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Response monitoring during neoadjuvant targeted treatment in early stage non‐
small cell lung cancer
van Gool, M.H.
Publication date
2019
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Citation for published version (APA):
van Gool, M. H. (2019). Response monitoring during neoadjuvant targeted treatment in early
stage non‐small cell lung cancer.
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Chapter
1
General introduction and outline of the thesis
1
General introduction and outline of the thesis
Lung cancer is the leading cause of cancer‐related mortality worldwide.1 In the Netherlands, lung cancer is diagnosed in more than 13.000 patients each year.2 The total number of patients with lung cancer has increased over the past decade by 32%. Prognosis is poor with a 1 year overall survival (OS) of 44% and a 5 year overall survival of only 17%.3
Non‐small cell lung cancer (NSCLC) accounts for 85% of all diagnosed lung cancers and comprises a range of histologic subtypes including squamous cell carcinoma and adenocarcinoma. Usually, symptoms of lung cancer do not appear until the disease has already spread. Even when lung cancer does cause symptoms, many people may mistake them for other problems, such as an infection or side effects from smoking, which may delay the diagnosis. This explains why only 20% of patients with NSCLC present with early stage disease.4
Lung cancer is staged according to the TNM staging system.5 The TNM staging system defines the size and extent of the main tumor (T), the spread to nearby lymph nodes (N) and the presence of metastases (M). Together these descriptors will classify cancer into four stages, based on prognosis.
Treatment for early‐stage disease has been focused on local curative treatment with surgery or radiotherapy. From an oncological point of view, an anatomical resection of the tumor area (preferably by lobectomy) and lymph node sampling or dissection is performed. Another local therapy is radiotherapy which can consist of stereotactic or intensity modulated treatment strategies.6 Five‐year OS rate for early stage NSCLC varies from 67‐93% for stage I, and 50‐56% for stage II. In more advanced stages, a multimodality approach is used. This includes combinations of local and systemic treatment for example chemoradiotherapy and maintenance immunotherapy. The five‐ year OS rate for more advanced stages NSCLC is considerably worse, from 36% to 13% for clinical stage III and from 10% to 0% for clinical stage IV.5
In this thesis, the focus is mainly on patients with localized disease. Despite the early stage which allows a radical treatment, recurrence occurs in 40% and mostly presents as a distant recurrence. This suggests that so‐called early‐stage NSCLC is in fact often micrometastatic disease at time of diagnosis. For this reason, adjuvant chemotherapy after radical surgical resection is advised in patients with tumors larger than 4 cm and/or lymph node metastases. Although a cisplatin‐based regimen is the treatment of choice, its significant toxicity may limit its use.7 The OS effect of these adjuvant therapies is
modest, with an estimated benefit of 4% to 8% at 5 years.4 Neoadjuvant chemotherapy postpones local treatment and, although it showed similar survival improvements, it was not adopted as standard treatment.8
In the last decades, extensive technical developments such as genomic sequencing have proceeded rapidly. These developments have refined the classification of NSCLC from histologic into oncogenic subsets, eventually leading to improved individual treatment efficacy based on serum‐ and tissue markers. With the discovery of relevant mutations and deregulated signaling pathways, a better understanding of tumor types within NSCLC is evolving, leading to new targets for individual patient treatment. Signals, sent out by stromal factors, can induce or inhibit growth, cell division or cell migration, contributing to tumor development and progression. Disturbed signal regulation (e.g. in receptors) is often due to one or multiple mutations in specific oncogenes or tumor‐ suppressor genes.
One of these receptors has become an important target for therapy for a subset of NSCLC patients. The epidermal growth factor receptor (EGFR) is overexpressed in the majority of NSCLC and was the first receptor for which targeted therapy has become available. Therefore, it was identified as a promising target.9 Moreover, targeted therapy with small molecules for EGFR has mild toxicity and can be orally administered. EGFR is a trans‐membrane glycoprotein which is expressed in many normal cells of epithelial origin as shown in Figure 1.1a. In a healthy cell, EGFR allows cells to grow and divide, as EGFR activation causes phosphorylation by ATP on specific sites of the tyrosine kinase domain, allowing ATP to trigger signaling cascades and activate various biochemical processes and pathways including angiogenesis, anti‐apoptotic signaling and proliferation. If EGFR is overstimulated, it can cause pro‐survival activities. Likewise, a mutation in this receptor can lead to unlimited growth and duplication of cancer cells. In NSCLC, mutations in EGFR occur in approximately 10‐15% of all tumors (in the European population).10 Over time, mutations in the EGFR domain rather than overexpression of EGFR proved to be the important determinant for response on EGFR‐inhibition therapy.11
Mutation(s) in the EGFR domain is just one of many different molecular changes in NSCLC. Specific therapies are developed that can block continued cell growth initiated by molecular changes in cancer cells, which is called targeted therapy. It provides a tailor‐ made approach by interfering with specific molecules rather than simply interfering with all rapidly dividing cells as with traditional chemotherapy.
1
Figure 1.1 Epidermal growth factor receptor function. Figure 1.1A shows the EGFR activation by ATP, Figure 1.1B shows the binding of a TKI hampering the signaling cascade. The development of EGFR tyrosine kinase inhibitors (TKIs) started before the complete understanding of the significance of (typical) EGFR mutations. EGFR‐TKIs such as erlotinib are small molecules that can bind reversibly to the intracellular adenosine triphosphate (ATP)‐binding pocket of the receptor. Inhibition of phosphorylation by ATP by erlotinib hampers the signaling cascades (Figure 1.1B). To identify patients who would respond to EGFR‐TKIs, small phase II studies were conducted in unselected, both pretreated and treatment naïve patients and some in combination with chemotherapy. Biomarkers such as overexpressing of EGFR (by PCR), non‐squamous histology and patient characteristics as female gender, non‐smoking and Asian origin were identified as predictive factors for response to EGFR‐TKI.9,12
The first study that reported on an advantage of EGFR‐TKI therapy for patients with an EGFR mutation was the Iressa Pan‐Asia Study (IPASS). This study evaluated the efficacy of gefitinib versus first line chemotherapy with carboplatin and paclitaxel in an Asian population of over 1,200 patients (unselected for EGFR mutations). They showed a better progression free survival (PFS) for gefitinib compared to chemotherapy (HR, 0.74 (95% CI, 0.65 to 0.85) P<0.001). EGFR mutation was a strong predictor for PFS in the group treated with an EGFR‐TKI (HR, 0.48 (95% CI, 0.36 to 0.64) P<0.001). Additionally, patients without an EGFR mutation (wild type) had a longer PFS treated with chemotherapy compared to gefitinib (HR, 2.85 (95% CI, 2.05 to 3.98) P<0.001).13 Since the IPASS study, several large phase III trials have demonstrated the superiority of EFGR‐ TKI TKI ATP ATP ADP Cell membrane
Activation of signal‐transduction cascades Invasion and metastasis Angiogenesis Cell proliferation Apoptosis A B TKI TKI ATP ATP ADP Cell membrane
Activation of signal‐transduction cascades Invasion and
metastasis Angiogenesis Cell
proliferation Apoptosis
TKI over chemotherapy in patients with EGFR mutated NSCLC in terms of overall response rate and PFS. Probably because of crossover study design no individual trial has shown an overall survival benefit of (first generation) EGFR TKI therapy in these patients. However, in patients harboring specific EGFR mutations with exon 19 deletion a meta‐ analysis showed that TKIs are associated with better OS compared with conventional chemotherapy.14 As result of the IPASS and other trials mutation analysis has become paramount to consider therapy targeting EGFR nowadays.15
Furthermore, with ongoing development in genomic sequencing better identification of mutations is available. Disappointingly, tumors of most patients with NSCLC do not harbor an EGFR mutation. The role of EGFR‐TKI in these patients is debatable since only some of them show a modest response without predictive biomarkers.16 Since the first‐ generation EGFR‐TKIs (gefitinib and erlotinib), several further‐generation EGFR‐TKIs have been approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of patients with advanced (chemotherapy‐ refractory/EGFR‐mutant) NSCLC.17
In general, the role of neoadjuvant therapy in early stage NSCLC is as limited as in the adjuvant setting and postpones local treatment.8 However, a practical benefit of giving preoperative therapy is that it will provide an in vivo assessment of tumor response to a drug regimen. Additionally, pathologic complete response after preoperative therapy was found to be a powerful surrogate of long‐term DFS in several cancers.18 Low toxicity, significant and rapid tumor response rates suggest that EGFR‐TKIs may be used in a neoadjuvant setting.12,19 According to clinical guidelines, patients diagnosed with early stage NSCLC should be operated within 5‐7 weeks.20 This period is used for preoperative evaluation of disease stage, comorbidity, information, preparation and planning. Treatment with a low‐toxicity targeted drug within this interval will not postpone local therapy, and provides an excellent in vivo assessment of tumor response to the drug. The resection specimen allows for measurement of the histopathologic response to the treatment.18
In this perspective we designed the M06NEL study. In operable patients with clinical stage I or II NSCLC, we intended to obtain proof of principle whether induction treatment by erlotinib can induce tumor responses. After a positive outcome, this agent might find a place in the (neo)adjuvant setting and make an extra contribution to the curative treatment of early stage NSCLC. We used the “pre‐operative window of opportunity” to administer patients erlotinib for a period of 3 weeks. Surgical resection was scheduled in the fourth week. We performed computed tomography (CT) and [18F]‐ fluorodeoxyglucose positron emission tomography acquired together with low dose
1
computed tomography (FDG‐PET/CT) prior to administration, during and after the 3 weeks period of erlotinib therapy. This study design allowed us to (non‐invasively) monitor radiologic and metabolic response in vivo during/after erlotinib treatment and correlate our findings with pathologic response in the resection specimen, and later with survival. CT‐scanning is used for radiologic assessment and shows the morphologic characteristics of the tumor. Response evaluation by CT is based on change in size of the tumor (e.g. before and after therapy, according to so‐called RECIST 1.1 criteria) and has been the golden standard for response evaluation. However, there are several concerns about radiologic assessment during preoperative window therapy. For example, according to RECIST 1.1 criteria radiologic response monitoring can be performed no sooner than 4 weeks after initiation of treatment and criteria can be confounded by structural abnormalities, before and after treatment, which may not actually contain tumor.21,22 Secondly, in the era of targeted therapy deficiencies of RECIST response evaluation became clear, as early tumor response may not translate in tumor shrinkage, as was illustrated for imatinib and sorafinib treatment in Gastrointestinal stromal tumors (GIST).23
Metabolic assessment by FDG‐PET/CT is based on the principle that highly active cells such as tumor cells demonstrate increased glucose uptake. Patients are injected with the glucose analogue 18F‐fluorodeoxyglucose and after approximately one hour a scan is performed to locate areas with increased FDG‐uptake. FDG‐Uptake in cells is registered in pixels or voxels on the FDG‐PET/CT scan. The standardized uptake value (SUV) is used to describe the FDG‐uptake in the tumor. However due to competitive inhibition of FDG‐ uptake by blood glucose a correction of SUVmax could be of additional value. SUVmax is the maximum intensity value within the region of interest (i.e. the tumor). Relating each pixel or voxel with each other gives information about the activity and heterogeneity of the tumor on a very detailed level. This information can be analyzed by texture parameters, assessing the global and local‐regional heterogeneity of FDG‐distribution in the tumor with feature analysis by using a variety of mathematical methods that describe the relationships between the gray‐level intensity of pixels or voxels and their position within an image.
We choose to evaluate the performance of FDG‐PET/CT because it has several (potential) applications in oncological imaging. FDG‐PET/CT has proven its role in mediastinal nodal staging and detection of remote metastases staging modality in patients with NSCLC.24‐26 Therefore it has become a cornerstone as staging tool and is
part of the (national) standard work‐up for NSCLC.20 FDG‐PET/CT has also the ability to characterize tumors based on the metabolic activity. Tumors with higher metabolic activity could be more aggressive which may explain its prognostic value in early stage disease.27 Furthermore, metabolic assessment of the tumor with FDG‐PET/CT has been evaluated as a method to monitor response to systemic treatment. Metabolic response is classified using criteria (e.g. according to EORTC recommendations) which categorize response in proportion to change (e.g. before and after therapy) in metabolic activity (SUVmax) of the tumor. Several studies demonstrated this potential for response monitoring in (advanced stage) NSCLC.28‐31 FDG‐PET/CT scanning is able to predict response to induction chemotherapy treatment early during therapy.32 Early assessment of the tumor response will allow for early treatment modulation or modification. In advanced disease PET scanning after 1 week of EGFR‐TKI treatment showed that the changes in metabolic activity observed were related to survival.31,33 Therefore, we choose to perform an additional FDG‐PET/CT scan within 1 week after the start of erlotinib treatment in the M06NEL study to search for (very) early metabolic response in the tumor during treatment. EGFR is expressed in many normal cells of epithelial origin, playing a role in cell growth and differentiation. Skin rash in response to EGFR‐TKI therapy may be an expression of the EGFR‐TKI therapeutic effect on tumors.34 Skin rash is the most common side effect of EGFR‐TKI and it was found to be associated with a clinical benefit in advanced stage NSCLC.35 In our search for a cheap non‐invasive biomarker we evaluated if skin rash could also serve as a predictor for response in a neoadjuvant setting.
In times of ever rising costs of health care, early decision making as to the effect of (experimental) treatment is essential because unnecessary toxicity and costs from inappropriate therapy should be minimized. Therefore, treatment options such as EGFR‐ TKI’s have intensified the need for timely estimates of clinical benefit.
1
Aim and outline of this thesis
In the current era of rapid developments of new treatments for small oncogenic subsets, early and rapid response monitoring is increasingly relevant. In this thesis, various aspects of these challenges and the potential of early response monitoring are investigated and outlined below.
The aim of the M06NEL study was to investigate whether erlotinib could make an extra contribution to the curative treatment of early non‐small cell lung cancer (NSCLC). If erlotinib is able to induce responses in patients with clinical stage I or II NSCLC, this agent might find a place in the (neo)adjuvant setting. Currently there is no agreement on the optimal modality for assessment of response to EGFR‐TKI therapy in lung cancer. Metabolic and radiologic assessment and biomarkers could provide information about response to neoadjuvant EGFR‐TKI treatment.
In Chapter 2, a review of literature is presented to use FDG‐PET/CT for response evaluation in patients with NSCLC, treated with EGFR‐TKI. This report includes a total of 7 studies analyzing the association of metabolic response and clinical and radiologic response with survival.
It is debated whether FDG‐PET/CT is superior to CT in response evaluation in the neoadjuvant setting. Chapter 3 describes the response evaluation with CT and FDG‐ PET/CT for identification of histopathologic response to neoadjuvant erlotinib.
Early decision making as to the effect of experimental treatment is essential. However, the optimal timing of early metabolic response monitoring is still under debate. In Chapter 4 metabolic response after 1 week and after 3 weeks in predicting histopathologic response is described.
Tumor heterogeneity on FDG‐PET/CT has been identified by others as potential response markers in targeted treatment. Chapter 5 is a commentary on the challenges that this additional window on metabolic response monitoring brings.
Because EGFR is expressed in many normal cells of epithelial origin, playing a role in cell growth and differentiation, skin rash in response to EGFR‐TKI therapy may be an expression of the EGFR‐TKI therapeutic effect on tumors. In Chapter 6 skin rash was investigated as (cheap) clinical marker for response to EGFR‐TKI in a neoadjuvant setting.
Accurate FDG measurements could suffer from competitive inhibition of FDG‐uptake by blood glucose. A correction of SUVmax according to a patient’s blood glucose level could be of additional value. Chapter 7 reports on the additional prognostic value of glucose corrected SUV in patients with complete surgical resection for NSCLC in a separate cohort.
Targeted treatment options have intensified the need for timely estimates of clinical benefit. Chapter 8 shows the potential of metabolic response monitoring as a surrogate marker for survival in patients treated with neoadjuvant erlotinib.
Chapter 9 provides a general discussion and future perspectives on response monitoring during neoadjuvant targeted therapy in early stage NSCLC.
1
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