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Lung Cancer

Table 1: Post-1995 Meta-analysis – Non-small-cell Lung Cancer Randomised Adjuvant Platinum Trials Trial






I–IIIA n 488

1,209 381

1,867 482 344 840

Chemotherapy Cis/VP16 Cis/MVd

Cis/4 options

Cis/Vinca or VP16 Cis/Vinca Carbo/Pac Cis/Vinca

Significant? No No No

Yes Yes Yes Yes

Survival Benefit NA NA NA

4% at 5 years 11% at 5 years 20% at 4 years 8.6% at 5 years

Long-term Follow-up NA NA NA

Benefit lost at 7 years Benefit retained >9 years

Benefit lost at 57 and 74 months Benefit retained at 7 years

ANITA = Adjuvant Navelbine® international trialist association trial; ALPI = Adjuvant lung project Italy; BLT = Big lung trial; CALGB = Cancer and leukemia group B; Carbo = carboplatin; Cis = cisplatin; IALT = International adjuvant lung cancer trial; MVd = mitomycin C and vindesine; Pac = paclitaxel; Vinca = vinca alkaloid, Vin = vinorelbine; VP16 = etoposide.

Table 2: Early-stage Non-small-cell Lung Cancer Prognostic Biomarkers

Marker MSH2 ERCC1

MRP1 p53

expression β-Tubulin III JBR.10 Ras

mutation MET



IALT JBR.10 n HR Survival Reference 768 HR 0.66; p=0.01 Kamal et al., 201051

761 HR 0.66; p=0.009 Olaussen et al., 200618

782 HR 1.37; p=0.007 Filipits et al., 200752 253 HR 1.89; p=0.03 Tsao et al., 200731

256 HR 1.72; p=0.04 Seve et al., 200739

253 Not prognostic Tsao et al., 200731

Retrospective 447 HR 0.66; p=0.04 Tsao et al., 200731

Retrospective 126 HR 1.98; p=0.02 Rosell et al., 58 HR 2.4; p=0.04 200733

BRCA1 = breast cancer 1; ERCC1 = excision repair cross-complementation group 1; HR = hazard ratio; IALT = International adjuvant lung cancer trial.

chemotherapy. The effect of the adjuvant therapy did not significantly differ between all the chemotherapy regimens, which incorporated cisplatin plus at least one additional drug.

The Evolving Role of Biomarkers for Choosing Chemotherapy in Resected Non-small-cell Lung Cancer

The limited benefit of using adjuvant chemotherapy seen so far in trials, and the lack of benefit in certain subsets, such as most stage IB tumours, highlight the fact that we do not yet understand who will be most helped by treatment and which agents to use. To make further improvements in survival, we will need to identify those patients most at risk for recurrence and determine which chemotherapy will work the best in each person. In addition, we will need to identify those at low risk to avoid the unnecessary toxicity of chemotherapy, a point highlighted by the long-term IALT data indicating potential harm in the form of increased non-cancer mortality.2

In this large trial, initial analysis indicated an overall

survival benefit, but with longer-term follow-up to 7.5 years, the significance of the benefit was lost and there was an indication of excess non-cancer mortality in the chemotherapy arm. This increased non- cancer death and loss of benefit over time has not been seen in other adjuvant trials, including JBR.10 and ANITA,3,4

but the IALT long-term data

are concerning. Although we still have a lot to learn about the basic biology of NSCLC, which is a very heterogeneous disease, there are some promising emerging prognostic and predictive markers that are beginning to be incorporated into our decisions for adjuvant therapy. A prognostic marker is one that indicates survival benefit (or detriment) regardless of therapy. Examples of this include tumour stage, tumour size


and patient sex. A predictive maker is one that predicts for differential benefit from a particular therapy. Although we will not discuss prognostic markers here in much detail, there have been several early-stage prognostic biomarkers published (see Table 2). The predictive markers and how they fit into the ongoing clinical trials are discussed below. Although there is a great need for biomarkers in NSCLC, each biomarker must be rigorously tested and validated before it is implemented.13–16

Excision Repair Cross-complementation Group 1 The excision repair cross-complementation group 1 (ERCC1) protein functions in the nucleotide excision repair pathway and is required for the proper repair of DNA after damage from insults such as ultraviolet (UV) light or cisplatin. ERCC1 was one of the first proteins to be studied in a retrospective fashion using immunohistochemistry (IHC) on operative specimens taken from patients who had participated in the IALT trial. In the ‘IALT-Bio’ analysis, 761 tumour specimens were evaluated and ERCC1 expression was positive in 335 (44%) and negative in 426 (56%). A benefit of cisplatin-based adjuvant chemotherapy was associated with the absence of ERCC1 (test for interaction; p=0.009).17 Adjuvant chemotherapy, as compared with observation, significantly prolonged survival among patients with ERCC1-negative tumours (HR 0.65; 95% confidence interval [CI], 0.50–0.86; p=0.002) but not among patients with ERCC1-positive tumours (HR 1.14, 95% CI 0.84–1.55; p=0.40). Patients with ERCC1-positive tumours who did not receive adjuvant chemotherapy survived longer than those with ERCC1- negative tumours (adjusted HR for death 0.66, 95% CI 0.49–0.90; p=0.009).18

Using realtime polymerase chain reaction (RT-PCR) analysis of ERCC normalised to 18S ribosomal RNA expression, an ERCC1 value of 50 revealed a statistically significant difference in median survival for patients with ERCC1 expression of >50 (94.6 months) compared with patients with ERCC1 expression of <50 (35.5 months, p=0.01). The value of ERCC1 has yet to be tested prospectively, but there are several randomised prospective clinical trials (Southwest Oncology Group [SWOG] S0720, Tailored post-surgical therapy in early- stage NSCLC [TASTE] and International tailored chemotherapy adjuvant [ITACA]) testing the utility of ERCC1 as a biomarker in adjuvant NSCLC treatment (see below).

The result suggested that completely resected ERCC1- negative NSCLC would benefit from a cisplatin-based adjuvant chemotherapy, whereas those with high ERCC1 levels were less likely to benefit. The rationale was that DNA damaged by cisplatin was unable to undergo repair, resulting in greater tumour cell death. In another study, Simon et al. evaluated the effect of intratumoural ERCC1 expression on survival in NSCLC patients who underwent surgical resection for cure.19

Ribonucleotide Reductase M1

The regulatory subunit of ribonucleotide reductase M1 (RRM1) is essential for nucleotide excision repair. RRM1 expression was studied


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