, 4.70) for pemetrexed+erlotinib (hazard ratio [HR] 0.63; 95% CI: (0.44, 0.90); P = 0.0047). The median OS (months; 95% CI) was 7.75 (5.29, 10.41) for pemetrexed versus 11.83 (8.18, 16.66) for pemetrexed+erlotinib (HR: 0.68; 95% CI: 0.46, 0.98; P = 0.019). The median TTTF (months: 95% CI) was 2.4 (1.74, 2.99) for pemetrexed versus 3.0 (2.23, 4.07) for pemetrexed+erlotinib (HR 0.64; 95% CI: 0.46, 0.89; P = 0.0034). One patient died in pemetrexed+erlotinib arm due to febrile neutropenia. Grades 3/4 drug-related toxicities (in ≥ 5% of patients) in pemetrexed/pemetrexed+erlotinib were febrile neutropenia (2.4%/10.5%), diarrhoea (1.2%/5.3%), rash (1.2%/9.2%); anaemia (6%/11.8%), leukopenia (9.6%/23.7%), neutropenia (9.6%/25.0%), and thrombocytopenia (4.8%/14.5%). CONCLUSIONS Pemetrexed+erlotinib treatment significantly improved PFS, OS and TTTF in 2nd line non-squamous NSCLC and was associated with an increase in grade 3/4 toxicities compared with pemetrexed alone.
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Pemetrexed versus docetaxel in second line non-small-cell lung cancer: results and subsets analyses of a multi-center, randomized, exploratory trial in Chinese patients.
Li, R, Sun, L, Wang, J, Qian, J, Wang, Z, Jiao, X
Pulmonary pharmacology & therapeutics. 2012;(5):364-70
Abstract
BACKGROUND Pemetrexed and docetaxel are established therapies in second line non-small cell lung cancer (NSCLC). Comparative data, concerning the two agents in the designated settings, however, are lacking in Chinese patients who account for the largest lung cancer population in the world. METHODS AND PATIENTS We designed and performed a multi-center, randomized, exploratory clinical trial of pemetrexed compared with docetaxel in second line chemotherapy in Chinese NSCLC patients. Eligible patients with histological or cytological diagnosis of stage IIIB or IV NSCLC, who were not suitable for curative therapy and had failed from prior first line chemotherapy regimen for at least 4 weeks, were randomized to receive either pemetrexed 500 mg/m(2) intravenously day 1 with vitamin B12, folic acid, and dexamethasone, or docetaxel 75 mg/m(2) intravenously day 1 with dexamethasone. Both regimens were implemented once every 21 days for 2 cycles. This study was designed to be a non-inferiority trial that compared tumor response for overall response rate (ORR) between the two drugs as primary endpoint. The secondary endpoints included disease control rate (DCR), Karnofsky performance status (KPS) scores and toxicities. RESULTS 260 patients were enrolled and randomly assigned to receive chemotherapy of either pemetrexed (132 patients) or docetaxel (128 patients). 106 patients in pemetrexed arm and 102 patients in docetaxel arm were evaluable for efficacy. The efficacy of pemetrexed was equivalent to that of docetaxel in the second-line treatment for Chinese NSCLC (ORR: pemetrexed vs. docetaxel = 9.4% vs. 4.9, p = 0.285, DCR: pemetrexed vs. docetaxel = 67.2% vs. 69.6%, p = 0.685). And pemetrexed seemed to slightly promote patients' average KPS score when comparing with docetaxel, although the difference was without statistical significance (changes of average KPS scores: pemetrexed vs. docetaxel = 0.28 ± 5.93 vs. -1.67 ± 8.57, p = 0.149). Patients receiving pemetrexed experienced significantly lower incidences of grade 3/4 neutropenia (7.0% vs. 27.6%, p < 0.001) and leucocytopenia (4.7% vs. 22.8%, p < 0.001) than those who received docetaxel. Also, there were lower incidences of alopecia, stomatitis, and neural abnormality for patients receiving pemetrexed than those receiving docetaxel. Incidence of serum glutamic oxaloacetic transaminase elevation, however, was higher in pemetrexed arm than in docetaxel arm (32.3% vs. 14.9%, p = 0.013). In addition, age ≥ 60 patients benefit from pemetrexed with equivalent efficacies yet much lower toxicities compared to docetaxel (DCR: pemetrexed vs. docetaxel = 66.67% vs. 81.58%, p = 0.146; grade 3/4 hematologic toxicities: pemetrexed vs. docetaxel = 17.25% vs. 39.6%, p = 0.016). CONCLUSION Treatment with pemetrexed resulted in equivalent efficacy outcomes and better safety profiles compared with docetaxel in second-line therapy for advanced NSCLC in Chinese lung cancer population. And age ≥ 60 patients may benefit from second-line single pemetrexed.
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CK2 enzyme affinity against c-myc 424-434 substrate in human lung cancer tissue.
Yaylim, I, Ozkan, NE, Isitmangil, T, Isitmangil, G, Turna, A, Isbir, T
Asian Pacific journal of cancer prevention : APJCP. 2012;(10):5233-6
Abstract
CK2 is a serine threonine kinase that participates in a variety of cellular processes with more than 300 defined substrates. This critical enzyme is known to be upregulated in cancers, but the role of this upregulation in carcinogenesis is not yet fully understood but c-myc, one of the defined CK2 substrates, is a well-known proto- oncogene that is normally essential in developmental process but is also involved in tumor development. We evaluated the optimal enzyme and substrate concentrations for CK2 activity in both neoplastic and non-neoplastic human lung tissues using the c-myc 424-434 peptide (EQKLISEEDL) as a substrate. The activities measured for the neoplastic tissue were 600-750 U/mg protein while those for the control tissue was in the range of 650-800 U/ mg. Km value for c-myc peptide was determined as 0.33 μM in non-neoplastic tissue and 0.18 μM in neoplastic tissue. In this study, we did not observe an increased activity in the neoplastic tissue when compared with the non-neoplastic lung tissue, but we recorded two times higher affinity for c-myc 424-434 in cancer tissue. Considering the metabolic position of c-myc 424-434, our results suggest that phosphorylation by CK2 may be important in dimerization and thus it might affect the regulation of c-myc in cancer tissues.