61 (at 24 mo)
* Estimated 5-year survival rates were 39% for the RT only group and 33% for the CT-RT group.
** Estimated 2-year survival rates were 60% for the observation group and 58% for the CT group.
## dose density of vinorelbine
E = etoposide; Cis = cisplatin; Mit = mitomycin; PCL = paclitaxel, VND = vindesine; Vin = vinblastine; If = ifosphamide; UFT = Uracil/tegafur; VNB = vinorelbine.
The North American Intergroup Trial INT0115 was the only trial that compared the combination of chemotherapy plus thoracic radiotherapy versus radiotherapy alone in patients with completely resected stage II or IIIA NSCLC and failed to demonstrate a benefit in favour of chemotherapy[3]. The negative results of the Adjuvant Lung Project Italy (ALPI)[4] and the Big Lung Trial (BIG)[5] further jeopardized the role of adjuvant chemotherapy in the treatment of NSCLC.
National Cancer Institute of Canada (NCIC) JBR10 trial
The National Cancer Institute of Canada (NCIC) JBR10 Trial randomly assigned 482 patients with completely resected, pathological stage IB and II (patients with T3N0 disease were excluded) to receive either post-operative adjuvant chemotherapy with cisplatin and vinorelbine or no chemotherapy[6].
At 5 years of follow-up, the 5-year survival rates were 69% for the chemotherapy arm and 54% for the control arm (HR 0.69; 95% CI 0.52–0.92; P = 0.011), with an absolute survival benefit of 15% for patients receiving chemotherapy[6]. An updated analysis after a median follow-up of 9.3 years continued to show a benefit in favour of adjuvant chemotherapy (HR 0.78; 95% CI 0.61 to 0.99; P = 0.04)[7]. Patients with stage II disease had a significant benefit in terms of 5-year OS (59 vs 44% for placebo), but in patients with stage I disease the benefit depended upon the size of tumour. For the whole group there was no benefit (5-year OS, chemotherapy vs placebo: 76 vs 69%; HR 1.03; P = 0.79). In patients with tumours < 4 cm, chemotherapy was associated with a detrimental effect (5-year OS chemotherapy vs placebo: 73 vs 79%; HR 1.73), while in those with tumours > 4 cm adjuvant treatment prolonged OS (5-year OS chemotherapy vs placebo: 79 vs 59%; HR 0.68). Compliance with chemotherapy was relatively low, with only 65% of the patients receiving three or four cycles. Neutropenia was the most common haematological toxicity, with 73% of the patients experiencing a grade III–IV neutropenia, while fatigue (15%) anorexia (10%) and vomiting (10%) were the most common grade III–IV non-haematological toxicities. Chemotherapy was not associated with an increase in secondary malignancies, but resulted in a statistically significant transient worsening of quality of life[8].
Adjuvant Navelbine International Trial Association (ANITA) trial
The Adjuvant Navelbine International Trial Association (ANITA) trial randomized 840 patients with stage IB-IIIA NSCLC to post-operative chemotherapy (4 cycles of cisplatin 100 mg/m2 every 4 weeks and 16 cycles of vinorelbine at 30 mg/m2 weekly) or observation only[9]. After a median follow-up of 76 months, OS was significantly longer in the chemotherapy arm (65.7 months in the chemotherapy arm vs 43.7 months in the observation arm; HR 0.80; 95% CI 0.66–0.96; p = 0.017). Overall survival at 5 years with chemotherapy improved by 8.6%, which was maintained at 7 years (8.4%). In a similar way to JBR10, chemotherapy did not improve survival in stage IB disease (HR 1·10; 95% CI 0·76–1·57). Significant chemotherapy-related toxicity was reported with 84.6 and 12.5% of the patients experiencing grade 3–4 neutropenia and febrile neutropenia, respectively. It should be noted that only 50% of the patients were able to complete the planned four cycles.
International Adjuvant Lung Cancer Trial (IALT) and CALGB9633 trial
The International Adjuvant Lung Cancer Trial (IALT) was the largest adjuvant trial (n = 1867 patients) and included patients with stage I–IIIA disease. Patients were randomized to cisplatin-based chemotherapy or observation[10]. After a median follow-up of 56 months, the 5-year OS was significantly longer in the chemotherapy arm (5-year OS chemotherapy vs placebo 44.5 vs 40.4%; HR 0.06; p = 0.03), but the significant effect was no longer present after a median follow-up of 90 months (HR 0.91; p = 0.10)[11]. The CALGB9633 trial was the only one to use a carboplatin-based regimen and focused only on patients with stage IB disease. It failed to maintain the benefit with longer follow-up (HR 0.83; p = 0.12)[12]. However, exploratory analysis demonstrated a significant survival difference in favour of adjuvant chemotherapy for patients who had tumours ≥ 4 cm (HR 0.69; 95% CI 0.48–0.99; p = 0.043).
Uracil/tegafur (UFT)
A large phase III trial (n = 999) tested the role of UFT in Japanese patients with stage I adenocarcinoma and demonstrated a significant increase in the 5-year OS rate in patients with T2 tumours (85 vs 74% for the UFT and observation groups, respectively; HR 0.48; 95% CI 0.29–0.81; p = 0.005), while for patients with T1 disease no significant difference was observed[13]. A subsequent meta-analysis with 2,000 patients further confirmed the role of UFT in the adjuvant setting[14]. It should be noted that UFT has not been tested in Caucasians in the adjuvant setting, and the drug is not registered in the European Union for this indication.
Targeted agents
Goss et al. evaluated the role of gefitinib in 503 stage IB-IIIA NSCLC, patients not selected by EGFR status. Patients were randomized to gefitinib 250 mg or placebo daily for 2 years. After a median follow-up of 4.7 years, median disease-free survival (DFS) was 4.2 years for gefitinib versus not yet reached (NYR) for placebo (HR 1.22; 95% CI 0.93–1.61, p = 0.15 and median OS) 5.1 years vs NYR (HR 1.24; 95% CI 0.94–1.64, p = 0.14). In multivariate analysis, tumour size > 4 cm was predictive of poor DFS (p < 0.0001) and never smoking for better OS with gefitinib (p = 0.02). EGFR copy whether low/high polysomy or amplification was neither prognostic (p = 0.77) nor predictive of OS benefit from gefitinib[15]. A trial of erlotinib after surgery (with or without adjuvant chemotherapy) in patients who have epidermal growth factor receptor (EGFR)–positive tumours (RADIANT) is currently ongoing (NCT00373425). Adjuvant chemotherapy with or without bevacizumab as adjuvant therapy for NSCLC patients with completely resected stage IB (≥4 cm)–IIIA is being tested in an ongoing ECOG (E1505) trial (NCT00324805). Melanoma associated antigen (MAGE)–A3 is a tumour-specific antigen that is expressed in a large variety of cancers, including NSCLC. Vaccination with the MAGE-A3 antigen in patients with early-stage NSCLC has shown encouraging results in the context of phase II trials[16]. The vaccine reduced the risk of relapse after surgery, and its role is currently under investigation in a phase III trial (MAGRITTE trial; NCT00480025).
Meta-analyses
The survival benefit observed with adjuvant chemotherapy was confirmed by a meta-analysis of five randomized trials[4–6,9,10] with 4584 patients registered in the LACE (lung adjuvant cisplatin evaluation) database[17]. This meta-analysis demonstrated a 5.4% increase in 5-year survival in favour of adjuvant chemotherapy compared to observation (HR 0.89; 95% CI 0.82–0.96). The survival benefit varied according to stage and was most pronounced for patients with stage II and IIIA disease. The improvement in survival in patients with stage IB disease did not reach statistical significance, and patients with stage IA disease appeared to do worse with adjuvant chemotherapy. All five trials included in the LACE meta-analysis used cisplatin-based chemotherapy, and all trials except the JBR10 allowed the use of post-operative radiotherapy at the discretion of the treating physician. A more recent meta-analysis by Arriagada et al. demonstrated a similar benefit (HR 0.86, 95% CI 0.81–0.92, p < 0.0001), with an absolute increase in survival of 4% (95% CI 3–6) at 5 years (from 60 to 64%)[18]. This meta-analysis did not show significant differences in the effect of platinum chemotherapy by stage. Also, no platinum-based regimen emerged as ‘goldstandard’. Numerous other meta-analyses have reported HR in the same range[19–22] (Table 14.2).
| Study | Intervention | No. of studies/pts. | HR (95% CI) | p-Value |
|---|---|---|---|---|
| Hotta et al.[19] | Adjuvant CMT Adjuvant C | 13/5360 8/3786 | 0.87 (0.80–0.94) 0.89 (0.81–0.98) | 0.001 0.012 |
| Sedrakyan et al.[20] | Adjuvant CMT Adjuvant C | 19/7200 12/4912 | 0.87 (0.81–0.93) 0.89 (0.82–0.96) | < 0.0001 0.004 |
| Berghmans et al.[21] | Adjuvant CMT Adjuvant C | 17/7644 16/NR | 0.84 (0.78–0.89) 0.86 (0.80–0.92) | NR NR |
| Bria et al.[22] | Adjuvant P | 12/7334 | ||
| LACE[17] | Adjuvant C | 5/4584 | 0.89 (0.82–0.96) | 0.005 |
| NSCLC CG[18] | Adjuvant C Adjuvant C +PORT | 30/8147 12/2763 | 0.86 (0.81–0.93) 0.90 (0.82–0.98) | < 0.001 0.02 |
Is there an optimal regimen for adjuvant chemotherapy?
All the aforementioned trials utilized a cisplatin-based regimen in the adjuvant treatment, while in the CALGB9633 the carboplatin/paclitaxel doublet was used[12]. In the LACE meta-analysis, the effect of cisplatin plus vinorelbine was marginally better than the effect of other drug combinations[17]. However, it should be noted that these trials used relatively older drugs (etoposide, ifosphamide, vinca alkaloids) in combination with cisplatin, and no trial utilized a third-generation agent (docetaxel, gemcitabine, pemetrexed). This meta-analysis also demonstrated that patients who received a total dose of cisplatin >300 mg/m2 had a trend towards better OS and disease-free survival compared to patients who received ≤300 mg/m2. The total dose of cisplatin varied according to the second drug used in each regimen. In the cisplatin/vinorelbine group, 86% of the patients were able to receive >300 mg/m2, while this percentage was 54% in the cisplatin/other drug group. Therefore, it can be questioned whether the benefit observed with the cisplatin/vinorelbine regimen is due to higher efficacy of this combination or to the fact that higher dose of cisplatin could be achieved with this doublet[17]. Finally, patients who were treated with a triplet received significantly (p < 0.001) less cisplatin compared to patients who were treated with a doublet[17].
According to these observations, the approach of many scientific societies is to recommend the use of any cisplatin-based doublet23–25.
Stage I treatment
With the exception of the IALT study[4], none of the studies described earlier included patients with stage IA disease. Furthermore, in the LACE meta-analysis, patients with stage IA disease (n = 347) appeared to do worse with adjuvant chemotherapy, although the number was too small to allow valid conclusions[17]. Therefore, adjuvant chemotherapy is not recommended for patients with stage IA disease[23–25].
The management of patients with stage IB disease is more controversial. CALGB9633[12], the only study that enrolled only patients with stage IB disease, failed to demonstrate a benefit. Similarly, subgroup analysis of the IALT[10], the JBR10 and the ANITA[9] studies demonstrated no benefit for these patients. Finally, in the LACE meta-analysis, there was only a trend towards an OS benefit in favour of adjuvant chemotherapy in patients with stage IB disease (HR 0.93; 95% CI 0.78–1.10)[17].
On the contrary, the more recent meta-analysis from the NSCLC Collaborative Group demonstrated an identical 5-year OS benefit in patients with stage IB, II and III disease (5% in all groups)[18]. Also, the CALGB9633 trial[12] and the JBR10 demonstrated a benefit in patients with tumours larger than 4 cm. However, these analyses were not pre-planned or adequately powered, and therefore, their results cannot be considered conclusive.
Currently, adjuvant chemotherapy is not considered as standard of care for patients with stage IB disease[23–25]. Further, prospective trials are needed in order to clearly address this issue. However, a prospective phase III trial especially for patients with stage III disease is unlikely given the large number of patients required.
Treatment of elderly patients
Despite the increasing incidence of NSCLC in elderly populations, this patient group is often under-represented in clinical trials, and therefore, it is difficult to reach evidence-based recommendations for this population[26]. Unfortunately, in the adjuvant setting, only retrospective data exist for elderly patients.
Patient data included in the LACE meta-analysis[17] were categorized into three age groups (<65 [n = 3,269, 71%], 65–69 [n = 901, 20%] and ≥70 [n = 414, 9%]). The analysis of these data according to age demonstrated that although patients ≥70 years received lower total doses of cisplatin (p < 0.0001) and fewer cycles of chemotherapy (p < 0.0001), there was no difference in terms of OS between age groups, and elderly patients had a similar survival benefit from adjuvant chemotherapy with their younger counterparts[27]. Furthermore, toxicity rates were similar across all age groups evaluated. As expected, a higher number of elderly patients died from non-cancer-related causes (p < 0.0001)[27]. The more recent meta-analysis from the NSCLC Collaborative Group also did not observe any differential effect of chemotherapy according to age[18].
In a retrospective age-specific subgroup analysis of the JBR10 study, outcomes in elderly patients (age ≥ 65) and matched younger patients (age < 65) were compared[6]. Despite older patients receiving fewer doses of chemotherapy and lower mean doseintensities, OS was significantly prolonged with chemotherapy (HR 0.61; 95% CI 0.38–0.98; p = 0.04)[28]. The survival benefit in the elderly group was similar to that demonstrated in younger patients with no significant differences in toxicities, hospitalization or treatment-related death. A recently published observational study based on data from the Surveillance, Epidemiology, and End Results (SEER) Registry also demonstrated that platinum-based adjuvant chemotherapy administered to elderly patients was associated with a significant OS benefit, although with higher toxicity[29].
According to these results, it can be argued that adjuvant chemotherapy should not be refused to elderly patients solely on the basis of age, and treatment decisions should take into account the estimated absolute benefit, life expectancy, treatment tolerance, presence of co-morbidities and patient preferences.[30]. However, it should also be noted that these results are based on retrospective analyses that are likely to suffer from selection bias in favour of treatment and their extrapolation to the general older population should be made with caution.
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
