Adjuvant chemotherapy for NSCLC
The case for inclusion of cisplatin – vinorelbine and carboplatin – paclitaxel in the cancer “drug basket” for
Submission to CaTSOP and the MOH Service Improvement Group, October
Adjuvant therapy for NSCLC 3
The evidence for adjuvant chemotherapy in NSCLC 5 Adjuvant radiation therapy 5 Adjuvant chemotherapy 5 ALPI trial 6
ECOG trial 7
NCIC BR10 8
CALGB 9633 8
Conclusions regarding adjuvant chemotherapy in NSCLC 9
Implications for practice 11 References 12
rdNSCLC is the commonest cause of cancer death in NZ men and the 3 commonest cause of cancer
death in NZ women. Although the mortality rate is falling with a reduction in smoking uptake in men, the mortality rate continues to rise in women as a consequence of an increase in smoking uptake after World War II. It is a major health issue for Māori, in whom both incidence and mortality is nearly 3 times higher than in non- Māori. The age-standardised incidence rate in men is 64 per 100 000 (1996) and the
mortality rate 55 per 100 000. In women, the comparable figures are 32 and 28 per 100 000. The incidence and mortality is predicted to fall to 38 and 35 per 100 000 in men by 2010, but these figures are predicted to rise in women to 33 and 33 per 100 000 by 2010. This implies that prostate cancer will overtake NSCLC as the commonest cause of death in NZ men but that NSCLC will overtake colorectal cancer and breast cancer as the commonest cause of cancer death in NZ women (1).
Prevention strategies are central in the management of lung cancer in NZ and continued efforts need to be made to reduce smoking uptake and to encourage smoking cessation. However, even if a rapid and substantial reduction in smoking can be produced, the burden of the disease will not fall for some 20 to 30 years, reflecting the lengthy induction period involved in the tobacco – lung cancer relationship (2).
In patients with early stage (I and II disease) the treatment of choice is surgical resection. In patients treated with lobectomy or pneumonectomy, survival depends on stage. However, even in patients with very early disease, the rate of recurrence is high and 5 year survival is less than 70% even in the most favourable prognostic groups (3). The great majority of patients with a diagnosis of lung cancer die will ultimately die of progression of their disease.
Adjuvant therapy for NSCLC
Until recently, there has been relatively little evidence that adjuvant chemotherapy is a useful strategy in resected non-small cell lung cancer. However, the results of a meta-analysis and several trials employing newer chemotherapy agents have shown that adjuvant chemotherapy is both beneficial and feasible.
Adjuvant platinum-based chemotherapy in patients with completely resected NSCLC offers
? A 5 to 11% improvement in 5 year survival
? A 12 to 24 month increase in median survival
? Moderate short-term toxicity
? No increase in long-term toxicity (compared with surgery alone)
Although no formal cost-benefit analysis has been performed, it is possible that such a strategy will reduce downstream health costs.
Depending on the regimen chosen and the numbers of patients eligible for treatment, drug costs are likely to be moderate. In 2000 there were 1600 cases of lung cancer registered in NZ. Assuming that 75% of
these were NSCLC and of these cases 50% underwent potentially curative surgery, approximately 400 patients a year in NZ may be candidates for adjuvant chemotherapy (assuming 1/3 of potentially eligible patients are excluded by preference or co-morbidity). The resulting drug cost (based on March 2005 prices) is $3.5 million to $3.9 million per year.
The survival advantage offered by adjuvant chemotherapy for NSCLC is of similar order of magnitude to that considered worthwhile in the adjuvant treatment of other common cancers. Although the optimal regimen has not been identified, both carboplatin-paclitaxel and cisplatin-vinorelbine have reasonable toxicity profiles. The effectiveness of cisplatin-vinorelbine has been confirmed in two trials and across a wider range of stages.
It is appropriate that cisplatin-vinorelbine and carboplatin-paclitaxel be funded for the adjuvant treatment of completely resected stage IB to IIIA NSCLC.
The evidence for adjuvant chemotherapy in NSCLC
Non-small cell lung cancer (NSCLC) is a diagnostic grouping that includes large cell carcinoma, adenocarcinoma and squamous cell carcinoma. The clinical behaviour and prognosis of these subtypes is similar, thus they are usually grouped together for the purposes of treatment.
Several strategies have been employed to try and improve outcome in patients with completely resected NSCLC. The majority of studies have employed adjuvant chemotherapy or radiation. The evidence for the effectiveness of these approaches is summarised below.
Adjuvant radiation therapy
A substantial number of patients with resected NSCLC will relapse within the mediastinum. Several randomised trials have been conducted to see whether adjuvant radiation therapy to the mediastinum reduces the risk of recurrence or reduces mortality. The trials were summarised in a meta-analysis published in 1998. The trial showed an overall increase in mortality for patients treated with adjuvant radiation (5 year survival 55% vs. 48%) (4). Although the meta-analysis has been criticised on several
1points, there is currently no major role for adjuvant radiation treatment in resected NSCLC. Indeed, it is
possible that adjuvant radiation may have a negative impact on survival. This point is important in interpreting the result of trials of adjuvant chemotherapy in NSCLC.
There have been many randomised trials conducted to assess the benefit of adjuvant chemotherapy in patients with completely resected NSCLC. In 1995 a meta-analysis of trials of chemotherapy in NSCLC was published. Included within the analysis were trials comparing patients treated with chemotherapy following surgery against those who received surgery alone (5).
Data were available from 14 trials (4357 patients, 2574 deaths) considering patients treated with either surgery or surgery plus adjuvant chemotherapy. Five early trials used long-term alkylating agents, mainly cyclophosphamide or nitrosoureas. Eight more recent trials used chemotherapy containing cisplatin. Three trials used chemotherapy containing tegafur, an oral fluoropyrimidine.
1 Some analyses suggest that there may be a role for adjuvant radiation in patients with either microscopic involvement of resection margins or resected mediastinal (N2 stage) disease
Trials using long-term alkylating agents
The results for trials using long-term alkylating agents favour surgery alone. The combined hazard ratio
is 1.15 (P=0.005) in favour of surgery alone. This 15% increase in the relative risk of death is equivalent
to absolute an detriment of chemotherapy of 4% at 2 years, reducing survival from 70% to 66% and 5%
at 5 years, reducing survival from 50% to 45%.
Trials using cisplatin-based regimens
For regimens containing cisplatin, the results of most trials favour chemotherapy. The overall hazard
ratio of 0.87 (P=0.08), or 13% reduction in the risk of death, suggests an absolute benefit from
chemotherapy of 3% at 2 years, improving survival from 70% to 73% and 5% at 5 years, improving
survival from 50 to 55%. These results are not conclusive because the 95% confidence intervals for
absolute difference in survival are consistent with a 0.5% detriment to a 7% benefit of chemotherapy at 2
years and similarly consistent with a 1% detriment to a 10% benefit at 5 years.
An additional 3 trials are still underway or pending and are summarised in the table.
Trial Population Intervention BLT Cisplatin – based chemotherapy
EORTC 08922 Resected NSCLC with Ifosfamide – carboplatin-etoposide vs.
k-RAS activation cisplatin-etoposide vs. observation
NCCTG-822451 Resected Stage I-IIII Cisplatin-doxorubicin-cyclophosphamide vs.
Since the publication of the meta-analysis, 7 trials of adjuvant chemotherapy have been published either
in abstract or in peer-reviewed publications. Their results are summarised below.
Patients undergoing resection with curative intent were stratified by centre, T stage, N stage and
whether they were to receive adjuvant radiation. They were randomised to receive either adjuvant
chemotherapy or observation. Individual investigators decided whether patients should receive radiation
or not. Patients allocated to receive chemotherapy were treated with three cycles of mitomycin C 8mg
-2-2-2m day 1, vinblastine 3mg m day 1 and 8 and cisplatin 100mg m three weekly for a total of 3 cycles.
The trial was powered to detect a 20% reduction in the risk of death requiring 1200 patients to allow a
power of 80% and a type I error rate of 5% (control survival 35%).
606 patients received adjuvant chemotherapy and 603 observation. The groups were balanced with
respect to age, stage, histological subtype. 43% of patients in each group received radiation treatment.
Only 70% of patients in the MVP group completed the planned chemotherapy and only 34% completed without dose adjustments. At a median followup of 64 months, 638 events had occurred in the trial population. The HR for event-free survival was 0.89 (p=0.14) favouring the chemotherapy group. However, the 95% confidence interval included 1 and was consistent the risk of recurrence or death being reduced by up to 34% or increased by up to 4% (0.76 to 1.04). The HR for overall survival was 0.96 and in a multivariate analysis, only stage was associated with survival.
ECOG trial (7)
Patients were stratified according to histologic findings (squamous-cell carcinoma vs. other types), extent of weight loss during the six months preceding enrollment (<5 percent of body weight vs. ?5
percent of body weight), extent of nodal involvement, and the type of lymphnode dissection (systematic sampling vs. complete dissection).
Patients assigned to the control group received 50.4 Gy in 28 fractions adjuvant radiation. The combined-treatment group received identical radiotherapy administered concomitantly with etoposide
-2-2(120 mg m on days 1, 2, and 3) and cisplatin (60mg m on day 1). Chemotherapy started within 24
hours of the commencement of radiotherapy and repeated every 28 days for a total of four cycles. The median duration of follow-up for all 488 patients was 44 months. The median
survival was 39 months in the control group and 38 months chemotherapy and radiotherapy (p=0.56). When the two groups were compared in subgroups
defined according to the four stratification factors, there was no significant difference in survival.
Eligible patients had NSCLC of stage I, II, or III and had undergone a complete surgical resection. Patients were stratified by treating centre, type of surgery (pneumonectomy vs. other surgical procedures) and pathological stage (I vs. II vs. III). The trial was designed to detect an absolute improvement in survival of 5 percent, from 50 percent to 55 percent, at five years. 3300 patients were required to provide the study with 90 percent power with a 5 percent type I one-sided error rate. Interim analyses were planned after 320 and 640 deaths. A total of 1867 patients underwent randomisation. The chemotherapy regimens were chosen by the treating centre. Forty nine
-2percent of the patients received cisplatin 100 mg m with etoposide for three or four cycles. The rest of the patients
received a number of other regimens, most commonly cisplatin-vinblastine. Postoperative radiotherapy was
-planned for 31 percent of patients. In the chemotherapy group, 74 percent of patients received at least 240 mg m
2 of cisplatin and 8 percent never received chemotherapy, mainly because of the patient’s or physician’s refusal.
Among the 1867 randomized patients, 973 died: 469 in the chemotherapy group and 504 in the control group. The hazard ratio for death was 0.86 favouring chemotherapy The two-year survival rates were 70.3 and 66.7 percent in
the control group, and the five-year survival rates were 44.5 percent and 40.4 percent. In multivariate analysis,
there were no definable patient groups who accrued more or less benefit from treatment.
The JLCRG trial randomised patients who had completely resected stage I adenocarcinoma to either
-2observation or oral uracil-tegafur (250 mg m of tegafur per day) for two year. Tegafur is an oral
fluoropyrimidine analogue. From January 1994 through March 1997, 498 patients received uracil–tegafur and
501 patients received no additional treatment. The five-year overall survival rate was 88 percent (95 percent
confidence interval, 85 to 91%) in the uracil–tegafur group and 85 percent (95 percent confidence interval, 82 to
89%) in the control group.
There was a significant interaction between T stage and outcome. The five-year survival rate among patients with
T2 disease was 85 percent 95 percent confidence interval, 79 to 91 percent) in the uracil–tegafur group and 74 percent (95 percent confidence interval, 66 to 81%) in the control group (p=0.005 by log-rank test). The five-year survival rate among patients with T1 disease was 89 percent in the uracil–tegafur group and 90 percent in the control group.
Patients with completely resected T2N0, T1N1 or T2N1 disease were eligible. They were stratified by
nodal status (N0 vs. N1) and ras oncogene status (positive vs. negative vs. unknown) and randomised
to receive either cisplatin-vinorelbine or observation. Patients randomised to chemotherapy received
-2-2cisplatin 50mg m day 1 and 8 every 4 weeks and vinorelbine 25mg m weekly for 16 weeks. In order to detect a 10% improvement in survival from 60% to 70% 450 patients were required.
Patients were balanced with respect to age, gender, histological type and stage. The median number of
chemotherapy cycles was 3 and all patients required at least one dose reduction or delay due to toxicity,
mainly neutropenia. Non hematological toxicity was moderate. The on-treatment death rate was 1%.
The HR for survival was 0.7 (p=0.012) favouring chemotherapy, equivalent to a 15% increase in 5 year
survival from 54% to 69%. The median survival in the control arm was 73 months compared with 94
months in the chemotherapy group. QOL measures were equivalent between the groups with the
exception of neurotoxicity which was more common and long lasting in the group treated with cisplatin –
CALGB 9633 (11)
Patients with stage IB NSCLC who underwent complete surgical resection were randomised to either
-2observation or adjuvant chemotherapy with paclitaxel 200mg m and carboplatin AUC6 every 3 weeks
for 4 cycles. Patients were stratified by mediastinoscopic staging, histology and grade. 344 patients were randomised, 173 to adjuvant chemotherapy and 171 to observation.
There were no toxic deaths and 85% of patients received 4 cycles of chemotherapy, 65% without dose–
The hazard ratio for death from any cause was 0.62 (p=0.028) favouring chemotherapy. The four year survivals were 71% and 59% in the chemotherapy and . In a multivariate analysis, only adjuvant chemotherapy was significantly associated with survival.
Patients with completely resected stage I to IIIA NSCLC were randomized to receive adjuvant cisplatin-
-2-1 -2vinorelbine (vinorelbine 30 mg m weekfor 16 weeks and cisplatin 100 mg m d1 q4 weeks for 4
cycles) or observation. Radiotherapy policy was predetermined by each center. The study was powered to detect a 10% improvement in survival at 2 years. 840 patients from 101 centers in 14 countries were enrolled. The median age was 59 (range 18-75); 86% male; 95% WHO PS 0-1; 59% squamous cell carcinoma; 35% stage I, 30% II, 35% IIIA. Pneumonectomy was performed in 37% of patients and lobectomy in 58%. At a median followup of >70 months, median survival was 69 months in the cisplatin – vinorelbine arm and 44 months in the observation arm (HR for survival 1.26, 95% CI 1.05
to 1.52). Survival at 5 years was 51% in the cisplatin-vinorelbine arm and 43% in the observation arm. The survival advantage appeared to be confined to patients with stage II and III disease. The treatment-related mortality was 1%.
Conclusions regarding adjuvant chemotherapy in NSCLC
It is likely that adjuvant chemotherapy increases the survival in patients with completely resected stage I to III NSCLC. The absolute benefit of treatment is unlikely to be less than a 5% increase in 5 year survival and may be greater. Data from the meta-analysis suggests an absolute improvement in survival of 5% at 5 years. This is in keeping with the results of the IALT trial, but not the ECOG or ALPI trials. However, the results of all earlier trials may be distorted by the use of adjuvant radiation in many of the patients treated. The results of two more recent trials BR10 and CALGB 9633 suggest that in carefully selected patients, treated without radiation therapy and treated using modern agents may have a survival advantage similar to that obtained by many patients treated with adjuvant chemotherapy in the setting of breast cancer or colorectal cancer (13, 14).
The reason for the discrepancy in results between the recent trials is not entirely clear. All were powered appropriately to detect small differences in overall survival. However, in both the negative trials (ALPI and ECOG) a substantial number of patients received radiation. Although the numbers were balanced between the arms of the trial, it is possible that a deleterious effect of radiation masked a small benefit from chemotherapy. In the IALT trial, only 34% of the patients received adjuvant radiation and in the BR10, CALGB 9633 and JLCSG trials, no patients received adjuvant radiation. Patients in the ANITA trial received radiation although it was found to be a negative prognosticator in multivariate analysis.
Although the results from BR10 and CALGB trials are relatively immature, it appears that the benefit gained from
rd generation” agents may be greater. There are several possible explanations for adjuvant chemotherapy with “3
Firstly, third generation agents and regimens may be more active against NSCLC. Four trials have directly compared cisplatin–containing third– generation regimens with an older treatment, usually cisplatin–etoposide (15-
19). Third generation regimens have proven to be equivalent or superior for response rate or progression–free
survival and in one trial, cisplatin–paclitaxel resulted in survival superior to cisplatin – etoposide (median survival
9.9 vs. 7.7 months) (17).
Second, it is possible that treatment is delaying the progression of occult metastatic disease and that the greater difference in survival simply reflects shorter followup. If this is the case, the survival curves of the treated and untreated groups will come together with further followup.
Third, it is likely that patients in modern trials are better staged than in older trials. If the effect of chemotherapy on survival is lessened by the treatment of patients with metastatic disease, the true survival advantage may be underestimated in older trials that included patients with occult metastatic disease.
Fourth, it is possible that the beneficial effects of treatment are seen in particular subgroups of patients with stage I to III disease. There is some evidence that the survival advantage in the BR10 trial was confined to patients with lymph-node metastases (20) and that survival is not improved in patients with T1N0 and T2N0 disease. This is similar to the conclusion of ANITA trial, which showed a survival benefit in patients with stage II and III disease. However, this is obviously at odds with the conclusions of CALGB 9633. At this stage, it is not possible to identify specific subsets of patients who do or do not benefit from adjuvant chemotherapy although it would be reasonable to confine its use to patients with stage IB and higher disease.
It appears that cisplatin-based chemotherapy increases survival in NSCLC. Data from the JLCSG trial suggests that adjuvant UFT chemotherapy may also increase survival. Six trials have been conducted that compare surgery alone with adjuvant chemotherapy with uracil–tegafur. A meta-analysis of those six trials published only in
abstract shows that adjuvant chemotherapy with uracil–tegafur improved the overall survival (hazard ratio for