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Early Response Evaluation in Malignant Pleural Mesothelioma by Positron Emission Tomography With [¹⁸F]Fluorodeoxyglucose

Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Marcello Rodari, Romano F. Lutman, Silvia Salamina, Matteo Incarbone, Marco Alloisio, Armando Santoro

From the Departments of Medical Oncology and Hematology, Nuclear Medicine, Radiology, and Thoracic Surgery, Istituto Clinico Humanitas IRCCS (Isituto di Ricovero e Cura a Carattere Scientifico), Rozzano, Milan, Italy

Address reprint requests to Giovanni L. Ceresoli, MD, Department of Medical Oncology and Hematology, Istituto Clinico Humanitas IRCCS, Rozzano, Milan, Italy; e-mail: giovanni_luca.ceresoli{at}humanitas.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
PURPOSE: Response evaluation with conventional criteria based on computed tomography (CT) is particularly challenging in malignant pleural mesothelioma (MPM) due to its diffuse pattern of growth. There is growing evidence that therapy-induced changes in tumor [¹⁸F]fluorodeoxyglucose (FDG) uptake as measured by positron emission tomography (PET) may predict response and patient outcome early in the course of treatment.

PATIENTS AND METHODS: Patients with histologically proven MPM, not candidates to curative surgery, scheduled to undergo palliative chemotherapy with a pemetrexed-based regimen were eligible for this study. Patients were evaluated by FDG-PET and CT at baseline and after two cycles of therapy. A decrease of 25% or more in tumor FDG uptake as measured by standardized uptake value was defined as a metabolic response (MR). Best overall response from CT scans was determined according to previously published criteria.

RESULTS: Twenty-two patients were included in the study, and 20 were assessable for early metabolic response with FDG-PET. Of these, eight were classified as responders (40%) and 12 as nonresponders (60%). Early MR was significantly correlated to median time-to-tumor progression (TTP) with a median TTP for metabolic responders of 14 months versus 7 months for nonresponders (P = .02). No correlation was found between TTP and radiologic response evaluated by CT. Patients with a MR had a trend toward longer overall survival.

CONCLUSION: The use of MR evaluated by FDG-PET in the assessment of treatment efficacy in MPM appears promising. Our observations need to be validated in a larger prospective series.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Malignant pleural mesothelioma (MPM) is an aggressive tumor, which usually has a poor prognosis. Its incidence is increasing throughout most of the world, peaking in the United States in 2000 and expected to rise in the next 10 to 15 years in Europe.¹ A minority of patients is eligible for radical surgery² and most are candidates for chemotherapy during the course of their disease. Recently, the novel multitargeted antifolate pemetrexed was shown to have activity in MPM as a single agent and in combination with platinum compounds.^3,4 Response evaluation with conventional criteria based on computed tomography (CT) measurements is particularly challenging in MPM due to its diffuse pattern of growth. Such difficulties hinder an accurate evaluation of clinical study results, particularly in phase II trials.⁵ Several response criteria have been proposed, but the optimal evaluation method has yet to be defined.⁶

The use of [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of MPM has been described recently. FDG-PET has proved useful in detecting malignant pleural lesions⁷ and assessing the extent of tumor involvement. In one study with a large series of patients, this imaging technique correctly detected extrathoracic metastases, but failed to reliably identify the locoregional (tumor and mediastinal nodal) status of MPM.⁸ Further studies have demonstrated an independent prognostic value of FDG uptake, measured at diagnosis by standardized uptake value (SUV), in this disease.⁹ FDG-PET is increasingly used for monitoring tumor response to chemotherapy and chemoradiotherapy in several neoplasms, and there is growing evidence that therapy-induced changes in tumor FDG uptake may predict response and patient outcome early in the course of therapy.^10,11 The aim of this study was to prospectively explore the role of FDG-PET response (measured by SUV variations) in patients with MPM treated with pemetrexed-based chemotherapy.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Patients
Patients with histologically proven MPM not candidates for curative surgery and scheduled to undergo palliative chemotherapy with a pemetrexed-based regimen were eligible for this study. The presence of unidimensionally and/or bidimensionally measurable disease was mandatory. Previous surgery (extrapleural pneumonectomy) was permitted only if there was evidence of disease recurrence thereafter. Eligibility criteria included age older than 18 years, Eastern Cooperative Oncology Group performance status 2 or lower, and an estimated life expectancy of 12 weeks or longer. Patients were excluded if they were diabetic. Disease stage was classified according to the TNM staging system proposed by the International Mesothelioma Interest Group.¹² The European Organization for Research and Treatment of Cancer (EORTC) prognostic score for MPM (good v poor score) was calculated for every patient.¹³

Treatment
The chemotherapy regimens administered in this study were single-agent pemetrexed at a dose of 500 mg/m² every 3 weeks or pemetrexed 500 mg/m² in combination with carboplatin at an area under the plasma concentration-time curve of 5 mg/mL/min, both given on day 1 of every 21-day cycle. All patients were supplemented with folic acid and vitamin B12. Treatment was repeated for a maximum of six cycles, or until progression or unacceptable toxicity. Most patients were treated within a phase II trial of pemetrexed plus carboplatin conducted at our institution.⁴ Pemetrexed was provided by Eli Lilly (Indianapolis, IN) within the expanded access program. This study was conducted after approval by the appropriate ethical review boards. Written informed consent was obtained from each patient before study entry.

Imaging
PET imaging was performed at baseline within the 2 weeks before initiation of chemotherapy, and was repeated after two cycles of chemotherapy treatment. All patients fasted for at least 8 hours before examination to ensure standardized glucose metabolism. At the time of FDG administration, fasting plasma glucose values lower than 150 mg/dL were required. An activity from 250 to 450 MBq of FDG, depending on the patient's weight, was injected intravenously. Attenuation corrected whole body PET scans in three-dimensional mode were acquired 60 minutes after FDG administration, using a dedicated full-ring scanner (ECAT ACCELL; Siemens Medical Systems, Enlargen, Germany) equipped with lutetium oxyorthosilicate crystals, with a 162 mm axial field of view. Scans were performed from the inferior pelvis to the skull base, acquiring six to eight bed positions, depending on patients' heights. Acquisition time for scanning was 2 minutes for emission and 1 minute for transmission per bed position. If possible, the supine patients were examined with their arms above their head. Image reconstruction was performed with an iterative reconstruction algorithm (OSEM algorithm, ECAT software, version 7.2; Siemens Medical Systems). Resolution was 6 mm at full width half maximum at the center of the field of view. The reconstructed images were displayed in axial, coronal, and sagittal planes on a Siemens Syngo workstation and were separately interpreted by two experienced nuclear medicine physicians.

Quantitative analysis was applied to the attenuation-corrected images by computing the standardized uptake value (SUV) of areas of FDG accumulation, corrected for the injected dose of FDG and adjusted for the patient's weight, as previously described.¹⁰ Tumor mass was identified by areas of pathologically increased glucose uptake avoiding cardiac, hepatic, and renal physiologic uptake. SUV was independently measured by two observers using an elliptical three-dimensional region of interest (ROI) drawn on the area of maximal metabolic activity on every axial, coronal, and sagittal slice tumor related increased uptake. In post-therapy scans, ROI were placed in identical positions utilizing predefined anatomic landmarks. SUVmax was defined as the highest pixel value related to the tumor burden in each study.

CT scans of the chest and abdomen were performed at baseline and after every two cycles of chemotherapy, and within 7 days of PET examination. Patients underwent basal and contrast enhanced CT on a Philips Aura single slice spiral system (Philips Medical Systems, Cleveland, OH). The acquisitions were obtained 60 seconds after the beginning of contrast administration and were performed caudal-cranially, so as to minimize artifacts from respiratory movements, with the following parameters: 7 mm slice thickness and 5 mm no gap reconstruction index.

Response Evaluation and Follow-up
CT tumor response (also defined as radiological response) was evaluated by a single observer (R.F.L.) after two cycles of chemotherapy for patients with bidimensionally measurable disease, unidimensionally measurable disease, or both according to the criteria used by Vogelzang et al³ in the phase III trial testing pemetrexed and cisplatin versus cisplatin alone. A complete response (CR) was defined as the complete disappearance of all disease with no new lesions. A partial response (PR) was defined as 50% or more reduction from baseline of the sum of the products of the perpendicular diameters of target lesions when only bidimensionally measurable disease was present, or as 30% or more decrease in the sum of the greatest diameters of target lesions when only unidimensionally measurable lesions were present. When both types of disease were present, PR was defined as a reduction of either type of disease as defined above, with the other type at least stable, with non-measurable lesions being at least stable, and no new lesions. Tumor progressive disease (PD) was defined as the appearance of new or relapsed lesions, a 50% or higher increase in the sum of products of all bidimensionally measurable lesions over the smallest sum observed when only bidimensional disease was present, or a 25% or higher increase in the sum of the longest dimension of unidimensionally measurable lesions over smallest sum observed when only unidimensional disease was present. In the presence of both disease types, PD was defined as progression of either type as defined above and at least stable disease for the other, worsening of assessable disease, or death from disease. Stable disease (SD) was defined as disease that did not qualify for CR, PR, or PD. All these evaluations were performed without knowledge of the results of PET studies. No confirmatory scans were conducted on patients exhibiting CR/PR or SD.

PET response (also defined as metabolic response [MR]) was measured at the same time point (after two cycles of chemotherapy) according to recommendations of the EORTC PET study group.¹⁴ The complete resolution of FDG uptake within the tumor volume so that it was indistinguishable from surrounding normal tissue was considered as complete metabolic response. A partial MR was defined as a 25% or more reduction in tumor FDG uptake. An increase in tumor SUV 25% or more within the ROI defined on the baseline scan, or the appearance of new FDG uptake in another region, was classified as progressive metabolic disease. Stable metabolic disease was classified as an increase in tumor SUV of less than 25% or a decrease of less than 25%.

After completion of the study treatment, patients were evaluated every 2 months with chest and abdominal CT scans until disease progression. Patients were also observed for survival until death or until last contact if still alive.

Statistical Analyses
Time to disease progression (TTP) was defined as time from study entry (day of baseline PET scan) until time of patient progression (as shown by radiologic— CT—or clinical examination) or death from any cause. Patients who had no evidence of progressive disease were censored at the date of the last follow-up. Overall survival (OS) was calculated as the time from study entry until death from any cause; patients who were alive on the date of last follow-up were censored on that date.

Actuarial survival curves were generated using the method of Kaplan and Meier.¹⁵ Survival rates were analyzed according to metabolic (FDG-PET) and radiologic (CT) response. The impact of these categoric variables on TTP and OS was evaluated using the Gehan's Wilcoxon test.¹⁶ Statistical analyses were performed using the software package Stata 9 (STATA Corp, College Station, TX).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
From February 2004 to July 2005, a total of 22 patients were included in the study and underwent baseline and post-treatment PET and CT evaluations. Their characteristics are listed in Table 1. The chemotherapy regimen was carboplatin/pemetrexed in 20 patients and single-agent pemetrexed in two patients. Patients received two to six cycles of chemotherapy (median, six cycles). PET response assessment was not performed in two patients due to early disease progression. Therefore, 20 patients with early PET assessments were evaluated for the response and survival analysis. Four patients had a pleurodesis within 2 months of baseline PET scanning; because this could have influenced the baseline SUVmax values, patients without previous talc pleurodesis (indicated as the no-talc group) were also analyzed separately. One patient (Table 2; patient No. 12) had talc pleurodesis as only treatment in another hospital more than 6 months before and was enrolled in this study because of disease progression; due to the long interval between pleurodesis and baseline PET, he was included in the no-talc group.

View larger version (5K): [in this window] [in a new window]   Fig 1. Relative changes in standardized uptake value (SUVmax) between baseline and post-treatment (after two cycles of chemotherapy) positron emission tomography scans in patients achieving partial response (PR), stable disease (SD) or progressive disease (PD) according to computed tomography criteria.

View larger version (44K): [in this window] [in a new window]   Fig 2. Patient (No. 10) classified as stable by computed tomography (CT) and responder by positron emission tomography (PET). Standardized uptake value max (SUVmax) dropped from 5.09 at baseline to 2.78 after two cycles of chemotherapy. PET coronal and axial slices before (A and C) and after (B and D) treatment are shown in the upper and mid panels. Lower panels show CT images (E) before and (F) after therapy.

View larger version (10K): [in this window] [in a new window]   Fig 3. Kaplan-Meier plots showing time to disease progression by (A) positron emission tomography response and by (B) computed tomography response. A significant difference between patients with (solid line) and without (dotted line) metabolic response is observed (P = .02); no significant difference is noted between patients with (solid line) and without (dotted line) radiologic response (P = .57).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
Tumor measurement in MPM is challenging due to its unique growth pattern. Several radiologic response systems have been proposed, but neither WHO criteria¹⁷ nor the more recent Response Evaluation Criteria in Solid Tumors (RECIST) unidimensional criteria¹⁸ seem to apply to tumor measurement in this disease.^19,20 Hybrid uni- and bidimensional criteria were used by other authors,^3,4,21 in particular in the landmark phase III trial of pemetrexed and cisplatin. However, considerable discrepancy was reported among study investigators and independent reviewers in the evaluation of patients treated in this trial where tumor response could be confirmed in only one half of patients.²² Recently, modified RECIST criteria have been published.²³ Although they are already being used in current clinical trials, further validation in a larger series of patients is needed, taking into account the high grade of interobserver variability documented in the assessment of tumor response classification in MPM.²⁴

In the past few years, a variety of studies have explored the role of PET, mostly with the use of FDG as tracer, in monitoring response to treatment.¹¹ In several neoplasms, such as lymphomas,²⁵ gastrointestinal stromal tumors,²⁶ and non–small-cell lung cancer,²⁷ an early decline in FDG tumor uptake was mostly predictive of a subsequent response documented by standard CT or histopathologic assessment. More importantly, in some studies a significant correlation was found between metabolic response and patient outcome as measured by TTP or OS.²⁷

The results of this study showed a significant correlation between MR evaluated by PET assessment after two cycles of pemetrexed-based chemotherapy and patient outcome, as measured by TTP. The median TTP of metabolic responders was twice that of nonresponders. On the contrary, radiologic response assessed by CT scan was not predictive of improved TTP. The OS was also related to PET response, although this correlation only approached statistical significance, possibly due to poststudy chemotherapy received by the majority of the patients. Interestingly, seven of eight metabolic responders were alive at a median follow-up of 15.1 months.

In our study MR was measured according to the 25% EORTC criteria.¹⁴ A 20% to 25% decrease in tumor FDG uptake is a widely accepted definition in patients undergoing palliative chemotherapy, while higher threshold values seem more adequate for neoadjuvant therapy.²⁸ Notably, in our study all the patients classified as metabolic responders had a SUV decrease greater than 30% and the absolute difference between baseline and post-treatment SUVs was always higher than .9 (Table 2), that is reported as a criterion by which a change can be considered significant.¹⁰

Considering the difficulties in assessing radiologic response to therapy in MPM, the survival outcomes seem to remain the best treatment end points in this disease. In a combined analysis of three prospective trials, radiologic responses did not appear to be correlated with survival improvement.²⁹ In a phase II trial of the combination of pemetrexed and carboplatin as first-line treatment in patients with MPM, despite the apparently lower radiologic response rate, TTP and OS were similar to the data reported with the standard combination of pemetrexed and cisplatin.⁴ Novel phase II studies using TTP as primary end point should be explored.^5,30 A recent overview of the EORTC Lung Cancer Group on 10 mesothelioma trials with 523 total patients has pointed out that replacement of the response rate by TTP as the primary end point in future MPM phase II trials would allow a better selection of clinically active drugs.³¹

Our data confirm preliminary observations by other authors (Table 3). ^7,32-36 In most of these studies, relative changes in tumor glucose uptake over time was measured by determining SUVmax values at baseline and early in the course of chemotherapy. Flores et al³² reported a statistically significant association between a decrease in FDG-PET SUV after chemotherapy and OS in 24 MPM patients treated with cisplatin-based induction chemotherapy and surgery. However, no quantitative cutoff was used to define metabolic response. No difference in OS was observed in the same series according to CT response. In some other trials, different parameters taking the whole tumor volume into account were considered.^33,34 A decrease in total glycolytic volume, a composite parameter, which takes into account both FDG uptake and tumor size, was correlated to an improvement in median TTP.³⁴ However, despite its limitations SUVmax appears to be a simple and reproducible approach to quantify tumor metabolic response.^10,28

In conclusion, our observations, although conducted in a small sample population, showed that in MPM treated with pemetrexed-based chemotherapy an early reduction of FDG uptake, as measured by SUVmax relative changes, is significantly correlated to patient outcome. Due to difficulties in assessing radiologic response to therapy by CT criteria, the use of FDG-PET for prediction of response and, more importantly, of survival outcomes appears promising and warrants validation in larger prospective series of MPM patients.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
The authors indicated no potential conflicts of interest.

	Author Contributions

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 

Conception and design: Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Armando Santoro Provision of study materials or patients: Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Marcello Rodari, Romano F. Lutman, Silvia Salamina, Matteo Incarbone, Marco Alloisio Collection and assembly of data: Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Marcello Rodari, Romano F. Lutman, Silvia Salamina, Matteo Incarbone, Marco Alloisio Data analysis and interpretation: Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Marcello Rodari, Romano F. Lutman, Armando Santoro Manuscript writing: Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Armando Santoro Final approval of manuscript: Giovanni L. Ceresoli, Arturo Chiti, Paolo A. Zucali, Marcello Rodari, Romano F. Lutman, Silvia Salamina, Matteo Incarbone, Marco Alloisio, Armando Santoro

 

	NOTES

 
Presented in part at the 11th World Conference on Lung Cancer in Barcelona, Spain, July 3-6, 2005.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... Author Contributions REFERENCES

 
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Submitted April 5, 2006; accepted July 28, 2006.

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