Multiparametric imaging of patient and tumour heterogeneity in non-small-cell lung cancer: quantification of tumour hypoxia, metabolism and perfusion.

PURPOSE: Multiple imaging techniques are nowadays available for clinical in-vivo visualization of tumour biology. FDG PET/CT identifies increased tumour metabolism, hypoxia PET visualizes tumour oxygenation and dynamic contrast-enhanced (DCE) CT characterizes vasculature and morphology. We explored the relationships among these biological features in patients with non-small-cell lung cancer (NSCLC) at both the patient level and the tumour subvolume level. METHODS: A group of 14 NSCLC patients from two ongoing clinical trials (NCT01024829 and NCT01210378) were scanned using FDG PET/CT, HX4 PET/CT and DCE CT prior to chemoradiotherapy. Standardized uptake values (SUV) in the primary tumour were calculated for the FDG and hypoxia HX4 PET/CT scans. For hypoxia imaging, the hypoxic volume, fraction and tumour-to-blood ratio (TBR) were also defined. Blood flow and blood volume were obtained from DCE CT imaging. A tumour subvolume analysis was used to quantify the spatial overlap between subvolumes. RESULTS: At the patient level, negative correlations were observed between blood flow and the hypoxia parameters (TBR >1.2): hypoxic volume (-0.65, p = 0.014), hypoxic fraction (-0.60, p = 0.025) and TBR (-0.56, p = 0.042). At the tumour subvolume level, hypoxic and metabolically active subvolumes showed an overlap of 53 ± 36 %. Overlap between hypoxic sub-volumes and those with high blood flow and blood volume was smaller: 15 ± 17 % and 28 ± 28 %, respectively. Half of the patients showed a spatial mismatch (overlap <5 %) between increased blood flow and hypoxia. CONCLUSION: The biological imaging features defined in NSCLC tumours showed large interpatient and intratumour variability. There was overlap between hypoxic and metabolically active subvolumes in the majority of tumours, there was spatial mismatch between regions with high blood flow and those with increased hypoxia.

Prognostic value of metabolic metrics extracted from baseline positron emission tomography images in non-small cell lung cancer.

BACKGROUND: Maximum, mean and peak SUV of primary tumor at baseline FDG-PET scans, have often been found predictive for overall survival in non-small cell lung cancer (NSCLC) patients. In this study we further investigated the prognostic power of advanced metabolic metrics derived from intensity volume histograms (IVH) extracted from PET imaging. METHODS: A cohort of 220 NSCLC patients (mean age, 66.6 years; 149 men, 71 women), stages I-IIIB, treated with radiotherapy with curative intent were included (NCT00522639). Each patient underwent standardized pre-treatment CT-PET imaging. Primary GTV was delineated by an experienced radiation oncologist on CT-PET images. Common PET descriptors such as maximum, mean and peak SUV, and metabolic tumor volume (MTV) were quantified. Advanced descriptors of metabolic activity were quantified by IVH. These comprised five groups of features: absolute and relative volume above relative intensity threshold (AVRI and RVRI), absolute and relative volume above absolute intensity threshold (AVAI and RVAI), and absolute intensity above relative volume threshold (AIRV). MTV was derived from the IVH curves for volumes with SUV above 2.5, 3 and 4, and of 40% and 50% maximum SUV. Univariable analysis using Cox Proportional Hazard Regression was performed for overall survival assessment. RESULTS: Relative volume above higher SUV (80%) was an independent predictor of OS (p = 0.05). None of the possible surrogates for MTV based on volumes above SUV of 3, 40% and 50% of maximum SUV showed significant associations with OS [p (AVAI3) = 0.10, p (AVAI4) = 0.22, p (AVRI40%) = 0.15, p (AVRI50%) = 0.17]. Maximum and peak SUV (r = 0.99) revealed no prognostic value for OS [p (maximum SUV) = 0.20, p (peak SUV) = 0.22]. CONCLUSIONS: New methods using more advanced imaging features extracted from PET were analyzed. Best prognostic value for OS of NSCLC patients was found for relative portions of the tumor above higher uptakes (80% SUV).

Stability of 18F-deoxyglucose uptake locations within tumor during radiotherapy for NSCLC: a prospective study.

PURPOSE: Because individual tumors are heterogeneous, including for (18)F-deoxyglucose (FDG) uptake and, most likely, for radioresistance, selective boosting of high FDG uptake zones within the tumor has been suggested. To do this, it is critical to know whether the location of these high FDG uptake patterns within the tumor remain stable during radiotherapy (RT). METHODS AND MATERIALS: Twenty-three patients with Stage I-III non-small-cell lung cancer underwent repeated FDG positron emission tomography computed tomography scans before radical RT (Day 0) and at Days 7 and 14 of RT. On all scans, the high and low FDG uptake regions were autodelineated using several standardized uptake value thresholds, varying from 34% to 80% of the maximal standardized uptake value. The volumes and overlap fractions of these delineations were calculated to demonstrate the stability of the high FDG uptake regions during RT. RESULTS: The mean overlap fraction of the 34% uptake zones at Day 0 with Days 7 and 14 was 82.8% +/- 8.1% and 84.3% +/- 7.6%, respectively. The mean overlap fraction of the high uptake zones (60%) was 72.3% +/- 15.0% and 71.3% +/- 19.7% at Day 0 with Days 7 and 14, respectively. The volumes of the thresholds varied markedly (e.g., at Day 0, the volume of the 60% zone was 16.8 +/- 20.3 cm(3)). In contrast, although the location of the high FDG uptake patterns within the tumor during RT remained stable, the delineated volumes varied markedly. CONCLUSION: The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: a planning study.

BACKGROUND AND PURPOSE: To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). MATERIAL AND METHODS: Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. RESULTS: FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. CONCLUSIONS: Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

Can an FDG-PET/CT predict tumor clearance of the mesorectal fascia after preoperative chemoradiation of locally advanced rectal cancer?

BACKGROUND AND PURPOSE: More effective preoperative treatment in locally advanced rectal cancer gives rise to a more individualized, conservative surgical treatment strategy. This, however, requires accurate information on tumor response after chemoradiation (CRT). So far, MRI and CT have failed to provide such information. Therefore, the value of a combined FDG-PET/CT in predicting tumor clearance of the mesorectal fascia (MRF) was determined. PATIENTS AND METHODS: 20 rectal cancer patients with MRF tumor invasion underwent preoperative PET/CT before and on average 6.3 weeks after CRT. The SUV(max)(maximal standard uptake value) on sequential PET/CT and the shortest distance between the outlined tumor volume and the MRF measured by using autocontouring software on post-CRT PET/CT were registered. The surgical specimen was evaluated for tumor clearance of the MRF and the tumor regression grade (TRG). RESULTS: The TRG significantly corresponded with the SUV(max)changes induced by CRT (p = 0.025), and showed a trend with the post-CRT SUV(max)(TRG 1-2 vs. TRG 3-5: SUV(max)= 3.0 vs. 5.0; p = 0.06). However, the pathologically verified tumor clearance of the MRF was not correlated with any of the tested SUV parameters nor with the shortest distance between the residual tumor and the MRF. CONCLUSION: Post-CRT PET/CT is not a useful tool for evaluating anatomic tumor changes and, therefore, not accurate in predicting tumor clearance of the MRF. However, it might be a useful tool in predicting pathologic tumor response after CRT.

A qualitative synthesis of the evidence behind elective lymph node irradiation in oesophageal cancer.

BACKGROUND AND PURPOSE: Oesophageal cancer is the sixth leading cause of cancer death worldwide and radiotherapy plays a prominent role in its treatment. The presence of lymph node (LN) metastasis has been demonstrated to be one of the most significant prognostic factors related to oesophageal cancer. The use of elective lymph node irradiation (ENI) is still a topic of persistent controversy. The conservative school is to irradiate positive lymph nodes only; the other school is to prophylactically irradiate the regional lymph node area according to different tumour sites. This review investigated the justification for including ENI in the treatment of patients with oesophageal cancer. MATERIAL AND METHODS: We performed a systematic literature search to find surgical data about lymph node distribution depending on different tumour subgroups: early, cervical, thoracic and gastroesophageal junction cancer. Furthermore, we performed a qualitative assessment of recurrence patterns in patients treated with or without ENI to derive estimates of the potential area at risk for lymph node harvest. RESULTS: We identified and reviewed 49 studies: 10 in early, 8 in cervical, 10 in thoracic and the remaining 21 in gastroesophageal junction cancer. In general, these studies were conclusive in incidence and location of pathologic lymph nodes for different subgroups. Data for lymph node recurrence patterns are scarce and contributed little to our review. CONCLUSIONS: This review resulted in five recommendations for radiation oncologists in daily practice. We used the available evidence about metastatic lymph node distribution to develop a careful reasonable radiation protocol for the corresponding tumour subgroups.

Individualised isotoxic accelerated radiotherapy and chemotherapy are associated with improved long-term survival of patients with stage III NSCLC: a prospective population-based study.

BACKGROUND: Individualised, isotoxic, accelerated radiotherapy (INDAR) allows the delivery of high biological radiation doses, but the long-term survival associated with this approach is unknown. METHODS: Patients with stage III NSCLC in the Netherlands Cancer Registry/Limburg from January 1, 2002 to December 31, 2008 were included. RESULTS: Patients (1002) with stage III NSCLC were diagnosed, of which 938 had T4 and/or N2-N3 disease. Patients treated with curative intent were staged with FDG-PET scans and a contrast-enhanced CT or an MRI of the brain. There were no shifts over time in the patient or tumour characteristics at diagnosis. The number of stage III NSCLC patients remained stable over time, but the proportion treated with palliative intent decreased from 47% in 2002 to 37% in 2008, and the percentage treated with chemo-radiation (RT) increased from 24.6% in 2002 to 47.8% in 2008 (p<0.001). The proportion of surgical patients remained below 5%. Sequential chemotherapy and conventional RT resulted in a median and a 5-year survival of 17.5 months and 8.4%, respectively, whereas with sequential chemotherapy and INDAR this was 23.6 months and 31%, respectively (p<0.001). Concurrent chemotherapy and INDAR was associated with a median and 2-year survival that was not reached and 66.7%, respectively (p=0.004). CONCLUSIONS: The proportion of patients treated with a curative intention with chemo-RT has increased markedly over time of observation. INDAR is associated with longer survival when compared to standard dose RT alone given with or without chemotherapy.

Accurate automatic delineation of heterogeneous functional volumes in positron emission tomography for oncology applications.

PURPOSE: Accurate contouring of positron emission tomography (PET) functional volumes is now considered crucial in image-guided radiotherapy and other oncology applications because the use of functional imaging allows for biological target definition. In addition, the definition of variable uptake regions within the tumor itself may facilitate dose painting for dosimetry optimization. METHODS AND MATERIALS: Current state-of-the-art algorithms for functional volume segmentation use adaptive thresholding. We developed an approach called fuzzy locally adaptive Bayesian (FLAB), validated on homogeneous objects, and then improved it by allowing the use of up to three tumor classes for the delineation of inhomogeneous tumors (3-FLAB). Simulated and real tumors with histology data containing homogeneous and heterogeneous activity distributions were used to assess the algorithm's accuracy. RESULTS: The new 3-FLAB algorithm is able to extract the overall tumor from the background tissues and delineate variable uptake regions within the tumors, with higher accuracy and robustness compared with adaptive threshold (T(bckg)) and fuzzy C-means (FCM). 3-FLAB performed with a mean classification error of less than 9% +/- 8% on the simulated tumors, whereas binary-only implementation led to errors of 15% +/- 11%. T(bckg) and FCM led to mean errors of 20% +/- 12% and 17% +/- 14%, respectively. 3-FLAB also led to more robust estimation of the maximum diameters of tumors with histology measurements, with <6% standard deviation, whereas binary FLAB, T(bckg) and FCM lead to 10%, 12%, and 13%, respectively. CONCLUSION: These encouraging results warrant further investigation in future studies that will investigate the impact of 3-FLAB in radiotherapy treatment planning, diagnosis, and therapy response evaluation.

Comparison between perfusion computed tomography and dynamic contrast-enhanced magnetic resonance imaging in rectal cancer.

PURPOSE: To compare pretreatment scans with perfusion computed tomography (pCT) vs. dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in rectal tumors. METHODS AND MATERIALS: Nineteen patients diagnosed with rectal cancer were included in this prospective study. All patients underwent both pCT and DCE-MRI. Imaging was performed on a dedicated 40-slice CT-positron emission tomography system and a 3-T MRI system. Dynamic contrast enhancement was measured in tumor tissue and the external iliac artery. Tumor perfusion was quantified in terms of pharmacokinetic parameters: transfer constant K(trans), fractional extravascular-extracellular space v(e), and fractional plasma volume v(p). Pharmacokinetic parameter values and their heterogeneity (by 80% quantile value) were compared between pCT and DCE-MRI. RESULTS: Tumor K(trans) values correlated significantly for the voxel-by-voxel-derived median (Kendall's tau correlation, tau = 0.81, p < 0.001) and 80% quantile (tau = 0.54, p = 0.04), as well as for the averaged uptake (tau = 0.58, p = 0.03). However, no significant correlations were found for v(e) and v(p) derived from the voxel-by-voxel-derived median and 80% quantile and derived from the averaged uptake curves. CONCLUSIONS: This study demonstrated for the first time that pCT provides K(trans) values comparable to those of DCE-MRI. However, no correlation was found for the v(e) and v(p) parameters between CT and MRI. Computed tomography can serve as an alternative modality to MRI for the in vivo evaluation of tumor angiogenesis in terms of the transfer constant K(trans).

Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study.

PURPOSE: To evaluate the results of selective nodal irradiation on basis of (18)F-deoxyglucose positron emission tomography (PET) scans in patients with limited-disease small-cell lung cancer (LD-SCLC) on isolated nodal failure. METHODS AND MATERIALS: A prospective study was performed of 60 patients with LD-SCLC. Radiotherapy was given to a dose of 45 Gy in twice-daily fractions of 1.5 Gy, concurrent with carboplatin and etoposide chemotherapy. Only the primary tumor and the mediastinal lymph nodes involved on the pretreatment PET scan were irradiated. A chest computed tomography (CT) scan was performed 3 months after radiotherapy completion and every 6 months thereafter. RESULTS: A difference was seen in the involved nodal stations between the pretreatment (18)F-deoxyglucose PET scans and computed tomography scans in 30% of patients (95% confidence interval, 20-43%). Of the 60 patients, 39 (65%; 95% confidence interval [CI], 52-76%) developed a recurrence; 2 patients (3%, 95% CI, 1-11%) experienced isolated regional failure. The median actuarial overall survival was 19 months (95% CI, 17-21). The median actuarial progression-free survival was 14 months (95% CI, 12-16). 12% (95% CI, 6-22%) of patients experienced acute Grade 3 (Common Terminology Criteria for Adverse Events, version 3.0) esophagitis. CONCLUSION: PET-based selective nodal irradiation for LD-SCLC resulted in a low rate of isolated nodal failures (3%), with a low percentage of acute esophagitis. These findings are in contrast to those from our prospective study of CT-based selective nodal irradiation, which resulted in an unexpectedly high percentage of isolated nodal failures (11%). Because of the low rate of isolated nodal failures and toxicity, we believe that our data support the use of PET-based SNI for LD-SCLC.

Follow-up with 18FDG-PET-CT after radical radiotherapy with or without chemotherapy allows the detection of potentially curable progressive disease in non-small cell lung cancer patients: a prospective study.

BACKGROUND: Follow-up of patients treated with curative intent for non-small cell lung cancer (NSCLC) with X-ray or CT-scans is of unproven value. Furthermore, most patients with progressive disease present with symptoms outside of follow-up visits. Because the accuracy of (18)FDG-PET-CT is superior to CT, we hypothesised that FDG-PET-CT scans 3 months post-treatment could lead to early detection of progressive disease (PD) amenable for radical treatment. PATIENTS AND METHODS: Hundred patients with NSCLC, treated with curative intent with (chemo) radiation, were prospectively evaluated. All patients underwent a planned FDG-PET-CT scan 3 months after the start of radiotherapy. RESULTS: Twenty four patients had PD 3 months post-treatment. 16/24 patients were symptomatic. No curative treatment could be offered to any of these patients. In 3/8 asymptomatic patients progression, potentially amenable for radical therapy was found, which were all detected with PET, not with CT only. CONCLUSIONS: PET-scanning after curative treatment for NSCLC led to the detection of progression potentially amenable for radical treatment in a small proportion (3%) of patients. Selectively offering a PET-CT scan to the patient group without symptoms could possibly lead to an effective follow-up method.

Identification of residual metabolic-active areas within individual NSCLC tumours using a pre-radiotherapy (18)Fluorodeoxyglucose-PET-CT scan.

BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) tumours are mostly heterogeneous. We hypothesized that areas within the tumour with a high pre-radiation (18)F-deoxyglucose (FDG) uptake, could identify residual metabolic-active areas, ultimately enabling selective-boosting of tumour sub-volumes. MATERIAL AND METHODS: Fifty-five patients with inoperable stage I-III NSCLC treated with chemo-radiation or with radiotherapy alone were included. For each patient one pre-radiotherapy and one post-radiotherapy FDG-PET-CT scans were available. Twenty-two patients showing persistent FDG uptake in the primary tumour after radiotherapy were analyzed. Overlap fractions (OFs) were calculated between standardized uptake value (SUV) threshold-based auto-delineations on the pre- and post-radiotherapy scan. RESULTS: Patients with residual metabolic-active areas within the tumour had a significantly worse survival compared to individuals with a complete metabolic response (p=0.002). The residual metabolic-active areas within the tumour largely corresponded (OF>70%) with the 50%SUV high FDG uptake area of the pre-radiotherapy scan. The hotspot within the residual area (90%SUV) was completely within the GTV (OF=100%), and had a high overlap with the pre-radiotherapy 50%SUV threshold (OF>84%). CONCLUSIONS: The location of residual metabolic-active areas within the primary tumour after therapy corresponded with the original high FDG uptake areas pre-radiotherapy. Therefore, a single pre-treatment FDG-PET-CT scan allows for the identification of residual metabolic-active areas.