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Journal of Clinical Oncology, Vol 25, No 18 (June 20), 2007: pp. 2534-2539 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.1337 Prognostic Significance of 99mTc Hynic-rh-Annexin V Scintigraphy During Platinum-Based Chemotherapy in Advanced Lung Cancer
From the Departments of Nuclear Medicine, Radiotherapy, Thoracic Oncology, and Biometrics, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands Address reprint requests to Renato Alfredo Valdés Olmos, MD, Department of Nuclear Medicine, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands; e-mail: r.valdes{at}nki.nl
Purpose: The purpose of this study was to evaluate if sequential 99mTc Hynic-rh- annexin V scintigraphy (TAS) can predict outcome in patients with advanced lung cancer, shortly after the start of platinum-based chemotherapy. Patients and Methods: In 16 consecutive chemotherapy-naive patients with advanced stage non–small-cell lung cancer scheduled for platinum-based chemotherapy, TAS was performed before and within 48 hours after the start of therapy. Chemotherapy-induced changes in tumor annexin V uptake, calculated as maximum count per pixel and expressed as percentage to baseline value, were compared with treatment response determined according to Response Evaluation Criteria in Solid Tumors. Results: A significant correlation (r2 = 0.86; P = .0001) was found between annexin V metabolic changes and treatment outcome. All patients with notably increased annexin V tumor uptake showed complete or partial response. Less prominently increased or decreased uptake correlated with stable or progressive disease. Conclusion: TAS is a promising test to predict tumor response in patients with advanced lung cancer early in the course of platinum-based chemotherapy.
Lung cancer remains the leading cause of cancer-related deaths worldwide. More than 40% of the patients are diagnosed with advanced and/or metastatic disease and are not eligible for surgical treatment or curative radiotherapy.1,2 Platinum-based chemotherapy is still recognized as the best available treatment in patients with advanced lung cancer. It results in a modest improvement in survival, symptom palliation, and improvement in the quality of life, but it is also associated with significant toxicity.3,4 Thus, it is of high importance to distinguish patients who will benefit from the treatment from those patients who are more prone to experience only the adverse effects without significant improvement. Current state-of-art response evaluation in patients with advanced non–small-cell lung cancer (NSCLC) is based on detection of changes in tumor size using computer tomography (CT) during treatment. However, it fails to visualize the early therapy-induced changes that precede reduction of tumor size and is not useful to predict therapy response early after the start of anticancer therapy.5 Molecular imaging of apoptosis offers an alternative way to study tumor response. Apoptosis or programmed cell death plays an important role in the cytotoxic effect of most anticancer drugs. Early therapy-induced cell death correlates well with objective tumor volume reduction after the end of treatment,6,7 and thus, it could be used as a reliable criterion to predict therapy outcome. It is generally accepted that cytotoxicity of cisplatin is mediated through induction of apoptosis resulting from its interaction with DNA.8 Formation of cisplatin-DNA adducts activates cell death pathways at different levels, including p53, bcl-2 family, caspases, and cyclins. Overexpression of the antiapoptotic genes and mutations in the apoptotic pathways may cause inability of cells to recognize DNA damage and induce apoptosis, thus contributing to cisplatin resistance.9 Therefore, cisplatin-induced cell death may be an important marker to predict therapy outcome in patients with NSCLC. Annexin V belongs to the family of annexin proteins, it binds selectively to the membrane phospholipid phosphatidylserine, normally limited to the inner layer of the cell membrane and externalized early in the apoptotic cascade, thus allowing real-time in vivo monitoring of apoptosis during the chemotherapy and radiotherapy.10-14 Recent analysis of the chemotherapy- and radiotherapy-induced cell death has demonstrated that exposition of phosphatidylserine also is present in cells undergoing autophagy.15 Finally, annexin V also can bind phosphatidylserine on the inner leaflet of the cell wall because of increased permeability of the cell membrane in necrotic cells.16 Thus, 99mTc Hynic-rh-annexin V scintigraphy (TAS), a so-called "apoptosis-targeting" assay, currently used to visualize chemotherapy- and radiotherapy-induced apoptosis in various malignant tumors,17-20 may actually reflect a complex of different processes, including all three types of cell death: apoptosis (type I), autophagy (type II), and necrosis (type III).21 The purpose of this study was to evaluate the prognostic value of sequential TAS before and shortly after the start of the first course of platinum-based chemotherapy in a group of patients with advanced NSCLC to differentiate responders from nonresponders.
Eligibility Criteria Chemotherapy- and radiotherapy-naive patients with a histologic or cytologic diagnosis of stage IIIB, IV, or recurrent NSCLC were eligible for this study. Other eligibility criteria included measurable extra-abdominal lesions, with at least one larger than 2 cm; a WHO performance score 1 or 2; and a life expectancy of longer than 16 weeks. Radiotherapy to the primary or index lesion (planned radiotherapy to a metastatic brain or bone lesions was allowed); surgical resection of the primary or index lesion; age of younger than 18 years; pregnant or lactating female patients and patients who had been imaged with 99mTechnetium in the previous 48 hours or with 67Gallium, 111Indium, or 201Thallium 7 days before TAS were ineligible for the trial entry. Approval from the institutional ethics committee was obtained, and all patients provided written informed consent.
Chemotherapy
99mTc -Annexin V Scintigraphy
Computed Tomography
Tumor Uptake Evaluation
Response Evaluation A complete response (CR) was defined as the complete disappearance of all clinically detectable tumors for at least 4 weeks. A PR was defined as there being at least a 30% decrease in the sum of the longest diameters of the target lesions for more than 4 weeks with no new area of malignant disease. Stable disease was defined as insufficient shrinkage to qualify for partial response (PR) and insufficient increase to qualify for progressive disease (PD). PD indicated at least a 20% increase in the sum of the longest diameter of the target lesions or a new malignant lesion.
Statistical Analysis
A total of 16 consecutive patients were enrolled onto this study. One patient died from bleeding not related to the primary tumor before the follow-up CT scan could be obtained. Another patient refused to undergo a follow-up TAS examination. Fourteen patients with a total of 40 lesions (24 pulmonary lesions, 15 metastatic lymph nodes, and one extrapulmonary metastasis) were eligible for further analysis. All patients received four courses of platinum-based combination chemotherapy. Overall response rate according to RECIST criteria was 36% with a mean follow-up of 3.9 months (range, 2.1 to 9 months). Patient characteristics, changes in the annexin V tumor uptake and therapy outcome are summarized in Table 1.
Annexin V tumor uptake before treatment and within 48 hours after the start of treatment was detected in all target lesions. It varied from 26 to 91 counts per pixel (mean, 55), and the posttreatment uptake varied from 27 to 122 counts per pixel (mean, 62). Objective response to chemotherapy according to the RECIST criteria was detected in five patients: one patient with CR and four patients with PR. All responders have demonstrated substantial increase of annexin V tumor uptake from 16% to 121% above the baseline (mean, 42%). Figure 1 shows typical example of a responding tumor.
Nine patients (64%) were classified as nonresponders, with seven demonstrating SD and two demonstrating PD according to RECIST. Therapy-induced annexin V tumor uptake in this group varied from –30% to 24% (mean, –1%). Three patients with SD showed increase of the tracer uptake up to 15%, 19%, and 24%. These values correlated with the tumor size reduction 20%, 22%, and 21%, respectively. No correlation was found between the baseline annexin V tumor uptake and therapy outcome. This is in agreement with other studies showing inconsistent correlations between spontaneous, pretreatment apoptosis, and response to therapy.25 All patients with PD demonstrated therapy-induced decrease of the tracer uptake. A typical example of a patient with nonresponding tumor is presented in Figure 2. None of the patients without increase of the annexin V tumor uptake achieved even partial remission. The pattern of the annexin V tumor uptake in the lymphatic nodes (Fig 3) and one rib metastasis (Fig 4) was similar to the pattern, observed in the primary tumors. Linear regression analysis demonstrated a strong statistically significant correlation between therapy-induced changes in the annexin V tumor uptake and treatment outcome (r2 = 0.86; P = .0001; Fig 5).
This study demonstrated that effective platinum-based chemotherapy causes a fast increase of the annexin V tumor uptake within 48 hours after the first injection of cisplatin, whereas a less successful treatment is associated with a merely increased, unchanged, or even decreased annexin V tumor uptake (r2 = 0.86; P = .001). Patients with partial and complete remission have shown increase of the annexin V tumor uptake within 48 hours after the first injection of cisplatin. Patients with progressive disease demonstrated significant decrease of the annexin V tumor uptake. Heterogeneous response was found in the group of patients with stable disease: three patients with the therapy-induced increase of tracer uptake have shown considerable reduction of the tumor size, and four patients without changes in the annexin V tumor uptake did not show any substantial tumor response. A significant increase of annexin V uptake was observed in three patients who were classified as stable disease by RECIST criteria, whereas their tumors demonstrated significant shrinkage. This apparent discrepancy between molecular parameters and morphological criteria is intriguing and might indicate that in selected cases the former method is more useful to identify responders. This phenomenon clearly deserves further investigation. Although tumor shrinkage would seem to be a necessary condition for improved survival, it can be determined only late in the course or at the end of the treatment. In contrast, TAS could offer a simple, noninvasive tool to separate responders, including those with stable disease from nonresponders, as none of the patients with therapy-induced increase of annexin V uptake showed progression. To the best of our knowledge, this is the first study to evaluate the predictive value of TAS in a group of patients with advanced NSCLC treated with platinum-based chemotherapy. Our data are consistent with the study of Belhocine et al,19 which demonstrated feasibility and safety of TAS for imaging of apoptosis in breast cancer, lung cancer, and lymphoma before and shortly after the start of chemotherapy. In this study, it was already suggested that early annexin V tumor uptake may be a predictor of response to treatment in patients with late-stage lung cancer and lymphoma. It is hypothesized that the difference between therapy-induced changes and the baseline tracer uptake may deliver pivotal information about the therapy outcome. The baseline annexin V uptake represents, in this case, spontaneous tumor apoptosis, tumor necrosis, and probably apoptotic changes in the tumor-infiltrating lymphocytes. The tracer uptake on the follow-up scan would represent the combination of the processes, mentioned earlier, and additional therapy-induced tumor apoptosis and necrosis. Therefore, the difference between the two scans could represent pure therapy-induced changes, presuming that the scans were performed shortly one after another to avoid significant changes of the baseline conditions. Despite the promising results, caution should be taken when generalizing our findings, as only a limited number of patients (N = 16) had been included in this study. As only responders were scheduled for radical radiotherapy after the chemotherapy, only short-term outcome could be determined, and no survival data attributed solely to platinum-based chemotherapy or to combined chemoradiotherapy could be obtained. If further studies confirm our preliminary results, annexin V tumor uptake may then be interpreted as a universal hallmark of the dying cell valuable for in vivo imaging of cumulative therapy-related cell death response10,26 and, thus, providing a simple noninvasive test to predict therapy outcome on a patient-to-patient basis. In conclusion, TAS is a promising test to predict response to platinum-based chemotherapy in patients with advanced NSCLC within 48 hours after the start of treatment.
The authors indicated no potential conflicts of interest.
Conception and design: Marcel Verheij, Renato Alfredo Valdés Olmos Administrative support: Marcel Verheij, Renato Alfredo Valdés Olmos Provision of study materials or patients: Nico van Zandwijk, Sjaak Burgers Collection and assembly of data: Marina Kartachova, Renato Alfredo Valdés Olmos Data analysis and interpretation: Marina Kartachova, Nico van Zandwijk, Sjaak Burgers, Harm van Tinteren, Marcel Verheij, Renato Alfredo Valdés Olmos Manuscript writing: Marina Kartachova Final approval of manuscript: Marina Kartachova, Nico van Zandwijk, Sjaak Burgers, Harm van Tinteren, Marcel Verheij, Renato Alfredo Valdés Olmos
We gratefully acknowledge Theseus Imaging Corporation, Boston, MA, for supply and technical support.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
U). Maximal parameters were used to minimize partial volume effects on the uptake values. For lesions not visible on either baseline or follow-up scan, regions of interest were drawn after SPECT/CT coregistration, as described in detail in our previous publication.
