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Randomized study of vinorelbine–gemcitabine versus vinorelbine–carboplatin in patients with advanced non-small cell lung cancer
Abstract
The objective of this trial was to compare two vinorelbine-based doublets with carboplatin (CBDCA-VC) or with gemcitabine (VG) in patients with stage IIIB-IV non-small cell lung cancer (NSCLC).
A total of 316 patients with advanced NSCLC previously untreated were randomized to either vinorelbine 30 mg/m(2) D1,8 with carboplatin AUC 5 D1 (VC) or vinorelbine 25mg/m(2) with gemcitabine (VG) 1000 mg/m(2) both given D1,8 every 3 weeks. The primary endpoint was response rate with secondary parameters being survival (OS), progression-free survival (PFS), tolerance and clinical benefit.
The median number of cycles was four in each arm with a total of 1268 cycles. The objective response (OR) on intent-to-treat was 20.8% in VC and 28% in VG (p=0.15). Median PFS was 3.9 months in VC and 4.4 months (mo) in VG (p=0.18). Median survival was significantly longer (p=0.01) for VG with 11.5 mo compared to 8.6 mo in VC with 1 year survival at 48.9 and 34.4%, respectively. Tolerance was better in the VG arm as compared to the VC patients. Four toxic deaths were recorded in the VC group. Clinical benefit response rate was 32.4% compared to 40.9% in 111 and 110 evaluable patients in VC and VG, respectively.
VG compared to VC resulted in a similar overall response rate, favourable median survival and a better toxicity profile. For non-cisplatin-based chemotherapy, VG is a useful alternative.
... Several randomised controlled trials have compared a platinum combination with vinorelbine and gemcitabine (VG) (Laack et al, 2004;Zhang et al, 2004;Barlesi and Pujol, 2005;Lilenbaum et al, 2005;Tan et al, 2005;Yamamoto et al, 2006;Greco et al, 2007;Han et al, 2008;Kubota et al, 2008). Most of these studies demonstrated that VG is as effective but less toxic than the respective platinum combinations. ...
... Most of these studies demonstrated that VG is as effective but less toxic than the respective platinum combinations. One study (Tan et al, 2005), however, compared VG with vinorelbine plus carboplatin (VC), both regimens administered in a 3-week schedule to a maximum of six cycles. They found superior survival of 3 months and a more favourable toxicity profile for the VG combination. ...
... As a response to the improved survival by VG over VC presented by Tan et al (2005), the Norwegian Lung Cancer Study Group designed a randomised study comparing VG with VC as a first-line treatment in patients with advanced NSCLC. We chose to administer three cycles of chemotherapy, based on the results of three randomised studies assessing the length of therapy in advanced NSCLC (Smith et al, 2001;Socinski et al, 2002;von Plessen et al, 2006). ...
Phase III study comparing vinorelbine/gemcitabine with vinorelbine/carboplatin as first-line chemotherapy of advanced NSCLC: A Norwegian Lung Cancer Study Group trial.
Ø. Fløtten, R. M. Bremnes, B. H. Grønberg, S. Sundstrøm, T. Amundsen, H. Rolke, U. Aasebø, K. Hornslien, T. Wentzel-Larsen, C. von Plessen,
Background: Platinum based chemotherapy is the standard first line treatment for advanced non- small cell lung cancer (NSCLC). However, side-effects are common and earlier studies have suggested that non-platinum combinations are equally effective but less toxic. This may improve health related quality of life (HRQoL) during the treatment. Methods: Eligible patients had stage IIIB (ineligible for curative radiotherapy) or stage IV, performance status (PS) 0-2 and adequate bone marrow/kidney/liver function. They were randomized to receive up to three courses of vinorelbine 60 mg/m2 PO + gemcitabine 1,000 mg/m2 IV day 1 and day 8 (VG) or vinorelbine 60 mg/m2 PO day 1 + 8 + carboplatin AUC = 5 (Calvert's formula) IV day 1 (VC). Patients > 75 years received 75% of the dose. The primary endpoint was overall survival. Secondary endpoints were HRQoL (global health status, pain, nausea/vomiting, dyspnea and fatigue) reported on the EORTC QLQ-C30 + LC13 at week 9, toxicity and use of palliative radiotherapy. Results: 444 patients from 35 Norwegian hospitals were randomized from September 07 until April 09. Their median age was 65 years, 254 (58%) were men and 112 (25%) had PS 2. There were no differences in median overall survival (VG: 6.3 months, VC: 7.0 months; log rank p = 0.89) or in HRQoL. Preliminary toxicity analyses of 414 patients showed more grade IV neutropenia and need for blood transfusions in the VC arm, but no differences in numbers of infections or hospitalisations. Conclusions: The two regimens yielded similar results with respect to survival and HRQoL. Complete data on toxicity/adverse events and use of palliative radiotherapy will be presented at the annual meeting.
... For regimens with an incidence of febrile neutropenia less than 10%, routine prophylactic use of CSF is not recommended. 58,59 Because febrile neutropenia was reported in 1% to 14% of patients in the trials of gemcitabine and vinorelbine reviewed, [3][4][5]8,9,25 ...
... Grade 1 thrombocytopenia, delay day 1 dose. 8 i. Grade 2 thrombocytopenia, postpone treatment by 1 week. 41 j. ...
... 8 g. Grade 3 neutropenia, omit day 8 dose.8 h. ...
The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net.
... Several randomised controlled trials have compared a platinum combination with vinorelbine and gemcitabine (VG) (Laack et al, 2004;Zhang et al, 2004;Barlesi and Pujol, 2005;Lilenbaum et al, 2005;Tan et al, 2005;Yamamoto et al, 2006;Greco et al, 2007;Han et al, 2008;Kubota et al, 2008). Most of these studies demonstrated that VG is as effective but less toxic than the respective platinum combinations. ...
... Most of these studies demonstrated that VG is as effective but less toxic than the respective platinum combinations. One study (Tan et al, 2005), however, compared VG with vinorelbine plus carboplatin (VC), both regimens administered in a 3-week schedule to a maximum of six cycles. They found superior survival of 3 months and a more favourable toxicity profile for the VG combination. ...
... As a response to the improved survival by VG over VC presented by Tan et al (2005), the Norwegian Lung Cancer Study Group designed a randomised study comparing VG with VC as a first-line treatment in patients with advanced NSCLC. We chose to administer three cycles of chemotherapy, based on the results of three randomised studies assessing the length of therapy in advanced NSCLC (Smith et al, 2001;Socinski et al, 2002;von Plessen et al, 2006). ...
Platinum-based doublet chemotherapy is the standard first-line treatment for advanced non-small cell lung cancer (NSCLC), but earlier studies have suggested that non-platinum combinations are equally effective and better tolerated. We conducted a national, randomised study to compare a non-platinum with a platinum combination.
Eligible patients had stage IIIB/IV NSCLC and performance status (PS) 0-2. Patients received up to three cycles of vinorelbine 60 mg m(-2) p.o.+gemcitabine 1000 mg m(-2) i.v. day 1 and 8 (VG) or vinorelbine 60 mg m(-2) p.o. day 1 and 8+carboplatin area under the curve=5 (Calvert's formula) i.v. day 1 (VC). Patients ≥75 years received 75% of the dose. Endpoints were overall survival, health-related quality of life (HRQoL), toxicity, and the use of radiotherapy.
We randomised 444 patients from September 2007 to April 2009. The median age was 65 years, 58% were men and 25% had PS 2. Median survival was VG: 6.3 months; VC: 7.0 months, P=0.802. Vinorelbine plus carboplatin patients had more grade III/IV nausea/vomiting (VG: 4%, VC: 12%, P=0.008) and grade IV neutropenia (VG: 7%, VC: 19%, P<0.001). Infections, HRQoL and the use of radiotherapy did not differ significantly between the treatment groups.
The two regimens yielded similar overall survival. The VG combination had only a slightly better toxicity profile.
... One only study has reported that a non-platinum combination regimen was superior to carboplatin-based regimen in terms of ORR, PFS, OS and clinical benefit [29]. ...
... The GLOB-2 trial [29] compared two VNR-based doublets with carboplatin or with GEM in 316 patients with advanced NSCLC with ORR as the primary endpoint and PFS and OS, tolerance and clinical benefit as secondary ones. The ORR on intent-to-treat was 20.8% in VC and 28% in VG (P = 0.15). ...
... Prior studies have most often focused on comparing overall survival (OS), objective response rate (ORR), and toxicity between non-platinum chemotherapy regimens and platinumcontaining chemotherapy regimens (Georgoulias et al., 2001a;Gridelli et al., 2003;Laack et al., 2004;Georgoulias et al., 2005;Tan et al., 2005;Esteban et al., 2006;Yamamoto et al., 2006;Rubio et al., 2009). OS and 1-year survival rates of non-platinum chemotherapy regimens are comparable to those of platinumcontaining chemotherapy regimens. ...
Objectives: The purpose of this study was to quantify the efficacies and safety profiles of the three first-line non-platinum chemotherapy regimens recommended in the National Comprehensive Cancer Network guidelines.
Materials and Methods: The PubMed and Cochrane Library databases were searched comprehensively, and clinical trials involving patients with advanced non-small cell lung cancer treated with one of three first-line non-platinum regimens (gemcitabine combined with vinorelbine, gemcitabine combined with docetaxel, or gemcitabine alone) were included in the analysis. A parametric proportional hazard survival model was established to analyze the time course of overall survival (OS). The objective response rate (ORR) and incidence rates of grade 3–4 adverse events (AEs) were summarized using a single-arm meta-analysis with a random-effects model.
Results: Seventeen studies met the inclusion criteria. Age and performance status (PS) scores were significant predictors of OS. For each 10-years increase in age, mortality risk increased by 18.5%, and the mortality risk increased by 4% for every 10% increase in the proportion of patients with a PS score of 2. After correcting for the above factors, we found that the three first-line non-platinum chemotherapy regimens did not differ based on OS or toxicity.
Conclusion: There was no significant difference in OS or toxicity among the three first-line non-platinum chemotherapy regimens. Age and PS scores were significant predictors of OS, and their heterogeneity across different studies should be considered in cross-study comparisons and sample size estimations when designing clinical trials.
... Разработка бесплатиновых режимов комбинированной ХТ является актуальной задачей, так как помогает определить оптимальную лечебную тактику у пациентов, которые не могут получать производные платины. В РКИ III фазы провели сравнение двух дублетов на основе винорелбина: с карбоплатином (CBDCA-VC) или с гемцитабином (VG) у пациентов с IIIB-IV стадией НМРЛ (n = 316) [19]. Использованы следующие режимы лечения: винорелбин 30 мг/м 2 день 1-й, 8-й плюс карбоплатин AUC 5 день 1-й (VC) или винорелбин 25 мг/м 2 плюс гемцитабин 1000 мг/м 2 день 1-й, 8-й каждые 3 недели. ...
... Scale bars, 1 mm (b) and 100 μm (c-h). Original × 40 magnification (c-h) and some of which were changed when apparent allergic reactions developed (4 courses of carboplatin + paclitaxel as an adjuvant therapy [6], gefitinib [7], gemcitabine + vinorelbine [8], S1 (an oral 5-fluorouracil-based drug) [9], carboplatin + pemetrexed + bevacizumab [10], erlotinib [11], nivolumab [12], afatinib [13], and carbo-platin+ S1 [14]). The disease continued to progress, however, and radiation therapy had been undertaken for local control of left and right iliac bone metastases (40 Gy in 20 fractions and 50 Gy in 25 fractions, respectively). ...
Background:
Rectal metastasis from pulmonary adenocarcinoma is rare, and it has been regarded as an end-stage phenomenon. Recently, however, advances in lung cancer treatment have improved the chance of long-term survival of patients with unresectable distant metastases. We describe the occurrence and management of metastatic spread of a pulmonary carcinoma to the rectum.
Case presentation:
The patient was a 79-year-old woman who had undergone thoracoscopic left lobectomy for pulmonary adenocarcinoma and then, over the next 11 years, various drugs (carboplatin + paclitaxel (as adjuvant therapy), gefitinib, gemcitabine + vinorelbine, S1 (an oral 5-fluorouracil-based drug), carboplatin + pemetrexed + bevacizumab, erlotinib, nivolumab, afatinib, and carboplatin+ S1) were administered, especially for hilar and mediastinal lymph node recurrences. During the eleventh postoperative year, left and right iliac bone metastases were detected, and radiation therapy was undertaken for local control of these lesions. When 18F-fluorodeoxyglucose positron emission tomography was performed for evaluation of the disease, tracer accumulation in the upper rectum was seen. Colonoscopic examination of the rectum revealed an intramural mass with central ulceration, and the mass was diagnosed histologically as an adenocarcinoma. The bone metastases appeared to be controlled, and the patient's performance status was good, but she had suffered constipation for about a year and desired treatment. Thus, laparoscopic low anterior resection was performed. Histopathologic analysis revealed a moderately differentiated adenocarcinoma existing mainly between the submucosa and serosa, and immunohistochemical analysis showed the tumor to be positive for cytokeratin (CK) 7, negative for CK20, positive for thyroid transcription factor-1, and negative for special AT-rich sequence-binding protein 2 and caudal type homeobox 2, confirming the diagnosis of rectal metastasis from the primary pulmonary adenocarcinoma. The patient recovered well without any change in her functional status. Systemic chemotherapy was resumed, and she continues to do well, now 6 months after surgery.
Conclusions:
Surgery may be a good option for the management of an isolated rectal metastasis from pulmonary cancer in patients whose functional status is good.
... In patients who cannot tolerate platinum agents, nonplatinum regimens-that is, gemcitabine plus docetaxel or gemcitabine plus vinorelbine-can be used as reasonable alternatives. 9,10 ROLE OF BEVACIZUMAB In the ECOG 4599 trial, bevacizumab in combination with carboplatin/paclitaxel in the first-line setting in patients with nonsquamous NSCLC demonstrated improved survival (median OS, 12.3 months v 10.3 months; P 5 .003) compared with paclitaxel/carboplatin alone. ...
Lung cancer is the leading cause of cancer-related death worldwide. The majority of these cancers are non-small-cell lung cancer, of which adenocarcinoma is the most common histologic subtype. Most patients are diagnosed at advanced stages when systemic treatment is needed. Whereas prognosis has improved for patients with targetable driver mutations, the majority of patients do not possess tumors with such molecular mutations. Platinum-based chemotherapy has traditionally been the mainstay of treatment, although in recent years immunotherapy has emerged as a treatment option and can result in robust and durable treatment responses in a subset of patients. Recent clinical trials on novel immunotherapy combinations and immunochemotherapy combinations may broaden the number of patients that may benefit from checkpoint inhibitors and elicit responses in those who otherwise may not have experienced a response to monotherapy with an immunotherapy drug. This review will outline the currently available therapies for the first-line treatment of metastatic adenocarcinoma that do not possess a driver mutation and provide a recommended approach and algorithm by which to select the best first-line therapy.
... (GRADE A1) R. No se recomienda el uso de bevacizumab asociado con pemetrexed y sales platinadas como terapia de primera línea. (GRADE A1) R. En pacientes con ECOG 0-1, se prefiere QT basada en un agente platinado (carboplatino o cisplatino), en combinación con un segundo fármaco: paclitaxel o pemetrexed 68,[87][88][89][90][91][92][93][94][95][96][97] . (GRADE A1) R. El tratamiento de mantenimiento se recomienda con bevacizumab o pemetrexed, de acuerdo con el esquema iniciado 85,86,98 . ...
Background: Lung cancer is a health issue all over the world; its incidence and mortality increase uninterruptedly. In Mexico,
it is one of the most frequent neoplasms. Material and methods: Specialists from ISSSTE conducted systematic bibliograph-
ic searches, which were distributed by subtopics in order to outline recommendations on pathology, molecular alterations of
non-small cell lung cancer, molecular diagnosis, and imaging studies (positron emission tomography/computed tomography)
which were assessed and accepted by consensus. Discussion: The therapeutic approach for advanced lung cancer not only
requires an effective treatment but more accurate diagnostic tools which timely identified lesions in order to avoid cancer
progression to more advanced stages. It is desirable that such methods be as comprehensive as possible and that they
include imaging studies, immunohistochemistry panel, molecular and genetic analysis of the samples to determine the pres-
ence or absence of mutations, translocations, and amplifications to establish grade, treatment and prognosis. The ISSSTE
experts’ treatment recommendations for advanced lung cancer are based on the GRADE system to unify criteria regarding
diagnosis and treatment and include all the available drugs in our country. The access to these types of treatments should
be carried out according to the codes and institutional and regulatory approvals; thus, the therapeutic options may vary or
be different from these recommendations.
... In addition to the clinical research of gemcitabinecisplatin combinations, gemcitabine has also been tested in various double and triple combinations with, paclitaxel, docetaxel, vinorelbine ( Table 2) with similar response rate and overall survival among platinum combinations. [19][20][21][22][23][24][25][26][27][28] To test efficacy and tolerability of non-platinum regimens for advanced non-smallcell lung cancer, our group compared gemcitabinedocetaxel versus gemcitabine-cisplatin in a phase II randomized trial for advanced NSCLC, with similar results. 19 Non platinum combinations provide a suitable alternative when toxicity is of concern or there are contraindications to platinum. ...
Lung cancer contributes to 31% of male and 26% of female cancer-related deaths and is the largest cause of cancer-related mortality in both men and women. Evaluation of new treatment strategies is ongoing to identify more effective treatments to overcome this dismal prognosis. Numerous studies and meta-analyses have proved the superiority of cisplatin-based third generation chemotherapy in NSCLC first line treatment but no gold standard exists. Two-drug third-generation chemotherapy provides a suitable alternative for patients with contraindications to platinum. Gemcitabine is a third generation agent successfully tested in non small lung cancer, either alone or in platinum and non platinum combination, and has become a drug of choice due to its advantageous toxicity profile. It has also been successfully combined with premetrexed, a new antitoxic agent, as well as with the vascular endothelial growth factor (VEGF) inhibitor bevacizumab, for adenocarcinoma histological nonsmall cell subtype. On the other hand, the identification of potential prognostic and predictive molecular markers in the latest years, not only for novel targeted tyrosine kinase inhibitors but also for gemcitabine and other agents, may enable customized therapies for specific patient populations, allowing improved efficacy and reduced toxicity and cost. This review aims to provide an update on gemcitabine and its therapeutic value in modern molecular sitting.
... The vinorelbine and carboplatin combination has proved to be active in first line treatment of advanced NSCLC. The response rates across studies have ranged from 13% to 40% with a median survival from 4.5 to 14.6 months (Crawford and O'Rourke, 1994;Jacoulet et al., 1995;Masotti et al., 1995;Garst et al., 1996;Pronzato et al., 1999;Tan et al., 2005). ...
Adding more than four cycles of the combination regimen increase toxicities. The availability of an intravenous (i.v.) and oral form of vinorelbine appeared as a particularly convenient way to provide a consolidation treatment to patients who have achieved an objective response or stable disease.
This study was retrospectively designed to investigate the efficacy in terms of response and safety of i.v. vinorelbine 25 mg/m(2) on day 1 and oral vinorelbine 60 mg/m(2) on day 8 given with carboplatin area under the curve (AUC) 5 once every 3 weeks (q3w) for four cycles followed by consolidation therapy with single-agent vinorelbine in non-progressive patients with advanced non-small-cell lung cancer (NSCLC).
Seventy-two patients enrolled into the study from October 2006 to July 2009 received the combination regimen. Thirty-seven patients (51.3%) also received the subsequent consolidation treatment. Partial tumor responses were obtained in 25 patients (34.7%) of 72 evaluable patients. Stable disease was observed in 26 (36.1%) of patients. The median progression free-survival was 4 months (95% CI 3.1-4.8). The median overall survival time was 10 months (95% CI 8.2-11.7) and the 1 year survival was 38.1%. The main toxicities recorded were hematological. Grade 3-4 neutropenia were observed in 17 patients (23.6%). Only two patients experienced grade three febrile neutropenia in the induction period, and there was no occurrence of febril neutropenia in the consolidation period. Nausea and vomiting were the major non-hematological toxicities reported. Toxicities occurred primarily during the initial combination phase of the chemotherapy.
Despite the low dose of vinorelbine (25mg/m(2) i.v. on day 1 and only 60 mg/m(2) oral on day 8, every 3 weeks) achieved during the study, the response rate of 34.7%, the disease control of 70.8% and the 10 months median overall survival with tolerable toxicity profile, confirmed that this combination, offers an active and safe regimen for patients with advanced NSCLC.
... The meta-analysis of D'Addario et al (27), which included 14 trials (n=3307), did not find a survival benefit with platinum-based agents over non-platinum chemotherapy regimens (OR Table 3. Median survival in these four trials ranged from 7.6 to 13.8 months. Tan et al (70), in a secondary endpoint, detected a better median survival in patients receiving gemcitabinevinorelbine (11.5 months) versus those receiving vinorelbine-carboplatin (8.6 months) (p=0.01). The trial by Kawahara et al (50) found worse neutropenia and neuropathy in the platinum arm, but more pneumonitis, including two deaths, on the non-platinum arm. ...
Non-small cell lung cancer (NSCLC) frequently presents at an incurable stage, and a majority of patients will be considered for palliative chemotherapy at some point in their disease. This article reviews the growing evidence for first-line treatment in NSCLC.
Studies of first-line chemotherapy regimens including new agents (docetaxel, gemcitabine, irinotecan, paclitaxel, pemetrexed, and vinorelbine) and targeted agents (bevacizumab, erlotinib, and gefitinib) were identified through Medline, Embase, the Cochrane databases, and web sites of guideline organizations.
Two evidence-based guidelines, 10 systematic reviews, and forty-six randomized trials were eligible for inclusion. Randomized studies suggest that platinum-based doublets (platinum plus new agent) are the standard of care for first-line systemic therapy. No one new agent is clearly superior for use in combination with a platinum agent. The survival advantage of platinum-based doublets over nonplatinum combinations or older combinations is modest. The addition of bevacizumab to carboplatin and paclitaxel has shown improved survival, although multiple exclusion criteria limit the applicability of these data to a subset of patients. In patients at least 70 years of age or with Eastern Collaborative Oncology Group performance status 2, a new single agent is an alternative. Treatment beyond four to six cycles impedes quality of life without prolonging life. Emerging data suggest that the choice of chemotherapy agent may be influenced by histologic subtype.
In NSCLC, a combination of a platinum agent plus a new agent continues to be the standard of care. As differences between regimens are small, toxicity and patient preference should help guide regimen choice.
... Reasons for exclusion were not stated in eight studies [30,31,40,42,43,48,57,64], whereas we were unable to assess if any exclusion criteria were applied in a trial published in Chinese only [46]. Response was assessed according to the World Health Organization standard criteria [72] in 19 trials [22,23,25,29,32,34,35,39,44,45,47,49,50,52,53,59,62,65,68], according to the Southwest Oncology Group guidelines [73] in two studies [21,24], and according to the Response Evaluation Criteria in Solid Tumors [74] in four trials [60,61,66,67]. ...
The therapeutic equivalence of different third-generation agents in the first-line treatment of advanced non-small cell lung cancer (NSCLC) has long been accepted, although recent studies seem to suggest some superiority of gemcitabine- or docetaxel-containing regimens over other third-generation doublets.
To assess the relative impact of different third-generation drugs on the activity of first-line chemotherapy in advanced non-small cell lung cancer by considering both response and progressive disease (PD) rates as outcome measures.
Published and unpublished data were collected from randomized trials comparing a gemcitabine-, docetaxel-, vinorelbine- or paclitaxel-containing regimen with one or more gemcitabine-, docetaxel-, vinorelbine- or paclitaxel-free combinations. For each study, 2 x 2 tables were constructed for both response and immediate progression. Pooled odds ratios were calculated using a general variance-based method.
Forty-five trials (11,867 patients) were eligible. The odds of obtaining an objective response to treatment were similar across different regimens. Gemcitabine-based chemotherapy was associated with a 14% lower risk for immediate progression, whereas patients receiving paclitaxel showed a 22% higher risk for having PD as the best response. Docetaxel treatment provided a nonsignificant 9% lower odds for progression.
These data demonstrate that different third-generation regimens have comparable activity in chemotherapy-naïve patients with advanced NSCLC. Gemcitabine-based chemotherapy provides better disease control, whereas the risk for immediate progression is significantly higher when paclitaxel-containing regimens are used.
... All other societies recommend first-line platinum-based chemotherapy for advanced NSCLC patients. There are multiple randomised published trials on this topic [71][72][73][74][75][76][77][78][79][80][81][82][83][84][85][86][87][88][89][90]. In terms of survival, there is no statistically significant difference between the two types of treatment in all but one trial. ...
The objectives for the treatment of advanced nonsmall cell lung cancer are palliative and include improvement of survival, symptom control, quality of life and cost. The level of evidence of these benefits is based on multiple randomised trials and meta-analyses. Cisplatin-based chemotherapy with one of the regimens shown to be effective should be preferred. Carboplatin may be substituted for cisplatin if medical contraindications exist. Nonplatinum-based regimens are indicated as first-line treatment for advanced nonsmall cell lung cancer in patients for whom platinum-based chemotherapy is contraindicated. Single drug chemotherapy may be considered in patients with poor performance status. The choice of the active drugs depends on the patient's medical condition. There is no conclusive evidence that high doses of cisplatin (100-120 mg.m(-2)) provide better results than standard lower doses (50-60 mg.m(-2)) in terms of survival. The optimal duration of chemotherapy is poorly documented in advanced nonsmall cell lung cancer. A minimum of four to six cycles is advised in responding patients. Second-line chemotherapy is now accepted as a standard and should be offered to patients with good performance status and failing platinum-based first-line chemotherapy. Evidence is in favour of docetaxel and in the case of adenocarcinoma and adequate renal function, pemetrexed is recommended.
Systemic therapy for the treatment of lung cancer has changed drastically over the past several decades. Chemotherapy has remained a mainstay of treatment for both non-small cell and small cell lung cancer, though immunotherapy has begun to shift that paradigm. For non-small cell lung cancer specifically, targeted therapies against identified driver mutations have yielded significant improvement in prognosis for patients whose tumors harbor these mutations. Determining the optimal timing and combination of these therapies as well as identifying new molecular targets and therapeutic agents are areas of ongoing research interest.KeywordsNon-small cell lung cancerSmall cell lung cancerChemotherapyImmunotherapyTargeted therapyAdenocarcinomaSquamous cell carcinoma
Introduction
The study objective was to estimate the relationship between objective response and survival-based endpoints by drug class, in first-line advanced non-small cell lung cancer (aNSCLC).
Materials and methods
A systematic literature review identified randomized controlled trials (RCTs) of first-line aNSCLC therapies reporting overall survival (OS), progression-free survival (PFS), and/or objective response rate (ORR). Trial-level and arm-level linear regression models were fit, accounting for inclusion of immunotherapy (IO)-based or chemotherapy-only RCT arms. Weighted least squares-based R² were calculated along with 95% confidence interval (CIs). For the main trial-level analysis of OS vs. ORR, the surrogate threshold effect was estimated. Exploratory analyses involved further stratification by: IO monotherapy vs. chemotherapy, dual-IO therapy vs. chemotherapy, and IO+chemotherapy vs. chemotherapy.
Results
From 17,040 records, 57 RCTs were included. In the main analysis, trial-level associations between OS and ORR were statistically significant in both the IO-based and chemotherapy-only strata, with R² estimates of 0.54 (95% CI: 0.26-0.81) and 0.34 (0.05-0.63), respectively. OS gains associated with a given ORR benefit were statistically significantly larger within IO vs. chemotherapy comparisons compared to chemotherapy vs. chemotherapy comparisons (p <0.001). Exploratory analysis suggested a trend by IO type: for a given change in ORR, ‘pure’ IO (IO monotherapy and dual-IO) vs. chemotherapy RCTs tended to have a larger OS benefit than IO+chemotherapy vs. chemotherapy RCTs. For ORR vs. PFS, trial-level correlations were strong in the IO-based vs. chemotherapy (R² = 0.84; 0.72-0.95), and chemotherapy vs. chemotherapy strata (R² = 0.69; 0.49-0.88). For OS vs. PFS, correlations were moderate in both strata (R² = 0.49; 0.20-0.78 and R² = 0.49; 0.23-0.76).
Conclusion
The larger OS benefit per unit of ORR benefit in IO-based RCTs compared to chemotherapy-only RCTs provides an important addition to the established knowledge regarding the durability and depth of response in IO-based treatments.
Based on the GRADE system, a group of specialists in Medical Oncology from ISSSTE produced a set of recommendations for the systemic treatment of advanced lung cancer —specifically non-small cell lung cancer and small-cell lung cancer— with immunotherapy, chemotherapy with or without antiangiogenic agents. Regarding the diagnosis, extension studies and lung grades are analyzed. Likewise, basic pathology, molecular biology, and imaging features are described to determine the treatment protocols for advanced lung cancer with actionable mutations or biomarkers related to domains such as actionable mutations, anaplastic lymphoma kinase, and reactive oxygen species (ROS1). The recommendations comprise the most important clinical issues: immunotherapy in lung cancer, first-line treatment for non-small cell lung cancer, non-squamous (wild-type) metastatic cancer, second-line immunotherapy regimes, chemotherapy without first-line immunotherapy for adenocarcinoma, firstline chemotherapy with antiangiogenic agents, as well as the characteristics a patient should present to be a candidate to receive immunotherapy. Dosages are stated in the different treatment protocols; the chemotherapy regimes for unresectable, locally-advanced lung cancer are being reviewed, as well as for ECOG 0-1 until ECOG 2, limited and extended stages. Even though there is no consensus on certain topics, this document includes clear guidelines whose aim is standardizing the criteria, and that will be subject to be reviewed and updated.
PurposeTo evaluate the efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with stage IIIB/IV and advanced non-small cell lung cancer (NSCLC).Methods
The PubMed, Embase, Cochrane library, Wanfang, and CNKI databases were searched for relevant studies. The overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and incidence of severe adverse events (grade ≥ 3 adverse events; grade 3/4 AEs) were calculated using the methods of merging ratios and means. Merged ratios and means and their 95% confidence intervals (CIs) were used to descriptively analyze the efficacy and toxicity of metronomic oral vinorelbine monotherapy in patients with stage IIIB/IV and advanced NSCLC.ResultsThe ORR and DCR achieved with metronomic oral vinorelbine monotherapy were 12% (95% CI 5–20) and 48% (95% CI 38–59), respectively. Median PFS and OS were 3.46 months (95% CI 2.49–4.43) and 8.22 months (95% CI 7.21–9.24), respectively. The incidence of grade 3/4 AEs was 16% (95% CI 10–22). The more common grade 3/4 AEs were neutropenia 9% (95% CI 2–20) and leukopenia 8% (95% CI 1–19).Conclusion
Metronomic oral vinorelbine monotherapy has a certain effect on patients with stage IIIB/IV and advanced NSCLC, especially for untreated elderly patients. It offers the advantages of convenience, lower cost and acceptable incidence of severe adverse events.
Introduction
Recently updated three-year survival data from the PACIFIC trial showed that durvalumab consolidation therapy improved OS rates versus placebo for patients with unresectable stage III non-small cell lung cancer (NSCLC) after chemoradiotherapy. Considering the impact of the high cost of durvalumab, its cost-effectiveness should be updated to see if its cost-effectiveness has changed from the US payers’ perspective.
Methods
A comprehensive Markov model was used to evaluate mean lifetime costs and effectiveness of first-line durvalumab consolidation therapy versus placebo for patients with unresectable stage III NSCLC imputing updated survival and quality-of-life data from the PACIFIC trial. The main endpoints include total costs, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). One-way, two-way, and probabilistic sensitivity analyses were conducted to access the uncertainty in the variables. We also considered durvalumab cost-effectiveness in the subgroups.
Results
Durvalumab consolidation therapy resulted in additional 1.34 LYs and 1.01 QALYs, resulting in an ICER of $138,920 per QALY versus the placebo treatment. One-way sensitivity analysis revealed that the utility values of two treatments, body weight, and unit cost of durvalumab have the greatest influence on the result. Subgroup analyses demonstrated that durvalumab was more cost effective for patients with non-squamous-cell lung cancer, followed by 25% or greater PD-L1 expression. Probabilistic sensitivity analysis showed that the probability of durvalumab being cost-effective versus the placebo is 62.6% at a willingness-to-pay (WTP) of $150,000 per QALY
Conclusion
Our analyses demonstrated that receiving durvalumab consolidation therapy was more cost-effective than placebo at a WTP threshold of $150,000. These results can be of use to US practitioners in the application of durvalumab and for durvalumab prescription and reimbursement policies.
Non-small-cell lung cancer (NSCLC) is a disease of the elderly, who are under-represented in clinical trials. This challenges the external validity of the evidence base for its management and of current guidelines, that we evaluated in a population of older patients. We retrieved randomized clinical trials (RCTs) supporting the guidelines and identified 18 relevant topics. We matched a cohort of NSCLC patients aged older than 80 years from the Moffitt Cancer Center database with the studies' eligibility criteria to check their qualification for at least 2 studies. Eligibility > 60% was rated full validity, 30% to 60% partial validity, and < 30% limited validity. We obtained data from 760 elderly patients in stage-adjusted groups and collected 244 RCTs from the National Comprehensive Cancer Network (NCCN) and 148 from the European Society for Medical Oncology (ESMO) guidelines. External validity was deemed insufficient for neoadjuvant chemotherapy in stage III disease (27.37% and 25.26% of patients eligible for NCCN and ESMO guidelines, respectively) and use of bevacizumab (13.86% and 16.27% of patients eligible). For ESMO guidelines, it was inadequate regarding double-agent chemotherapy (25.90% of patients eligible), its duration (24.10%) and therapy for Eastern Cooperative Oncology Group performance status 2 patients (17.74%). For NCCN guidelines external validity was lacking for neoadjuvant chemoradiotherapy in stage IIIA disease (25.86% of patients eligible). Our analysis highlighted the effect of RCT eligibility criteria on guidelines' external validity in elderly patients. Eligibility criteria should be carefully considered in trial design and more studies that do not exclude elderly patients should be included in guidelines.
Introduction: Non-small cell lung cancer (NSCLC) frequently presents at an incurable stage, and a majority of patients will be considered for palliative chemotherapy at some point in their disease. This article reviews the growing evidence for first-line treatment in NSCLC. Methods: Studies of first-line chemotherapy regimens including new agents (docetaxel, gemcitabine, irinotecan, paclitaxel, pemetrexed, and vinorelbine) and targeted agents (bevacizumab, erlotinib, and gefitinib) were identified through Medline, Embase, the Cochrane databases, and web sites of guideline organizations. Results: Two evidence-based guidelines, 10 systematic reviews, and forty-six randomized trials were eligible for inclusion. Randomized studies suggest that platinum-based doublets (platinum plus new agent) are the standard of care for first-line systemic therapy. No one new agent is clearly superior for use in combination with a platinum agent. The Survival advantage of platinum-based doublets over nonplatinum combinations or older combinations is modest. The addition of bevacizumab to carboplatin and paclitaxel has shown improved survival, although multiple exclusion criteria limit the applicability of these data to a subset of patients. In patients at least 70 years of age or with Eastern Collaborative Oncology Group performance status 2, a new single agent is an alternative. Treatment beyond four to six cycles impedes quality of life without prolonging life. Emerging data Suggest that the choice of chemotherapy agent may be influenced by histologic subtype. Conclusion: In NSCLC, a combination of a platinum agent plus a new agent continues to be the standard of care. As differences between regimens are small, toxicity and patient preference should help guide regimen choice.
Introduction: Gemcitabine (G), vinorelbine (V) and their combination (GV) have shown to be useful in patients with non-small cell lung cancer (NSCLC). The purpose of this study is to confirm the activity of GV administration and to identify prognostic factors related with the clinical outcome. Methods: A retrospective analysis was carried out in relation to 144 patients with NSCL treated between October 1996 and April 2005 with G (1000-1250 mg/m2) + V (25-30 mg/m2) both administered on days 1 and 8 every three weeks. Results: Treatment was well tolerated, grade 3-4 neutropenia being registered as the worse toxic effect in 18% cases, including 7% of neutropenic fever. The objective response rate was 36.8% (95% CI: 28.9-44.7) and the median progression free survival and overall survival rates were 21 (18-25) and 33 (26-40) weeks respectively. In multivariate analysis only the histology of adenocarcinoma (HR 3; p<0.001), less than two metastatic sites (HR 1.7; p<0.02) and Karnofsky index (KI) above 70% (HR 1.5; p<0.02) showed a significant association with longer survival. Conclusion: The GV combination therapy is well tolerated and active in patients with advanced NSCLC. The histology of adenocarcinoma, less than two metastatic sites and KI above 70% were identified as independent variables related with longer survival.
Background:
Approximately 50% of patients with newly diagnosed non-small cell lung cancer (NSCLC) are over 70 years of age at diagnosis. Despite this fact, these patients are underrepresented in randomized controlled trials (RCTs). As a consequence, the most appropriate regimens for these patients are controversial, and the role of single-agent or combination therapy is unclear. In this setting, a critical systematic review of RCTs in this group of patients is warranted.
Objectives:
To assess the effectiveness and safety of different cytotoxic chemotherapy regimens for previously untreated elderly patients with advanced (stage IIIB and IV) NSCLC. To also assess the impact of cytotoxic chemotherapy on quality of life.
Search methods:
We searched the following electronic databases: Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 10), MEDLINE (1966 to 31 October 2014), EMBASE (1974 to 31 October 2014), and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to 31 October 2014). In addition, we handsearched the proceedings of major conferences, reference lists from relevant resources, and the ClinicalTrial.gov database.
Selection criteria:
We included only RCTs that compared non-platinum single-agent therapy versus non-platinum combination therapy, or non-platinum therapy versus platinum combination therapy in patients over 70 years of age with advanced NSCLC. We allowed inclusion of RCTs specifically designed for the elderly population and those designed for elderly subgroup analyses.
Data collection and analysis:
Two review authors independently assessed search results, and a third review author resolved disagreements. We analyzed the following endpoints: overall survival (OS), one-year survival rate (1yOS), progression-free survival (PFS), objective response rate (ORR), major adverse events, and quality of life (QoL).
Main results:
We included 51 trials in the review: non-platinum single-agent therapy versus non-platinum combination therapy (seven trials) and non-platinum combination therapy versus platinum combination therapy (44 trials). Non-platinum single-agent versus non-platinum combination therapy Low-quality evidence suggests that these treatments have similar effects on overall survival (hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.72 to 1.17; participants = 1062; five RCTs), 1yOS (risk ratio (RR) 0.88, 95% CI 0.73 to 1.07; participants = 992; four RCTs), and PFS (HR 0.94, 95% CI 0.83 to 1.07; participants = 942; four RCTs). Non-platinum combination therapy may better improve ORR compared with non-platinum single-agent therapy (RR 1.79, 95% CI 1.41 to 2.26; participants = 1014; five RCTs; low-quality evidence).Differences in effects on major adverse events between treatment groups were as follows: anemia: RR 1.10, 95% 0.53 to 2.31; participants = 983; four RCTs; very low-quality evidence; neutropenia: RR 1.26, 95% CI 0.96 to 1.65; participants = 983; four RCTs; low-quality evidence; and thrombocytopenia: RR 1.45, 95% CI 0.73 to 2.89; participants = 914; three RCTs; very low-quality evidence. Only two RCTs assessed quality of life; however, we were unable to perform a meta-analysis because of the paucity of available data. Non-platinum therapy versus platinum combination therapy Platinum combination therapy probably improves OS (HR 0.76, 95% CI 0.69 to 0.85; participants = 1705; 13 RCTs; moderate-quality evidence), 1yOS (RR 0.89, 95% CI 0.82 to 0.96; participants = 813; 13 RCTs; moderate-quality evidence), and ORR (RR 1.57, 95% CI 1.32 to 1.85; participants = 1432; 11 RCTs; moderate-quality evidence) compared with non-platinum therapies. Platinum combination therapy may also improve PFS, although our confidence in this finding is limited because the quality of evidence was low (HR 0.76, 95% CI 0.61 to 0.93; participants = 1273; nine RCTs).Effects on major adverse events between treatment groups were as follows: anemia: RR 2.53, 95% CI 1.70 to 3.76; participants = 1437; 11 RCTs; low-quality evidence; thrombocytopenia: RR 3.59, 95% CI 2.22 to 5.82; participants = 1260; nine RCTs; low-quality evidence; fatigue: RR 1.56, 95% CI 1.02 to 2.38; participants = 1150; seven RCTs; emesis: RR 3.64, 95% CI 1.82 to 7.29; participants = 1193; eight RCTs; and peripheral neuropathy: RR 7.02, 95% CI 2.42 to 20.41; participants = 776; five RCTs; low-quality evidence. Only five RCTs assessed QoL; however, we were unable to perform a meta-analysis because of the paucity of available data.
Authors' conclusions:
In people over the age of 70 with advanced NSCLC who do not have significant co-morbidities, increased survival with platinum combination therapy needs to be balanced against higher risk of major adverse events when compared with non-platinum therapy. For people who are not suitable candidates for platinum treatment, we have found low-quality evidence suggesting that non-platinum combination and single-agent therapy regimens have similar effects on survival. We are uncertain as to the comparability of their adverse event profiles. Additional evidence on quality of life gathered from additional studies is needed to help inform decision making.
Background:
Gefitinib is known as one of the agents for treating patients with both advanced lung cancer and an epidermal growth-factor receptor mutation. In the epidermal growth-factor receptor-mutant advanced non-small-cell lung cancer population, gefitinib therapy has been associated with increased response rate, longer progression-free survival, and better quality of life compared to other anticancer drugs. However, gefitinib has to be discontinued for patients in whom adverse events occur, even if it is still effective. Here, we retrospectively assessed the clinical course of patients receiving gefitinib therapy, with a particular focus on liver damage.
Patients and methods:
Of 24 Asian patients treated with 250 mg gefitinib daily at Kanagawa National Hospital, Japan, between January 2008 and June 2012, grade 3 liver damage (Common Terminology Criteria for Adverse Events, version 4.0) occurred in nine and were eligible for our assessment. The regimen was subsequently changed to alternate-day administration. The relationships between liver damage and each clinical factor were retrospectively examined using Fisher's exact test.
Results:
Of the nine patients with liver damage, seven had previous exposure to another anticancer drug. There was a significant relationship between the incidence of liver damage and previous chemotherapy (P = 0.009). The objective response rates of patients treated with daily gefitinib 250 mg and alternate-day gefitinib following liver damage were 66.7% and 46.7%, respectively; these were not significantly different (P = 0.597).
Conclusion:
Gefitinib for advanced adenocarcinoma patients who have previously undergone chemotherapy should be used cautiously and liver function monitored closely, because it frequently induces significant liver damage. The alternate-day administration of gefitinib may be a suitable option for patients in whom daily gefitinib therapy induces liver damage.
Aim: While meta-analyses and clinical trials show improved survival in advanced NSCLC treated with platinum-containing chemotherapy, there are few data concerning front-line platinum-free ifosfamide-based regimens. We aimed to compare cisplatin-based chemotherapy to ifosfamide-gemcitabine (IG) with pre-defined second-line docetaxel.
693 Untreated advanced inoperable NSCLC cases were randomised to either GIP (gemcitabine, ifosfamide, cisplatin), DP (docetaxel, cisplatin) or IG. Primary outcome was overall survival.
Median age of the patients was 58 years with a predominance of males (75%), adenocarcinoma (56%), Karnofsky PS 80-100 (77%) and stage-IV disease (81%). Median survival times were 8.7, 8.8 and 8.3 months for IG, GIP and DP (p=0.79). GIP presented with (p<0.05) greater neutropenia, thrombopenia, vomiting, while greater cardiotoxicity, diarrhea, peripheral neuropathy were observed for DP and encephalopathy for IG.
In advanced NSCLC, cisplatin-based CT is not superior to a platinum-free regimen (ifosfamide-gemcitabine) with a favourable toxicity profile.
Malignant pleural mesothelioma (MPM) is an aggressive neoplasm that responds poorly to chemotherapy. Although treatment with pemetrexed in combination with cisplatin serves as first-line chemotherapy for MPM, the optimal second-line and beyond therapy has not yet been fully examined.
Between March 2008 and October 2011, 17 consecutive Japanese patients pretreated with at least one regimen of platinum plus pemetrexed chemotherapy received gemcitabine and vinorelbine. Responses, survival time, and toxicity were retrospectively evaluated.
Response [partial response (PR) + complete response (CR)] and disease control [stable disease (SD) + PR + CR] rates were 18 and 82 %, respectively. The median progression-free survival (PFS) after combination chemotherapy was 6.0 months, whereas the median overall survival (OS) was 11.2 months. Grade 3 or 4 neutropenia and anemia were observed in 41 and 29 % of patients, respectively, and one patient experienced febrile neutropenia. Grade 3 or 4 nonhematologic toxicities included constipation (6 %) and phlebitis (6 %).
Combination chemotherapy using gemcitabine with vinorelbine was shown to have moderate activity in Japanese MPM patients pretreated with platinum plus pemetrexed chemotherapy. A further multicenter phase II trial is warranted to confirm the efficacy and safety of this combination treatment.
In the past 12–18 months, there have been an incredible number of studies in lung cancer. This is partly reflected by an increased interest by drug companies to develop agents for this disease, given the large number of patients developing lung cancer, but also because the understanding of the biology of this tumor has led to significant advances in the development of targeted agents. A very large number of novel agents have been tested, especially in non-small cell lung cancer (NSCLC) either as single agents or in combination with chemotherapy. Some novel targeted agents have now shown definite activity in NSCLC, such as EGFR tyrosine kinase inhibitors and bevacizumab. As in previous years, this chapter will be divided into non-small cell lung cancer, small cell lung cancer and then mesothelioma and thymoma.
Gemcitabine has been associated with an increased risk of arterial and venous thromboembolic events (VTEs and ATEs), although the overall risk remains unclear. As indications for its use in oncology are expanding, a comprehensive characterization of these complications becomes imperative.
Pubmed was searched for articles published from January 1, 1990 to December 31, 2012. Eligible studies included prospective randomized controlled phase II and III trials evaluating gemcitabine-based vs non-gemcitabine-based chemotherapy in patients with solid tumors. Data on VTEs and ATEs were extracted. Overall incidence rates, odds ratio (OR), and 95% confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of included trials.
A total of 4,845 patients from 19 trials were included. Among patients treated with gemcitabine-based chemotherapy, the overall incidence of VTEs (13 studies comprising 3823 patients) and ATEs (8 studies consisting of 2431 patients) was 2.1% (95% CI, 1.2%-3.8%) and 2.2% (95% CI, 1.4%-3.2%). The associated ORs of VTEs and ATEs were 1.56 (95%CI: 0.86-2.83, p=0.15) and 1.82 (95%CI: 0.89-3.75, p=0.10) compared with non-gemcitabine-based therapy. A tendency to increase the risk of ATE and VTEs were also detected in any prespecified subgroup.
The use of gemcitabine does not significantly increase the risk of VTEs and ATEs in patients with solid tumors when compared with non-gemcitabine-based chemotherapy.
Chemotherapy is a cornerstone in the treatment of metastatic non-small cell lung cancer due to the high frequency of metastatic stages at diagnosis. By introducing new drugs, the efficacy and tolerability of chemotherapy could be improved. Chemotherapy with a platinum based doublet containing a third generation drug for four to six cycles is standard in first-line treatment. Neither a three or four drug schedule, nor the application of more cycles could demonstrate any increase in efficacy. Patients with reduced performance status and elderly patients with comorbidity should receive monotherapy with gemcitabine, vinorelbine or taxanes. Elderly patients with a good performance status, however, might be candidates for a modified combination therapy. Pemetrexed, docetaxel and the EGFR inhibitor erlotinib are options as second-line treatment following progression or relapse.
The Hellenic Oncology Research Group (HORG) initiated a randomized phase III trial
in order to compare the docetaxel-gemcitabine (DG) and oral vinorelbine-gemcitabine (oVG)
regimens as front-line treatment for patients with advanced NSCLC. Chemo-naïve patients
were randomly assigned to receive either oVG (n=219) (oral vinorelbine 70mg/m2 followed by
gemcitabine 900 mg/m2, days 1 and 15, in cycles of 4 weeks), or DG (n=218) (gemcitabine 900
mg/m2, days 1 and 8, and docetaxel 75mg/m2 on day 8 of the cycle, every 3weeks). The primary
end-point of the trial was OS. After a median follow-up time of 20.2 months (range, 0.5-46.1)
for the oVG armand 18.8months (range, 0.5-41.8) for the DG arm(p=0.349), overall survival (OS)
was not significantly different between the two arms; median OS was 9.7 months (95%
confidence interval [CI] 7.7-11.7) for the oVG arm vs. 12.2 months (95% CI 10.3-14.2) for the DG
arm (p=0.391). Similarly, no significant difference was observed in terms of time to tumor
progression (TTP) between the two arms. Median TTP was 3.4 months (95% CI 2.9-3.8) for the
oVG arm and 4.2 months (95% CI 3.3-5.0) for the DG arm (p=0.249). The overall response rate
was significantly higher for patients treated in the DG arm(15.4% vs. 29.4% (p=0.001). This trial
failed to reach its primary end-point of showing an OS benefit in favor of oVG.
Treatment for advanced-stage NSCLC generally includes the use of systemic chemotherapy as well as biologic therapies (targeted therapy) at later stages of the disease. However, in general, NSCLC is moderately sensitive to the currently available cytotoxic drugs, so the intention of chemotherapeutic treatment in the advanced setting is mainly palliative. Several treatment regimens are available, but in the first-line setting, treatment traditions differ both within countries and between various parts of the world. The role of taxane-platinum chemotherapeutic combinations (mainly used in North America) has been questioned in the palliative setting since these combinations are known to cause neutropenia, skin and nail problems, as well as neurological toxicity.
This review aims to summarize the current knowledge about the role of non-taxane therapy for patients with advanced NSCLC, with a focus on gemcitabine, vinorelbine, etoposide, pemetrexed, irinotecan, epidermal growth factor receptor (EGFR)-inhibiting agents, angiogenesis inhibitors, and small molecules. The compilation of literature in the present review indicates that the use of non-taxane treatment for patients with advanced NSCLC has an anti-tumor effect that is not different from that which can be seen with various taxane combinations. Furthermore, the combination of cisplatin with gemcitabine or vinorelbine seems to be a most compelling regimen in the first-line setting because of its modest toxicity (when administered by experienced staff), favorable clinical response, and relatively low drug cost. It is also clear that the novel therapies (EGFR inhibitors and inhibitors of angiogenesis) that have been approved so far will be of great clinical value; however, their use will be restricted to small, well defined, subpopulations of patients. The great challenge now is to define the populations benefiting from these novel therapies.
Platinum-based chemotherapy regimens have been the mainstay of systemic chemotherapy in advanced NSCLC. However, substantial toxicity impairs the survival and symptom control advantages of cisplatin- and even carboplatin-containing regimens. With the advent of newer active agents in the 1990s, investigators began conducting clinical studies with the aim of potentially eliminating platinum from initial therapy for patients with advanced NSCLC. Conceptually, three major hypotheses were tested in phase III trials: (i) single, non-platinum agents are equal in efficacy to platinum in combination with these agents; (ii) non-platinum combinations are potentially more effective than platinum-based therapy; and (iii) non-platinum combinations are at least equally efficacious, but less toxic than, platinum-based therapy. An overall analysis of phase III data indicates that combinations of these newer agents with platinum are superior to the single agent alone and that combinations of non-platinum agents are no more effective than platinum-based therapy. Non-platinum therapy has a different and perhaps marginally improved toxicity spectrum compared with platinum-based therapy. In the few studies utilizing a formal quality-of-life analysis, no differences have been detected. Therefore, while several non-platinum regimens have been validated in phase III trials as reasonable alternatives to platinum-based therapy, they have not been proven to be clearly superior.
Purpose:
The aim was to compare the efficacy between doublets of third-generation agents (non-platinum) and doublets of platinum plus a third-generation agent (platinum-based) for chemotherapy-naïve advanced non-small-cell lung cancer (NSCLC).
Methods:
We conducted a literature-based meta-analysis to compare the efficacy between doublets of third-generation agents and doublets of platinum plus a third-generation agent for chemotherapy-naïve advanced NSCLC. The primary end point was overall survival, and the secondary end points were progression-free survival (PFS) and response rate. Subgroup analyses were also conducted by different non-platinum doublet regimens or different platinum-based doublets. A descriptive review for toxicity was performed.
Results:
Sixteen randomized controlled trials were identified ultimately. Results demonstrated that the efficacy of non-platinum doublets was comparable with platinum-based doublets according to the overall survival (HR = 1.03, 95 % CI = 0.98-1.08, p = 0.29). Subgroup analyses by different non-platinum doublets also showed the efficacy of all the third-generation doublets, such as vinorelbine plus gemcitabine, vinorelbine plus paclitaxel, gemcitabine plus paclitaxel, and gemcitabine plus docetaxel, was comparable with platinum-based doublets (HR = 1.00, 95 % CI = 0.78-1.27, p = 0.98; HR = 0.97, 95 % CI = 0.80-1.18, p = 0.79; HR = 1.05, 95 % CI = 0.99-1.12, p = 0.11; HR = 1.01, 95 % CI = 0.92-1.10, p = 0.87; respectively). Subgroup analyses by different platinum-based doublets indicated that the efficacy of the third-generation doublets were equal to both cisplatin-based doublets and carboplatin-based doublets (HR = 1.08, 95 % CI = 1.00-1.17, p = 0.05; HR = 1.00, 95 % CI = 0.94-1.05, p = 0.94; respectively). The secondary end points indicated that platinum-based doublets might have an advantage in PFS but not in response rate (HR = 1.06, 95 % CI = 1.01-1.12, p = 0.03; RR = 0.99, 95 % CI = 0.90-1.08, p = 0.81; respectively).
Conclusions:
Non-platinum doublets were as effective as platinum-based doublets with different toxicity profile for chemotherapy-naïve advanced NSCLC in the era of third-generation agents.
ZET: İleri evre küçük hücreli dışı akciğer kanserinin tedavi amaçları palyatiftir ve sağkalım, semp-tom kontrolü, yaşam kalitesi ve maliyetin daha iyi hale getirilmesini içermektedir. Bu faydalara dair elde edilen kanıtlar birçok randomize çalışma ve meta-analize dayanmaktadır. Etkili olduğu gösterilmiş sisplatin bazlı kemoterapi rejimlerinden biri tercih edilmelidir. Tıbbi açıdan kontrendi-kasyonlar varsa, sisplatin karboplatin ile yer değiştirebilir. Platin-bazlı kemoterapinin kontrendike olduğu ileri evre küçük hücreli dışı akciğer kanseri hastalarında birinci basamak tedavi olarak platin bazlı olmayan rejimler yer almaktadır. Performans durumu düşük olan hastalarda tekli ilaç ile kemoterapi düşünülebilir. Aktif ilaçların seçimi hastanın tıbbi durumuna bağlıdır. Yüksek dozlarda sisplatinin (100-120 mg·m-2) standart düşük dozlara göre (50-60 mg·m-2) sağkalım açısından daha iyi sonuçlar sağladığına dair kesin bir kanıt yoktur. İleri evre küçük hücreli dışı akciğer kanserinde optimal kemoterapi süresi tam belirlenmemiştir. Yanıt veren hastalarda en az dört-altı kür önerilme-ktedir. İkinci-basamak tedavi artık standart olarak kabul edilmektedir ve performans durumu iyi olan, platin bazlı birinci-basamak kemoterapinin başarısız olduğu hastalara önerilmelidir. Kanıtlar dose-takselin lehinedir ve adenokarsinom ve yeterli böbrek fonksiyonu durumunda pemetrexed önerilme-ktedir.
Gemcitabine is one of the most widely used pyrimidine analogues, with a well-established role as a first- and second-line treatment of several types of tumors. Several preclinical and clinical studies have been done to obtain information on molecular determinants of gemcitabine activity and metabolism, in order to predict whether this drug will be effective and safe for the individual patient. Among these molecular determinants, the mRNA and protein expression of equilibrative transporter-1 (ENT1) and ribonucleotide reductase (RR) emerged as possible predictors of drug activity in studies on pancreatic and non-small cell lung cancer. However, cytidine deaminase polymorphisms and activity were correlated with clinical outcome and severe toxicities, whereas further studies should evaluate both P53 dependent and independent pathways involved in gemcitabine induced apoptosis. Improved knowledge on these determinants is critical for the optimal development of combination of gemcitabine with other conventional or biological therapies, as well as to exploit the radiosensitizing potential of gemcitabine. Emerging technologies such as massive parallel sequencing, gene expression arrays and proteomics may identify novel biomarkers in tumor material, while polymorphisms and phenotyping analysis should unravel factors involved in drug toxicity. Validation of these markers in preclinical models should be used for the appropriate patient enrolment into subsequent prospective studies. Hopefully, novel pharmacogenetic biomarkers will be validated in these prospective studies and used to select cancer patients to be treated with gemcitabine-based regimens in the near future or to enroll them in studies with prodrugs in order to bypass resistance mechanisms.
A randomized phase II trial was conducted to determine if two non-platinum protocols are able to yield a similar efficacy and toxicity profile as compared to two platinum-based doublets in advanced non-small cell lung cancer (NSCLC).
A total of 61 patients were randomly assigned to a reference regimen of carboplatin and paclitaxel (repeated every 3 weeks) or to one of three experimental regimens: paclitaxel plus vinorelbine (repeated every 3 or 4 weeks) and carboplatin plus paclitaxel (repeated every 4 weeks).
The objective remission rate for all the patients was 34.1%. The median progression-free survival for all the patients was 3 months. The median overall survival and one-year overall survival were 6 months and 21.5%, respectively. Toxicity was moderate and manageable. Response, survival and toxicity did not significantly differ between the four treatment groups.
The efficacy and toxicity profile of platinum-free combinations is comparable to that of platinum-based doublets.
The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.
ASCO published a guideline on use of chemotherapy in advanced stage non-small-cell lung cancer in 1997. The latest update covers treatment with chemotherapy and biologic agents and reviews literature from 2002 to 2009.
The purpose of this article is to provide updated recommendations for the treatment of patients with stage IV non-small-cell lung cancer. A literature search identified relevant randomized trials published since 2002. The scope of the guideline was narrowed to chemotherapy and biologic therapy. An Update Committee reviewed the literature and made updated recommendations. One hundred sixty-two publications met the inclusion criteria. Recommendations were based on treatment strategies that improve overall survival. Treatments that improve only progression-free survival prompted scrutiny of toxicity and quality of life. For first-line therapy in patients with performance status of 0 or 1, a platinum-based two-drug combination of cytotoxic drugs is recommended. Nonplatinum cytotoxic doublets are acceptable for patients with contraindications to platinum therapy. For patients with performance status of 2, a single cytotoxic drug is sufficient. Stop first-line cytotoxic chemotherapy at disease progression or after four cycles in patients who are not responding to treatment. Stop two-drug cytotoxic chemotherapy at six cycles even in patients who are responding to therapy. The first-line use of gefitinib may be recommended for patients with known epidermal growth factor receptor (EGFR) mutation; for negative or unknown EGFR mutation status, cytotoxic chemotherapy is preferred. Bevacizumab is recommended with carboplatin-paclitaxel, except for patients with certain clinical characteristics. Cetuximab is recommended with cisplatin-vinorelbine for patients with EGFR-positive tumors by immunohistochemistry. Docetaxel, erlotinib, gefitinib, or pemetrexed is recommended as second-line therapy. Erlotinib is recommended as third-line therapy for patients who have not received prior erlotinib or gefitinib. Data are insufficient to recommend the routine third-line use of cytotoxic drugs. Data are insufficient to recommend routine use of molecular markers to select chemotherapy.
This is phase II study evaluating a non-platinum-containing regimen, used in conjunction with radiotherapy, in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with non-resectable stage III NSCLC were treated with two cycles of induction gemcitabine (1000mg/m(2)) and vinorelbine (25mg/m(2)) given on D(1,8) every 21 days, followed by thoracic radiotherapy (60-66Gy) with concurrent weekly vinorelbine (15mg/m(2)). The primary objective was to assess response rate and secondary objectives to assess tolerability and to determine the progression-free survival (PFS) and overall survival (OS). Of the 42 patients enrolled on the study, 15 (36%) achieved a partial response (PR) after induction chemotherapy. After chemo-radiotherapy, five patients had complete response (CR) and 19 patients had PR, giving an overall response rate of 52%. The median PFS was 8 months and median OS was 17 months. The regimen was tolerable, with a 21% grade 3/4 neutropenia rate and 38% grade 2/3 esophagitis rate.
This phase II study assessed the efficacy and safety of oral vinorelbine given weekly in combination with carboplatin (CBDCA) AUC 5 once every 3 weeks for four cycles in chemonaive patients with advanced non-small cell lung carcinoma (NSCLC), followed by consolidation therapy with single-agent oral vinorelbine in non-progressive patients.
Chemonaive advanced NSCLC patients received four cycles of combination therapy with CBDCA AUC 5 day 1 and oral vinorelbine, 60 mg/m2 on days 1, 8 and 15 (cycle 1), dose increased to 80 mg/m2 (cycles 2-4) in absence of grades 3-4 neutropenia (NCI-CTCv2). Consolidation therapy with oral vinorelbine was continued (cycle 5) at same dosage; if dose was decreased during combination therapy, it was given at 60 mg/m2, then increased at 80 mg/m2 (cycle 6) in absence of grades 3-4 neutropenia until PD, toxicity or patient's refusal.
A total of 57 patients were registered and 56 patients were treated (ITT population), median age was 61 years (37-71). Objective response evaluated by RECIST was 17.9% (95% confidence interval, CI [8.9-30.4]) and disease control (CR, PR, NC) 73.2% (95% CI [59.7-84.2]), median progression-free survival 4.3 months (95% CI [3.1-5.1]) with median overall survival 9.7 months (95% CI [7.7-11.9]) and 1-year survival 37.1% (95% CI [24.4, 49.9]). Grades 3-4 neutropenia occurred in 67.9% of patients during combination and 20% during consolidation; febrile neutropenia occurred in 4 patients (7.1%) during combination therapy. Non-hematological toxicities occurred primarily during combination (grade 3 nausea and grade 3 vomiting in 7.1% of patients).
The combination of oral vinorelbine given weekly in 3-week cycles in combination with carboplatin followed by consolidation therapy with oral vinorelbine as a single-agent was able to achieve efficacy results in line with other doublets including carboplatin in terms of response as well as survival. This regimen reported a good profile of tolerability in the treatment of advanced NSCLC, allowing that this combination can be easily proposed for the palliative care of NSCLC patients where the advantages of carboplatin over cisplatin are still appreciated.
Background:
Platinum-containing two-drug combinations improve survival and cancer-related symptoms in patients with advanced non-small-cell lung cancer (NSCLC). However, survival benefit is modest and platinum-containing regimens cause substantial toxic effects. We did a prospective randomised open-label phase III study to compare an experimental platinum-free, triplet, sequential regimen of vinorelbine plus gemcitabine followed by docetaxel with the standard platinum-containing, doublet regimen paclitaxel plus carboplatin in patients with advanced NSCLC.
Methods:
Between March, 2001, and April, 2005, patients with stage IIIB (positive pleural effusion) or IV NSCLC, performance status 0 to 1, and adequate organ function, were randomly assigned to experimental treatment or to standard treatment. Randomisation was done centrally by use of a dynamic balancing algorithm. Patients were stratified by weight loss, lactate dehydrogenase concentration, and disease stage. Patients in the experimental group were scheduled to receive intravenous vinorelbine (25 mg/m(2)) plus gemcitabine (1000 mg/m(2)) on days 1 and 8 every 21 days for three cycles, followed by intravenous docetaxel (60 mg/m(2)) on day 1 every 21 days for three cycles. Patients in the standard group were scheduled to receive intravenous paclitaxel (225 mg/m(2)) plus carboplatin (area under the curve=6) for 3 h on day 1, every 21 days for six cycles. The primary endpoint was overall survival, and secondary endpoints were progression-free survival, response, and toxic effects. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00079287.
Findings:
Of the 401 patients enrolled and randomised in the trial, five patients in the experimental group and three in the standard group were ineligible for analysis; thus 196 patients in the experimental group and 197 in the standard group were included in analyses. Patient characteristics were well-balanced between the two groups with regard to major prognostic factors. Median overall survival was 13.6 months (range 12.0-16.4) in the experimental group versus 14.1 months (11.9-17.5) in the standard group (p=0.97). 49 of 196 patients (25%) in the experimental group had a partial response compared with 73 of 197 patients (37%) in the standard group (p=0.012). There were no complete responses. Median progression-free survival was 5.5 months (95% CI 4.9-6.3) in the experimental group compared with 5.8 months (5.3-6.1) in the standard group (p=0.74). The incidence of grade 3 and 4 neutropenia, neuropathy, arthralgia, and myalgia was lower in the experimental group than in the standard group, although the incidence of pulmonary toxic effects was higher.
Interpretation:
Although platinum-containing regimens remain the standard treatment for advanced NSCLC, non-platinum regimens could provide equivalent efficacy with a different toxicity profile.
Health-related quality-of-life (QOL) endpoints in clinical trials provide decision makers with a more comprehensive picture of a specific treatment than activity-related endpoints alone. Such endpoints are increasingly being reported in cancer clinical trials. We reviewed phase III clinical trials that involved gemcitabine in the treatment of unresectable non-small-cell lung cancer. A systematic literature search was undertaken and 16 phase III clinical trials were found in which gemcitabine therapy was included in a treatment arm and QOL was an endpoint. Twelve of the 16 trials compared a gemcitabine-based treatment with a non-gemcitabine-based treatment.
Not all data were reported in the trials, and the findings are mixed. However, a review of these 12 trials generally shows that gemcitabine-containing chemotherapy treatments had either no different or more favourable QOL outcomes than non-gemcitabine-containing chemotherapy treatments. Ten of the 16 trials that were reviewed had a primary endpoint or objective that was not QOL. Of these ten trials, only four concluded that one treatment arm could be therapeutically favoured over another in terms of the non-QOL primary endpoint. Two of the trials reported no difference in QOL and two reported that QOL favoured the arm that was therapeutically favoured.
Many more trials will need to be conducted in order to conclude that gemcitabine-containing arms are associated with a more desirable QOL than non-gemcitabine-containing arms and that QOL necessarily favours the therapeutically favoured arm in the treatment of non-small-cell lung cancer.
Approximately 30-40% of non-small cell lung cancer patients will present with metastatic disease, and its associated poor prognosis. Chemotherapy has an established palliative role within late-stage disease, but is also being used increasingly in the neoadjuvant and adjuvant settings. Platinum-based chemotherapy has been shown to produce definite improvements in efficacy and quality of life in non-small cell lung cancer patients, and is now the standard of care. Carboplatin has similar biochemical properties to those of cisplatin. However, carboplatin has much less renal, otologic, neurologic and upper gastrointestinal toxicities than cisplatin, and treatment can be conveniently delivered in an out-patient setting. Furthermore, platinum combinations with third-generation cytotoxics have shown additional gains in survival rates. Gemcitabine and carboplatin is a well-tolerated regime. Recent meta- and cost analyses have discovered that gemcitabine-based regimes may have an advantage over other third-generation agent platinum combinations. This article reviews the evidence demonstrating that gemcitabine-carboplatin is effective, convenient and cost effective.
Differences in survival outcomes with various treatments for advanced non-small cell lung cancer are very modest. Despite this, end points looking at the patients' subjective benefit, such as symptom control, quality of life or clinical benefit, have only been sparsely implemented into clinical trials as primary points of interest. This review focuses on available evidence regarding these patients' subjective end points in recent clinical trials. Compared with best supportive care, chemotherapy offers symptom control, not only in patients with objective response to chemotherapy, but also in a proportion of patients with disease stabilization. However, interpretation of quality-of-life objectives is more difficult, owing to several methodological problems, but improvement in various domains of quality of life is also reported. Different treatment options, such as older platinum-based schedules, modern platinum-based doublets, single-agent treatment with a new drug or nonplatinum-based doublets, are comprehensively reviewed. Future randomized studies should take up the challenge of looking at the patients' benefit as a primary end point.
The majority of non-small cell (NSC) lung cancers express epidermal growth factor receptor (EGFR). Many studies have evaluated the clinical effect from targeted therapy achieved by blocking EGFR in patients with NSC lung cancer. Treatment of biologically unselected patients with NSC lung cancer with two reversible quinazole EGFR inhibitors, gefitinib and erlotinib, gave negative results in all controlled trials but one. Ten percent to 20% of patients with NSC lung cancers have somatic mutations in EGFR, and these patients have a significantly higher response rate (73%) to treatment with EGFR inhibitors than patients with wild-type EGFR (10%). Patients with Asian background, women, non-smokers, and patients with adenocarcinoma had higher response rates than other patients, and the differences may be due to an association between the clinical characteristics and EGFR mutations. Further studies are needed to fully evaluate the effect of EGFR inhibitor-treatment for subgroups of patients with NSC lung cancer with favorable biological and clinical characteristics.
Our aim was to study the activity and toxicity of the gemcitabine plus vinorelbine (Gem Vin) combination and to identify the optimal dose. Previously untreated patients aged < 70 years, with stage IV or IIIb (not candidates for radiotherapy) non-small cell lung cancer were eligible. Studied dose-levels of Gem Vin, administered on days 1 and 8 every 3 weeks, were (mg m–2): level I = 1000/25; level II = 1200/25; level III = 1000/30; level IV = 1200/30. A feasibility study was performed at each dose-level, followed by a single-stage phase II study. Dose-level IV was unfeasible because of grade 4 neutropenia. Overall, out of 126 patients enrolled in phase II studies, there were one complete and 32 partial responses (response rate 26%: 95% CI 18–34%). Response rates were 27.9%, 21.4% and 29.3% at levels I, II and III, respectively. The treatment was well tolerated. Toxicity was less frequent and severe at level I. Overall median survival was 33 weeks (95% CI 28–40). Descriptive quality of life analysis showed that patients with a worse baseline global health status score tended to drop out of the study earlier than those with a better score. Gem Vin is feasible at different doses. It is sufficiently active and well tolerated. A phase III study to compare the effect on quality of life of Gem Vin (level I) vs cisplatin-based chemotherapy is ongoing. © 2000 Cancer Research Campaign
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Background: Although doublet chemotherapy is a standard treatment regimen for PS 0–1 patients with advanced non- small cell lung cancer (NSCLC), the optimal chemotherapy for PS 2 patients with advanced NSCLC still remains to be established. We conducted a randomized phase II study to compare the efficacy and safety of a platinum-doublet regimen (CP) versus a non-platinum doublet regimen (GV) in PS 2 patients with advanced NSCLC. Methods: Chemotherapy-naive patients with stage IIIB (malignant effusion) and IV NSCLC were eligible for this study. The patients were randomly assigned to carboplatin area under the curve of 6 plus paclitaxel 200 mg/m ² on day 1 every 3 weeks (the CP arm) or gemcitabine 1000 mg/m ² plus vinorelbine 25 mg/m ² on days 1 and 8 every 3 weeks (the GV arm). The primary endpoint was the 1-year survival rate while the secondary endpoints were the response rate, the time to progression and the quality-of-life (QOL). The sample size was 41 assessable patients in each arm. Results: Of the 89 patients enrolled, 84 were assessable for efficacy and toxicity: 41 patients (median age 65 years, male/female 30/11, stage IIIB/IV 7/34) in the CP arm and 43 patients (median age 67 years, male/female 31/12, stage IIIB/IV 7/36) in the GV arm. The overall response and 1-year survival rates were 29.3% (95% CI, 16.1 to 45.5%) and 22% (95% CI, 9.3 to 34.6%) for the CP and 20.9% (95% CI, 10 to 36%) and 27.9% (95% CI, 14.5 to 41.3%) for the GV arm, respectively. The median survival time and time to progression were 5.9 and 2.9 months, respectively, for the CP arms and 6 and 2.6 months for the GV arm. The selected Grade 3/4 toxicity in the CP and GV arms included neutropenia (67.5% vs 65.1%, respectively), anemia (12.5% vs 30.2%), thrombocytopenia (7.5% vs 11.6%), febrile neutropenia (17.1% vs 11.6%), infection (29.3% vs 23.3%), pneumonitis (4.9% vs 11.6%), liver dysfunction (2.5% vs 9.3%), and neuropathy (5.1% vs 0%). The QOL improved after each treatment and it was similar between the two arms. Conclusions: Both CP and GV appear to be active in PS 2 patients with advanced NSCLC . The toxicity profiles were different between the two arms.
[Table: see text]
PURPOSECisplatin has played a major role in the treatment of non-small-cell lung cancer (NSCLC). This randomized trial was performed by the Southwest Oncology Group (SWOG) to determine whether the combination of vinorelbine and cisplatin has any advantage with regard to response rate, survival, and time to treatment failure over single-agent cisplatin in the treatment of patients with advanced NSCLC.METHODS
Between October 1993 and April 1995, 432 patients with advanced stage NSCLC were randomized to receive arm I (cisplatin 100 mg/m2 every 4 weeks) or arm II (cisplatin 100 mg/m2 every 4 weeks and vinorelbine 25 mg/m2 weekly). All patients were chemotherapy-naive, had performance status (PS) 0 or 1, and had adequate hematologic, renal, and hepatic function.RESULTSFour hundred fifteen patients were eligible and assessable. On arm I (cisplatin), there was a 12% partial response rate. Arm II (cisplatin and vinorelbine) had a 26% response rate (2% complete responses and 24% partial responses, P = .0002). There...
BACKGROUND
The authors conducted a Phase II study to evaluate the activity of the combination of gemcitabine and vinorelbine in patients with advanced nonsmall cell lung carcinoma (NSCLC).METHODS
Patients were eligible if they had Stage IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and Cancer and Leukemia Group B performance status (PS) 0–2. Patients with brain metastases were eligible if they were neurologically stable after brain irradiation. Thirty-three patients from participating institutions were enrolled. One patient was ineligible due to untreated brain metastases. Patients were treated with gemcitabine 1250 mg/m2 over 30 minutes (1000 mg/m2 for the first 6 patients) and vinorelbine 25 mg/m2 over 6 minutes, both administered intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of six cycles or more if the patient had persistent benefit. Growth factors were not allowed.RESULTSAmong all 32 eligible patients, there were 8 partial responses, for an overall response rate of 25% (95% confidence interval [CI], 11.5–43.4%). The median survival time was 8.3 months and the 1-year survival rate was 38% (95% CI, 24–59%). Patients with PS 0–1 had a median survival of 11.7 months and a 1-year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25% of the 148 treatment cycles, respectively. One patient died of neutropenic sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed. Nonhematologic toxicity was minimal.CONCLUSIONS
Gemcitabine and vinorelbine is an active and well-tolerated regimen in patients with advanced NSCLC, with response and survival rates at least comparable to those achieved with standard platinum-based regimens. This combination may be particularly suitable for the elderly or for patients who cannot tolerate more toxic platinum-based regimens. Cancer 2000;88:557–62. © 2000 American Cancer Society.
The aim of this study was to identify a chemotherapy combination that would be active and well tolerated for palliative treatment of advanced non-small-cell lung cancer (NSCLC). From February 1992 to December 1994, a total of 77 patients affected by stage-IIIB and stage-IV NSCLC were treated with carboplatin 350 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 of each cycle, with cycles repeated every 28 days. All patients were evaluable for response and toxicity. A total of 24 patients showed a partial response (31% response rate; 95% CI = 21-41%). The median duration of overall survival was 41 weeks (95% CI = 31-51), and the median time to disease progression was 34 weeks (95% CI = 25-43). The treatment was well tolerated: no grade-4 toxicity was observed. The carboplatin-vinorelbine combination deserves to considered as a valid alternative to regimens that include cisplatin for palliative treatment of advanced NSCLC.
The aim of the study was to assess the activity and toxicity of the vinorelbine-carboplatin combination in advanced adenocarcinoma or large-cell carcinoma of the lung. The new vinca derivative, vinorelbine, shows promising activity when combined with cisplatin, but toxicity of the combination is substantial.
Accordingly, we substituted carboplatin for cisplatin in the combination in order to improve the therapeutic index. From March 1992 to March 1994, 55 untreated patients with undifferentiated unresectable or metastatic adenocarcinoma or large-cell carcinoma of the lung were recruited. The treatment consisted of a course of carboplatin (300 mg/m2) and vinorelbine (25 mg/m2) repeated every 4 weeks. The only grade 3 toxicity observed was 16 cases of grade 3 vomiting and 2 cases of grade 3 stomatitis.
The positive response rate was 40% (partial response, 22 patients). In conclusion, the vinorelbine-carboplatin combination may be regarded as an active, safe regimen for the palliative treatment of advanced adenocarcinoma or large-cell carcinoma of the lung.
We designed a prospective randomized trial to compare vinorelbine and cisplatin (NVB-P) with vindesine and cisplatin (VDS-P) and to evaluate whether the best of these regimens affords a survival benefit compared with vinorelbine alone (NVB), an outpatient regimen, in patients with non-small-cell lung cancer (NSCLC).
Forty-five centers included 612 patients in this study: 206 on NVB-P, 200 on VDS-P, and 206 on NVB. Vinorelbine was administered at a dose of 30 mg/m2 weekly, cisplatin at 120 mg/m2 on days 1 and 29 and then every 6 weeks, and vindesine at 3 mg/m2 weekly for 6 weeks and then every other week. Treatment was continued until progression or toxicity. Four percent of the patients entered were ineligible and 59% had metastatic disease.
An objective response rate was observed in 30% of patients in the NVB-P arm versus 19% in the VDS-P arm (P = .02) and 14% in the NVB arm (P < .001). The median duration of survival was 40 weeks in the NVB-P arm, compared with 32 weeks in the VDS-P arm and 31 weeks in the NVB arm. Comparison of survival among the three groups demonstrated an advantage for NVB-P compared with VDS-P (P = .04) and NVB (P = .01). Neutropenia was significantly higher in the NVB-P group (P < .001), and neurotoxicity was more frequent with VDS-P (P < .004).
Since our results have demonstrated that NVB-P yields a longer survival duration and a higher response rate than VDS-P or NVB alone, with acceptable toxicity, this combination should be considered a relevant regimen in advanced NSCLC.
Simon A. Broadley, Michael H. Barnett, Mike Boggild, Bruce J. Brew, Helmut Butzkueven, Robert Heard, Suzanne Hodgkinson, Allan G. Kermode, Jeannette Lechner-Scott, Richard A.L. Macdonell, Mark Marriott, Deborah F. Mason, John Parratt, Stephen W. Reddel, Cameron P. Shaw, Mark Slee, Judith Spies, Bruce V. Taylor, William M. Carroll, Trevor J. Kilpatrick, John King, Pamela A. McCombe, John D. Pollard, Ernest Willoughby. (2014) Therapeutic approaches to disease modifying therapy for multiple sclerosis in adults: An Australian and New Zealand perspective Part 3 Treatment practicalities and recommendations. Journal of Clinical Neuroscience 21, 1857-1865
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A.J. Ullmann, M. Akova, R. Herbrecht, C. Viscoli, M.C. Arendrup, S. Arikan-Akdagli, M. Bassetti, J. Bille, T. Calandra, E. Castagnola, O.A. Cornely, J.P. Donnelly, J. Garbino, A.H. Groll, W.W. Hope, H.E. Jensen, B.J. Kullberg, C. Lass-Flörl, O. Lortholary, W. Meersseman, G. Petrikkos, M.D. Richardson, E. Roilides, P.E. Verweij, M. Cuenca-Estrella. (2012) ESCMID* *This guideline was presented in part at ECCMID 2011. European Society for Clinical Microbiology and Infectious Diseases. guideline for the diagnosis and management of Candida diseases 2012: adults with haematological malignancies and after haematopoietic stem cell transplantation (HCT). Clinical Microbiology and Infection 18, 53-67
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Roy A. Beveridge, John A. Miller, Arthur N. Kales, Richard A. Binder, Nicholas J. Robert, Jimmie H. Harvey, Kevin Windsor, Ira Gore, James Cantrell, Keith A. Thompson, William R. Taylor, Harry M. Barnes, Steven A. Schiff, John A. Shields, Richard J. Cambareri, Thomas P. Butler, Robert J. Meister, John M. Feigert, Michael J. Norgard, Manoel A. Moraes, William W. Helvie, Gregory A. Patton, Larry J. Mundy, David Henry, Bernard Mason, Arthur Staddon, Patricia Ford, Daniel Katcher, William Houck, William B. Major, Nicholas W. Gemma, Gary Kay, Edwin Priest, Paul Sowroy, Bruce Bank, Steven Leibach, Herbert Reisel, Gary Grad, Robert D. Warren, Winston M. Ueno, Lee F. Smith, Robert F. Dobrzynski, Michael J. Sheridan. (1998) A Comparison of Efficacy of Sargramostim (Yeast-Derived RhuGM-CSF) and Filgrastim (Bacteria-Derived RhuG-CSF) in the Therapeutic Setting of Chemotherapy-Induced Myelosuppression. Cancer Investigation 16, 366-373
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Meta-analyses of randomized clinical studies comparing combination chemotherapy versus "best supportive care" for advanced non-small-cell lung cancer have revealed a small, but statistically significant survival advantage for patients who receive chemotherapy. However, overall increases in lifespan have been short, and the great majority of patients die within 1 year of diagnosis. In the last few years, several new drugs with promising activity have been identified. Of these, vinorelbine has already been shown to increase survival rates in randomized clinical trials. In particular, one such trial showed the combination of vinorelbine and cisplatin to result in statistically superior survival rates, compared with "standard" therapy of cisplatin and vindesine, and with single-agent vinorelbine. A second study comparing vinorelbine to fluorouracil/leucovorin also demonstrated a survival benefit for patients treated with vinorelbine. Therefore, the combination of vinorelbine and cisplatin represents one new option for initial therapy of newly diagnosed stage IV non-small-cell lung cancer.
Platinum compounds and vinorelbine have been demonstrated to be active in non-small-cell lung cancer (NSCLC). The aims of the study were to assess tolerability and feasibility of increasing doses of carboplatin (level 1: 300 mg/ m2 on day 1, level 2: 350 mg/m2 on day 1, level 3: 400 mg/m2 on day 1) in combination with a fixed dose of vinorelbine (25 mg/m2 on days 1 and 8) in advanced NSCLC. Forty-two patients entered the study and were evaluable for toxicity and response. The patients were not treated using systemic chemotherapy, had TNM stage IIIB-IV, performance status ECOG 0-2, and their median age was 62 (range 41-70) years. The number of patients evaluable for each dose level was 14. A total of 138 (median 3) courses was administered. Nonhematologic side effects included grade I-II mucositis (9%), neurotoxicity (6%), and infections (4%). Myelotoxicity was manageable and generally of short duration, with 19% of the patients having grade III-IV neutropenia. No significant difference was observed for the three treatment groups. No drug-related death was observed. An objective remission was observed in 10 patients (24% response rate; 95% confidence interval 12-39%), with 5 responses in 14 patients treated with the 400-mg/m2 dose. In conclusion, the combination of carboplatin at a dose of 400 mg/m2 on day 1 and vinorelbine at a dose of 25 mg/m2 on days 1 and 8 can be safely administered as first-line cytotoxic therapy in advanced NSCLC and warrants further evaluation.
Cisplatin has played a major role in the treatment of non-small-cell lung cancer (NSCLC). This randomized trial was performed by the Southwest Oncology Group (SWOG) to determine whether the combination of vinorelbine and cisplatin has any advantage with regard to response rate, survival, and time to treatment failure over single-agent cisplatin in the treatment of patients with advanced NSCLC.
Between October 1993 and April 1995, 432 patients with advanced stage NSCLC were randomized to receive arm I (cisplatin 100 mg/m2 every 4 weeks) or arm II (cisplatin 100 mg/m2 every 4 weeks and vinorelbine 25 mg/m2 weekly). All patients were chemotherapy-naive, had performance status (PS) 0 or 1, and had adequate hematologic, renal, and hepatic function.
Four hundred fifteen patients were eligible and assessable. On arm I (cisplatin), there was a 12% partial response rate. Arm II (cisplatin and vinorelbine) had a 26% response rate (2% complete responses and 24% partial responses, P = .0002). There was a statistically significant advantage with regard to progression-free survival (median, 2 v 4 months; P = .0001) and overall survival (median, 6 v 8 months; P = .0018) for the cisplatin and vinorelbine arm. One-year survival was 20% for cisplatin alone and 36% for the combination arm. There was more hematologic toxicity on arm II of the study (81% grades 3 and 4 granulocytopenia v 5% on arm I). Other toxicities, such as renal insufficiency, ototoxicity, and nausea and vomiting, and neuropathy were similar.
The results of this study indicate that the combination of cisplatin and vinorelbine is a superior treatment when compared with single-agent cisplatin in the treatment of advanced NSCLC. Cisplatin and vinorelbine is the new standard for SWOG against which new therapies will be evaluated.
The authors conducted a Phase II study to evaluate the activity of the combination of gemcitabine and vinorelbine in patients with advanced nonsmall cell lung carcinoma (NSCLC).
Patients were eligible if they had Stage IIIB (malignant pleural effusion) or Stage IV NSCLC, no prior chemotherapy, and Cancer and Leukemia Group B performance status (PS) 0-2. Patients with brain metastases were eligible if they were neurologically stable after brain irradiation. Thirty-three patients from participating institutions were enrolled. One patient was ineligible due to untreated brain metastases. Patients were treated with gemcitabine 1250 mg/m(2) over 30 minutes (1000 mg/m(2) for the first 6 patients) and vinorelbine 25 mg/m(2) over 6 minutes, both administered intravenously on Days 1 and 8 every 21 days. Treatment was planned for a total of six cycles or more if the patient had persistent benefit. Growth factors were not allowed.
Among all 32 eligible patients, there were 8 partial responses, for an overall response rate of 25% (95% confidence interval [CI], 11.5-43. 4%). The median survival time was 8.3 months and the 1-year survival rate was 38% (95% CI, 24-59%). Patients with PS 0-1 had a median survival of 11.7 months and a 1-year survival rate of 48%. Grade 3 and 4 neutropenia was observed in 13% and 25% of the 148 treatment cycles, respectively. One patient died of neutropenic sepsis. Only 2 episodes of Grade 3 and 4 thrombocytopenia were observed. Nonhematologic toxicity was minimal.
Gemcitabine and vinorelbine is an active and well-tolerated regimen in patients with advanced NSCLC, with response and survival rates at least comparable to those achieved with standard platinum-based regimens. This combination may be particularly suitable for the elderly or for patients who cannot tolerate more toxic platinum-based regimens.
The purpose of this phase II study was to investigate the efficacy and safety of gemcitabine plus vinorelbine as first-line chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). Eligibility criteria included cytologically or histologically confirmed NSCLC (stage IIIB or IV), no previous chemotherapy, and bidimensionally measurable disease. Patients received 1000 mg/m(2) gemcitabine and 30 mg/m(2) vinorelbine on days 1, 8 and 15 every 4 weeks up to eight courses. From December 1997 to November 1998, 70 patients (59 stage IV and 11 stage IIIB disease), with a median age of 59 years (range 38-74 years) were enrolled. The intent-to-treat response rate was 41% (95% confidence interval (CI) 30-54%) with 1 complete responder (CR) and 28 partial responders (PRs), 15 patients had stable disease (SD) and 26 progressed (PD). Median survival was 8.3 months (95% CI 6.0-9.9 months), median progression-free survival (PFS) was 4.8 months (95% CI 3.9-5.5 months), and 1-year survival rate was 33.5% (95% CI 24.0-46.8%). Patients received a total of 229 cycles. Haematological and non-haematological toxicities were moderate. Transient World Health Organization (WHO)-grade IV leucopenia and thrombocytopenia occurred in 13 (6%) and two (1%) cycles, respectively. The predominant non-haematological toxicity was local reactions of the veins in 19 (27%) patients (WHO-grade II and III). Neurotoxicity was infrequent, non-cumulative, and reversible. The combination of gemcitabine and vinorelbine has demonstrated activity in metastatic NSCLC, with response and survival rates similar to those of cisplatin-based regimens and a more favourable toxicity profile that is well tolerated in an outpatient setting.
The aim of this study was to assess the activity and toxicity of carboplatin/vinorelbine combination chemotherapy in unresectable locally advanced and metastatic non-small cell lung cancer. Between April 1997 and June 1999 30 patients (22 M, eight F, median age 62) received treatment with carboplatin AUC 6 on day 1, and vinorelbine 25mg/m(2) on days 1, 8 and 15. Treatment was given every 28 days for six cycles unless progressive disease occurred. Twenty-three patients (77%) had stage IV disease, and seven (23%) stage IIIB. Ninety-three percent were WHO performance status 0-1. Twenty-three patients were fully assessable. Nine patients achieved partial responses (9/23, 39%) for an overall objective response rate of 9/30 (30%; 95% CI 15-49%). The median duration of response was 2.75 months (range 1-13 months). The median progression-free survival was 2 months and the median survival 5.25 months. The actuarial 1-year survival was 20%. The median number of cycles completed was two (range 1-6). Day 15 vinorelbine was administered in only 18% of cycles. The main toxicity was myelosuppression. WHO grade III/IV neutropenia was experienced in 50% of patients, however, there were only three episodes of febrile neutropenia. Eight patients required blood transfusion and one developed grade III thrombocytopenia. Treatment was ceased in one patient because of grade IV autonomic neuropathy. No patient had significant nausea and vomiting. There were no treatment-related deaths. These results indicate that carboplatin/vinorelbine is well tolerated and has similar activity to cisplatin/vinorelbine in patients with unresectable non-small cell lung cancer, however, the median survival was considerably shorter.
Docetaxel in combination with cisplatin or gemcitabine are active chemotherapy reigimes against non-small-cell lung cancer. We compared the efficacy and safety of a combination of cisplatin and docetaxel (group 1) with that of gemcitabine and docetaxel (group 2) in the treatment of advanced non-small-cell lung cancer in a prospective, randomised, multicentre trial.
Patients with stage IIIB or IV lung cancer who had not had prior chemotherapy were allocated either to group 1 and treated with docetaxel (100 mg/m(2), day 1) and cisplatin (80 mg/m(2), day 2) or to group 2 and treated with gemcitabine (1100 mg/m(2), days 1 and 8) and docetaxel (100 mg/m(2), day 8). All patients received recombinant human granulocyte colony-stimulating factor (150 mg/m(2)). All patients received recombinant human granulocyte colony-stimulating factor (150 mg/m(2)) had appropriate standard premedication. Response and toxicity were assessed using WHO criteria. Analysis was by intention to treat.
441 patients were randomly assigned to receive docetaxel/cisplatin (group 1, n=219) or gemcitabine/docetaxel (group 2, n=222). 14 patients in group 1 and 21 patients in group 2 were not evaluable. Objective response rates were similar in the two groups: group 1, 32.4% (95% CI 26.2-38.6%; 1.4% complete response and 31% partial response); group 2, 30.2% (24.5-36.2%; 0.9% complete response and 29.3% partial response). The two groups did not differ in median duration of response, time to tumour progression, overall survival, or 1 year or 2 year survival rates.
Both drug combinations had comparable activity in patients with advanced cancer who had not previously had chemotherapy; however, gemcitabine and docetaxel had the most favourable toxicity profile.
We conducted this randomized study comparing the activity and toxicity of paclitaxel and gemcitabine (PG) and paclitaxel and carboplatin (PC) combinations for the treatment of advanced non-small-cell lung cancer (NSCLC).
Chemotherapy-naive patients were randomized to paclitaxel 200 mg/m(2) on day 1 plus either carboplatin at an area under the concentration-time curve of 6 on day 1 (group A) or gemcitabine 1,000 mg/m(2) on days 1 and 8 (group B) every 3 weeks. A retrospective cost analysis was conducted using Student's t test to compare independent samples between groups.
A total of 509 patients (group A, 252 patients; group B, 257 patients) were enrolled; all characteristics were well balanced. The median survival time was 10.4 months (95% confidence interval [CI], 8.8 to 12 months) for group A and 9.8 months (95% CI, 8.0 to 11.7 months) for group B (P =.32). Respective 1-year survival rates were 41.7% and 41.4%. The response rate for group A was 28.0% (2% complete response [CR], 26% partial response [PR] [95% CI, 22% to 34%]), and the response rate for group B was 35.0% (5% CR, 30% PR) [95% CI, 29% to 41%]) (P =.12). Toxicity was mild. Grades 3/4 neutropenia, thrombocytopenia, and anemia for groups A and B were seen in 15% and 15%, 2% and 1%, and 5% and 2%, respectively. The mean total cost (outpatient clinic visits plus chemotherapy drug fee) for group A (euro; 7,612.64) versus group B (euro; 7,484.77) was not statistically significant (P <.66).
The PG combination is as equally active and well tolerated as the PC combination in patients with advanced NSCLC.
The authors compared the toxicity, response rate, and progression free survival of four chemotherapy regimens for patients with advanced (Stage IIIB and IV) nonsmall cell lung carcinoma.
A total of 267 patients entered this randomized Phase II trial on one of four arms: paclitaxel, carboplatin, and gemcitabine (Arm A); paclitaxel, carboplatin, and vinorelbine (Arm B); paclitaxel and gemcitabine (Arm C); and gemcitabine and vinorelbine (Arm D). Patient characteristics were similar in all treatment arms. At the time of tumor progression, patients were removed from study and were treated at the discretion of their physician.
Patients received a median of four courses of chemotherapy in all arms, and there was no difference in the dose delivered. There were no statistical differences in response rates (range, 32-45%), median progression free survival (range, 4.9-6.6 months), or progression free survival at 1 year (range, 8-19%). Actuarial survival in all four arms was not different, with a median survival ranging from 8.7 months to 10.7 months and a 1-year survival rate of 38-44%. Each arm was compared with a historic control with a median survival of 8 months. Arm D (gemcitabine and vinorelbine) approached significance at the 0.05 level.
Two-drug combinations containing the newer drugs without a platinum drug were less toxic than three-drug, platinum-based regimens. There were no significant differences in objective response rates or progression free survival when the four regimens were compared. The two-drug combination of gemcitabine and vinorelbine was the least toxic and, thus, may be superior. A Phase III trial comparing combined gemcitabine and vinorelbine with combined paclitaxel, carboplatin, and gemcitabine is ongoing.
Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non-small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient's quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens.
Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis.
Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment.
Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.
Vinorelbine (V) and gemcitabine (G) are two active single agents used in the treatment of non-small cell lung cancer (NSCLC). A multicenter clinical trial (West Japan Thoracic Oncology Group (WJTOG) 9908) was conducted to evaluate the efficacy and toxicity of V and G in patients (pts) with advanced NSCLC.
Eligibility criteria: no previous chemotherapy; performance status (PS) 0 or 1; age <75 years old. V, 25mg/m2, was given as a 2-3 min IV infusion, followed by a 30 min IV infusion of G, 1000 mg/m2, on days 1 and 8 of each 21-day cycle.
From April 2000 to September 2000, 52 pts were enrolled in the study. Two pts were ineligible. Baseline characteristics: median age 60, males 30 (60%), Eastern Cooperative Oncology Group (ECOG) PS 0/1=21/29 (58%), stage IIIB/IV=12/38 (76%), adenocarcinoma=35 (70%). The median number of cycles administered was 2. Fifty pts were evaluable for response. The response rate was 18% by the Response Evaluation Criteria in Solid Tumors (RECIST) (no complete response (CR), 9 partial response (PR), 25 stable disease, 12 progressive disease, 4 not evaluable). Grade III/IV toxicities were as follows: neutropenia grade III/IV=66%, anemia grade III/IV=16%, thrombocytopenia grade III/IV=2%, nausea grade III/IV=10%, vomiting grade III/IV=0%, documented infection grade III/IV=10%, skin rash grade III/IV=2%, and hepatic grade III/IV=8%. There were no treatment-related deaths. The median time to progression was 4.1 months. The overall median survival time (MST) was 13.9 months (range, 2.4 to >16.2 months) with a median follow-up time of 13.9 months. The MST for stage IIIB and stage IV was >14.5 and 12.7 months, respectively. The overall estimated 1-year survival rate was 55.4%.
This regimen has modest activity and is very well tolerated, with an encouraging 1-year survival rate.
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