TORAKOCHIRURGIA
Do NSCLC patients become sensitive to second-line erlotinib treatment after previous radiotherapy?

Introduction

Thoracic radiotherapy (RT) in combination with chemotherapy is standard first-line treatment for locally advanced or unresectable non-small cell lung cancer (NSCLC) patients. However, chemotherapy alone is applied for patients with metastatic NSCLC. The addition of RT to cisplatin-based chemotherapy results in further tumour growth inhibition, lengthening disease-free survival and overall survival but, in most cases, does not ensure complete recovery of patients [1].

Erlotinib is an EGFR tyrosine kinase inhibitor (EGFR-TKI) that has shown activity in recurrent NSCLC. The objective response for erlotinib treatment occurs only in about 10% of Caucasian patients. Sensitivity to EGFR-TKI is dependent on the activated form of EGFR gene mutation in tumour cells. Molecular abnormalities occur more frequently among never-smoking female patients with adenocarcinoma [2, 3]. Nevertheless, independent predictive factors for unambiguous qualification for EGFR-TKI treatment have not been assessed [4].

The randomised trials evaluating the effectiveness of EGFR-TKI therapy as an addition to radiotherapy in head and neck cancer indicated that this combination of therapy significantly improves the outcome of radiotherapy [5]. High level of EGFR protein expression is correlated with resistance to radiation therapy in a variety of cancers, mostly in squamous cell carcinoma of the head and neck. Moreover, susceptibility to radiation therapy is improved by blockage of the EGFR domain by EGFR-TKI agents [6, 7]. An individual case report showed that erlotinib-induced skin rash could spare skin irradiated in previous RT [8]. Moreover, EGFR gene mutation is an independent, good predictive factor for response to whole-brain radiation therapy in adenocarcinoma metastases [9]. However, the radiation-induced activation of the EGFR pathway and EGFR gene mutation in cancer cells could stimulate the response to EGFR-TKI agents [7]. Finally, we could not clearly state whether erlotinib is more effective in recurrent NSCLC patients after radiotherapy combined with chemotherapy than after chemotherapy alone.

Material and methods

Locally advanced and advanced NSCLC patients (n = 102) treated with erlotinib (150 mg per day) in second- and third-line therapy were divided into two groups: Group A included patients treated first-line with a combination of thoracic radiotherapy and cisplatin-based chemotherapy (n = 40). The patients treated with chemotherapy alone (n = 62) were classified into Group B. The patients’ characteristics are presented in Table I.

The chi-square test and Cox regression model were used to test potential predictive and prognostic factors that affected clinical response and overall survival. The Kaplan-Meier method was used for the comparison of survival probability in different groups. The following predictive and prognostic factors were included in the analysis: age, gender, smoking status, performance status (ECOG-WHO), weight loss, anaemia, serum LDH level, histopathological diagnosis, initial stage of disease, stage of disease (IIIB or IV), time from diagnosis to erlotinib treatment, response to first-line treatment, progression-free survival after first-line treatment, erlotinib therapy toxicity (rash), EGFR protein expression by immunohistochemistry method (in 29 patients), EGFR gene copy number by FISH method (in 23 patients) and EGFR gene mutation status (exon 19 and 21) by allele-specific refractory mutation PCR method (ARMS-PCR) and DNA fragment length analysis (in 26 patients).

Results

Group A and Group B were well matched, except for histopathological diagnosis and clinical response to first-line treatment. Group A had fewer adenocarcinoma-bearing patients than Group B (p < 0.05). However, disease control after first-line treatment was observed significantly more frequently in Group A than in Group B (p < 0.05). Progression-free survival was longer, but not significantly (p = 0.07), for Group A than Group B (Table I). Moreover, the initial stage of NSCLC was different between these two groups. Locally advanced lung cancer was diagnosed initially only in 18 patients from Group B.

Disease control and survival longer than 6 months during erlotinib administration were observed significantly more frequently in patients treated with both RT and chemotherapy than in patients who received only chemotherapy in first-line treatment (p < 0.05 and p < 0.005, respectively). This observation was applied only to patients with stable disease (Table I). Neither expression of EGFR protein nor amplification of the EGFR gene, but the presence of EGFR gene mutation (p < 0.05, 2 = 7.094) significantly reduced the risk of early progression in erlotinib-treated patients. Clinical factors which affected the risk of early progression were similar to factors specified in clinical trials, e.g. BR.21. However, response to first-line treatment and stage of disease had no significant influence on the risk of early progression or on survival time shortening.

The median time of overall survival measured from the beginning of erlotinib treatment was 16 months for Group A and only 5 months for Group B. Probability of survival was significantly higher in Group A than in Group B (p < 0.005, HR = 2.179, 95% CI: 1.339-3.546, Fig. 1). Moreover, survival probability was significantly higher for patients with disease control after first-line treatment compared to patients with early progression (p < 0.005, HR = 2.045, 95% CI: 1.163-3.596).

Based on the Cox regression model with stepwise se-lection procedures by minimum AIC, we established 6 pro-

gnostic risk factors of overall survival shortening for erloti-nib-treated patients: poor performance status (p < 0.0001, HR = 4.937, 95% CI: 2.601-9.369), heavy smoking (p < 0.0005, HR = 3.614, 95% CI: 1.765-7.398), lack of radiotherapy in first-line treatment (p < 0.005, HR = 2.636, 95% CI: 1.385-5.015), rash at the beginning of the erlotinib treatment

(p < 0.005, HR = 2.478, 95% CI: 1.336-4.595), weight loss > 5% (p < 0.01, HR = 2.225, 95% CI: 1.247-3.969) and time from diagnosis to erlotinib treatment (p < 0.05, HR = 2.084, 95% CI: 1.14-3.807). Overall model fit was as follows:

p < 0.0001, 2 = 73,769. Overall survival did not significantly depend on response to first-line treatment or disease stage (both initial and during erlotinib treatment).

Conclusion

In most clinical trials prior cisplatin-based chemotherapy was a necessary requirement for qualification for second- and third-line therapy with erlotinib in recurrent NSCLC [2]. The role of RT in probability of response to erlotinib first-line treatment was not carefully considered. Generally, it was ascertained that the response to first-line chemotherapy has an impact on response to erlotinib in second- or third-line treatment. It is established that the application of both chemo- and radiotherapy gives better results than chemotherapy alone [1]. In the light of these conclusions we have to face the question: does the radiotherapy or rather the response to first-line treatment have predictive and prognostic value in erlotinib second- or third-line therapy outcome?

In this report we have shown that application of radio-therapy and chemotherapy in first-line treatment results in higher probability of disease control after erlotinib treatment as well as in the prolongation of overall survival. Consequently, this combination of therapy has a predictive and prognostic impact on erlotinib treatment.

One could speculate that RT can induce the EGFR gene mutation and activate carcinogenesis through the EGFR pathway. It would be advisable to examine the EGFR gene mutation before and after radiotherapy.

On the other hand, a lower percentage of adenocar-cinoma in an initial lower stage of cancer was observed in the group of patients who were treated with thoracic radiotherapy, which distinguishes them from the group of patients treated with chemotherapy alone. The differences in natural disease course may have a crucial prognostic role. It was confirmed by the high percentage of patients with stable disease (but not with response) after erlotinib therapy in the group of patients treated with a combination of radiotherapy and chemotherapy in first-line treatment. However, these factors were of lower significance concerning erlotinib effectiveness than the application of radiotherapy in first-line treatment. Moreover, a histopathological diagnosis other than adenocarcinoma should be associated with poorer response to erlotinib therapy. In conclusion, our observations indicate that application of radiotherapy in first-line treatment has predictive rather than prognostic value for the efficacy of erlotinib second-line therapy.



Competing interests

The authors declare that they have no competing interests.

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