Accepted Manuscript Title: Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC Author: Steffen Filskov Sorensen Andreas Carus Peter Meldgaard PII: DOI: Reference:
S0169-5002(15)00117-8 http://dx.doi.org/doi:10.1016/j.lungcan.2015.02.010 LUNG 4795
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
25-10-2014 13-1-2015 13-2-2015
Please cite this article as: Sorensen SF, Carus A, Meldgaard P, Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.02.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Highlights (for review)
Highlights: Intravenous or oral administration of vinorelbine/cisplatin appear equally effective.
No statistical significant difference in disease-free and overall survival was observed
Equality of was significant across all clinico-pathological subgroups.
Ac ce pt e
d
M
an
us
cr
ip t
Page 1 of 21
Intravenous or oral administration of vinorelbine in adjuvant
chemotherapy
with
cisplatin
and
vinorelbine for resected NSCLC
1
ip t
Steffen Filskov Sorensen*1, Andreas Carus1, Peter Meldgaard1 Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark.
*Corresponding author: Steffen Filskov Sorensen, Department of Oncology, Aarhus University
cr
Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. Phone: +45 29 93 79 80. E-mail: [email protected]
us
Abstract
Objectives: Cisplatin and vinorelbine given intravenously is a well-established
an
adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We assessed the overall
M
survival (OS) and disease-free survival (DFS) of patients treated with adjuvant iv. vinorelbine or po. vinorelbine, in combination with iv. cisplatin.
ed
Materials and Methods: We reviewed two time-separated cohorts of patients referred to the Department of Oncology at Aarhus University Hospital (Denmark) from 2005– 2012 for adjuvant chemotherapy after surgery for NSCLC.
ce pt
Results and Conclusion: Of the 265 patients included in this study, 126 patients received iv. and 139 received po. vinorelbine/cisplatin. The two groups were comparable with respect to important baseline characteristics. Median OS for all patients was 78.7 months and the median DFS was 35.7 months. No statistically
Ac
significant difference in OS or DFS for patients treated with iv. or oral vinorelbine was detected. The DFS rates of the two groups were comparable across all variables in subgroup analysis. In conclusion we observed that intravenous or oral administration of vinorelbine in combination with cisplatin after surgery for NSCLC appear equally effective in terms of overall and disease-free survival.
Keywords: Non-small cell lung cancer, adjuvant chemotherapy, cisplatin, oral vinorelbine, intravenous vinorelbine, early-stage
1
Page 2 of 21
1. Introduction Curative surgery is possible for approximately 20% of patients diagnosed with non small-cell lung cancer (NSCLC). However, in spite of radical surgery, a large proportion of patients resected for early-stage NSCLC will relapse (30–60 %), and the overall prognosis of NSCLC is poor (1, 2). The efficacy of adjuvant chemotherapy has been evaluated in several randomized trials and meta-analyses. The most
ip t
frequently studied combination is cisplatin/vinorelbine. Adjuvant cisplatin-based
doublet-chemotherapy results in an improvement of overall survival of approximately
cr
5% over 5 years for patients radically resected for stage Ib to IIIa NCSLC. The absolute survival benefit for patients with stage II and III is reported to be 13%-16%
us
in a single trial (3). However, the benefit for stage IB remains less clear (2-5). Cisplatin can only be administered intravenously (iv.) and is usually given every 3
an
weeks. Vinorelbine, a semisynthetic vinca-alkaloid, is usually administered on day 1 and 8 in a 3-week schedule and can be given both iv. and orally (po.) (6-8). This allows the dose on day 8 to be taken per oral by the patients themselves at home, thus
M
sparing a visit to the hospital. The oral formulation of vinorelbine has a nearly similar toxicity profile to the iv. formulation, but may cause some more gastrointestinal
ed
toxicity. This could be omitted by prescription of relevant antiemetics (7). Intravenous administration of chemotherapeutics is associated with discomfort and distress to patients, and the establishment of an iv. access is also associated with the risks of
ce pt
infection, bleeding, thrombosis, and extravasation of chemotherapy. Vinorelbine is a vesicant agent that can cause severe tissue damage upon extravasation (9). The majority of patients prefer oral administration of chemotherapeutics when available (10-13). Oral versus iv. administration of vinorelbine in combination with a platinum
Ac
agent has previously been reported as equally effective in studies concerning patients with advanced NSCLC and breast cancer (14-21). However, the efficacy of orally administrated vinorelbine in adjuvant treatment of resected NSCLC is unknown. In the landmark studies of adjuvant cisplatin/vinorelbine, NSCLC patients were treated with iv. vinorelbine 25-30 mg/m2 weekly x 16 and iv. cisplatin 100-120 mg/m2 (or 50 mg/m2 x 2) every 3 weeks x 4 (2-5). We retrospectively analysed the clinical characteristics and survival data of two time-separated cohorts from a single institution treated with either adjuvant intravenous vinorelbine/cisplatin or oral vinorelbine/cisplatin.
2
Page 3 of 21
2. Patients and methods 2.1 Patients The clinico-pathological data of patients referred to the Department of Oncology at Aarhus University Hospital (Denmark) from 2005–2012 for adjuvant chemotherapy after surgery for NSCLC were reviewed. Iv. vinorelbine/cisplatin was the standard adjuvant treatment from 2005 until April 2008 and po. vinorelbine/cisplatin from
ip t
April 2008 and onwards. The eligibility criteria were radical surgery for NSCLC (all
stages, including radically treated oligometastatic advanced disease) and a minimum
cr
of 2 cycles of adjuvant chemotherapy with cisplatin/vinorelbine (po. or iv.) completed. Patients treated with neoadjuvant chemotherapy or adjuvant chemo-
us
radiotherapy were excluded. TNM-stage was classified according to the IASLC 7th edition (22). Comorbidities were recorded according to Charlson Comorbidity Index
an
(2011, updated version) (23).
The study was conducted in accordance with relevant national and local guidelines, and with ethics committee approval (ref.: 1-10-72-219-14).
M
2.2 Diagnostic work-up, treatment and follow-up
Preoperative staging included a CT-scan of the thorax and upper abdomen, a tumor
ed
biopsy, bronchoscopy and mediastinoscopy. A supplementary FDG-PET-CT scan was systematically performed from 1/4-2008 and onwards and a full endoscopic mediastinal staging with ultrasound was systematically performed from 1/1-2011 and
ce pt
onwards. The patients received cisplatin iv. on day 1 every 3 weeks in a dosage of 75 mg/m2. Vinorelbine was given iv. in a dosage of 25 mg/m2 or orally in a dosage of 60 mg/m2 on days 1 and 8 every 3 weeks. If tolerated, oral doses were escalated to 80 mg/m2 in the subsequent 3 cycles (24). A maximum of 4 cycles was given in both
Ac
groups. Standard prophylactic anti-emetics and hydration in relation to cisplatin infusion was administered. The patient took the day 8 po. vinorelbine at home and to ensure compliance, the patient received a phone call from a nurse. Toxicity was scored as the primary reason for discontinuation or dose reduction of treatment according to the medical records. After completion of adjuvant chemotherapy, followup visits were scheduled every fourth month within the first year, and subsequently every sixth month for a total follow-up time of 5 years. A CT-scan with iv. contrast of the thorax and upper abdomen was performed prior to each follow-up visit. 2.3 Statistical analysis
3
Page 4 of 21
Chi-Square test or Students t-test were used to compare group distributions where appropriate. Survival was estimated by the Kaplan-Meier method and the cox proportional hazards model, and was compared between groups by use of the log-rank test. Survival time was calculated from the start of adjuvant chemotherapy until death or lost to follow-up. The disease free survival time was calculated from the start of adjuvant chemotherapy until relapse or death of any cause. Survival and follow-up
ip t
data were last updated May 15th 2014. Subgroup analysis for relevant clinicopathological factors was performed by comparing the hazard ratios for DFS between
cr
the two treatment groups. Data were analysed by the use of SPSS statistical software
(SPSS Inc. V21.0, Chicago, IL). A two-sided p-value
S0169-5002(15)00117-8 http://dx.doi.org/doi:10.1016/j.lungcan.2015.02.010 LUNG 4795
To appear in:
Lung Cancer
Received date: Revised date: Accepted date:
25-10-2014 13-1-2015 13-2-2015
Please cite this article as: Sorensen SF, Carus A, Meldgaard P, Intravenous or oral administration of vinorelbine in adjuvant chemotherapy with cisplatin and vinorelbine for resected NSCLC, Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.02.010 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
*Highlights (for review)
Highlights: Intravenous or oral administration of vinorelbine/cisplatin appear equally effective.
No statistical significant difference in disease-free and overall survival was observed
Equality of was significant across all clinico-pathological subgroups.
Ac ce pt e
d
M
an
us
cr
ip t
Page 1 of 21
Intravenous or oral administration of vinorelbine in adjuvant
chemotherapy
with
cisplatin
and
vinorelbine for resected NSCLC
1
ip t
Steffen Filskov Sorensen*1, Andreas Carus1, Peter Meldgaard1 Department of Oncology, Aarhus University Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark.
*Corresponding author: Steffen Filskov Sorensen, Department of Oncology, Aarhus University
cr
Hospital, Noerrebrogade 44, 8000 Aarhus C, Denmark. Phone: +45 29 93 79 80. E-mail: [email protected]
us
Abstract
Objectives: Cisplatin and vinorelbine given intravenously is a well-established
an
adjuvant chemotherapy regimen after surgery for early-stage NSCLC. Vinorelbine can also be administered orally. However, the efficacy of orally administrated vinorelbine in adjuvant treatment of NSCLC is unknown. We assessed the overall
M
survival (OS) and disease-free survival (DFS) of patients treated with adjuvant iv. vinorelbine or po. vinorelbine, in combination with iv. cisplatin.
ed
Materials and Methods: We reviewed two time-separated cohorts of patients referred to the Department of Oncology at Aarhus University Hospital (Denmark) from 2005– 2012 for adjuvant chemotherapy after surgery for NSCLC.
ce pt
Results and Conclusion: Of the 265 patients included in this study, 126 patients received iv. and 139 received po. vinorelbine/cisplatin. The two groups were comparable with respect to important baseline characteristics. Median OS for all patients was 78.7 months and the median DFS was 35.7 months. No statistically
Ac
significant difference in OS or DFS for patients treated with iv. or oral vinorelbine was detected. The DFS rates of the two groups were comparable across all variables in subgroup analysis. In conclusion we observed that intravenous or oral administration of vinorelbine in combination with cisplatin after surgery for NSCLC appear equally effective in terms of overall and disease-free survival.
Keywords: Non-small cell lung cancer, adjuvant chemotherapy, cisplatin, oral vinorelbine, intravenous vinorelbine, early-stage
1
Page 2 of 21
1. Introduction Curative surgery is possible for approximately 20% of patients diagnosed with non small-cell lung cancer (NSCLC). However, in spite of radical surgery, a large proportion of patients resected for early-stage NSCLC will relapse (30–60 %), and the overall prognosis of NSCLC is poor (1, 2). The efficacy of adjuvant chemotherapy has been evaluated in several randomized trials and meta-analyses. The most
ip t
frequently studied combination is cisplatin/vinorelbine. Adjuvant cisplatin-based
doublet-chemotherapy results in an improvement of overall survival of approximately
cr
5% over 5 years for patients radically resected for stage Ib to IIIa NCSLC. The absolute survival benefit for patients with stage II and III is reported to be 13%-16%
us
in a single trial (3). However, the benefit for stage IB remains less clear (2-5). Cisplatin can only be administered intravenously (iv.) and is usually given every 3
an
weeks. Vinorelbine, a semisynthetic vinca-alkaloid, is usually administered on day 1 and 8 in a 3-week schedule and can be given both iv. and orally (po.) (6-8). This allows the dose on day 8 to be taken per oral by the patients themselves at home, thus
M
sparing a visit to the hospital. The oral formulation of vinorelbine has a nearly similar toxicity profile to the iv. formulation, but may cause some more gastrointestinal
ed
toxicity. This could be omitted by prescription of relevant antiemetics (7). Intravenous administration of chemotherapeutics is associated with discomfort and distress to patients, and the establishment of an iv. access is also associated with the risks of
ce pt
infection, bleeding, thrombosis, and extravasation of chemotherapy. Vinorelbine is a vesicant agent that can cause severe tissue damage upon extravasation (9). The majority of patients prefer oral administration of chemotherapeutics when available (10-13). Oral versus iv. administration of vinorelbine in combination with a platinum
Ac
agent has previously been reported as equally effective in studies concerning patients with advanced NSCLC and breast cancer (14-21). However, the efficacy of orally administrated vinorelbine in adjuvant treatment of resected NSCLC is unknown. In the landmark studies of adjuvant cisplatin/vinorelbine, NSCLC patients were treated with iv. vinorelbine 25-30 mg/m2 weekly x 16 and iv. cisplatin 100-120 mg/m2 (or 50 mg/m2 x 2) every 3 weeks x 4 (2-5). We retrospectively analysed the clinical characteristics and survival data of two time-separated cohorts from a single institution treated with either adjuvant intravenous vinorelbine/cisplatin or oral vinorelbine/cisplatin.
2
Page 3 of 21
2. Patients and methods 2.1 Patients The clinico-pathological data of patients referred to the Department of Oncology at Aarhus University Hospital (Denmark) from 2005–2012 for adjuvant chemotherapy after surgery for NSCLC were reviewed. Iv. vinorelbine/cisplatin was the standard adjuvant treatment from 2005 until April 2008 and po. vinorelbine/cisplatin from
ip t
April 2008 and onwards. The eligibility criteria were radical surgery for NSCLC (all
stages, including radically treated oligometastatic advanced disease) and a minimum
cr
of 2 cycles of adjuvant chemotherapy with cisplatin/vinorelbine (po. or iv.) completed. Patients treated with neoadjuvant chemotherapy or adjuvant chemo-
us
radiotherapy were excluded. TNM-stage was classified according to the IASLC 7th edition (22). Comorbidities were recorded according to Charlson Comorbidity Index
an
(2011, updated version) (23).
The study was conducted in accordance with relevant national and local guidelines, and with ethics committee approval (ref.: 1-10-72-219-14).
M
2.2 Diagnostic work-up, treatment and follow-up
Preoperative staging included a CT-scan of the thorax and upper abdomen, a tumor
ed
biopsy, bronchoscopy and mediastinoscopy. A supplementary FDG-PET-CT scan was systematically performed from 1/4-2008 and onwards and a full endoscopic mediastinal staging with ultrasound was systematically performed from 1/1-2011 and
ce pt
onwards. The patients received cisplatin iv. on day 1 every 3 weeks in a dosage of 75 mg/m2. Vinorelbine was given iv. in a dosage of 25 mg/m2 or orally in a dosage of 60 mg/m2 on days 1 and 8 every 3 weeks. If tolerated, oral doses were escalated to 80 mg/m2 in the subsequent 3 cycles (24). A maximum of 4 cycles was given in both
Ac
groups. Standard prophylactic anti-emetics and hydration in relation to cisplatin infusion was administered. The patient took the day 8 po. vinorelbine at home and to ensure compliance, the patient received a phone call from a nurse. Toxicity was scored as the primary reason for discontinuation or dose reduction of treatment according to the medical records. After completion of adjuvant chemotherapy, followup visits were scheduled every fourth month within the first year, and subsequently every sixth month for a total follow-up time of 5 years. A CT-scan with iv. contrast of the thorax and upper abdomen was performed prior to each follow-up visit. 2.3 Statistical analysis
3
Page 4 of 21
Chi-Square test or Students t-test were used to compare group distributions where appropriate. Survival was estimated by the Kaplan-Meier method and the cox proportional hazards model, and was compared between groups by use of the log-rank test. Survival time was calculated from the start of adjuvant chemotherapy until death or lost to follow-up. The disease free survival time was calculated from the start of adjuvant chemotherapy until relapse or death of any cause. Survival and follow-up
ip t
data were last updated May 15th 2014. Subgroup analysis for relevant clinicopathological factors was performed by comparing the hazard ratios for DFS between
cr
the two treatment groups. Data were analysed by the use of SPSS statistical software
(SPSS Inc. V21.0, Chicago, IL). A two-sided p-value
