The treatment of non-small cell lung cancer has undergone a remarkable transformation
within the past decade. However, overall survival is still relatively poor.
Biological response modifiers may play an increasingly important role as an
adjuvant therapy.
| CHEMOTHERAPY |
|
| BETA CAROTENE |
|
Incidence of Cancer and Mortality Following {alpha}-Tocopherol and {beta}-Carotene
Supplementation: A Postintervention Follow-up.
The ATBC Study Group.
ATBC Study Group Authors: Jarmo Virtamo, MD, Pirjo Pietinen,
DSc, Jussi K. Huttunen, MD, Pasi Korhonen, PhD, Nea Malila, MD, and
Mikko J. Virtanen, MSc, National Public Health Institute, Helsinki,
Finland.
|
JAMA. 2003 Jul 23;290(4):476-485. Abstract quote
CONTEXT: In the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention
(ATBC) Study, alpha-tocopherol supplementation decreased prostate cancer
incidence, whereas beta-carotene increased the risk of lung cancer and
total mortality. Postintervention follow-up provides information regarding
duration of the intervention effects and may reveal potential late effects
of these antioxidants.
OBJECTIVE: To analyze postintervention effects of alpha-tocopherol and
beta-carotene on cancer incidence and total and cause-specific mortality.
DESIGN, SETTING, AND PARTICIPANTS: Postintervention follow-up assessment
of cancer incidence and cause-specific mortality (6 years [May 1, 1993-April
30, 1999]) and total mortality (8 years [May 1, 1993-April 30, 2001])
of 25 563 men. In the ATBC Study, 29 133 male smokers aged 50 to 69
years received alpha-tocopherol (50 mg), beta-carotene (20 mg), both
agents, or placebo daily for 5 to 8 years. End point information was
obtained from the Finnish Cancer Registry and the Register of Causes
of Death. Cancer cases were confirmed through medical record review.
MAIN OUTCOME MEASURES: Site-specific cancer incidence and total and
cause-specific mortality and calendar time-specific risk for lung cancer
incidence and total mortality.
RESULTS: Overall posttrial relative risk (RR) for lung cancer incidence
(n = 1037) was 1.06 (95% confidence interval [CI], 0.94-1.20) among
recipients of beta-carotene compared with nonrecipients. For prostate
cancer incidence (n = 672), the RR was 0.88 (95% CI, 0.76-1.03) for
participants receiving alpha-tocopherol compared with nonrecipients.
No late preventive effects on other cancers were observed for either
supplement. There were 7261 individuals who died by April 30, 2001,
during the posttrial follow-up period; the RR was 1.01 (95% CI, 0.96-1.05)
for alpha-tocopherol recipients vs nonrecipients and 1.07 (95% CI, 1.02-1.12)
for beta-carotene recipients vs nonrecipients. Regarding duration of
intervention effects and potential late effects, the excess risk for
beta-carotene recipients was no longer evident 4 to 6 years after ending
the intervention and was primarily due to cardiovascular diseases.
CONCLUSIONS: The beneficial and adverse effects of supplemental alpha-tocopherol
and beta-carotene disappeared during postintervention follow-up. The
preventive effects of alpha-tocopherol on prostate cancer require confirmation
in other trials. Smokers should avoid beta-carotene supplementation.
|
| PHASE III TRIALS |
|
| Twenty-two years of phase III trials for patients
with advanced non-small-cell lung cancer: sobering results.
Breathnach OS, Freidlin B, Conley B, Green MR, Johnson DH, Gandara
DR, O'Connell M, Shepherd FA, Johnson BE.
Lowe Center for Thoracic Oncology, Department of Adult Oncology,
Dana-Farber Cancer Institute, Boston, MA 02115, USA. |
Clin Oncol 2001 Mar 15;19(6):1734-42 Abstract quote
PURPOSE: To determine the changes in clinical trials and outcomes of
patients with advanced-stage non-small-cell lung cancer (NSCLC) treated
on phase III randomized trials initiated in North America from 1973
to 1994.
PATIENTS AND METHODS: Phase III trials for patients with advanced-stage
NSCLC were identified through a search of the National Cancer Institute's
Cancer Therapy Evaluation Program database from 1973 to 1994, contact
with Cooperative Groups, and by literature search of MEDLINE. Patients
with advanced NSCLC treated during a similar time interval were also
examined in the SEER database. Trends were tested in the number of trials,
in the number and sex of patients entered on the trials, and in survival
over time.
RESULTS: Thirty-three phase III trials were initiated between 1973
and 1994. Twenty-four trials (73%) were initiated within the first half
of this period (1973 to 1983) and accounted for 5,359 (64%) of the 8,434
eligible patients. The median number of patients treated per arm of
the trials rose from 77 (1973 to 1983) to 121 (1984 to 1994) (P <.001).
Five trials (15%) showed a statistically significant difference in survival
between treatment arms, with a median prolongation of the median survival
of 2 months (range, 0.7 to 2.7 months).
CONCLUSION: Analysis of past trials in North America shows that the
prolongation in median survival between two arms of a randomized study
was rarely in excess of 2 months. Techniques for improved use of patient
resources and appropriate trial design for phase III randomized therapeutic
trials with patients with advanced NSCLC need to be developed. |
| DOCATAXEL |
|
| Review of two phase III randomized trials of single-agent docetaxel
in previously treated advanced non--small cell lung cancer.
Lynch TJ Jr.
Department of Medical Oncology, Massachusetts General Hospital,
Boston, MA, USA. |
Semin Oncol 2001 Jun;28(3 Suppl 9):5-9 Abstract quote
Randomized phase III studies reported this year prove that docetaxel
is superior both to best supportive care (BSC) and to a standard regimen
of vinorelbine or ifosfamide as second-line therapy for advanced non--small
cell lung cancer.
In a landmark study authored by Dr Frances Shepherd, 204 patients
with stage IIIB/IV non--small cell lung cancer who had failed previous
cisplatin-based chemotherapy were randomized to receive either docetaxel
(100 mg/m(2) or 75 mg/m(2) every 3 weeks) or BSC. The median survival
of patients assigned to docetaxel was 7.6 months, significantly longer
than the median of 4.6 months in patients treated with BSC alone. The
rate of febrile neutropenia was 22% in patients receiving 100 mg/m(2)
docetaxel but only 1.8% when the dose was 75 mg/m(2). Patients treated
with docetaxel required less additional opioid analgesia and palliative
radiotherapy than those receiving BSC. Patients in the docetaxel 75
mg/m(2) arm also were significantly less likely to lose 10% or more
body weight and to experience severe fatigue.
In a second phase III study led by Dr Frank Fossella, 373 patients
were randomized to docetaxel 100 mg/m(2), docetaxel 75 mg/m(2), or a
control arm of vinorelbine 30 mg/m(2) or ifosfamide 2 g/m(2). Median
survival was similar between the two groups (range, 5.5 to 5.7 months).
However, the survival rate at I year was significantly higher in patients
assigned to 75 mg/m(2) than in the control arm. Patients receiving docetaxel
75 mg/m(2) experienced better global quality of life (Lung Cancer Symptom
Scale: patient-rated) than patients receiving vinorelbine or ifosfamide.
A higher incidence of grade 4 neutropenia and febrile neutropenia was
observed in the docetaxel arms of the study, but the incidence of infections
was low and nonhematologic toxicities were similar across all treatment
arms.
These studies show docetaxel provides meaningful survival and clinical
benefits in second-line non-small cell lung cancer. The dose recommended
in this setting is 75 mg/m(2) every 3 weeks. |
| Phase III randomized trial of docetaxel in combination with cisplatin
or carboplatin or vinorelbine plus cisplatin in advanced non--small
cell lung cancer: interim analysis.
Belani C
TAX 326 Study Group. Division of Medical Oncology, Department of
Medicine, the University of Pittsburgh School of Medicine, Pittsburgh,
PA 15213, USA. |
Semin Oncol 2001 Jun;28(3 Suppl 9):10-4 Abstract quote
In the TAX 326 trial, 1,220 chemotherapy-naive patients with advanced
or metastatic non--small cell lung cancer have been randomized to receive
one of three regimens: docetaxel 75 mg/m(2) plus cisplatin 75 mg/m(2)
every 3 weeks; docetaxel 75 mg/m(2) plus carboplatin to an area under
the curve of 6 mg/mL x min every 3 weeks; or a control arm of vinorelbine
25 mg/m(2) weekly plus cisplatin 100 mg/m(2) monthly.
The treatment and toxicity data presented are based on a planned preliminary
analysis conducted after 601 patients had been enrolled. The median
age of patients randomized was 60 years and 73% were male. The majority
of patients had a Karnofsky score of 80 or greater, two thirds had stage
IV disease and 35% had three or more sites of organ involvement. While
the relative dose intensity for docetaxel was 0.97 both when combined
with cisplatin and when combined with carboplatin, the corresponding
figure for vinorelbine was 0.68, reflecting the frequent need for dose
reduction when combined with cisplatin on the schedule used. Hematologic
toxicities were tolerable and comparable across the three arms of the
trial, and the rate of febrile neutropenia was below 5% in all cases.
The incidence of nonhematologic toxicities also was similar, although
nausea and vomiting appeared to be less frequent among patients assigned
to docetaxel plus carboplatin than among patients receiving comparator
regimens. |
| ISOTRETINOIN |
|
| Randomized phase III intergroup trial of isotretinoin
to prevent second primary tumors in stage I non-small-cell lung cancer.
Lippman SM, Lee JJ, Karp DD, Vokes EE, Benner SE, Goodman GE, Khuri
FR, Marks R, Winn RJ, Fry W, Graziano SL, Gandara DR, Okawara G, Woodhouse
CL, Williams B, Perez C, Kim HW, Lotan R, Roth JA, Hong WK.
Department of Clinical Cancer Prevention, The University of Texas
M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 236, Houston,
TX 77030-4095, USA. |
J Natl Cancer Inst 2001 Apr 18;93(8):605-18 Abstract
quote
BACKGROUND: Promising data have suggested that retinoid chemoprevention
may help to control second primary tumors (SPTs), recurrence, and mortality
of stage I non-small-cell lung cancer (NSCLC) patients.
METHODS: We carried out a National Cancer Institute (NCI) Intergroup
phase III trial (NCI #I91-0001) with 1166 patients with pathologic stage
I NSCLC (6 weeks to 3 years from definitive resection and no prior radiotherapy
or chemotherapy). Patients were randomly assigned to receive a placebo
or the retinoid isotretinoin (30 mg/day) for 3 years in a double-blind
fashion. Patients were stratified at randomization by tumor stage, histology,
and smoking status. The primary endpoint (time to SPT) and the secondary
endpoints (times to recurrence and death) were analyzed by log-rank
test and the Cox proportional hazards model. All statistical tests were
two-sided.
RESULTS: After a median follow-up of 3.5 years, there were no statistically
significant differences between the placebo and isotretinoin arms with
respect to the time to SPTs, recurrences, or mortality. The unadjusted
hazard ratio (HR) of isotretinoin versus placebo was 1.08 (95% confidence
interval [CI] = 0.78 to 1.49) for SPTs, 0.99 (95% CI = 0.76 to 1.29)
for recurrence, and 1.07 (95% CI = 0.84 to 1.35) for mortality. Multivariate
analyses showed that the rate of SPTs was not affected by any stratification
factor. Rate of recurrence was affected by tumor stage (HR for T(2)
versus T(1) = 1.77 [95% CI = 1.35 to 2.31]) and a treatment-by-smoking
interaction (HR for treatment-by-current-versus-never-smoking status
= 3.11 [95% CI = 1.00 to 9.71]). Mortality was affected by tumor stage
(HR for T(2) versus T(1) = 1.39 [95% CI = 1.10 to 1.77]), histology
(HR for squamous versus nonsquamous = 1.31 [95% CI = 1.03 to 1.68]),
and a treatment-by-smoking interaction (HR for treatment-by-current-versus-never-smoking
= 4.39 [95% CI = 1.11 to 17.29]). Mucocutaneous toxicity (P<.001) and
noncompliance (40% versus 25% at 3 years) were higher in the isotretinoin
arm than in the placebo arm.
CONCLUSIONS: Isotretinoin treatment did not improve the overall rates
of SPTs, recurrences, or mortality in stage I NSCLC. Secondary multivariate
and subset analyses suggested that isotretinoin was harmful in current
smokers and beneficial in never smokers. |
| PACLITAXEL |
|
| Randomized phase III trial of paclitaxel plus carboplatin
versus vinorelbine plus cisplatin in the treatment of patients with
advanced non--small-cell lung cancer: a Southwest Oncology Group trial.
Kelly K, Crowley J, Bunn PA Jr, Presant CA, Grevstad PK, Moinpour
CM, Ramsey SD, Wozniak AJ, Weiss GR, Moore DF, Israel VK, Livingston
RB, Gandara DR.
University of Colorado, Denver, CO, USA |
J Clin Oncol 2001 Jul 1;19(13):3210-8 Abstract quote
PURPOSE: This randomized trial was designed to determine whether paclitaxel
plus carboplatin (PC) offered a survival advantage over vinorelbine
plus cisplatin (VC) for patients with advanced non--small-cell lung
cancer. Secondary objectives were to compare toxicity, tolerability,
quality of life (QOL), and resource utilization.
PATIENTS AND METHODS: Two hundred two patients received VC (vinorelbine
25 mg/m(2)/wk and cisplatin 100 mg/m(2)/d, day 1 every 28 days) and
206 patients received PC (paclitaxel 225 mg/m(2) over 3 hours with carboplatin
area under the curve of 6, day 1 every 21 days). Patients completed
QOL questionnaires at baseline, 13 weeks, and 25 weeks. Resource utilization
forms were completed at five time points through 24 months.
RESULTS: Patient characteristics were similar between the groups. The
objective response rate was 28% in the VC arm and 25% in the PC arm.
Median survival was 8 months in both arms, with 1-year survival rates
of 36% and 38%, respectively. Grade 3 and 4 leukopenia (P =.002) and
neutropenia (P =.008) occurred more frequently on the VC arm. Grade
3 nausea and vomiting were higher on the VC arm (P =.001, P =.007),
and grade 3 peripheral neuropathy was higher on the PC arm (P <.001).
More patients on the VC arm discontinued therapy because of toxicity
(P =.001). No difference in QOL was observed. Overall costs on the PC
arm were higher than on the VC arm because of drug costs.
CONCLUSION: PC is equally efficacious as VC for the treatment of advanced
non--small-cell lung cancer. PC is less toxic and better tolerated but
more expensive than VC. New treatment strategies should be pursued. |
| RADIATION-COMBINED MODALITY |
CHARACTERIZATION |
| Hyperfractionated radiation therapy and concurrent
low-dose, daily carboplatin/etoposide with or without weekend carboplatin/etoposide
chemotherapy in stage III non-small-cell lung cancer: a randomized trial.
Jeremic B, Shibamoto Y, Acimovic L, Milicic B, Milisavljevic S,
Nikolic N, Dagovic A, Aleksandrovic J, Radosavljevic-Asic G.
Department of Oncology, University Hospital, Kragujevac, Yugoslavia.
|
Int J Radiat Oncol Biol Phys 2001 May 1;50(1):19-25
Abstract quote
PURPOSE: To investigate whether the addition of weekend chemotherapy
consisting of carboplatin/etoposide to hyperfractionated radiation therapy
(Hfx RT) and concurrent daily carboplatin/etoposide offers an advantage
over the same Hfx RT/daily carboplatin/etoposide.
METHODS AND MATERIALS: A total of 195 patients (Group I, 98; Group
II, 97) were treated with either Hfx RT to a total tumor dose of 69.6
Gy via 1.2 Gy b.i.d. fractionation and daily 50 mg each of carboplatin
and etoposide during the RT course (Group I) or the same Hfx RT with
daily carboplatin/etoposide consisting of 30 mg each of carboplatin
and etoposide and with weekend (Saturdays and Sundays) 100 mg each of
carboplatin and etoposide during the RT course (Group II).
RESULTS: No difference was found regarding median survival time and
5-year survival rates (20 vs. 22 months and 20% vs. 23%; p = 0.57).
Median time to local progression was 20 and 19 months, respectively,
while 5-year local progression-free survival rates were 28% and 27%,
respectively (p = 0.66). Also, there was no difference regarding either
median time to distant metastasis and 5-year distant metastasis-free
survival (21 vs. 25 months and 29% vs. 34%, p = 0.29). There was no
difference in the incidence of various nonhematologic toxicities between
the two treatment groups, but patients treated with the weekend CHT
had significantly more high-grade (> or = 3) hematologic toxicity (p
= 0.0046). Late high-grade toxicity was not different between the two
treatment groups.
CONCLUSION: The addition of weekend carboplatin/etoposide did not improve
results over those obtained with Hfx RT and concurrent low-dose, daily
carboplatin/etoposide, but it led to a higher incidence of acute high-grade
hematologic toxicity. |
| Influence of interfraction interval on the efficacy
and toxicity of hyperfractionated radiotherapy in combination with concurrent
daily chemotherapy in Stage III non-small-cell lung cancer.
Shibamoto Y, Jeremic B, Acimovic L, Milicic B, Nikolic N.
Department of Oncology, Institute for Frontier Medical Sciences,
Kyoto University, Kyoto, Japan |
Int J Radiat Oncol Biol Phys 2001 Jun 1;50(2):295-300
Abstract quote
Purpose: To investigate the influence of the interfraction interval
(IFI) on treatment outcome and toxicity in hyperfractionated (HF) radiotherapy
(RT) for Stage III non-small-cell lung cancer.
Methods and Materials: Data for 301 patients treated with 1.2 Gy b.i.d.
to a total of 69.6 Gy and concurrent chemotherapy in our 3 prospective
studies were analyzed. The chemotherapy regimen was either (1) 50 mg
each of carboplatin and etoposide (CE) given on RT days (163 patients)
or (2) 30 mg of CE on RT days and 100 mg of CE on Saturdays and Sundays
during the RT course (138 patients). An IFI of 4.5-5 h or 5.5-6 h had
been nonrandomly assigned for each patient, and this interval was kept
throughout the treatment.
Results: No difference was observed in treatment outcome due to the
chemotherapy protocol, and the 2 groups were combined. Patients treated
with the shorter IFI had a better local control rate (38% at 5 years)
and survival rate (30% at 5 years) than those treated with the longer
interval (23% and 14%, respectively; p < 0.001). However, female patients
and those with a high Karnofsky performance status score (KPS), weight
loss of
Conclusions: The possible influence of the IFI on local control and
survival could not be verified using multivariate analysis. To better
understand the influence of the IFI, randomized studies with more patients
and wider ranges of intervals (e.g., 5 h vs. 8 h) seem to be necessary. |
