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Background: When combined with adequate tumoricidal doses, accurate target volume delineation remains to be the one of the most important predictive factors for radiotherapy (RT) success in locally advanced or medically inoperable malignant pleural mesothelioma (MPM) patients. Recently, 18-fluorodeoxyglucose positron emission tomography (PET) has demonstrated significant improvements in diagnosis and accurate staging of MPM. However, role of additional PET data has not been studied in RT planning (RTP) of patients with inoperable MPM or in those who refuse surgery. Therefore, we planned to compare CT with co-registered PET-CT as the basis for delineating target volumes in these patients group. Methods: Retrospectively, the CT and co-registered PET-CT data of 13 patients with histologically proven MPM were utilized to delineate target volumes separately. For each patient, target volumes (gross tumor volume [GTV], clinical target volume [CTV], and planning target volume [PTV]) were defined using the CT and PET-CT fusion data sets. The PTV was measured in two ways: PTV1 was CTV plus a 1-cm margin, and PTV2 was GTV plus a 1-cm margin. We analyzed differences in target volumes. Results: In 12 of 13 patients, compared to CT-based delineation, PET-CT-based delineation resulted in a statistically significant decrease in the mean GTV, CTV, PTV1, and PTV2. In these 12 patients, mean GTV decreased by 47.1% ± 28.4%, mean CTV decreased by 38.7% ± 24.7%, mean PTV1 decreased by 31.1% ± 23.1%, and mean PTV2 decreased by 40.0% ± 24.0%. In 4 of 13 patients, hilar lymph nodes were identified by PET-CT that was not identified by CT alone, changing the nodal status of tumor staging in those patients. Conclusion: This study demonstrated the usefulness of PET-CT-based target volume delineation in patients with MPM. Co-registration of PET and CT information reduces the likelihood of geographic misses, and additionally, significant reductions observed in target volumes may potentially allow escalation of RT dose beyond conventional limits potential clinical benefits in tumor control rates, which needs to be tested in future studies. Page 1 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:35 http://www.ro-journal.com/content/4/1/35 cera [10,17,18]. In this context, integrated PET-CT pro- Background Malignant pleural mesothelioma (MPM) is a relatively vides more information, compared with ametabolic CT or rare but highly aggressive tumor with expected median nonanatomic PET. The high sensitivity and specificity of survival of only 9 to 17 months [1,2]. Although currently PET-CT in patients with MPM have been well docu- it appears to be a rare tumor, its incidence is increasing mented. Benard et al analyzed 28 patients with suspected throughout most of the world including Turkey, where it MPM and reported that specificity of PET was 100% with is epidemic in three villages of the Cappadocia region. sensitivity of 91% in differentiating benign and malignant Also, familial forms with autosomal dominant inherit- lesions . Caretta et al found similar results, with accu- ance have been reported in this region [3,4]. racy of PET at 92% in the differential diagnosis of pleural diseases . Similarly, in their recent report Plathow et Although there is no universally accepted standard treat- al analyzed 54 patients with stage II and III MPM, and the ment for MPM, currently the EPP is the most widely pre- authors reported accuracy of 77% for CT, 86% for PET, ferred treatment modality. However, due to significant 80% for Magnetic Resonance Imaging (MRI), and 100% procedure related modality and mortality 85 to 90% of for PET-CT in patients with stage II disease, and accuracy patients are not eligible for this aggressive procedure [5,6]. of 75% for CT, 83% for PET, 90% for MRI, and 100% for In this context, radiation therapy (RT) as the sole treat- PET-CT in patients with stage III disease . ment in the presence or absence of concurrent chemother- apy may be a good alternative in suitable patient To our knowledge, no studies address the role of PET-CT- population. However, RT planning (RTP) for MPM is dif- based RTP in patients with medically inoperable MPM or ficult due to the large, irregularly shaped area at risk, the in those who refuse surgery. Largely based on the afore- high doses required for local control, and the proximity of mentioned data, we hypothesized that using PET-CT data many radiosensitive structures such as the liver, ipsilateral rather than CT data alone would change RT fields and pos- kidney, heart, spinal cord, esophagus, contralateral lung, sibly result in fewer geographic misses for unresected and the ipsilateral lung itself in inoperable cases. In the MPM. Therefore, in the present study, we compared CT- latter setting, which is a therapeutic challenge, the recent, based and integrated PET-CT-based gross tumor volume more sophisticated RT techniques, including intensity- (GTV) delineation and its subsequent expansion to clini- modulated radiotherapy (IMRT), image guided radiother- cal target volume (CTV) and planning target volume apy (IGRT), and especially helical tomotherapy (HT), are (PTV). promising. However, similar with all other tumor sites, accurate target delineation is crucial when RT is consid- Methods ered as the sole treatment or as a component of oncologic Thirteen patients with histological diagnosis of MPM who treatment, and additionally when combined with ade- were not candidate for a curative resection due to medical quate tumoricidal doses, accurate target volume delinea- reasons or self refusal those who were treated with thora- tion remains to be the one of the most important sic irradiation with a palliative intent are planned to be predictive factors for RT success in MPM. reassessed whether the intented target volumes may have changed if additional PET data was used in conjunction Computed tomography (CT) is the primary imaging with CT compared to CT alone. This study was largely modality used in staging and RT planning for MPM. Rind- based on recent impressive high sensitivity and specifity like extension of the tumor on the pleural surfaces is the data of PET in MPM diagnosis and staging as mentioned most common CT feature . However, CT often fails to previously [10,17,18]. This pure delineation study proto- accurately demonstrate transdiaphragmatic invasion and col to evaluate the potential differences via implementa- mediastinal lymph nodes [8,9]. Recently, 18-fluorodeox- tion of PET-CT on palliative MPM cases was approved by yglucose positron emission tomography (PET) has dem- the institutional ethic committee. Patients' charts were onstrated significant improvements in diagnosis, accurate reviewed for the search of characteristics with nonmeta- staging, RTP, and assessment of tumor response to the static mesothelioma classified as T2-4 and/or N0-3 prescribed treatment in a variety of tumor sites including according to the International Mesothelioma Interest the MPM [10-16]. PET imaging is based on biochemical Group staging system , and no previous surgical resec- processes that may offer better detection of tumors even tion. before they become anatomically apparent. Integration of functional PET data with the detailed anatomical infor- As we acknowledged from patients' hospital records, each mation of CT (PET-CT) has markedly increased the sensi- patient was placed in the supine position with both arms tivity, specificity and accuracy of discrimination between raised above their heads in a manner identical to treat- benign and malignant diseases, determination of tumoral ment positioning during PET-CT. The PET-CT scan was extensions in to the mediastinum, abdominal cavity or performed in an integrated PET-CT system (Discovery-STE pleural surfaces, medistinal lymph nodes or distant vis- 8, General Electric System, Milwaukee, WI, USA). Patients Page 2 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:35 http://www.ro-journal.com/content/4/1/35 were advised to fast for at least 6 hours before the PET the window and level for the PET images according to appointment. After 370 to 555 MBq (10-15 mCi) 18- method previously described by Erdi et al for accurate tar- fluorodeoxyglucose was injected, patients rested for get volume definition . In this protocol, we first meas- approximately 60 minutes in a comfortable chair. Prein- ured the value of the hottest pixel in the lesion and then jection blood glucose levels were measured to ensure that set the upper window level to this maximum value and set they were below 150 mmol/L. The patients were scanned the lower window level to 42% of the maximum level. on a flat-panel carbon fiber composite table insert. An enhanced CT scan from the base of the skull to the inferior Statistical Analysis border of the pelvis was acquired with 5-mm slice thick- On the basis of the literature, we hypothesized that inte- ness, using a standardized protocol with 140 kV and 80 gration of PET into RTP would change the target volumes MA with contrast injection. The subsequent PET scan was in approximately 30% of the patients. To detect such a acquired from the base of the skull to the inferior border change with a 95% confidence interval of 5% to 55%, we of the pelvis as in the CT scan, using multiple-bed posi- needed to enroll at least 13 patients. Statistical differences tion. Attenuation was corrected by using the CT images. between paired parameters from CT-based versus PET-CT- The processed images were displayed in coronal, trans- based treatment plans were evaluated with the Wilcoxon verse, and saggital planes. signed rank test. Results are expressed as mean ± standard deviation (SD). Differences were considered statistically After image acquisition, PET-CT data sets were transferred significant when the two-tailed P value was less than .05. to our treatment planning system, Eclipse 7.5 (Varian Medical Systems, Palo Alto, CA, USA) into DICOM RT for- Results mat, and the available data was utilized for planning pur- Demographic and clinical characteristics of the 13 poses following image fusion. The CT-based and PET-CT- patients are depicted in Table 1. Four of the 13 patients based treatment planning was computed for each patient. were women. Median age was 50 years, with range of 38 The target volumes were defined by the radiation oncolo- to 74 years. In all but one patient, compared with CT- gist (BP and checked by ET) with specific experience in based delineation, PET-CT-based delineation resulted in MPM cancer treatment on the CT and integrated PET-CT significantly decreased mean GTV, CTV, PTV1, and PTV2 images. The GTV was defined as the volume of macro- (Table 2). In these 12 patients, mean GTV decreased by scopic primary tumor and involved hilar and mediastinal 47.1% ± 28.4%, mean CTV decreased by 38.7% ± 24.7%, lymph nodes identified on the planning CT. The CTV was mean PTV1 decreased by 31.1% ± 23.1%, and mean PTV2 created automatically with a 1-cm margin around the GTV decreased by 40.0% ± 24.0%. In all 12 patients the respec- with respecting to the natural anatomical barriers, such as tive target volume reductions were solely due to reduced vertebral column. The PTV1 encompassed the CTV plus a primary tumor volumes on PET-CT fusion compared to mean 1-cm margin, and PTV2 was created with a 1-cm CT with no change in nodal disease exclusion by PET data. margin to the GTV. All volumes were defined again on In one patient, volumes were increased by PET-CT com- integrated PET-CT images. Lungs (right and left sepa- pared with CT; these increases were 19%, 2%, 10% and rately), liver, heart, esophagus, and kidneys (right and 15% in GTV, CTV, PTV1 and PTV2, respectively. This left) were counted as organs at risk in each patient. We set Table 1: Patient characteristics. Patient # Sex Age, y ECOG Stage SUV SUVmean max 1 Male 50 1 T4N3M0 11.5 7.5 2 Female 54 1 T3N1M0 21.8 12.5 3 Male 74 0 T1aN3M0 10.9 5.1 4 Male 38 1 T4N1M0 4.2 2.3 5 Male 43 0 T1aN2 M0 6.7 3.5 6 Male 47 0 T2N0M0 6.5 4.1 7 Male 42 0 T1aN3M0 7.2 6.9 8 Female 71 1 T1aN3M0 9.8 5.6 9 Male 46 0 T3N0M0 13.2 8.6 10 Female 64 1 T1aN2M0 7.9 4.7 11 Male 74 0 T1aN2M0 15.3 8.4 12 Male 47 1 T4N2M0 12.0 6.9 13 Female 50 0 T3N1M0 9.5 6.8 *Abbreviations: ECOG, Eastern Cooperative Oncology Group; M, distant metastasis; N, lymph-nodal disease; T, tumor extension. Stage was determined using the International Mesothelioma Interest Group criteria. Page 3 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:35 http://www.ro-journal.com/content/4/1/35 Table 2: Volumes by CT and PET-CT in 13 Patients with ing, and treatment, it presents a unique therapeutic Malignant Pleural Mesothelioma. challenge. Currently, EPP with en bloc resection of the lung, pleura, ipsilateral diaphragm, and pericardium is Volume, cc CT PET-CT P Value the treatment of choice. However, only 10% to 15% of patients are eligible for this extensive surgery [5,6], and GTV Mean ± S.D. 788.9 ± 845.1 441.4 ± 420.0 0.01 significant procedure-related morbidity and mortality Min-max (101.4 - 3352.1) (38.5 - 1250.2) limit its use. In addition, even with EPP, R0 resection is CTV theoretically impossible, and microscopic or macroscopic Mean ± S.D. 2040.6 ± 1360.5 1533.1 ± 1483.6 0.002 disease almost always remains at the resection margins. Min-max (479.6 - 5615.8) (254.4 - 5615.82) When EPP is the sole treatment modality, locoregional PTV1 recurrence is unacceptably high, ranging from 31% to Mean ± S.D. 3824.7 ± 1777.7 2936.7 ± 1940.1 0.003 64% [21-23]. Therefore, postoperative RT is usually indi- Min-max (1062.5 - 7523.8) (608.9 - 6971.9) PTV2 cated. In a number of studies, high-dose hemithoracic RT Mean ± S.D. 2385.5 ± 1449.9 1627.9 ± 1254.2 0.003 of 45 to 50 Gy with a boost to 54 to 60 Gy targeted to areas Min-max (488.2 - 5853.1) (278.9 - 4088.4) at higher risk for local recurrence significantly improved local control [24-27]. In a study by Perrot et al, only 10% *Abbreviations: CT = computed tomography; CTV = clinical target of patients developed recurrence in the ipsilateral hemith- volume; GTV = gross tumor volume; PET-CT = positron emission orax after completion of intended 60 Gy RT . Simi- tomography-computed tomography; PTV1 = planning target volume 1 (defined as CTV plus a 1-cm margin); PTV2 = planning target volume larly, Rusch et al demonstrated that adjuvant 2 (defined as GTV plus a 1-cm margin). hemithoracic RT of 54 Gy following EPP improved local control with a 13% risk of local failure . However, as increament was due to additional involved lymph node was the case in our current cohort, the majority of patients detection by PET data which was not appearent on CT. with malignant pleural mesothelioma are not good candi- dates for curative EPP due to presence of either advanced In 4 of 13 patients (31%), PET-CT identified increased 18- local disease or unfavorable medical conditions that fluorodeoxyglucose uptake in hilar lymph nodes that did render them unfit for surgery. not appear on CT, thereby changing the N stage in those 4 patients. In 3 patients (23%), PET-CT showed subdia- In the setting of unresectable or medically inoperable/ phragmatic extension of the disease which did not appear patient refusal conditions, RT when applied with pallative on CT. Representative images of a patient with different intent may offer good symptom control in conventional GTV delineations are seen in the Figure 1 and Figure 2. palliative doses. However, there is strong evidence sug- gesting better symptom and possibly loco-regional tumor control with higher doses approaching to that is used for Discussion On background of a nonexistent radiotherapeutic consen- curative intent. In one study, Ball et al showed that only 1 sus for unresected nonmetastatic MPM in the literature, (4%) of 23 patients who received < 40 Gy achieved symp- we performed a pure delineation study to evaluate the dif- tomatic relief while 4 (66%) of 6 patients treated with > ferences via implementation of PET-CT in order to gener- 40 Gy had satisfactory symptom palliation impacting the ate potential possibilities for future radiotherapy importance of total dose even for palliative purposes . decisions with current and coming cutting edge techno- Largely based on this data we planned to reassess our logic advances. The results of the current study revealed patients those who were treated with an palliative that compared to CT, integrated PET-CT-based target vol- approach whether they were suitable for higher RT doses ume delineation significantly reduced the GTV and its in the range of curative 54 Gy, as these patients theorati- expansions, CTV and PTV, in 12 of 13 patients and cally still bear a chance for cure with higher RT doses even increased target volumes in 1 patient, all together impact- in absence of EPP. However, absence of a HT unit or a ing the importance of accurate target volume delineation similar volumetric arc technology in our clinics signifi- in this patients group. Additionally, we found that func- cantly limited our ability to create clinically relevant and tional PET data changed the N stage in 4 of 13 patients, acceptable RTPs based on compatible pulmonary toxicity and subdiaphragmatic tumor extension was evident in criteria. Therefore we planned to only compare the con- further 3 (23%) patients that was not shown by CT, which ventional CT- and PET-CT based target volume delinea- may explain the possibility of geographic misses experi- tions which may positively impact and alter the future enced with CT-based RTP and its influence on poor out- RTPs either for curatively or palliatively intended comes in patients with MPM. approaches in presence of HT facilities. There is currently no universally accepted standard ther- Despite the evident advantages offered by escalated doses apy for MPM. Regarding the difficulties in diagnosis, stag- with use of 3D- conformal RT it is not usually possible to Page 4 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:35 http://www.ro-journal.com/content/4/1/35 Re CT, ( Figure 1 pres d) co entativ ronal PET- e image o CT f a patient with CT- and PET- CT based GTV delineations; (a) axial CT (b) axial PET-CT, (c) coronal Representative image of a patient with CT- and PET- CT based GTV delineations; (a) axial CT (b) axial PET- CT, (c) coronal CT, (d) coronal PET-CT. *Abbreviations: GTV = gross tumor volume; CT = computed tomography; PET- CT = positron emission tomography-computed tomography. escalate RT dose because of significant toxicity concerns zing et al compared step-and-shoot IMRT with HT . Linden et al treated 47 MPM patients with a dose of 40 Gy They observed that while both modalities achieved excel- in 20 fractions with and without chemotherapy and they lent dose distributions, target coverage and homogenity informed that all of patients experienced radiation could be increased significantly with HT, additionally induced pulmonary fibrosis . However, in this setting, contralateral lung dose could be lowered beyond 5 Gy. more sophisticated RT techniques such as IMRT, IGRT, They concluded that HT is an excellent option for the and especially helical-slit IMRT (HT) and cone-beam IMRT of MPM. In our current study, as aforementioned it IMRT (RapidArc and VMAT)  might become appropri- was impossible to create appropriate RTPs and guiding ate alternatives for either definitive or palliative treatment DVHs in absence of further technical advances such as HT for suitable patients based on compatible pulmonary tox- oppurtunities, yet, we believe that the significant reduc- icity criteria. Helical tomotherapy is a promising method, tions observed in target volumes, additional subdiaphrag- and achieves a better dose conformity in several tumor matic extension and involved lymph nodes shown only sites including MPM [31-33]. In their recent study, Ster- Page 5 of 7 (page number not for citation purposes) Radiation Oncology 2009, 4:35 http://www.ro-journal.com/content/4/1/35 by PET data might be accepted as a useful evidence for tial reduction in local and regional treatment failures. future studies with appropriate technologies. However, we believe that before reaching more definite conclusions, more clinical studies are required to better Although CT is the primary imaging modality for both define the role of PET-CT fusion in this setting. staging and RTP in patients with MPM, the results of CT fail to identify the true extent of local invasion through Competing interests the extrathoracic fascia, diaphragmatic surfaces, and inter- We have no personal or financial conflict of interest and lobar fissures. Results of CT cannot accurately distinguish have not entered into any agreement that could interfere between malignant and benign conditions, such as with our access to the data on the research, or upon our inflammation and pleural fluid, which are common find- ability to analyze the data independently, to prepare man- ings of MPM. Webb et al showed that the desmoplastic uscripts, and to publish them. reaction caused by tumor-induced proliferation of benign connective tissue adjacent to the tumor can result in an Authors' contributions overestimation of the stage of the tumor . Addition- All authors read and approved the final manuscript. BP ally, CT has poor sensitivity for defining the malignant and ET carried out all CT evaluations, study design, target status of mediastinal lymph nodes [8,9]. Earlier studies in delineations, interpretation of the study, and drafted the lung cancer showed significant changes when PET infor- manuscript. GNN carried out all PET evaluations and mation was applied, with decreased volumes mostly delineation of target volumes based on PET findings. CO attributed to exclusion of atelectasis [15,35-37]. We found carried out statistical analysis. OZ participated in manu- that 18-fluorodeoxyglucose PET led to better definition of script preparation and study design. YD made the treat- target volumes with additional metabolic information, ment planning. MNY, AAY gave advice on the work and and it was more successful in discriminating between helped in the interpretation of the data. tumor and benign connective tissue changes. Acknowledgements We would thank to Dr Ali Fuat Yapar (AFY) for revision of PET data. The additional volume and intratumoral functional varia- tions uniquely identified by PET may be even more References important in the near future when so-called dose-painting 1. Ruffie P, Feld R, Minkin S, Cormier Y, Boutan-Laroze A, Ginsberg R, intensity-modulated radiotherapy becomes widely used Ayoub J, Shepherd FA, Evans WK, Figueredo A: Diffuse malignant in clinical practice, opening the possibility of controlled mesothelioma of the pleura in Ontario and Quebec: A retro- spective study of 332 patients. J Clin Oncol 1989, 7:1157-1168. and reproducible internal-dose escalation to functionally 2. 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Flores RM, Krug LM, Rosenzweig KE, Venkatraman E, Vincent A, Hee- lan R, Akhurst T, Rusch VW: Induction chemotherapy, extrap- "BioMed Central will be the most significant development for leural pneumonectomy, and postoperative high-dose disseminating the results of biomedical researc h in our lifetime." radiotherapy for locally advanced malignant pleural mes- Sir Paul Nurse, Cancer Research UK othelioma: A phase III trial. J Thorac Oncol 2006, 1:289-295. 26. Rusch VW, Rosenzweig K, Venkatraman E, Leon L, Raben A, Harrison Your research papers will be: L, Bains MS, Downey RJ, Ginsberg RJ: A phase II trial of surgical available free of charge to the entire biomedical community resection and adjuvant high-dose hemithoracic radiation for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2001, peer reviewed and published immediately upon acceptance 122:788-795. cited in PubMed and archived on PubMed Central 27. Krug LM, Pass HI, Rusch VW, Kindler HL, Sugarbaker DJ, Rosenzweig KE, Flores R, Friedberg JS, Pisters K, Monberg M, Obasaju CK, Vogel- yours — you keep the copyright zang NJ: Multicenter phase II trial of neoadjuvant pemetrexed BioMedcentral plus cisplatin followed by extrapleural pneumonectomy and Submit your manuscript here: http://www.biomedcentral.com/info/publishing_adv.asp Page 7 of 7 (page number not for citation purposes)
Radiation Oncology – Springer Journals
Published: Sep 16, 2009
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