With these premises at heart, we decided to set up a new trial (SICOG 9909) restricted to elderly or unfit NSCLC patients with a Charlson score ?4. The primary aim of this trial was to assess whether the combination of gemcitabine plus either vinorelbine or paclitaxel could prolong the survival of patients in comparison with gemcitabine or paclitaxel alone. Secondary end points were time to treatment failure, response rate and toxicity. Furthermore, because at that time there was no agreement on the optimal dosage of these compounds for managing aged patients, and given the unpredictable tolerability of chemotherapy in elderly people, we used an individual dose optimisation (Frasci IV), PS (0C1 2), and Charlson score (0C2 3C4), and allocated using a computer-generated random list into one of four arms: gemcitabine (GEM), paclitaxel (PTX), gemcitabine plus paclitaxel (GT), or gemcitabine plus vinorelbine (GV). In all arms of the trial, at least three cycles had been planned prior to the evaluation of activity, and additional treatment was administered up to optimum of six cycles only when at least a disease control was demonstrated. In the absence of World Health Organization (WHO) grade ?2 toxicity on previous cycle, an intra-patient dose escalation over the first three cycles was planned in all arms of the trial, and the dosage reached in the third cycle was used thereafter. In the GEM arm, the first cycle consisted of gemcitabine 1200?mg?m?2 infused intravenously (i.v.) over 30?min on days 1, 8 and 15, recycling every 4 weeks. Gemcitabine could be increased to 1400?mg?m?2 on the second cycle, and to 1600?mg?m?2 on the third cycle. In the PTX arm, initial dose was 100?mg?m?2 infused i.v. over 1?h on times 1, 8 and 15, recycling every four weeks. PTX could possibly be risen to 120?mg?m?2 on the next cycle, also to 140?mg?m?2 on the 3rd routine. In the GT arm, paclitaxel 80?mg?m?2 (over 1?h), accompanied by gemcitabine 1000?mg?m?2 (over 30?min), was administered i actually.v. on times 1 and 8, recycling every 3 several weeks. Gemcitabine could possibly be risen to 1200?mg?m?2 on the next routine, while paclitaxel could reach 100?mg?m?2 on the 3rd routine. In the GV arm, gemcitabine 1000?mg?m?2 (in 30?min), and vinorelbine 25?mg?m?2 (in 15?min) received i actually.v. on times 1 and 8, recycling every 3 several weeks; gemcitabine could possibly be increased to 1200?mg?m?2 on the second cycle, while vinorelbine could be risen to 30?mg?m?2 on the 3rd cycle. In each arm of the trial, chemotherapy was administered in the current presence of neutrophil count ?1500?dl?1, platelet count ?100?000?dl?1 and after complete recovery from prior nonhaematologic toxicity. In the current presence of neutrophil count 1500 but ?1000?dl?1 and/or platelet count 100?000 but ?75?000?dl?1, a 50% dosage reduction was requested each medication. If lower ideals happened on the original day of every routine, chemotherapy was postponed for weekly, while doses had been omitted if indeed they did take place on time 8 or 15. Anti-emetic treatment and avoidance of allergies were provided regarding to regular guidelines. Supportive treatment was not described in the analysis process, and it had been still left to 163222-33-1 investigator’s choice. Treatment was discontinued regarding documented tumour progression after three cycles, or earlier regarding serious toxicity, deterioration of scientific condition, or withdrawal of patient’s consent. Administration of palliative radiotherapy was still left to the discretion of the going to doctor. After discontinuation of research treatment, no more cytotoxic treatment was administered. Sufferers received symptomatic treatment, and were implemented on a monthly basis for the evaluation of disease position and survival. Evaluation of toxicity and response Toxicity was assessed after every routine of treatment and scored according to Just who criteria (Miller evaluation of survival for sufferers enrolled until that time, allowing for a 6-month minimum follow-up after the last patient had been recruited. A multivariate analysis with a backward selection process 163222-33-1 (Cox, 1972) was also applied to evaluate the best factors individually affecting survival, which includes as discrete covariates: age of sufferers (pretty much than 70 years), performance status (0C1 or 2), previous weight reduction (yes or not really), Charlson score (0C2 or 3C4), histologic subtype (squamous carcinoma, adenocarcinoma, or various other subtypes), stage of disease (IIIB or IV) and treatment (one agent or doublet). RESULTS Patient characteristics From May 1999 to March 2003, 271 patients were authorized into this study. However, seven sufferers weren’t randomised due to incorrect histology (one individual), or no offered baseline information regarding requirements of eligibility (six sufferers). In every, 264 sufferers were randomly assigned to among four arms (Amount 1). A complete of 16 sufferers did not obtain treatment as allocated, due to withdrawal of patient’s consent (five cases), or due to going to physician’s decision (11 situations): these patients weren’t regarded in the evaluation of activity and toxicity, but had been contained in the survival analysis. Open in another window Figure 1 Consolidation of Criteria for Reporting Trials (CONSORT) stream chart of the study. As detailed in Table 1 , most patients (89%) were males. In all, 220 (83%) patients were older than 70 years. Among these, 93 (35%) patients were aged ?75 years, and 14 (5%) were aged ?80 years. However, 44 (17%) patients aged ?70 years were also enrolled because of their poor PS. Regardless of age, 77 (29%) patients got an ECOG PS 2. Squamous cellular carcinoma accounted for 48% of most diagnoses, accompanied by adenocarcinoma (27%). Altogether, 98 (37%) individuals were categorized in stage IIIB, and 166 (63%) individuals had been in stage IV; 41 (25%) of the patients had several metastatic site of disease. A recently available weight reduction was authorized in 91 (34%) individuals. In 87 (33%) individuals no associated illnesses were documented, while 161 (61%) individuals got a Charlson rating one or two 2, and 16 (6%) individuals had a rating ?3 (Table 2 ). All pre-treatment features resulted sensible across the four arms of the trials. Table 1 Characteristics of patients enrolled in the SICOG trial 9909 according to the arm of treatment value=0.051), while difference between GV and GEM was not significant. Open in a separate window Figure 2 Actuarial survival curves of patients according to the four arms of the trial: GEM arm (black diamond), PTX arm (white diamond), GV arm (open circle), GT arm (close circle). The differences did not reach a significant patients treated with either GV or GT showed a significant difference in favour of doublet regimens (Figure 3). Indeed, the MST and 1-year SR were 5.7 (95% CI, 3.9C7.5) months and 28% for single-agent treatments, and 9.2 (95% CI, 7.6C10.8) months and 39% for the combinations (15% in the GEM arm, 17 5% in PTX arm, 28% no response in the GT arm and 38 9.5% in the GV arm. Conversely, no substantial difference of activity was apparent among patients age ?75 years: RR was 15 and 5% in the GEM and PTX arms, respectively, while it resulted 29% in both combination arms. The overall activity of GT resulted significantly greater than that of PTX (either single agent did not reach a level of significance. Noteworthy, the proportion of patients achieving a control of tumour growth (major response or stabilisation) was 37% in the GEM arm, 34% in the PTX arm, 60% in the GT arm and 53% in the GV arm. In this respect, both doublets resulted significantly more active than single agents. Considering the patients treated with at least three cycles, a higher proportion of responses happened among patients in a position to tolerate a dose escalation of both medicines in the GT or GV arm, instead of those in who escalation was limited by gemcitabine, or not really feasible at most: responders were 12 out of 24 (50%) individuals in the GT arm, and seven out of 12 (58%) individuals in the GV arm, instead of seven out of 24 (29%) and 8 out of 40 (20%) individuals, respectively. Conversely, no considerable difference in RR relating to medication escalation was seen in GEM or PTX arm. Responders had been four out of 14 (29%) and four out of 16 (25%) individuals, respectively, finding a full dosage escalation over three cycles, and seven out of 22 (32%) and four out of 21 (19%) individuals, respectively, with partial or no dose escalation. Duration of major responses ranged from 4.6 to 15.0 months, with no substantial differences across the four arms of the study (Table 4 ). Table 4 Summary of activity according to arms of treatment either single agent (MST, 28 and 36 weeks, respectively) (Gridelli em et al /em , 2003). However, 20% of patients entered in the MILES trial were affected by three, and 25% of patients by four or more associated diseases. We wonder whether the greater toxicity, without any survival advantage, elicited in the MILES trial by the combination as compared with each one of the elements could be described by this observation. Another feasible description for the obvious discrepancy between Kilometers and SICOG 9909 studies may depend on the somewhat lower dosages found in that trial for the mixture (vinorelbine 25?mg?m?2 in addition gemcitabine 1000?mg?m?2) than for every single-agent arm (vinorelbine 30?mg?m?2 and gemcitabine 1200?mg?m?2). Although a doseCresponse romantic relationship is certainly unproven in NSCLC, chances are that at least an additive impact might occur when complete dosages of both medications are mixed. As a matter of known fact, in both doublet hands of our research, however, not in the single-agent hands, RR was better among sufferers who could tolerate a dosage escalation over the initial three cycles. Noteworthy, we could actually boost both gemcitabine and vinorelbine in in regards to a quarter of individuals treated with GV. On the other hand, vinorelbine in the MILES trial produced an unexpectedly long-enduring MST, not only longer than the combination, but also greater than that acquired in the previous ELVIS study (Elderly Lung cancer Vinorelbine Italian Study Group, 1999), and even superior to those (ranging from 30 to 32 weeks) reported with this drug in three large randomised trials unrestricted to elderly individuals (Depierre em et al /em , 1994; Le Chevalier em et al /em , 1994; Crawford em et al /em , 1996). As for the single agents of our trial, we would stress that MST (5.1 months) and 1-year SR (30%) obtained in the GEM arm were comparable to those attained by gemcitabine either in the series without an top age limit for inclusion, or in trials specifically designed for elderly patients. Indeed, an MST of 5.7 months and a 25% 1-12 months SR were reported for individuals treated with GEM in a randomised study comparing this drug to the best supportive care (Anderson em et al /em , 2000). In a phase II study restricted to individuals aged more than 70 years, an MST of 6.7 months was achieved with GEM alone (Ricci em et al /em , 2000). Moreover, Quoix (Quoix em et al /em , 2003) recently explored in elderly individuals the activity of two different schedules of gemcitabine (either 1000?mg?m?2 for 3 consecutive weeks every 4 weeks, or 1125?mg?m?2 for 2 consecutive weeks every 3 weeks), reporting a MST of 5.1 and 6.8 months, respectively. In the MILES trial, gemcitabine 1200?mg?m?2 on days 1 and 8 every 3 weeks acquired a MST of 28 several weeks, and a 28% 1-calendar year SR (Gridelli em et al /em , 2003). For the PTX arm, MST (6.4 several weeks) and 1-year SR (24%) achieved inside our research were much like those (6.8 months, and 35%, respectively) reported in a stage III trial comparing this medication with supportive care alone (Ranson em et al /em , 2000). Furthermore, in a big randomised research analyzing the addition of carboplatin to PTX in NSCLC sufferers, the single-agent PTX treatment yielded in the subset of elderly sufferers a MST of 5.0 months, with 1-year SR of 31% (Bunn and Lilenbaum, 2003). Among the secondary end factors of the research was to assess whether there is a considerable difference safely between your regimens utilised. In this respect, we can declare that no extra toxicity derived from the combination of two medicines in comparison with a single agent. Among doublets, similar proportions of individuals treated with either GV or GT were affected by side effects of any grade, and few episodes of grade 4 neutropenia and/or febrile neutropenia, and also of severe nonhaematologic toxicity, occurred in both hands. These results were most likely a rsulting consequence the tailored strategy we’ve used, applying extremely cautious guidelines for dose decrease/omission in the current presence of haematologic toxicity, escalating the cytotoxic medicines just in the lack of relevant toxicity on earlier routine, and discontinuing any chemotherapy in individuals showing no very clear reap the benefits of such treatment. This prudential strategy has been used in thought of the unpredictable occurrence in elderly topics of unwanted effects from cytotoxic medicines also in the current presence of apparently regular organ features (Lichtman em et al /em , 1999; Aapro em et al /em , 2000). As a matter of known fact, the occurrence of serious bone marrow toxicity was actually lower in today’s trial than inside our previous study (Frasci em et al /em , 2000), in which full doses of gemcitabine (1200?mg?m?2) plus vinorelbine (30?mg?m?2) were administered from the beginning, while dose-reduction rules during treatment were exactly the same. Besides the PS of patients, we were unable to identify other pre-treatment features significantly affecting the treatment compliance in this study. Since the proportion of patients with poor PS did not differ in this and in our previous trial, we may argue that the pragmatic adaptation of treatment intensity represents a good way to improve the tolerability of cytotoxic drugs in elderly people. In conclusion, this trial showed that survival of elderly advanced NSCLC patients, carefully selected on the basis of their Charlson score, may be prolonged using a non-cisplatin-based doublet, at the price of acceptable side effects. The significantly greater efficacy of doublets over a single agent was confirmed in the multivariate analysis. GT combination was associated with the best therapeutic index, and should certainly be a reference routine for these individuals. However, an unhealthy performance position was independently connected with a even worse survival no matter treatment employed. As a result, potential trials exploring fresh regimens ought to be restricted to individuals with an ECOG PS ?1. Acknowledgments We desire to gratefully thank Ms Marina Licenziato on her behalf invaluable function in the info administration. We are also deeply indebted to Dr Maurizio Montella (Head, Assistance of Epidemiology and Biostatistics, National Tumour Institute of Naples) for his tips and remarks in the statistical evaluation of the trial.. limited to elderly or unfit NSCLC individuals with a Charlson rating ?4. The principal goal of this trial was to assess whether the combination of gemcitabine plus either vinorelbine or paclitaxel could prolong the survival of patients in comparison with gemcitabine or paclitaxel alone. Secondary end points were time to treatment failure, response rate and toxicity. Furthermore, because at that time there was no agreement on the optimal dosage of these compounds for managing aged patients, and given the unpredictable tolerability of chemotherapy in elderly people, we used an individual dose optimisation (Frasci IV), PS (0C1 2), and Charlson score (0C2 3C4), and allocated using a computer-generated random list into one of four arms: gemcitabine (GEM), paclitaxel (PTX), gemcitabine plus paclitaxel (GT), or gemcitabine plus vinorelbine (GV). In all arms of the trial, at least three cycles were planned before the evaluation of activity, and additional treatment was administered up to optimum of six cycles only when at least an illness control was demonstrated. In the lack of World Wellness Organization (WHO) quality ?2 toxicity on previous routine, an intra-patient dosage escalation over the initial three cycles was planned in every arms of the trial, and the dosage reached in the third cycle was used thereafter. In the GEM arm, the first cycle consisted of gemcitabine 1200?mg?m?2 infused intravenously (i.v.) over 30?min on days 1, 8 and 15, recycling every 4 weeks. Gemcitabine could be increased to 1400?mg?m?2 on the second cycle, and to 1600?mg?m?2 on the 3rd routine. In the PTX arm, initial dosage was 100?mg?m?2 infused i.v. over 1?h in times 1, 8 and 15, recycling every four weeks. EM9 PTX could possibly be risen to 120?mg?m?2 on the next cycle, also to 140?mg?m?2 on the 3rd routine. In the GT arm, paclitaxel 80?mg?m?2 (over 1?h), accompanied by gemcitabine 1000?mg?m?2 (over 30?min), was administered i actually.v. on times 1 and 8, recycling every 3 several weeks. Gemcitabine could possibly be risen to 1200?mg?m?2 on the next routine, while paclitaxel could reach 100?mg?m?2 on the 3rd routine. In the GV arm, gemcitabine 1000?mg?m?2 (in 30?min), and vinorelbine 25?mg?m?2 (in 15?min) received i actually.v. on times 1 and 8, recycling every 3 several weeks; gemcitabine could possibly be increased to 1200?mg?m?2 on the second cycle, while vinorelbine could be increased to 30?mg?m?2 163222-33-1 on the third cycle. In each arm of the trial, chemotherapy was administered in the presence of neutrophil count ?1500?dl?1, platelet count ?100?000?dl?1 and after complete recovery from previous nonhaematologic toxicity. In the presence of neutrophil count 1500 but ?1000?dl?1 and/or platelet count 100?000 but ?75?000?dl?1, a 50% dose reduction was applied for each drug. If lower values occurred on the initial day of each cycle, chemotherapy was postponed for a week, while doses were omitted if they did occur on day 8 or 15. Anti-emetic treatment and prevention of allergic reactions were provided regarding to regular guidelines. Supportive treatment was not described in the analysis process, and it had been still left to investigator’s choice. Treatment was discontinued regarding documented tumour progression after three cycles, or earlier regarding serious toxicity, deterioration of scientific condition, or withdrawal of patient’s consent. Administration of palliative radiotherapy was still left to the discretion of the going to doctor. After discontinuation of research treatment, no more cytotoxic treatment was administered. Sufferers received symptomatic treatment, and were implemented on a monthly basis for the evaluation of disease position and survival. Evaluation of toxicity and response Toxicity was assessed after every routine of treatment and have scored regarding to WHO criteria (Miller analysis of survival for individuals enrolled until that day, allowing for a 6-month minimum follow-up after the last individual had been recruited. A multivariate analysis with a backward selection process (Cox, 1972) was also applied to evaluate the best factors independently affecting survival, including as discrete covariates: age of individuals (more or less than 70 years), performance status (0C1 or 2), previous weight loss (yes or not), Charlson score (0C2 or 3C4), histologic subtype (squamous carcinoma, adenocarcinoma, or additional subtypes), stage of disease (IIIB or IV).