Ingrid Kappers

Is 18F-FDG PET/CT Useful for the Early Prediction of Histopathologic Response to Neoadjuvant Erlotinib in Patients with Non–Small Cell Lung Cancer?

Early prediction of treatment response is of value in avoiding the unnecessary toxicity of ineffective treatment. The objective of this study was to prospectively evaluate the role of integrated 18F-FDG PET/CT for the early identification of response to neoadjuvant erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. Methods: From October 2006 to March 2009, 23 patients with non–small cell lung cancer eligible for surgical resection were evaluated for this study. Patients received preoperative erlotinib (150 mg) once daily for 3 wk. 18F-FDG PET/CT was performed before and at 1 wk after the administration of erlotinib. Changes in tumor 18F-FDG uptake during treatment were measured by standardized uptake values and assessed prospectively according to the criteria of the European Organization for Research and Treatment of Cancer. Patients with a decrease in standardized uptake values of 25% or more after 1 wk were classified as “metabolic responders.” The metabolic response was compared with the pathologic response, obtained by histopathologic examination of the resected specimen. Results: Following the 18F-FDG PET/CT criteria of the European Organization for Research and Treatment of Cancer, 6 patients (26%) had a partial response within 1 wk, 16 patients (70%) had stable disease, and 1 patient (4%) had progressive disease. The median percentage of necrosis in the early metabolic responder group was 70% (interquartile range, 30%–91%), and the median percentage of necrosis in the nonresponder group was 40% (interquartile range, 20%–50%; P = 0.09). The κ-agreement between the metabolic and pathologic responders was 0.55 (P = 0.008). Conclusion: The results of this study suggest that early during the course of epidermal growth factor receptor tyrosine kinase inhibitor therapy, 18F-FDG PET/CT can predict response to erlotinib treatment in patients with non–small cell lung cancer.

Tumor Response and Toxicity of Neoadjuvant Erlotinib in Patients With Early-Stage Non–Small-Cell Lung Cancer

PURPOSE The development of targeted therapy has introduced new options to improve treatment outcome in selected patients. The objective of this prospective study was to investigate the safety of preoperative erlotinib treatment and the (in vivo) response in patients with early-stage resectable non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS This study was designed as an open-label phase II trial, performed in four hospitals in the Netherlands, according to a Simons minimax two-stage procedure. Initially, operable patients with early-stage NSCLC (n = 15) were entered from an enriched population (never-smoker, female sex, nonsquamous histology, or Asian ethnicity); thereafter, unselected patients were included to a total of N = 60. Patients received preoperative erlotinib 150 mg once daily for 3 weeks. Response to treatment was evaluated using [18F] fluorodeoxyglucose positron emission tomography (PET) and computed tomography (CT) scans during treatment and histologic examination of the resection specimen. Primary end points were toxicity and pathologic response. RESULTS Sixty patients were included. Seven patients stopped treatment prematurely (12%). Skin toxicity was present in 37 patients (62%), and diarrhea was present in 21 patients (35%). PET evaluation revealed metabolic response (> 25% standardized uptake value decrease) in 16 patients (27%); CT evaluation using Response Evaluation Criteria in Solid Tumors (RECIST) showed response in three patients (5%). At surgery, no unexpected complications occurred. Pathologic examination showed more than 50% necrosis in 14 patients (23%), of whom three (5%) had more than 95% tumor necrosis. The response rate in the enriched population was 34% (10 of 29 patients). CONCLUSION According to predefined criteria, neoadjuvant erlotinib has low toxicity and sufficient activity to deserve further testing in future studies in an enriched population.

Results of combined modality treatment in patients with non-small-cell lung cancer of the superior sulcus and the rationale for surgical resection

OBJECTIVE Superior sulcus tumours (SSTs) or Pancoast tumours are preferably treated with chemoradiotherapy (CRT) followed by surgical resection. However, when followed by surgery, it is associated with an increased complication rate. This study aims to evaluate the efficacy and safety of a concurrent induction protocol of 66Gy radiotherapy with cisplatinum and evaluate the rationale for subsequent surgery. METHODS Patients with SST treated in our institute from 1994 to 2006 were identified. The preferred induction treatment consisted of accelerated radiation (66 Gy in fractions of 2.75 Gy) with concurrent daily cisplatinum 6 mgm(-2). Surgical resection was planned 4-6 weeks thereafter. Performance status, co-morbidity, clinical and pathological tumour stage, (response to) treatment and survival were reviewed. Survival analysis was performed using the Kaplan-Meier method. RESULTS Over these 12 years, 85 patients with Pancoast tumours, 57 men and 28 women, were referred. Mean follow-up was 42 months (range: 2-120 months). Twenty-five patients had stage IIB (29%), seven had stage IIIA (8%), 32 had stage IIIB (38%) and 21 had stage IV (25%). Of the 64 patients presenting with stage II or III disease, 38 medically operable patients with potentially resectable tumours received induction therapy. After restaging, 22 patients underwent resection. All resections were complete and local recurrences were not observed. In 13 patients (62%) a pathologic complete response was found. In most cases, pathologic response was not evident from radiological imaging. The morbidity of surgery after induction treatment was acceptable. There was no fatal toxicity or treatment-related mortality. The 2- and 5-year overall survival of this selected group was 70% and 37%, respectively. CONCLUSION This schedule of induction therapy with high-dose radiation and concurrent cisplatinum was safe and highly effective in fit patients. At this time, pathologic complete response cannot be reliably recognised preoperatively, and better tools for response assessment are critical for more tailored treatment of patients with SST.

Ligands of Epidermal Growth Factor Receptor and the Insulin-Like Growth Factor Family as Serum Biomarkers for Response to Epidermal Growth Factor Receptor Inhibitors in Patients with Advanced Non-small Cell Lung Cancer

Introduction: The selection of patients with non-small cell lung cancer (NSCLC) for epidermal growth factor receptor (EGFR) inhibitor (EGFR-tyrosine kinase inhibitors [TKIs]) therapy is suboptimal as tumor tissue is often unavailable. Ligands of EGFR, transforming growth factor-alpha (TGFa) and amphiregulin (ARG), and the insulin-like growth factor (IGF) family have been associated with resistance to EGFR-TKIs. The aim of our study was to explore whether concentrations of these factors measured in serum were predictive of response to EGFR-TKIs. Methods: We assessed serum levels of marker candidates using enzyme-linked immunosorbent (TGFa and ARG) and chemiluminescent (IGF1 and IGF-binding protein-3) assays in 61 patients with advanced NSCLC treated with EGFR-TKIs and 63 matched advanced NSCLC control patients without EGFR-TKIs treatment. We dichotomized marker levels at the 20th, 50th, or 80th percentile and evaluated whether the effect of EGFR-TKIs treatment on disease-specific survival (DSS) differed by marker level based on multivariate proportional hazards regression with an interaction term. Results: The effect of EGFR-TKIs treatment on DSS showed a significant difference by TGFa and ARG (interaction p = 0.046 and p = 0.004, respectively). Low concentrations of TGFa and high concentrations of ARG were associated with a better DSS in EGFR-TKIs patients compared with control patients. Patients with high concentrations of IGF-binding protein-3 had significantly longer DSS, independent of treatment (hazard ratio: 0.60 per 1 mg/liter, 95% confidence interval: 0.46–0.79). Conclusion: Our results suggest that concentrations of TGFa and ARG measured in serum are predictive of EGFR-TKI response. The combination of these two biomarkers could be of value in the process of selecting patients for treatment with EGFR-TKIs.

Surgery after induction chemotherapy in stage IIIA-N2 non-small cell lung cancer: Why pneumonectomy should be avoided

BACKGROUND The role of surgery in the treatment of patients with stage IIIA (N2) non-small cell lung cancer (NSCLC) is a hot topic. Since variable results of surgery versus radiotherapy after induction chemotherapy are being reported, this study aimed to analyze results of surgery after induction chemotherapy and to identify relevant factors influencing outcome in patients with stage IIIA NSCLC. METHODS Patients with stage IIIA (N2) NSCLC, treated with platinum-based induction chemotherapy between 1994 and 2006, were identified. By a retrospective review of hospital records, response to induction treatment, short-term outcome, recurrence of disease and survival were evaluated. RESULTS Ninety-nine patients, 66 men and 33 women, were identified. Median follow-up was 54 months (range 13-129). Median age at treatment was 62 (range 36-77). Mediastinal downstaging was seen in 32 patients. Forty-three patients received radical radiotherapy and 39 patients underwent surgery: 19 pneumonectomies, 19 lobectomies and one exploratory thoracotomy. Microscopic complete resection (R0) was reached in 30 patients. Pathological response to induction therapy was CR in 5%, PR in 59% and SD in 36%. Postoperative mortality was 3%. The 1-year mortality was 26% after pneumonectomy and 11% after lobectomy. Five-year survival after surgery was 28%, and was better after lobectomy than after pneumonectomy (43% versus 16%; p=0.03). Other factors as age, weight loss, clinical mediastinal downstaging, radicality, and histology did not substantially contribute to this difference. CONCLUSION Type of surgical resection was the major factor influencing outcome in patients with stage IIIA (N2) NSCLC after induction chemotherapy. These results suggest that patients with stage IIIA (N2) NSCLC may benefit from surgical resection, as long as a lobectomy can be performed.

Concurrent high-dose radiotherapy with low-dose chemotherapy in patients with non-small cell lung cancer of the superior sulcus

BACKGROUND AND PURPOSE In the treatment of patients with tumours of the sulcus superior (SST), achieving local control is essential because residual or recurrent disease is associated with severe locoregional problems. This study evaluates the efficacy of concurrent daily low-dose cisplatin (6 mg/m(2)) and high-dose radiotherapy (66 Gy) followed by surgical resection in selected patients. MATERIAL AND METHODS Clinical charts, imaging and pathology reports were retrospectively reviewed. Survival was analysed using the Kaplan-Meier method. RESULTS Forty-nine patients with stage II/III SST were treated with concurrent high-dose radiotherapy and low-dose chemotherapy (CRT). Mean follow-up was 49 months (range 2-152). Nineteen patients underwent additional resection after CRT. In 53% a pathological complete response (pCR) was observed (10/19 pts). Acute severe toxicity occurred in 49% (9/19 pts). Late severe toxicity occurred in 3 patients. The 2- and 5-year overall survival was 74% and 33%, respectively. Local tumour control was 100%. Thirty patients received CRT only. Acute severe toxicity occurred in 23% (7/30 pts). Treatment-related mortality was 2%. The 2- and 5-year overall survival was 31% and 18%, respectively. Locoregional disease-free survival was 48% at 5 years. CONCLUSIONS Concurrent high-dose (66 Gy) radiotherapy and daily low-dose cisplatin was associated with a high pCR rate. Excellent local control was achieved after additional resection in selected patients. However, the occurrence of severe toxicity in long-term survivors after concurrent chemoradiation followed by surgery must be considered.

Soluble epidermal growth factor receptor (sEGFR) and carcinoembryonic antigen (CEA) concentration in patients with non-small cell lung cancer: correlation with survival after erlotinib and gefitinib treatment.

Background: In patients with non-small cell lung cancer (NSCLC), a higher response rate can be achieved with epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) when selection for therapy is guided by mutation analysis or gene amplification. However, both tests are complex and require tumour tissue. Simple methods to identify responders prior to EGFR-TKI treatment are urgently needed. This study aimed to define the relation between serum sEGFR levels, carcinoembryonic antigen (CEA) and survival in NSCLC patients treated with EGFR-TKIs. Methods: Patients with stage III/IV NSCLC treated with gefitinib or erlotinib between July 2002 and December 2005 were reviewed. Levels of serum soluble EGFR (sEGFR) were determined by a sandwich quantitative enzyme-linked immunosorbent assay. A chemiluminescence immunoassay was used for CEA. The relation between sEGFR and survival was investigated. Results: One hundred and two NSCLC patients, mainly stage IV (80%), were identified. Mean sEGFR at baseline was 55.9 μg/l (range 35.3–74.5 μg/l). The median CEA level was 11.1 μg/l (range <1.0–2938.0 μg/l). Median overall survival was 5.2 months (range 1–52 months). Decreasing log CEA values (HR 1.51, 95% CI 1.11–2.04, multivariate analysis) and increasing sEGFR values (HR 0.96, 95% CI 0.93–0.99, multivariate analysis) were both independently associated with prolonged survival. Higher levels of pre-treatment sEGFR were associated with lower risk of progressive disease within three months (p=0.04). Conclusions: Both baseline sEGFR and CEA levels in NSCLC patients receiving EGFR-TKIs showed a significant correlation with survival. To distinguish whether these factors have a predictive or a prognostic value, validation is warranted in an independent patient series containing a control arm without EGFR-TKI treatment.

Is Pneumonectomy Justified in Patients With Locally Advanced NSCLC and Persistent N2 Disease After Induction Chemotherapy

© P M SC ELLA N EO U S e should not pursue a procedure that is applied to limited tages only; rather, we should use a standardized approach that an be applied to a broad range of stages. We consider it very important to maintain the quality of the peration and to minimize the destruction and deformity of the horacic wall. There is no need to focus on whether the proceure is complete or assisted with the VATS approach. This epends on the surgeon’s preference and it is immaterial for the atient to determine the complete or VATS approach.

EGFR-TKI Treatment and Surgical Resection for Oligometastatic NSCLC?

not available, selection of patients for EGFR-TKI treatment can be based on patient-related factors, such as female gender, non-smoking status, Asian ethnicity, and adenoor bronchioloalveolar carcinoma histology. Such selection is associated with favourable responses in up to 30% of patients [5, 6]. The success of EGFR-TKIs in these subpopulations of NSCLC patients has been bittersweet. Certainly the high response rates and remarkable responses with no identifiable or minimal residual disease are exiting. However, these can hardly be seen as cure. Even dramatic responders eventually relapse, and the mechanism of acquired resistance is unclear. At recent conferences, several molecular strategies to overcome such resistance have been hypothesized which may provide a more sustainable ‘cure’ [2–7]. The paper of Levchenko et al. [1] describes the aspect of local consolidation therapy to overcome the problem of acquired resistance. To sustain a major response to EGFR-TKIs in patients with ‘oligometastatic’ NSCLC, surgical resection of the primary tumour (with regional lymph nodes) and a solitary metastasis may therefore be considered. However, the major problem of this strategy is the identification of patients who may benefit from surgical resection. Selection is highly dependent on the reliability of imaging, not only to evaluate disease extent but also for response assessment. Dissemination in NSCLC is often more widespread than the available imaging techniques show us. Even after complete resection of ‘early-stage’ NSCLC, long-term survival rates are disappointing. The International Association for the Study of Lung Cancer (IASLC) staging project reported 5year survival of 56 and 38% for pathologically staged N0 and N1 disease, respectively [8]. Recurrences most often arise at distant sites, confirming the idea that even early-stage operable NSCLC is often a (micro)metastatic disease at diagnosis. Positron emission tomography (PET) has shown to improve imaging accuracy especially in the identification of Clinicians who treat patients with lung cancer are familiar with the fact that non-small cell lung cancer (NSCLC) is a heterogeneous disease. Until recently, we could only rely on classic histopathological and radiological staging, and we lacked the ability to use molecular profiles to classify patients into more clinically meaningful subgroups. Novel therapies such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for NSCLC have had a transforming effect on both lung cancer research and clinical care. In this issue of OnkOlOgie, the article by Levchenko and colleagues focuses on up-front treatment with gefitinib in patients with advanced NSCLC, followed by surgery [1]. The report describes two patients with EGFR mutated tumours showing remarkable responses within 2–3 months of gefitinib treatment. Surgery was performed for minimal residual disease. Although only two cases are described, the treatment approach is interesting and requires further discussion. Two to four courses of chemotherapy for NSCLC may yield response rates of up to 40–50%, but (near) complete responses are rare [2]. Small-molecule EGFR-TKI, such as gefitinib and erlotinib, are able to induce swift and remarkable responses in selected patients. Gefitinib and erlotinib can be orally administered and block the tyrosine kinase domain of the EGFR, thereby inhibiting downstream signalling pathways involved in cell proliferation, angiogenesis, invasion, metastasis and prevention of apoptosis. (Near) complete responses and dramatic symptomatic relief have been described repeatedly. Responders are presumed to be those with a distinct tumour biology that relies heavily upon signalling via EGFR. They represent a subgroup of around 10–20% of the European patient population [2–4]. High response rates (>70%) can be achieved when selection of patients is applied through molecular EGFR (and KRAS) mutation analysis, which requires pre-treatment tumour tissue [5]. If pre-treatment tissue or EGFR mutation testing is