- Email: [email protected]
gemcitabine with or without vinorelbine or paclitaxel in advanced non-small cell lung cancer
Phase III Trial Vinorelbine Pasquale
Cornella,
In a randomized
phase
vanced good
cell lung status
non-small performance
men
consisting
and
8 every
mglm’
Lilly and
day
citabine
I and
at
1,000
I hour)
PGV
and
days
weeks; were
P < .05
for
increased
50
both).
vomiting either
the
was triplet
more fatigue
well
severe the PG
PC
arm. were
IN) days
on
1,000
paclitaxel
at
3 weeks
Times the
mglm’ (PGT).
durations
to disease
PGV
(24
with Both
were
progression
weeks)
the
the mild
new
with
patients with advanced non-small good performance status, without
PGT (I 9 com-
hematologic
was more comPGT group. Severe
in
the
and
the PG group triple-agent
Among
whereas
associated
125
group, 48% in the (P < .02 for both
survival
common
In summary,
on develgem-
the PGV and PGT groups (5 I weeks for both v 38
tolerated.
group,
I
mg/m’
8 every
thrombocytopenia arm than in
more
at
PG
arm
than
neuropathy arms and PGT group
PGVand improved
in was
grade than
PGT
3 in
triplet
outcome
in
cell lung cancer with an increase in major
toxicity. Semin Oncol28 (suf+l Saunders Company.
7):7-10.
Copyright
0 2001
by W.B.
T
HE ADDITION of vinorelbine, paclitaxel, docetaxel, or gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) to platinum therapy has improved outcomes in non-small cell lung cancer (NSCLC).1-8 Comparisons of doublets consisting of a platinum agent and one of these newer agents9 did not indicate striking differences, with response rates ranging from 17% to 21% and representative median survival times of approximately 8 months. To increase activity, there has been considerable interest in evaluating triple combinations of cisplatin with two of these newer agents; we observed good activity with combination regimens of cisplatin/gemcitabine/vinorelbine and cisplatin/gemcitabine/paclitaxel in early phase Seminon in Oncology. Vol 28, No 2, Suppl 7 (April),
Italy
Cooperative
Oncology
Group
studies in advanced NSCLC.lOJ1 The Southern Italy Cooperative Oncology Group thus initiated a phase III study to evaluate the effects of these new triplet regimens on survival in advanced NSCLC.‘zJ3
at IO0
and
common in the triple-agent was more common in the
regimens
gemcitabine
I and
Median
adwith regi-
of cisplatin at
in both PG group
in both
were
toxicities, mon in
with
Indianapolis, 25 mg/m’
a doublet
(29 weeks) groups compared weeks) (PGT v PG; P < .002). binations
mg/m’,
44% in the PGV in the PC group
v PC).
increased with the
patients
4 weeks (PG); or a newly of cisplatin at 50 mglm’,
mglm’,
on
PGT
at
of the Southern
aged 570 years a new triplet
gemcitabine
Response rates were PGT group, and 28% significantly compared
343
cancer received
(PGV);
I, 8, and I5 every triplet combination
(over
on behalf
and Company, vinorelbine at
3 weeks
on
days oped
III trial,
of cisplatin
(Gemzar; Eli 1,000 mg/m’,
of CisplatinlGemcitabine With or Without or Paclitaxel in Advanced Non-Small Cell Lung Cancer
200 I: pp 7-10
PATIENTS
AND
METHODS
Eligibility criteria included histologically and cytologically proven stage IIIB or IV NSCLC, aged 570 years, no prior chemotherapy, adequate bone marrow function (absolute neutrophil count 22 X 109/L, platelet count ~100 X 109/L, hemoglobin level 210 g/L), adequate liver function, creatinine clearance greater than 60 mL/min, and Eastern Cooperative Oncology Group performance status (PS) 5 1. Patients were randomized to receive either a standard doublet regimen including cisplatin at 100 mg/m’ on day 1 and gemcitabine at 1,000 mg/m’ on days 1,8, and 15 every 4 weeks (PC), or one of the two triplets: cisplatin at 50 mg/m’, gemcitabine at 1,000 mg/m’, and vinorelbine at 25 mg/m’ on days 1 and 8 every 3 weeks (PGV), or cisplatin at 50 mg/m”, gemcitabine at 1,000 mg/m’, and paclitaxel at 125 mg/m’ (over 1 hour) on days 1 and 8 every 3 weeks (PGT). After comparable periods of induction therapy consisting of three cycles in the PGV and PGT arms and two in the PG arm, only patients with complete response and partial response on tumor assessment received additional cycles of study treatment, consisting of two additional cycles in the PGV and PGT arms and three additional cycles in the PG arm. Randomization in the PG, PGV, and PGT arms started in October 1997. Survival was the primary study end point. Target enrollment was approximately 120 patients per arm to give an 80% power to detect 50% prolongation of median survival in three-drug arms compared with PV and PG. The survival curves were estimated with the Kaplan-Meier product-limit method and compared by the log rank test and Cox analysis, with age (~65 years pl older), PS (0 v l), disease stage (IIIB v IV), histology (squamous cell v others), and weight loss (>5% u ~5% of body weight) as covariates.
RESULTS Three hundred sixty patients were enrolled in this trial from 28 participating institutions. How-
From the Division of Medical Oncology A, National Tumor Institute, Naples, Italy. Address reprint requests to Pasquak Corn&, MD, Division of Medical Oncology A, National Tumor Institute, Via M. Semmola, 80131, Naples, Italy. Copyright 0 2001 by W.B. Saunders Company 0093.7754/01/2802-0705$35.00/O doi:J0.1053/sonc.2001.24366 7
8
PASQUALE
and the majority had an Eastern Cooperative Oncology Group PS of 1; stage IV disease was more common than stage IIIB disease in each treatment arm. Overall response rates were 44% (52 of 117, with 48 partial responses and four complete responses) in the PGV arm, 28% (31 of 112, with 31 partial responses) in the PG arm, and 48% (55 of 114, with 50 partial responses and five complete responses) in the PGT arm, with the rates in both triple-agent arms being significantly greater than that in the PG arm (P < .02). Both PGV and PGT regimens were associated with median survival durations of 51 weeks, compared with 38 weeks in the PG arm (I’ < .05) (Fig 1). Comparison of the pooled outcomes of the triple-agent arms with the PG arm increased the significance of the difference in survival (I? < .Ol). Moreover, the Cox regression analysis showed that a significant reduction in the risk of death was associated to triplets compared with doublet regimen (hazard ratio = 0.67; 95% confidence interval, 0.52 to 0.91; P < .Ol). Median times to disease progression were 24 weeks in the PGV arm, 29 weeks in the PGT arm, and 19 weeks in the PG arm (PGT w PG; P < .002) (Fig 2). Acute toxicities are enumerated in Table 2. Hematologic toxicities were comparable among the treatment groups, except for a significantly greater frequency of grade 3 and 4 thrombocytopenia in the PG group compared with PGT (I’ < .05). With regard to nonhematologic toxicities, the frequency of grade 3 vomiting was approxi-
-
j x
No. of Patients
Patient
PGV
PC
PGT
I17
II2
I I4
no.
Males/females Median age, yr (range) PS (ECOG)
106/l I 62 (3 I-70)
= 0
98114 60 (38-70)
25
28
21
92 68
84 60
93 63
Other
49 32
52 29
51 29
54 63
45 67
48 66
I5 5
IO 5
14 3
histologies
Weight loss >5% stage MB stage IV More than one metastatic site Brain metastasis Abbreviations: PS = performance
ECOG, Eastern status.
Cooperative
I
306137 6 I (30-70)
PS (ECOG) = I Squamous histology
Oncology
COMELLA
Group;
ever, eight patients did not meet the eligibility criteria (wrong diagnosis, three cases; poor F’S or low baseline hemoglobin level, two cases; incorrect staging, one case; absence of measurable lesion, two cases). Among the 354 eligible patients, 11 (two in PGV arm, six in the PG arm, and three in the PGT arm) were not assessable because of lack of complete information about baseline demographics and/or long-term outcome. The characteristics of 343 evaluable patients are reported in Table 1. Patients in the treatment groups did not differ with regard to baseline characteristics. Most patients were male, the median age was 62 years,
100 Median Survival Times -B- PGV = 51 weeks -0. PC = 38 weeks -0 - PGT = 51 weeks
0
13
26
39
52 Weeks
65
78
91
104
Fig I. Actuarial survival according to treatment arm. Log-rank test: P < .05 for PGV versus PG and for PGT versus PG.
TRIPLET
THERAPY
FOR ADVANCED
9
NSCLC
Median Time to Progression -w- PGV = 24 weeks -*- PG - 19 weeks -0 _ PGT = 29 weeks
Fig 2. Probability of remaining progression-free. Log-rank test: P < .002 for PGT versus PG.
13
26
39
52
65
78
91
104
Weeks
mately doubled in the PG group, who received a single dose of cisplatin at 100 mg/m2 on day 1, compared with the triple-agent combination groups, where it was split between days 1 and 8. Mild neuropathy was significantly more common in the two triple-agent groups than in the PG group (PGV v PG, P < .05; and PGT v PG, P < .Ol) , and grade 3 fatigue was significantly more common in the PGT group than in the PG group (P < .Ol).
and PGV were associated with significant increasesin responserate, median survival, and time to diseaseprogressioncompared with PG. Moreover, improvements in outcome achieved by the addition of either paclitaxel or vinorelbine to a cisplatin/gemcitabine combination were not associated with decreasedtolerance or increasedhematologic toxicity. Both triplet regimensshouldbe considered as standard treatment protocols for these patients.
CONCLUSIONS
In patients with advanced NSCLC aged 570 years with good PS, the new triplet regimensPGT
Table
2. Acute
Toxicities
Percentage Toxicity
(WHO
grade)
Neutropenia grade Thrombocytopenia grade 3-4 Anemia grade
3-4
Febrile neutropenia grade 3-4 Vomiting Mucositis
grade
PGT
(n = I 17)
(n = I 12)
(n = I 14)
43%
40%
48%
35% (<.05)* 12%
5%
grade 3-4 grade 3
14% (<.ol)t 3%
Diarrhea grade 3 Fatigue grade 3 Renal grade I-2 Neuropathy
PG
25% 14%
3-4
I% 13% 5% l-2
of Patients
PGV
17% (<.05)
3%
for PGV Y PG (chi-square
7%
26% (<.05)* 5%
15% 6%
3% 14% (<.ol)* 8%
6% 32% 6%
5% (<.Ol)*
38%
Abbreviation: WHO, World Health Organization. *P value for PGT Y PC (chi-square test). fP value
20% 21%
test).
APPENDIX The Southern Italy Cooperative Oncology Group carried out this trial with the co-operation of the following Investigators (Institutions): Pasquale Comella, Giuseppe Frasci, and Giuseppe Comella (Division of Medical Oncology A, National Tumour Institute, Naples); Gianpaolo Nicolella and Nicola Panza (Division of Medical Oncology, Cardarelli Hospital, Naples); Michele Natale (Division of Pneumology, Cardarelli Hospital, Naples); Domenico Bilancia, Luigi Manzione, and Angelo Di Nota (Division of Medical Oncology, San Carlo Hospital, Potenza); Pietro Carnicelli and Giuseppe De Cataldis (Division of Medical Oncology, Da Procida Hospital, Salerno); Vito Lorusso and Mario De Lena (Division of Medical Oncology, Oncology Institute, Bari); Gaetano Di Rienzo and Franc0 Carpagnano (Division of Thoracic Surgery, San Paolo Hospital, Bari); Riccardo Cioffi (Division of Pneumology, City Hospital, Caserta); Luigi Maiorino (Division of Medical Oncology, San Gennaro Hospital, Naples); Enrico Micillo and Paolo Marcatili (Chair of Respiratory Diseases, 2nd University School of Medicine, Naples); Bruno Massidda (Medical Oncology, University School of Medicine, Cagliari); Alfred0 Lamberti and Franc0 Piantedosi (Division of Pneumology, Monaldi Hospital, Naples); Mario Belli and Filomena Del Gaizo (Division of Medical Oncology, City Hospital, Avellino); Antonio Contu (Division of Medical Oncology, City Hospital, Sassari), Alessandra Mangiameli (Musumeci Clinic, Catania); Annunziato Iannelli (Division of Medical Oncology, City Hospital,
IO
Sidemo); Hospital,
PASQUALE
and Dario Muci Nardb).
(Service
of Medical
Oncology,
City
REFERENCES 1. Wozniak AJ, Crowley JJ, Balcezark SP, et al: Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer (NSCLC): A Southwest Oncology Group study. J Clin Oncol 16:2459-2465, 1998 2. Sandier AB, Nemunaitis J, Denham C, et al: Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 18:122-130, 2000 3. Crinb L, Scagliotti GV, Ricci S, et al: Gemcitabine and cisplatin versus mitomycin, ifosfamide, and cisplatin in advanced non-small-cell lung cancer: A randomized phase III study of the Italian Lung Cancer Project. J Clin Oncol 17: 3522-3530, 1999 4. Giaccone G, Splinter TA, Debruyne C, et al: Randomized study of paclitaxel-cisplatin versus cisplatin-teniposide in patients with advanced non-small-cell lung cancer. The European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group. J Clin Oncol 16:2133-2141, 1998 5. Bonomi P, Kim K, Fairclough D, et al: Comparison of survival and quality of life in advanced non-small-cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin. Results of an Eastern Cooperative Oncology Group Trial. J Clin Oncol 18:623-631, 2000 6. Niho S, Nagao K, Nishiwaki Y, et al: Randomized multicenter phase III trial of irinotecan (CPT-11) and cisplatin (CDDP) versus CDDP and vindesine (VND) in patients with
COMELLA
advanced non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 18:492a, 1999 (abstr 1897) 7. Masuda N, Fukuoka M, Negoro S, et al: Randomized trial comparing cisplatin (CDDP) and irinotecan (CPT-11) versus CDDP and vindesine (VDS) versus CPT-11 alone in advanced non-small cell lung cancer (NSCLC). A multicenter phase III study. Proc Am Sot Clin Oncol 18:459a, 1999 (abstr 1774) 8. van Pawel J, von Roemeling R, Gatzemeier U, et al: Tirapazamine plus cisplatin versus cisplatin in advanced non-small cell lung cancer. A report of the International CATAPULT I study group. J Clin Oncol 18:1351-1359, 2000 9. Schiller JH, Harrington D, Sandier A, et al: A randomized phase III trial of four chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Sot Clin Oncol 19:la, 2000 (abstr 2) 10. Comella P, Frasci G, Panza N, et al: Cisplatin-gemcitabine-vinorelbine combination in advanced non-small cell lung cancer. A phase II randomized study of the Southern Italy Cooperative Oncology Group. J Clin Oncol 17:1526-1534, 1999 11. Frasci G, Panza N, Comella P, et al: Cisplatin, gemcitabine and paclitaxel in locally advanced or metastatic nonsmall cell lung cancer: A phase I-II study. J Clin Oncol 17: 2316-2325, 1999 12. Comella I’, Frasci G, Panza N, et al: Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer. Interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 18:1451-1457, 2000 13. Comella P. Triple- vs. double-agent chemotherapy for advanced non-small-cell lung cancer: Interim analysis of a phase III trial. Oncology 14:35-40, 2000 (suppl 4)
Cornella,
In a randomized
phase
vanced good
cell lung status
non-small performance
men
consisting
and
8 every
mglm’
Lilly and
day
citabine
I and
at
1,000
I hour)
PGV
and
days
weeks; were
P < .05
for
increased
50
both).
vomiting either
the
was triplet
more fatigue
well
severe the PG
PC
arm. were
IN) days
on
1,000
paclitaxel
at
3 weeks
Times the
mglm’ (PGT).
durations
to disease
PGV
(24
with Both
were
progression
weeks)
the
the mild
new
with
patients with advanced non-small good performance status, without
PGT (I 9 com-
hematologic
was more comPGT group. Severe
in
the
and
the PG group triple-agent
Among
whereas
associated
125
group, 48% in the (P < .02 for both
survival
common
In summary,
on develgem-
the PGV and PGT groups (5 I weeks for both v 38
tolerated.
group,
I
mg/m’
8 every
thrombocytopenia arm than in
more
at
PG
arm
than
neuropathy arms and PGT group
PGVand improved
in was
grade than
PGT
3 in
triplet
outcome
in
cell lung cancer with an increase in major
toxicity. Semin Oncol28 (suf+l Saunders Company.
7):7-10.
Copyright
0 2001
by W.B.
T
HE ADDITION of vinorelbine, paclitaxel, docetaxel, or gemcitabine (Gemzar; Eli Lilly and Company, Indianapolis, IN) to platinum therapy has improved outcomes in non-small cell lung cancer (NSCLC).1-8 Comparisons of doublets consisting of a platinum agent and one of these newer agents9 did not indicate striking differences, with response rates ranging from 17% to 21% and representative median survival times of approximately 8 months. To increase activity, there has been considerable interest in evaluating triple combinations of cisplatin with two of these newer agents; we observed good activity with combination regimens of cisplatin/gemcitabine/vinorelbine and cisplatin/gemcitabine/paclitaxel in early phase Seminon in Oncology. Vol 28, No 2, Suppl 7 (April),
Italy
Cooperative
Oncology
Group
studies in advanced NSCLC.lOJ1 The Southern Italy Cooperative Oncology Group thus initiated a phase III study to evaluate the effects of these new triplet regimens on survival in advanced NSCLC.‘zJ3
at IO0
and
common in the triple-agent was more common in the
regimens
gemcitabine
I and
Median
adwith regi-
of cisplatin at
in both PG group
in both
were
toxicities, mon in
with
Indianapolis, 25 mg/m’
a doublet
(29 weeks) groups compared weeks) (PGT v PG; P < .002). binations
mg/m’,
44% in the PGV in the PC group
v PC).
increased with the
patients
4 weeks (PG); or a newly of cisplatin at 50 mglm’,
mglm’,
on
PGT
at
of the Southern
aged 570 years a new triplet
gemcitabine
Response rates were PGT group, and 28% significantly compared
343
cancer received
(PGV);
I, 8, and I5 every triplet combination
(over
on behalf
and Company, vinorelbine at
3 weeks
on
days oped
III trial,
of cisplatin
(Gemzar; Eli 1,000 mg/m’,
of CisplatinlGemcitabine With or Without or Paclitaxel in Advanced Non-Small Cell Lung Cancer
200 I: pp 7-10
PATIENTS
AND
METHODS
Eligibility criteria included histologically and cytologically proven stage IIIB or IV NSCLC, aged 570 years, no prior chemotherapy, adequate bone marrow function (absolute neutrophil count 22 X 109/L, platelet count ~100 X 109/L, hemoglobin level 210 g/L), adequate liver function, creatinine clearance greater than 60 mL/min, and Eastern Cooperative Oncology Group performance status (PS) 5 1. Patients were randomized to receive either a standard doublet regimen including cisplatin at 100 mg/m’ on day 1 and gemcitabine at 1,000 mg/m’ on days 1,8, and 15 every 4 weeks (PC), or one of the two triplets: cisplatin at 50 mg/m’, gemcitabine at 1,000 mg/m’, and vinorelbine at 25 mg/m’ on days 1 and 8 every 3 weeks (PGV), or cisplatin at 50 mg/m”, gemcitabine at 1,000 mg/m’, and paclitaxel at 125 mg/m’ (over 1 hour) on days 1 and 8 every 3 weeks (PGT). After comparable periods of induction therapy consisting of three cycles in the PGV and PGT arms and two in the PG arm, only patients with complete response and partial response on tumor assessment received additional cycles of study treatment, consisting of two additional cycles in the PGV and PGT arms and three additional cycles in the PG arm. Randomization in the PG, PGV, and PGT arms started in October 1997. Survival was the primary study end point. Target enrollment was approximately 120 patients per arm to give an 80% power to detect 50% prolongation of median survival in three-drug arms compared with PV and PG. The survival curves were estimated with the Kaplan-Meier product-limit method and compared by the log rank test and Cox analysis, with age (~65 years pl older), PS (0 v l), disease stage (IIIB v IV), histology (squamous cell v others), and weight loss (>5% u ~5% of body weight) as covariates.
RESULTS Three hundred sixty patients were enrolled in this trial from 28 participating institutions. How-
From the Division of Medical Oncology A, National Tumor Institute, Naples, Italy. Address reprint requests to Pasquak Corn&, MD, Division of Medical Oncology A, National Tumor Institute, Via M. Semmola, 80131, Naples, Italy. Copyright 0 2001 by W.B. Saunders Company 0093.7754/01/2802-0705$35.00/O doi:J0.1053/sonc.2001.24366 7
8
PASQUALE
and the majority had an Eastern Cooperative Oncology Group PS of 1; stage IV disease was more common than stage IIIB disease in each treatment arm. Overall response rates were 44% (52 of 117, with 48 partial responses and four complete responses) in the PGV arm, 28% (31 of 112, with 31 partial responses) in the PG arm, and 48% (55 of 114, with 50 partial responses and five complete responses) in the PGT arm, with the rates in both triple-agent arms being significantly greater than that in the PG arm (P < .02). Both PGV and PGT regimens were associated with median survival durations of 51 weeks, compared with 38 weeks in the PG arm (I’ < .05) (Fig 1). Comparison of the pooled outcomes of the triple-agent arms with the PG arm increased the significance of the difference in survival (I? < .Ol). Moreover, the Cox regression analysis showed that a significant reduction in the risk of death was associated to triplets compared with doublet regimen (hazard ratio = 0.67; 95% confidence interval, 0.52 to 0.91; P < .Ol). Median times to disease progression were 24 weeks in the PGV arm, 29 weeks in the PGT arm, and 19 weeks in the PG arm (PGT w PG; P < .002) (Fig 2). Acute toxicities are enumerated in Table 2. Hematologic toxicities were comparable among the treatment groups, except for a significantly greater frequency of grade 3 and 4 thrombocytopenia in the PG group compared with PGT (I’ < .05). With regard to nonhematologic toxicities, the frequency of grade 3 vomiting was approxi-
-
j x
No. of Patients
Patient
PGV
PC
PGT
I17
II2
I I4
no.
Males/females Median age, yr (range) PS (ECOG)
106/l I 62 (3 I-70)
= 0
98114 60 (38-70)
25
28
21
92 68
84 60
93 63
Other
49 32
52 29
51 29
54 63
45 67
48 66
I5 5
IO 5
14 3
histologies
Weight loss >5% stage MB stage IV More than one metastatic site Brain metastasis Abbreviations: PS = performance
ECOG, Eastern status.
Cooperative
I
306137 6 I (30-70)
PS (ECOG) = I Squamous histology
Oncology
COMELLA
Group;
ever, eight patients did not meet the eligibility criteria (wrong diagnosis, three cases; poor F’S or low baseline hemoglobin level, two cases; incorrect staging, one case; absence of measurable lesion, two cases). Among the 354 eligible patients, 11 (two in PGV arm, six in the PG arm, and three in the PGT arm) were not assessable because of lack of complete information about baseline demographics and/or long-term outcome. The characteristics of 343 evaluable patients are reported in Table 1. Patients in the treatment groups did not differ with regard to baseline characteristics. Most patients were male, the median age was 62 years,
100 Median Survival Times -B- PGV = 51 weeks -0. PC = 38 weeks -0 - PGT = 51 weeks
0
13
26
39
52 Weeks
65
78
91
104
Fig I. Actuarial survival according to treatment arm. Log-rank test: P < .05 for PGV versus PG and for PGT versus PG.
TRIPLET
THERAPY
FOR ADVANCED
9
NSCLC
Median Time to Progression -w- PGV = 24 weeks -*- PG - 19 weeks -0 _ PGT = 29 weeks
Fig 2. Probability of remaining progression-free. Log-rank test: P < .002 for PGT versus PG.
13
26
39
52
65
78
91
104
Weeks
mately doubled in the PG group, who received a single dose of cisplatin at 100 mg/m2 on day 1, compared with the triple-agent combination groups, where it was split between days 1 and 8. Mild neuropathy was significantly more common in the two triple-agent groups than in the PG group (PGV v PG, P < .05; and PGT v PG, P < .Ol) , and grade 3 fatigue was significantly more common in the PGT group than in the PG group (P < .Ol).
and PGV were associated with significant increasesin responserate, median survival, and time to diseaseprogressioncompared with PG. Moreover, improvements in outcome achieved by the addition of either paclitaxel or vinorelbine to a cisplatin/gemcitabine combination were not associated with decreasedtolerance or increasedhematologic toxicity. Both triplet regimensshouldbe considered as standard treatment protocols for these patients.
CONCLUSIONS
In patients with advanced NSCLC aged 570 years with good PS, the new triplet regimensPGT
Table
2. Acute
Toxicities
Percentage Toxicity
(WHO
grade)
Neutropenia grade Thrombocytopenia grade 3-4 Anemia grade
3-4
Febrile neutropenia grade 3-4 Vomiting Mucositis
grade
PGT
(n = I 17)
(n = I 12)
(n = I 14)
43%
40%
48%
35% (<.05)* 12%
5%
grade 3-4 grade 3
14% (<.ol)t 3%
Diarrhea grade 3 Fatigue grade 3 Renal grade I-2 Neuropathy
PG
25% 14%
3-4
I% 13% 5% l-2
of Patients
PGV
17% (<.05)
3%
for PGV Y PG (chi-square
7%
26% (<.05)* 5%
15% 6%
3% 14% (<.ol)* 8%
6% 32% 6%
5% (<.Ol)*
38%
Abbreviation: WHO, World Health Organization. *P value for PGT Y PC (chi-square test). fP value
20% 21%
test).
APPENDIX The Southern Italy Cooperative Oncology Group carried out this trial with the co-operation of the following Investigators (Institutions): Pasquale Comella, Giuseppe Frasci, and Giuseppe Comella (Division of Medical Oncology A, National Tumour Institute, Naples); Gianpaolo Nicolella and Nicola Panza (Division of Medical Oncology, Cardarelli Hospital, Naples); Michele Natale (Division of Pneumology, Cardarelli Hospital, Naples); Domenico Bilancia, Luigi Manzione, and Angelo Di Nota (Division of Medical Oncology, San Carlo Hospital, Potenza); Pietro Carnicelli and Giuseppe De Cataldis (Division of Medical Oncology, Da Procida Hospital, Salerno); Vito Lorusso and Mario De Lena (Division of Medical Oncology, Oncology Institute, Bari); Gaetano Di Rienzo and Franc0 Carpagnano (Division of Thoracic Surgery, San Paolo Hospital, Bari); Riccardo Cioffi (Division of Pneumology, City Hospital, Caserta); Luigi Maiorino (Division of Medical Oncology, San Gennaro Hospital, Naples); Enrico Micillo and Paolo Marcatili (Chair of Respiratory Diseases, 2nd University School of Medicine, Naples); Bruno Massidda (Medical Oncology, University School of Medicine, Cagliari); Alfred0 Lamberti and Franc0 Piantedosi (Division of Pneumology, Monaldi Hospital, Naples); Mario Belli and Filomena Del Gaizo (Division of Medical Oncology, City Hospital, Avellino); Antonio Contu (Division of Medical Oncology, City Hospital, Sassari), Alessandra Mangiameli (Musumeci Clinic, Catania); Annunziato Iannelli (Division of Medical Oncology, City Hospital,
IO
Sidemo); Hospital,
PASQUALE
and Dario Muci Nardb).
(Service
of Medical
Oncology,
City
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