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Gemcitabine (GEM) and Vindesine (VDS) in advanced non-small cell lung cancer (NSCLC): A phase II study in elderly or poor performance status patients
Lung Cancer (2006) 53, 355—360
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Gemcitabine (GEM) and Vindesine (VDS) in advanced non-small cell lung cancer (NSCLC): A phase II study in elderly or poor performance status patients Antonio Santo a,f,∗, Giovenzio Genestreti a,f, Alberto Terzi b,f, Paolo Azzoni c, Teodoro Sava a, Pietro Manno a, Annamaria Molino a, Cristian Pattaro d, Rocco Micciolo e, Gian Luigi Cetto a a
Department of Medical Oncology, University of Verona, Italy Department of Thoracic Surgery, OCM, Azienda Ospedaliera, Verona, Italy c Day Hospital of Medical Oncology, OC Bussolengo, Verona, Italy d Unit of Epidemiology & Medical Statistics, Department of Medicine and Public Health, University of Verona, Italy e University of Trento, Italy f Gruppo Interdisciplinare Veronese di Oncologia Polmonare (GIVOP), Italy b
Received 1 February 2006; received in revised form 13 April 2006; accepted 16 May 2006
KEYWORDS Advanced NSCLC; Non-platinum-based chemotherapy; Gemcitabine; Vindesine
Summary The aim of the study was to assess the activity and tolerability of the combination of gemcitabine (GEM) and vindesine (VDS) in elderly or poor performance patients with advanced non-small cell lung cancer. Forty four patients (36 males and 8 females with a median age of 70 years and a median Karnofsky performance score of 60) were recruited between January 1998 and June 2001; 9 (20.5%) were stage IIIB patients and 35 (79.5%) were stage IV patients; 20 (45.5%) had squamous carcinoma and 24 (54.5%) non-squamous carcinoma. The patients received GEM 1000 mg/m2 and VDS 3 mg/m2 (max 5 mg) on days 1 and 8 every 3 weeks, and were all evaluable for response and toxicity: 17 (38.6%) were partial responders, 17 (38.6%) experienced stable disease, and 10 (22.3%) progressive disease. Grade 3—4 anemia, neutropenia and thrombocytopenia were observed in, respectively, 6.8, 9.1 and 2.3% of the patients, and grade 2—3 fatigue, paresthesias and skin toxicity in, respectively, 11.4, 20.4 and 2.3%. After a median follow-up of 54 months, 43/44 patients died; median survival was 12 months, and a clinical benefit was observed in 54.5% of cases. GEM plus VDS is an active and well-tolerated schedule. © 2006 Elsevier Ireland Ltd. All rights reserved.
∗
Corresponding author at: Divisione Clinicizzata di Oncologia Medica, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. Tel.: +39 045 8072342; fax: +39 045 8341277. E-mail address: [email protected] (A. Santo). 0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.05.013
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1. Introduction Lung cancer is the leading cause of cancer deaths in Europe and North America, accounting for approximately 30% of all cancer deaths. Its incidence increases with advancing age, especially between 40 and 75, and peaks at 55 years. In the United States, 180,000 new cases are diagnosed annually, of which 75—80% are NSCLC [1]. More than 65% of NSCLCs are diagnosed with advanced stage, and are thus not suitable for surgical or radiotherapeutic loco-regional treatment; for this group of patients, cisplatin-based chemotherapy is the treatment of choice. A 1995 meta-analysis by the NSCLC Cooperative Group compared cisplatin-based chemotherapy with best supportive care, and showed that the benefit of the former included an absolute 10% increase in the 1-year survival rate and a 27% reduction in the risk of death [2]. However, very few studies have considered the role of chemotherapy in patients aged more than 70 years (onethird of the cases) or those with a poor performance status. Elderly patients have frequently been excluded from prospective clinical trials [3], and they are rarely offered cisplatin-based chemotherapy because of the high risk of toxicity and iatrogenic mortality related to their physiological reduction in functional reserve and the presence of comorbidities [4—6]. A number of promising new antineoplastic agents with different mechanisms of action and encouraging toxicity profiles have recently been shown to have significant activity in advanced NSCLC. These include gemcitabine (GEM), an antimetabolite analogue that is structurally similar to cytosina arabinoside, active in NSCLC which, alone or in combination with cisplatin, has shown a favourable toxicity profile in several phase II trials allowing its use in elderly patients [7—11]. The most frequent side effects are hematological events, flu-like syndrome, fever and hepatotoxicity. Vindesine (VDS) is also active in NSCLC, with response rates of 18% in monochemotherapy [12] and 22—30% in combination with cisplatin and mitomycin C, and has a favourable toxicity profile [13]. Its acute dose-limiting toxicities are myelosuppression and neurotoxicity. We planned this phase II study to assess the activity and tolerability of the GEM/VDS combination in elderly or poor performance status patients with locally advanced or metastatic NSCLC.
A. Santo et al. limit; AST and/or ALT less than three times the upper normal limit in the absence of liver metastasis, or less than five times in the presence of liver metastasis; a prothrombin time of <1.5 times that of control), and creatinine clearance of >60 mL/min. A life expectancy of at least 12 weeks was also required. The exclusion criteria included cardiac arrhythmia or heart failure, second- or third-degree heart block, and acute myocardial infarction in the 6 months preceding study entry. Patients with severe immunological defects or a diagnosis of other malignancies in the 5 years preceding the start of the trial were not enrolled with the exceptions of adequately treated basal cell carcinoma or in situ cervical carcinoma. Asymptomatic central nervous system metastasis was not considered as an exclusion criterion. The trial was approved by the Institutional Review Board of each trial centre, and all of the patients gave their written informed consent before enrolment.
2.2. Treatment GEM 1000 mg/m2 was administered as a 30-min intravenous infusion in 250 mL of saline solution, and VDS 3 mg/m2 (max 5 mg) as a 15-min intravenous infusion in 100 mL of saline solution: both treatments were given on days 1 and 8 every 3 weeks. This variation of the Sorensen regimen [14] was designed to reduce the risk of hematological (neutropenia and thrombocytopenia) and non-hematological toxicity (paresthesias). All of the patients received anti-emetic prophylaxis with 20 mg of metoclopramide. Before the GEM infusion, 8 mg of intravenous dexamethasone was administered to avoid flulike syndrome. The doses of both drugs were reduced by 25% on day 8 in patients with absolute neutrophil counts of (1000—1500) × 106 cells/L, and/or platelet counts of (75,000—100,000) × 106 cells/L. The treatment was delayed by 7 days in the case of an absolute neutrophil count of <1000 × 106 cells/L or a platelet count of <75,000 × 106 cells/L. If the absolute neutrophil count was <1500 × 106 cells/L and the platelet count <100,000 × 106 cells/L on day 21, treatment was delayed by 1 week or until complete bone marrow recovery. The patients whose therapy was delayed for more than 2 weeks were withdrawn from the trial.
2. Patients and methods 2.1. Eligibility criteria
2.3. Pretreatment evaluation and response criteria
The patients were considered eligible if they had a histological or cytological diagnosis of locally advanced (stage IIIB with positive cytological pleural effusion or metastatic supraclavicular lymph nodes) or advanced (stage IV) NSCLC, with controindications to platinum-based chemotherapy (a Karnofsky performance status of ≤60 with an age of ≤70 years, or age of >70 years). The enrolled patients had to have adequate bone marrow function (an absolute neutrophil count of ≥1.5 × 109 cells/L, platelets ≥100 × 109 cells/L, hemoglobin ≥10 g/dL), liver function (bilirubin level less than twice the upper normal
The pretreatment evaluation included a complete history and physical examination, ECG, chest X-ray, fiberoptic bronchoscopy, complete computed tomography scans of the brain, chest and abdomen, and radionuclide bone scans. Comordities were also carefully evaluated before starting chemotherapy, and the score was calculated for each patient according to the KPS criteria. A physical examination, with the assessment of KPS and disease-related symptoms (e.g. cough, dyspnea, pain, weight loss, hemoptysis and fatigue), and laboratory tests were performed before each chemotherapy cycle.
GEM and VDS in advance NSCLC: a phase II study in elderly or poor performance status patients After three cycles, all of the patients underwent a complete tumour response assessment using all of the procedures required to evaluate treatment response according to the WHO criteria. A complete response (CR) was defined as the disappearance of all known lesions, and a partial response (PR) as a >50% decrease in the total size of all the measurable lesions, without the progression of any lesion or the appearance of a new lesion. Stable disease (SD) was defined as a <25% decrease or a <25% increase in tumour size, and progressive disease (PD) as the appearance of any new lesion or a >25% increase in the sum of the perpendicular diameters of any measurable lesion or the estimated size of a non-measurable lesion [15]. Three more chemotherapy cycles were administered to the complete or partial responders, and those with stable disease. Patients were withdrawn from the study when progressive disease was documented clinically and/or radiographically. All adverse events were recorded regardless of their relationship to the chemotherapy.
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not be considered either positive or negative was classified as stable [16]. 2.4.3. Weight Patient weight at baseline was recorded at study entry and every visit thereafter. A positive result was defined as a weight gain of at least 7% in comparison with baseline. A non-positive result was the development of any third space fluid (ascites, pleural effusion or edema), a need for parenteral nutrition, or any other weight change or stabilisation [16].
2.5. Statistical methods and study design The primary study endpoint was treatment response. The secondary endpoints were clinical benefit, time to progression (TTP), and overall survival (OS). TTP and OS were defined as the time from the date of enrolment to the date of disease progression or death. Survival was analyzed using the Kaplan—Meier method and Cox’s proportional hazard regression model.
2.4. Measuring clinical benefit Clinical benefit is a composite assessment of the symptoms related to lung cancer. In order to be considered as receiving a clinical benefit, the patients had to show an improvement in at least one primary parameter (pain intensity and/or total analgesic intake and/or KPS) without any detriment in any of the others. The patients showing no change in all three primary measures (pain intensity, analgesic intake, KPS) but an improvement in the secondary measure (weight) were also classified as having received a clinical benefit [16]. 2.4.1. Pain Pain intensity was assessed before each chemotherapy cycle using a Pain Assessment Card with a scale from 0 (least severe pain) to 10 (the most severe pain). A positive result (i.e. reduced pain) was defined as a reduction of at least 50% from baseline, and an improvement as a reduction of at least 20% from baseline; a negative result (i.e. increased pain) was defined as any worsening in pain symptoms lasting at least four consecutive weeks. Any pain intensity that could not be considered either positive or negative was classified as stable. Baseline analgesic consumption was defined as the mean analgesic consumption (expressed as milligrams of morphine-equivalents or anti-inflammatory drugs per day) in the week before starting chemotherapy. A positive result was defined as a reduction in analgesic intake of at least 50% in comparison with baseline, and a negative result as any increase in analgesic intake. Any analgesic consumption that could not be considered either positive or negative was classified as stable [16]. 2.4.2. Performance status KPS was determined at the study entry and at each visit thereafter. In the case of patients with a baseline KPS of ≤60, a positive result was defined as a ≥20 point increase in comparison with baseline maintained for at least 4 weeks, and a negative result as a decrease of at least 20 points from baseline for at least 4 weeks. Any change in KPS that could
3. Results 3.1. Patient characteristics Forty-four patients with unresectable NSCLC were enrolled by the Oncology Unit of Verona and Bussolengo hospitals between January 1998 and June 2001, all of whom were assessable for response, toxicity and clinical benefit. There were 36 males (81.8%) and 8 females, with a median age at diagnosis of 70 years (range 43—79); KPS was >60 in 19 patients (43.2%) and ≤60 in 25. Twenty patients had squamous cell carcinomas (45.5%), 15 adenocarcinomas (34.1%), 6 large-cell carcinomas (13.6%) and 3 undifferentiated carcinomas (6.8%); 9 patients were in disease stage IIIB (20.5%) and 35 in stage IV (79.5%).
3.2. Treatment delivery A total of 205 cycles were delivered, 121 (59%) of which were administered at full doses; the patients received a median of five cycles (range 2—8). GEM dose-intensity was 94%, with dose reductions being required because of the onset of neutropenia and thrombocytopenia; VDS dose-intensity was 87%, with dose reductions being required because of the onset of grade 2—3 neurotoxicity and constipation.
3.3. Toxicity Toxicity was assessed according to the WHO criteria in all of the patients who completed at least one chemotherapy cycle. A complete blood count was made weekly in order to evaluate hematological toxicity at nadir. Table 1 summarises the most important hematological and non-hematological toxicities. The only grade 4 adverse event was febrile neutropenia in one patient and so the exact upper 95% CI for the probability of having grade 4 neutropenia was 0.066, whereas that for the other hematological toxicities was 0.103. The frequency of grade 3 or 4 hematological toxicities
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A. Santo et al.
Table 1 Hematological and non-hematological toxicities: number of patientsa (%) Toxicity
WHO grade 2
3
4
Hematological Neutropenia Anemia Thrombocytopenia
1 (2.3) 5 (11.4) 5 (11.4)
3 (6.8) 3 (6.8) 1 (2.3)
1b (2.3) 0 0
Non-hematological Vomiting Dermatological Paresthesias Fatigue Constipation Fever Hair loss
0 1 6 3 3 3 2
0 1 3 2 0 0 1
0 0 0 0 0 0 0
a b
(2.3) (13.6) (6.8) (6.8) (6.8) (4.6)
(2.3) (6.8) (4.6)
(2.3)
Patients evaluable after at least one cycle. Febrile neutropenia.
was 9.1% (95% CI: 2.5—21.7%); the frequency of grade 3 or 4 non-hematological toxicities was 6.8% (95% CI: 1.4—18.7%).
3.4. Response All of the patients received at least two chemotherapy cycles and were assessed for response: 17 showed a PR (38.6%; 95% CI: 24.4—54.5%), 17 (38.6%) SD, and 10 (22.8%) PD.
3.5. Survival Fig. 1 shows overall survival: 43 patients had died after 58 months. Median survival was 12.2 months (95% CI: 7.4—17.3), and the 1- and 2-year survival rates were, respectively, 50% (95% CI: 34—64%) and 20% (95% CI: 10—33%). Three patients died of causes unrelated to their tumour (one stroke, one myocardial infarction, one acute pulmonary edema). After 3 months of treatment, the patients were classified into two groups on the basis of their response (those with a PR and those with SD or PD), and the sur-
Fig. 1
Kaplan—Meier estimate of overall survival.
vival of the 40 patients who lived for at least 3 months was calculated. The median survival (after the 3-month assessment) of the 17 patients with a PR was 17.1 months (95% CI: 11.2—23.8), whereas that of the remaining 23 was 5.1 months (95% CI: 2.8—9.3). The non-responders had a hazard ratio that was 2.6 times that of the responders (95% CI: 1.3—5.2).
3.6. Time to progression The median time to progression was 7.1 months (95% CI: 5.1—9.0). Twelve months after enrolment, about 78% of the patients showed progression (95% CI: 64—89%).
3.7. Clinical benefit Twenty-four patients (54.5%; 95% CI: 38.8—69.6%) received a clinical benefit: 94% of the patients with a PR (16/17) and 47% of those with SD (8/17); this difference was highly significant at Fisher’s exact test (p < 0.001).
4. Discussion About one-third of all NSCLC patients are aged more than 70 years, but elderly patients are under-represented in clinical trials evaluating new treatments for advanced disease [3]. A number of randomised trials and meta-analyses have demonstrated that chemotherapy can improve the survival of patients with advanced disease [2], and cisplatinbased chemotherapy has so far played a pivotal role in the treatment of NSCLC. However, cisplatin-based chemotherapy (with its associated renal and neurological toxicities) is usually avoided in elderly patients because of their comorbidities and impaired organ function [6], and so identifying new regimens not based on cisplatin may improve the palliative therapy of elderly or poor performance patients with advanced NSCLC. New agents for the treatment of advanced NSCLC, such as GEM, vinorelbine (VNR), taxanes and camptothecin, have been introduced over the last 10 years, and their good activity (20% response rates in monotherapy) and favourable toxicity profiles have increased the possibility of treatment also for elderly patients [17]. A number of phase II studies have shown that single-agent GEM therapy leads to an overall response rate of approximately 20%, with little hematological (very dangerous in elderly patients) and non-hematological toxicity (nausea, alopecia, hepatic and renal toxicity) [9,18]. Furthermore, monotherapy with vinca alkaloids has been found to be active, with several phase II studies showing response rates of 30% for VNR [17,19] and 20% for VDS [11], with only mild toxicity. The randomised phase III Elderly Lung Cancer VNR Italian (ELVIS) trial unequivocally confirmed that chemotherapy with VNR alone is more advantageous than best supportive care in terms of survival and clinical benefit in patients aged more than 70 years with stage IIIB/IV NSCLC [20]. The gain in median survival was slight (7 weeks), but similar to that obtained with cisplatin-based chemotherapy in comparison with best supportive care. On the basis of the results of a
GEM and VDS in advance NSCLC: a phase II study in elderly or poor performance status patients recent meta-analysis confirming that polychemotherapy is more active than monochemotherapy [21], several phase II studies combined GEM and VNR in an attempt to exploit their different molecular mechanisms and good tolerability, all of which demonstrated the greater activity of the combination, with overall response rates of 25—40% and median survival rates of approximately 8—13 months [22—26]. However, the randomised phase III trials of monotherapy versus platinum-free polychemotherapy published have led to conflicting results in terms of OS and the quality of life. For example, the randomised phase III MILES study published in 2003 found that the GEM/VNR combination did not lead to any benefit over either drug alone in terms of survival or the control of disease-related symptoms [27], whereas Frasci et al. found that the combination offered elderly NSCLC patients statistically significant advantages in terms of response rate, OS and the quality of life in comparison with VNR alone [28]. Furthermore, at ASCO 2004, Abratt et al. presented the results of a phase III trial in which GEM/VNR was compared with carboplatin/VNR: there was no difference between the two arms in OS, but the schedule without platinum had a better tolerability profile [29]. In the present phase II study, we used GEM/VDS rather than GEM/VNR because of its greater synergism [30] and better tolerability profile. Kanzawa et al. have demonstrated in vitro that the synergism of GEM and VDS is comparable with that observed with GEM and cisplatin, whereas the interaction between GEM and VNR was only additive and not synergistic [30]. In a randomised study of VNR versus VDS in stage IIIB and IV NSCLC patients, Furuse et al. [31] found that VNR led to a higher response rate, but greater hematological and cutaneous toxicity. In our phase II study, 17 patients achieved a PR for an overall response rate of 39%, which is higher than that reported for single-agent GEM or VNR, but quite similar to the approximately 35% reported by other investigators in phase II trials of GEM and VNR [20—26]. The toxicity profile observed in our study was more favourable than that observed in other phase II studies of GEM and VNR, thus suggesting that our schedule can be easily administered to elderly or poor performance status patients. Our results contrast with those reported by Sorensen et al. [14], who tested GEM and VDS in previously untreated NSCLC patients and reported an overall response rate of 20% and a median survival of 31 weeks, with greater hematological and non-hematological toxicity, and a worse quality of life. However, their schedule consisted of GEM 1000 mg/m2 on day 1,8 and 15, and VDS 3 mg/m2 every week for the first 7 weeks and then every other week. These results can be interpreted according to the in vitro evidences of Kanzawa et al. who demonstrated a synergistic interaction between GEM and VDS at lower concentrations rather than at higher ones. In conclusion, the results of our study show that GEM/VDS is an active combination in the treatment of advanced NSCLC, and based on its good tolerability profile it can be proposed to patients with controindications to platinumbased chemotherapy, i.e. elderly patients with severe comorbidities or a KPS of ≤60. A phase III trial is currently ongoing in order to confirm that this combination has advantages over monochemotherapy in terms of survival or the quality of life.
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Acknowledgement This study was supported by GIVOP (Gruppo Interdisciplinare Veronese di Oncologia Polmonare).
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journal homepage: www.elsevier.com/locate/lungcan
Gemcitabine (GEM) and Vindesine (VDS) in advanced non-small cell lung cancer (NSCLC): A phase II study in elderly or poor performance status patients Antonio Santo a,f,∗, Giovenzio Genestreti a,f, Alberto Terzi b,f, Paolo Azzoni c, Teodoro Sava a, Pietro Manno a, Annamaria Molino a, Cristian Pattaro d, Rocco Micciolo e, Gian Luigi Cetto a a
Department of Medical Oncology, University of Verona, Italy Department of Thoracic Surgery, OCM, Azienda Ospedaliera, Verona, Italy c Day Hospital of Medical Oncology, OC Bussolengo, Verona, Italy d Unit of Epidemiology & Medical Statistics, Department of Medicine and Public Health, University of Verona, Italy e University of Trento, Italy f Gruppo Interdisciplinare Veronese di Oncologia Polmonare (GIVOP), Italy b
Received 1 February 2006; received in revised form 13 April 2006; accepted 16 May 2006
KEYWORDS Advanced NSCLC; Non-platinum-based chemotherapy; Gemcitabine; Vindesine
Summary The aim of the study was to assess the activity and tolerability of the combination of gemcitabine (GEM) and vindesine (VDS) in elderly or poor performance patients with advanced non-small cell lung cancer. Forty four patients (36 males and 8 females with a median age of 70 years and a median Karnofsky performance score of 60) were recruited between January 1998 and June 2001; 9 (20.5%) were stage IIIB patients and 35 (79.5%) were stage IV patients; 20 (45.5%) had squamous carcinoma and 24 (54.5%) non-squamous carcinoma. The patients received GEM 1000 mg/m2 and VDS 3 mg/m2 (max 5 mg) on days 1 and 8 every 3 weeks, and were all evaluable for response and toxicity: 17 (38.6%) were partial responders, 17 (38.6%) experienced stable disease, and 10 (22.3%) progressive disease. Grade 3—4 anemia, neutropenia and thrombocytopenia were observed in, respectively, 6.8, 9.1 and 2.3% of the patients, and grade 2—3 fatigue, paresthesias and skin toxicity in, respectively, 11.4, 20.4 and 2.3%. After a median follow-up of 54 months, 43/44 patients died; median survival was 12 months, and a clinical benefit was observed in 54.5% of cases. GEM plus VDS is an active and well-tolerated schedule. © 2006 Elsevier Ireland Ltd. All rights reserved.
∗
Corresponding author at: Divisione Clinicizzata di Oncologia Medica, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. Tel.: +39 045 8072342; fax: +39 045 8341277. E-mail address: [email protected] (A. Santo). 0169-5002/$ — see front matter © 2006 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.lungcan.2006.05.013
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1. Introduction Lung cancer is the leading cause of cancer deaths in Europe and North America, accounting for approximately 30% of all cancer deaths. Its incidence increases with advancing age, especially between 40 and 75, and peaks at 55 years. In the United States, 180,000 new cases are diagnosed annually, of which 75—80% are NSCLC [1]. More than 65% of NSCLCs are diagnosed with advanced stage, and are thus not suitable for surgical or radiotherapeutic loco-regional treatment; for this group of patients, cisplatin-based chemotherapy is the treatment of choice. A 1995 meta-analysis by the NSCLC Cooperative Group compared cisplatin-based chemotherapy with best supportive care, and showed that the benefit of the former included an absolute 10% increase in the 1-year survival rate and a 27% reduction in the risk of death [2]. However, very few studies have considered the role of chemotherapy in patients aged more than 70 years (onethird of the cases) or those with a poor performance status. Elderly patients have frequently been excluded from prospective clinical trials [3], and they are rarely offered cisplatin-based chemotherapy because of the high risk of toxicity and iatrogenic mortality related to their physiological reduction in functional reserve and the presence of comorbidities [4—6]. A number of promising new antineoplastic agents with different mechanisms of action and encouraging toxicity profiles have recently been shown to have significant activity in advanced NSCLC. These include gemcitabine (GEM), an antimetabolite analogue that is structurally similar to cytosina arabinoside, active in NSCLC which, alone or in combination with cisplatin, has shown a favourable toxicity profile in several phase II trials allowing its use in elderly patients [7—11]. The most frequent side effects are hematological events, flu-like syndrome, fever and hepatotoxicity. Vindesine (VDS) is also active in NSCLC, with response rates of 18% in monochemotherapy [12] and 22—30% in combination with cisplatin and mitomycin C, and has a favourable toxicity profile [13]. Its acute dose-limiting toxicities are myelosuppression and neurotoxicity. We planned this phase II study to assess the activity and tolerability of the GEM/VDS combination in elderly or poor performance status patients with locally advanced or metastatic NSCLC.
A. Santo et al. limit; AST and/or ALT less than three times the upper normal limit in the absence of liver metastasis, or less than five times in the presence of liver metastasis; a prothrombin time of <1.5 times that of control), and creatinine clearance of >60 mL/min. A life expectancy of at least 12 weeks was also required. The exclusion criteria included cardiac arrhythmia or heart failure, second- or third-degree heart block, and acute myocardial infarction in the 6 months preceding study entry. Patients with severe immunological defects or a diagnosis of other malignancies in the 5 years preceding the start of the trial were not enrolled with the exceptions of adequately treated basal cell carcinoma or in situ cervical carcinoma. Asymptomatic central nervous system metastasis was not considered as an exclusion criterion. The trial was approved by the Institutional Review Board of each trial centre, and all of the patients gave their written informed consent before enrolment.
2.2. Treatment GEM 1000 mg/m2 was administered as a 30-min intravenous infusion in 250 mL of saline solution, and VDS 3 mg/m2 (max 5 mg) as a 15-min intravenous infusion in 100 mL of saline solution: both treatments were given on days 1 and 8 every 3 weeks. This variation of the Sorensen regimen [14] was designed to reduce the risk of hematological (neutropenia and thrombocytopenia) and non-hematological toxicity (paresthesias). All of the patients received anti-emetic prophylaxis with 20 mg of metoclopramide. Before the GEM infusion, 8 mg of intravenous dexamethasone was administered to avoid flulike syndrome. The doses of both drugs were reduced by 25% on day 8 in patients with absolute neutrophil counts of (1000—1500) × 106 cells/L, and/or platelet counts of (75,000—100,000) × 106 cells/L. The treatment was delayed by 7 days in the case of an absolute neutrophil count of <1000 × 106 cells/L or a platelet count of <75,000 × 106 cells/L. If the absolute neutrophil count was <1500 × 106 cells/L and the platelet count <100,000 × 106 cells/L on day 21, treatment was delayed by 1 week or until complete bone marrow recovery. The patients whose therapy was delayed for more than 2 weeks were withdrawn from the trial.
2. Patients and methods 2.1. Eligibility criteria
2.3. Pretreatment evaluation and response criteria
The patients were considered eligible if they had a histological or cytological diagnosis of locally advanced (stage IIIB with positive cytological pleural effusion or metastatic supraclavicular lymph nodes) or advanced (stage IV) NSCLC, with controindications to platinum-based chemotherapy (a Karnofsky performance status of ≤60 with an age of ≤70 years, or age of >70 years). The enrolled patients had to have adequate bone marrow function (an absolute neutrophil count of ≥1.5 × 109 cells/L, platelets ≥100 × 109 cells/L, hemoglobin ≥10 g/dL), liver function (bilirubin level less than twice the upper normal
The pretreatment evaluation included a complete history and physical examination, ECG, chest X-ray, fiberoptic bronchoscopy, complete computed tomography scans of the brain, chest and abdomen, and radionuclide bone scans. Comordities were also carefully evaluated before starting chemotherapy, and the score was calculated for each patient according to the KPS criteria. A physical examination, with the assessment of KPS and disease-related symptoms (e.g. cough, dyspnea, pain, weight loss, hemoptysis and fatigue), and laboratory tests were performed before each chemotherapy cycle.
GEM and VDS in advance NSCLC: a phase II study in elderly or poor performance status patients After three cycles, all of the patients underwent a complete tumour response assessment using all of the procedures required to evaluate treatment response according to the WHO criteria. A complete response (CR) was defined as the disappearance of all known lesions, and a partial response (PR) as a >50% decrease in the total size of all the measurable lesions, without the progression of any lesion or the appearance of a new lesion. Stable disease (SD) was defined as a <25% decrease or a <25% increase in tumour size, and progressive disease (PD) as the appearance of any new lesion or a >25% increase in the sum of the perpendicular diameters of any measurable lesion or the estimated size of a non-measurable lesion [15]. Three more chemotherapy cycles were administered to the complete or partial responders, and those with stable disease. Patients were withdrawn from the study when progressive disease was documented clinically and/or radiographically. All adverse events were recorded regardless of their relationship to the chemotherapy.
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not be considered either positive or negative was classified as stable [16]. 2.4.3. Weight Patient weight at baseline was recorded at study entry and every visit thereafter. A positive result was defined as a weight gain of at least 7% in comparison with baseline. A non-positive result was the development of any third space fluid (ascites, pleural effusion or edema), a need for parenteral nutrition, or any other weight change or stabilisation [16].
2.5. Statistical methods and study design The primary study endpoint was treatment response. The secondary endpoints were clinical benefit, time to progression (TTP), and overall survival (OS). TTP and OS were defined as the time from the date of enrolment to the date of disease progression or death. Survival was analyzed using the Kaplan—Meier method and Cox’s proportional hazard regression model.
2.4. Measuring clinical benefit Clinical benefit is a composite assessment of the symptoms related to lung cancer. In order to be considered as receiving a clinical benefit, the patients had to show an improvement in at least one primary parameter (pain intensity and/or total analgesic intake and/or KPS) without any detriment in any of the others. The patients showing no change in all three primary measures (pain intensity, analgesic intake, KPS) but an improvement in the secondary measure (weight) were also classified as having received a clinical benefit [16]. 2.4.1. Pain Pain intensity was assessed before each chemotherapy cycle using a Pain Assessment Card with a scale from 0 (least severe pain) to 10 (the most severe pain). A positive result (i.e. reduced pain) was defined as a reduction of at least 50% from baseline, and an improvement as a reduction of at least 20% from baseline; a negative result (i.e. increased pain) was defined as any worsening in pain symptoms lasting at least four consecutive weeks. Any pain intensity that could not be considered either positive or negative was classified as stable. Baseline analgesic consumption was defined as the mean analgesic consumption (expressed as milligrams of morphine-equivalents or anti-inflammatory drugs per day) in the week before starting chemotherapy. A positive result was defined as a reduction in analgesic intake of at least 50% in comparison with baseline, and a negative result as any increase in analgesic intake. Any analgesic consumption that could not be considered either positive or negative was classified as stable [16]. 2.4.2. Performance status KPS was determined at the study entry and at each visit thereafter. In the case of patients with a baseline KPS of ≤60, a positive result was defined as a ≥20 point increase in comparison with baseline maintained for at least 4 weeks, and a negative result as a decrease of at least 20 points from baseline for at least 4 weeks. Any change in KPS that could
3. Results 3.1. Patient characteristics Forty-four patients with unresectable NSCLC were enrolled by the Oncology Unit of Verona and Bussolengo hospitals between January 1998 and June 2001, all of whom were assessable for response, toxicity and clinical benefit. There were 36 males (81.8%) and 8 females, with a median age at diagnosis of 70 years (range 43—79); KPS was >60 in 19 patients (43.2%) and ≤60 in 25. Twenty patients had squamous cell carcinomas (45.5%), 15 adenocarcinomas (34.1%), 6 large-cell carcinomas (13.6%) and 3 undifferentiated carcinomas (6.8%); 9 patients were in disease stage IIIB (20.5%) and 35 in stage IV (79.5%).
3.2. Treatment delivery A total of 205 cycles were delivered, 121 (59%) of which were administered at full doses; the patients received a median of five cycles (range 2—8). GEM dose-intensity was 94%, with dose reductions being required because of the onset of neutropenia and thrombocytopenia; VDS dose-intensity was 87%, with dose reductions being required because of the onset of grade 2—3 neurotoxicity and constipation.
3.3. Toxicity Toxicity was assessed according to the WHO criteria in all of the patients who completed at least one chemotherapy cycle. A complete blood count was made weekly in order to evaluate hematological toxicity at nadir. Table 1 summarises the most important hematological and non-hematological toxicities. The only grade 4 adverse event was febrile neutropenia in one patient and so the exact upper 95% CI for the probability of having grade 4 neutropenia was 0.066, whereas that for the other hematological toxicities was 0.103. The frequency of grade 3 or 4 hematological toxicities
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Table 1 Hematological and non-hematological toxicities: number of patientsa (%) Toxicity
WHO grade 2
3
4
Hematological Neutropenia Anemia Thrombocytopenia
1 (2.3) 5 (11.4) 5 (11.4)
3 (6.8) 3 (6.8) 1 (2.3)
1b (2.3) 0 0
Non-hematological Vomiting Dermatological Paresthesias Fatigue Constipation Fever Hair loss
0 1 6 3 3 3 2
0 1 3 2 0 0 1
0 0 0 0 0 0 0
a b
(2.3) (13.6) (6.8) (6.8) (6.8) (4.6)
(2.3) (6.8) (4.6)
(2.3)
Patients evaluable after at least one cycle. Febrile neutropenia.
was 9.1% (95% CI: 2.5—21.7%); the frequency of grade 3 or 4 non-hematological toxicities was 6.8% (95% CI: 1.4—18.7%).
3.4. Response All of the patients received at least two chemotherapy cycles and were assessed for response: 17 showed a PR (38.6%; 95% CI: 24.4—54.5%), 17 (38.6%) SD, and 10 (22.8%) PD.
3.5. Survival Fig. 1 shows overall survival: 43 patients had died after 58 months. Median survival was 12.2 months (95% CI: 7.4—17.3), and the 1- and 2-year survival rates were, respectively, 50% (95% CI: 34—64%) and 20% (95% CI: 10—33%). Three patients died of causes unrelated to their tumour (one stroke, one myocardial infarction, one acute pulmonary edema). After 3 months of treatment, the patients were classified into two groups on the basis of their response (those with a PR and those with SD or PD), and the sur-
Fig. 1
Kaplan—Meier estimate of overall survival.
vival of the 40 patients who lived for at least 3 months was calculated. The median survival (after the 3-month assessment) of the 17 patients with a PR was 17.1 months (95% CI: 11.2—23.8), whereas that of the remaining 23 was 5.1 months (95% CI: 2.8—9.3). The non-responders had a hazard ratio that was 2.6 times that of the responders (95% CI: 1.3—5.2).
3.6. Time to progression The median time to progression was 7.1 months (95% CI: 5.1—9.0). Twelve months after enrolment, about 78% of the patients showed progression (95% CI: 64—89%).
3.7. Clinical benefit Twenty-four patients (54.5%; 95% CI: 38.8—69.6%) received a clinical benefit: 94% of the patients with a PR (16/17) and 47% of those with SD (8/17); this difference was highly significant at Fisher’s exact test (p < 0.001).
4. Discussion About one-third of all NSCLC patients are aged more than 70 years, but elderly patients are under-represented in clinical trials evaluating new treatments for advanced disease [3]. A number of randomised trials and meta-analyses have demonstrated that chemotherapy can improve the survival of patients with advanced disease [2], and cisplatinbased chemotherapy has so far played a pivotal role in the treatment of NSCLC. However, cisplatin-based chemotherapy (with its associated renal and neurological toxicities) is usually avoided in elderly patients because of their comorbidities and impaired organ function [6], and so identifying new regimens not based on cisplatin may improve the palliative therapy of elderly or poor performance patients with advanced NSCLC. New agents for the treatment of advanced NSCLC, such as GEM, vinorelbine (VNR), taxanes and camptothecin, have been introduced over the last 10 years, and their good activity (20% response rates in monotherapy) and favourable toxicity profiles have increased the possibility of treatment also for elderly patients [17]. A number of phase II studies have shown that single-agent GEM therapy leads to an overall response rate of approximately 20%, with little hematological (very dangerous in elderly patients) and non-hematological toxicity (nausea, alopecia, hepatic and renal toxicity) [9,18]. Furthermore, monotherapy with vinca alkaloids has been found to be active, with several phase II studies showing response rates of 30% for VNR [17,19] and 20% for VDS [11], with only mild toxicity. The randomised phase III Elderly Lung Cancer VNR Italian (ELVIS) trial unequivocally confirmed that chemotherapy with VNR alone is more advantageous than best supportive care in terms of survival and clinical benefit in patients aged more than 70 years with stage IIIB/IV NSCLC [20]. The gain in median survival was slight (7 weeks), but similar to that obtained with cisplatin-based chemotherapy in comparison with best supportive care. On the basis of the results of a
GEM and VDS in advance NSCLC: a phase II study in elderly or poor performance status patients recent meta-analysis confirming that polychemotherapy is more active than monochemotherapy [21], several phase II studies combined GEM and VNR in an attempt to exploit their different molecular mechanisms and good tolerability, all of which demonstrated the greater activity of the combination, with overall response rates of 25—40% and median survival rates of approximately 8—13 months [22—26]. However, the randomised phase III trials of monotherapy versus platinum-free polychemotherapy published have led to conflicting results in terms of OS and the quality of life. For example, the randomised phase III MILES study published in 2003 found that the GEM/VNR combination did not lead to any benefit over either drug alone in terms of survival or the control of disease-related symptoms [27], whereas Frasci et al. found that the combination offered elderly NSCLC patients statistically significant advantages in terms of response rate, OS and the quality of life in comparison with VNR alone [28]. Furthermore, at ASCO 2004, Abratt et al. presented the results of a phase III trial in which GEM/VNR was compared with carboplatin/VNR: there was no difference between the two arms in OS, but the schedule without platinum had a better tolerability profile [29]. In the present phase II study, we used GEM/VDS rather than GEM/VNR because of its greater synergism [30] and better tolerability profile. Kanzawa et al. have demonstrated in vitro that the synergism of GEM and VDS is comparable with that observed with GEM and cisplatin, whereas the interaction between GEM and VNR was only additive and not synergistic [30]. In a randomised study of VNR versus VDS in stage IIIB and IV NSCLC patients, Furuse et al. [31] found that VNR led to a higher response rate, but greater hematological and cutaneous toxicity. In our phase II study, 17 patients achieved a PR for an overall response rate of 39%, which is higher than that reported for single-agent GEM or VNR, but quite similar to the approximately 35% reported by other investigators in phase II trials of GEM and VNR [20—26]. The toxicity profile observed in our study was more favourable than that observed in other phase II studies of GEM and VNR, thus suggesting that our schedule can be easily administered to elderly or poor performance status patients. Our results contrast with those reported by Sorensen et al. [14], who tested GEM and VDS in previously untreated NSCLC patients and reported an overall response rate of 20% and a median survival of 31 weeks, with greater hematological and non-hematological toxicity, and a worse quality of life. However, their schedule consisted of GEM 1000 mg/m2 on day 1,8 and 15, and VDS 3 mg/m2 every week for the first 7 weeks and then every other week. These results can be interpreted according to the in vitro evidences of Kanzawa et al. who demonstrated a synergistic interaction between GEM and VDS at lower concentrations rather than at higher ones. In conclusion, the results of our study show that GEM/VDS is an active combination in the treatment of advanced NSCLC, and based on its good tolerability profile it can be proposed to patients with controindications to platinumbased chemotherapy, i.e. elderly patients with severe comorbidities or a KPS of ≤60. A phase III trial is currently ongoing in order to confirm that this combination has advantages over monochemotherapy in terms of survival or the quality of life.
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Acknowledgement This study was supported by GIVOP (Gruppo Interdisciplinare Veronese di Oncologia Polmonare).
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