Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To assess the feasibility of intensity-modulated radiotherapy (IMRT) using positron emission tomography (PET)-guided dose escalation, and to determine the maximum tolerated dose in head and neck cancer. METHODS AND MATERIALS: A Phase I clinical trial was designed to escalate the dose limited to the [(18)-F]fluoro-2-deoxy-D-glucose positron emission tomography ((18)F-FDG-PET)-delineated subvolume within the gross tumor volume. Positron emission tomography scanning was performed in the treatment position. Intensity-modulated radiotherapy with an upfront simultaneously integrated boost was employed. Two dose levels were planned: 25 Gy (level I) and 30 Gy (level II), delivered in 10 fractions. Standard IMRT was applied for the remaining 22 fractions of 2.16 Gy. RESULTS: Between 2003 and 2005, 41 patients were enrolled, with 23 at dose level I, and 18 at dose level II; 39 patients completed the planned therapy. The median follow-up for surviving patients was 14 months. Two cases of dose-limiting toxicity occurred at dose level I (Grade 4 dermitis and Grade 4 dysphagia). One treatment-related death at dose level II halted the study. Complete response was observed in 18 of 21 (86%) and 13 of 16 (81%) evaluated patients at dose levels I and II (p < 0.7), respectively, with actuarial 1-year local control at 85% and 87% (p = n.s.), and 1-year overall survival at 82% and 54% (p = 0.06), at dose levels I and II, respectively. In 4 of 9 patients, the site of relapse was in the boosted (18)F-FDG-PET-delineated region. CONCLUSIONS: For head and neck cancer, PET-guided dose escalation appears to be well-tolerated. The maximum tolerated dose was not reached at the investigated dose levels.     

Planning study for available dose of hypoxic tumor volume using fluorine-18-labeled fluoromisonidazole positron emission tomography for treatment of the head and neck cancer

Purpose

To investigate the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography (¹⁸F-FMISO PET/CT)-guided intensity-modulated radiotherapy (IMRT) in dose escalation to attack the hypoxic volume of a tumor mass without increasing the normal tissue dose in head and neck cancer patients.

Materials and methods

Eight consecutive head and neck cancer patients underwent ¹⁸F-FMISO PET/CT simulation. Hypoxic tumor volume (HTV) was defined using a tumor-to-cerebellum ratio (T/C) of 1.3 as the threshold for ¹⁸F-FMISO PET/CT. Dose-escalation plans for treating HTVs using ¹⁸F-FMISO PET/CT-guided IMRT were performed for these patients. The standard plan was 72 Gy to the gross tumor volume (GTV) administered as 30 daily fractions of 2.4 Gy. In biologically optimized IMRT plans, the daily dose to the HTV ranged from 2.6 to 3.6 Gy. Dose-volume histograms (DVHs) were generated as part of each plan, and the results of planning were analyzed.

Results

Dose-escalation IMRT plans, delivering 30 daily doses of 2.6 Gy (total of 78 Gy) to the HTVs without increases in normal tissue doses, were feasible for six patients. Further acceptable dose escalation on HTV depended primarily on the primary tumor site and the extent of disease.

Conclusions

It was possible to dose escalate the HTV radiation to 78 Gy in six of eight head and neck cancer patients using ¹⁸F-FMISO PET/CT-guided IMRT.     

Reproducibility of intratumor distribution of (18)F-fluoromisonidazole in head and neck cancer

PURPOSE: Hypoxia is one of the main causes of the failure to achieve local control using radiotherapy. This is due to the increased radioresistance of hypoxic cells. (18)F-fluoromisonidazole ((18)F-FMISO) positron emission tomography (PET) is a noninvasive imaging technique that can assist in the identification of intratumor regions of hypoxia. The aim of this study was to evaluate the reproducibility of (18)F-FMISO intratumor distribution using two pretreatment PET scans. METHODS AND MATERIALS: We enrolled 20 head and neck cancer patients in this study. Of these, 6 were excluded from the analysis for technical reasons. All patients underwent an (18)F-fluorodeoxyglucose study, followed by two (18)F-FMISO studies 3 days apart. The hypoxic volumes were delineated according to a tumor/blood ratio >or=1.2. The (18)F-FMISO tracer distributions from the two (18)F-FMISO studies were co-registered on a voxel-by-voxel basis using the computed tomography images from the PET/computed tomography examinations. A correlation between the (18)F-FMISO intensities of the corresponding spatial voxels was derived. RESULTS: A voxel-by-voxel analysis of the (18)F-FMISO distributions in the entire tumor volume showed a strong correlation in 71% of the patients. Restraining the correlation to putatively hypoxic zones reduced the number of patients exhibiting a strong correlation to 46%. CONCLUSION: Variability in spatial uptake can occur between repeat (18)F-FMISO PET scans in patients with head and neck cancer. Blood data for one patient was not available. Of 13 patients, 6 had well-correlated intratumor distributions of (18)F-FMISO-suggestive of chronic hypoxia. More work is required to identify the underlying causes of changes in intratumor distribution before single-time-point (18)F-FMISO PET images can be used as the basis of hypoxia-targeting intensity-modulated radiotherapy.     

Diagnostic performance of Fluorine-18-Fluorodeoxyglucose positron emission tomography in the assessment of pleural abnormalities in cancer patients: A systematic review and a meta-analysis

Objective

To systematically review and meta-analyze published data about the diagnostic performance of Fluorine-18-Fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) and PET/computed tomography (PET/CT) in the assessment of pleural abnormalities in cancer patients.

Methods

A comprehensive literature search of studies published through June 2013 regarding the role of ¹⁸F-FDG-PET and PET/CT in evaluating pleural abnormalities in cancer patients was performed. All retrieved studies were reviewed and qualitatively analyzed. Pooled sensitivity, specificity, positive and negative likelihood ratio (LR+ and LR−) and diagnostic odd ratio (DOR) of ¹⁸F-FDG-PET or PET/CT on a per patient-based analysis were calculated. The area under the summary ROC curve (AUC) was calculated to measure the accuracy of these methods in the assessment of pleural abnormalities. Sub-analyses considering ¹⁸F-FDG-PET/CT and patients with lung cancer only were carried out.

Results

Eight studies comprising 360 cancer patients (323 with lung cancer) were included. The meta-analysis of these selected studies provided the following results: sensitivity 86% [95% confidence interval (95%CI): 80–91%], specificity 80% [95%CI: 73–85%], LR+ 3.7 [95%CI: 2.8–4.9], LR− 0.18 [95%CI: 0.09–0.34], DOR 27 [95%CI: 13–56]. The AUC was 0.907. No significant improvement considering PET/CT studies only and patients with lung cancer was found.

Conclusions

¹⁸F-FDG-PET and PET/CT demonstrated to be useful diagnostic imaging methods in the assessment of pleural abnormalities in cancer patients, nevertheless possible sources of false-negative and false-positive results should be kept in mind. The literature focusing on the use of ¹⁸F-FDG-PET and PET/CT in this setting remains still limited and prospective studies are needed.     

Adaptive 18fluoro-2-deoxyglucose positron emission tomography/computed tomography-based target volume delineation in radiotherapy planning of head and neck cancer

Aims

This study investigated an adaptive threshold-based method to delineate the target volume using ¹⁸fluoro-2-deoxyglucose (¹⁸FDG) positron emission tomography/computed tomography (PET/CT) before and during a course of radical radiotherapy or chemoradiotherapy in locally advanced squamous cell carcinoma of the head and neck.

Materials and methods

Ten patients were enrolled between March 2006 and May 2008. ¹⁸FDG PET/CT scans were carried out 72 h before the start of radiotherapy and then at three time points during radiotherapy (8-18, 36-50 and 66 Gy). Functional volumes were delineated using an adaptive iterative algorithm weighted according to the mean standard uptake value (SUV_mean) within the region of interest. The background ¹⁸FDG uptake, maximum standard uptake value (SUV_max) and SUV_mean within the volumes were assessed.

Results

There was no significant reduction in the primary target volumes defined by the adaptive threshold during radiotherapy. However, the SUV_max significantly reduced within the primary (P = 0.003-0.011) and lymph node (P < 0.0001) target volume at 36-50 and 36-66 Gy compared with 0 Gy. The SUV_mean was negatively correlated to radiation dose (P < 0.0001-0.014). The ratio between the background uptake of ¹⁸FDG and the SUV_mean significantly reduced for both the lymph node target volume at 36-50 Gy and the primary volume at 66 Gy. The lack of significant correlation between the defined volume and radiation dose was because the SUV_mean within the region of interest used to define the edge of the volume was equal to or less than the background ¹⁸FDG uptake and the software was unable to effectively differentiate between tumour and background uptake.

Conclusions

The adaptive threshold method may be of benefit when used to define the target volume before the start of radiotherapy. This method was not beneficial during radiotherapy because the software is not sensitive enough to distinguish tumour from background and define a volume. ¹⁸FDG PET/CT-guided volumes delineated by automatic adaptive thresholding methods should only be used for dose escalation with the pretreatment imaging.     

The role of Fluorine-18-Fluorodeoxyglucose positron emission tomography in staging and restaging of patients with osteosarcoma

Background

The objective of this study is to systematically review the role of positron emission tomography (PET) and PET/computed tomography (PET/CT) with Fluorine-18-Fluorodeoxyglucose (FDG) in patients with osteosarcoma (OS).

Methods

A comprehensive literature search of published studies through October 10^th, 2012 in PubMed/MEDLINE, Embase and Scopus databases regarding whole-body FDG-PET and FDG-PET/CT in patients with OS was performed.

Results

We identified 13 studies including 289 patients with OS. With regard to the staging and restaging of OS, the diagnostic performance of FDG-PET and PET/CT seem to be high; FDG-PET and PET/CT seem to be superior to bone scintigraphy and conventional imaging methods in detecting bone metastases; conversely, spiral CT seems to be superior to FDG-PET in detecting pulmonary metastases from OS

Conclusions

Metabolic imaging may provide additional information in the evaluation of OS patients. The combination of FDG-PET or FDG-PET/CT with conventional imaging methods seems to be a valuable tool in the staging and restaging of OS and may have a relevant impact on the treatment planning.     

Non-natural amino acids for tumor imaging using positron emission tomography and single photon emission computed tomography

Amino acids are required nutrients for proliferating tumor cells, and amino acid transport is upregulated in many tumor types. Studies of radiolabeled amino acids in animals and humans demonstrate that amino acid based tracers have advantageous characteristics relative to 2-[¹⁸F]fluoro-2-deoxyglucose in certain tumors, particularly brain gliomas. Non-natural amino acids for tumor imaging generally have greater metabolic stability and can be labeled with longer-lived radionuclides for positron emission tomography and single photon emission computed tomography such as fluorine-18 and iodine-123. Amino acids enter cells via amino acid transport with varying selectivity based on their chemical structure. This review focuses on the rationale, biological basis, current status and future prospects of radiolabeled non-natural amino acids for tumor imaging and discusses various classes of these compounds including aromatic, alicyclic and α,α-dialkyl amino acids.     

Patterns of failure and toxicity after intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To determine the outcome of patients treated with intensity-modulated radiotherapy (IMRT) for head and neck cancer. METHODS AND MATERIALS: We reviewed the charts of 100 consecutive patients treated with IMRT for squamous cell carcinoma of the oropharynx (64%), nasopharynx (16%), hypopharynx (14%), and larynx (6%). Most patients were treated with a concomitant boost schedule to 72 Gy. Of the 100 patients, 54 (54%) received adjuvant chemotherapy, mostly concurrent cisplatin. The dosimetry plans for patients with either locoregional failure or Grade 4-5 complications were reviewed and fused over the computed tomography images corresponding with the location of the event. Marginal failures were defined as those that occurred at a region of high-dose falloff, where conventional fields would have provided better coverage. RESULTS: The median follow-up of living patients was 3.1 years (range, 1-5.2 years). The 3-year rate of local control, locoregional control, freedom from relapse, cause-specific survival, and overall survival for all patients was 89%, 87%, 72%, 78%, and 71%, respectively. The 3-year rate of freedom from relapse, cause-specific survival, and overall survival for the 64 oropharynx patients was 86%, 92%, and 84%, respectively. Of the 10 local failures, 2 occurred at the margin of the high-dose planning target volume. Both regional failures occurred within the planning target volume. No locoregional failures occurred outside the planning target volume. Of the 100 patients, 8 and 5 had Grade 4 and 5 complications from treatment, respectively. All patients with Grade 5 complications had received adjuvant chemotherapy. No attempt was made to discriminate between the complications from IMRT and other aspects of the patients' treatment. CONCLUSION: Intensity-modulated radiotherapy did not compromise the outcome compared with what we have achieved with conventional techniques. The 2 cases of recurrence in the high-dose gradient region highlight the potential hazard of approaches that involve highly conformal dose distributions.     

Clinical application of intensity-modulated radiotherapy for head and neck cancer

Intensity-modulated radiotherapy (IMRT) is a modern treatment technique that allows one to shape the dose to the target volume and to reduce the dose delivered to healthy tissue. Over the last decade, IMRT has been implemented for head and neck cancer treatment, with the aim of reducing the dose delivered to the parotid glands and improving the dose coverage of complex target volumes located close to critical structures. The potential benefits of IMRT in terms of salivary function preservation and better local control have contributed to the rapid diffusion of this new technology. However, it should not be overlooked that IMRT is a novel treatment technique and that its clinical application represents a paradigm shift in the practice of radiation oncology. The purpose of this article is to review the clinical experience with IMRT for head and neck cancer treatment and to discuss some important issues related to its implementation.     

Comparison of five segmentation tools for 18F-fluoro-deoxy-glucose-positron emission tomography-based target volume definition in head and neck cancer

PURPOSE: Target-volume delineation for radiation treatment to the head and neck area traditionally is based on physical examination, computed tomography (CT), and magnetic resonance imaging. Additional molecular imaging with (18)F-fluoro-deoxy-glucose (FDG)-positron emission tomography (PET) may improve definition of the gross tumor volume (GTV). In this study, five methods for tumor delineation on FDG-PET are compared with CT-based delineation. METHODS AND MATERIALS: Seventy-eight patients with Stages II-IV squamous cell carcinoma of the head and neck area underwent coregistered CT and FDG-PET. The primary tumor was delineated on CT, and five PET-based GTVs were obtained: visual interpretation, applying an isocontour of a standardized uptake value of 2.5, using a fixed threshold of 40% and 50% of the maximum signal intensity, and applying an adaptive threshold based on the signal-to-background ratio. Absolute GTV volumes were compared, and overlap analyses were performed. RESULTS: The GTV method of applying an isocontour of a standardized uptake value of 2.5 failed to provide successful delineation in 45% of cases. For the other PET delineation methods, volume and shape of the GTV were influenced heavily by the choice of segmentation tool. On average, all threshold-based PET-GTVs were smaller than on CT. Nevertheless, PET frequently detected significant tumor extension outside the GTV delineated on CT (15-34% of PET volume). CONCLUSIONS: The choice of segmentation tool for target-volume definition of head and neck cancer based on FDG-PET images is not trivial because it influences both volume and shape of the resulting GTV. With adequate delineation, PET may add significantly to CT- and physical examination-based GTV definition.     

The diagnostic and prognostic utility of positron emission tomography/computed tomography‐based follow‐up after radiotherapy for head and neck cancer

BACKGROUND:

The detection of subclinical head and neck cancer recurrence or a second primary tumor may improve survival. In the current study, the authors investigated the clinical value of a follow‐up program incorporating serial ¹⁸F?fluorodeoxyglucose?positron emission tomography integrated with computed tomography (PET/CT) in the detection of recurrent disease in patients with head and neck cancer.

METHODS:

A total of 240 PET/CT scans were reviewed in 80 patients with head and neck cancer who were treated with radiotherapy (RT) from July, 2005 through August, 2007. All patients were followed with clinical examination, PET/CT, and correlative imaging for a minimum of 11 months (median follow?up, 21 months).

RESULTS:

The sensitivity, specificity, and positive and negative predictive values of PET/CT‐based follow‐up for detecting locoregional recurrence were 92%, 82%, 42%, and 98%, respectively. Corresponding values for distant metastases or second primary tumors were 93%, 96%, 81%, and 98%, respectively. Eight patients (10%) developed disease recurrences or second primary tumors that were amenable to salvage surgery with negative surgical margins. The 2‐year progression‐free survival and 2‐year overall survival rates were significantly different between patients who had a negative and those with a positive PET/CT result within 6 months of the completion of RT (93% vs 30% [P<.001] and 100% vs 32% [P<.001], respectively).

CONCLUSIONS:

Although post‐therapy follow‐up using PET/CT is reportedly associated with a high false‐positive rate in the irradiated head and neck, PET/CT appears to be a highly sensitive technique for the detection of recurrent disease. Furthermore, negative PET/CT results within 6 months of the completion of RT offer significant prognostic value. Cancer 2009. © 2009 American Cancer Society.     

Utility of 18F-fluorodeoxyglucose positron emission tomography in the preoperative staging of squamous cell carcinoma of the oropharynx.

BACKGROUND: 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) has been reported to be superior to computed tomography (CT)/magnetic resonance imaging (MRI) in the evaluation of head and neck cancers, but little is known about its usefulness in oropharyngeal squamous cell carcinoma (SCC). We therefore compared FDG PET and CT/MRI in the preoperative staging of previously untreated oropharyngeal SCC. METHODS: Thirty-two consecutive patients with oropharyngeal SCC underwent FDG PET and CT/MRI before surgery. Each method was interpreted separately to assess primary tumor and cervical node status. Their sensitivity and specificity were compared relative to histopathologic analysis. RESULTS: Histopathology revealed metastases in 29 of 39 dissected neck sides and in 47 of 163 dissected cervical levels. FDG PET had higher sensitivities than CT/MRI for primary tumor detection (25/32 vs. 30/32, P=0.063) and for identification of cervical metastases on neck side (22/29 vs. 28/29, P<0.05) and level-by-level (37/47 vs. 45/47, P<0.05) bases. In contrast, the specificity of the two methods did not differ significantly (P>0.5). FDG PET correctly interpreted the false-negative results of CT/MRI in 6 of 7 primary tumors and 8 of 10 cervical levels. CONCLUSIONS: The improved preoperative staging of FDG PET may help in planning treatment, but its accuracy is insufficient to replace pathologic staging based on neck dissection.     

FDG-PET for hepatobiliary and pancreatic cancer: Advances and current limitations

In Japan, the use of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) for some malignant tumors came to be covered by the National Health Insurance in 2002. In 2010, the health insurance coverage was expanded to all types of malignant tumors. However, since PET examination requires a large amount of capital investment, facilities at which PET is available are still limited. On the other hand, PET equipment has rapidly been introduced in large hospitals and in the diagnostic imaging centers of major cities during the past few years. Although numerous middle-sized and small hospitals cannot afford to perform PET, physicians can refer their patients to facilities where PET is available. Therefore, it is essential for general physicians to gain accurate knowledge on PET, including the appropriate indications for PET, in order to select patients for referral to PET facilities. PET is not always a useful tool, especially for lesions of the pancreas and hepatobiliary system, which is the main topic of this review. The indications of PET for lesions in these organs vary depending on the purpose of the examination. In this article, we review the indications for PET (or PET/computed tomography [CT]) using FDG of the liver, biliary tract, and pancreas.     

Impact of positron emission tomography/computed tomography surveillance at 12 and 24 months for detecting head and neck cancer recurrence

BACKGROUND:

In head and neck cancer (HNC), 3‐month post‐treatment positron emission tomography (PET)/computed tomography (CT) reliably identifies persistent/recurrent disease. However, further PET/CT surveillance has unclear benefit. The impact of post‐treatment PET/CT surveillance on outcomes is assessed at 12 and 24 months.

METHODS:

A 10‐year retrospective analysis of HNC patients was carried out with long‐term serial imaging. Imaging at 3 months included either PET/CT or magnetic resonance imaging, with all subsequent imaging comprised of PET/CT. PET/CT scans at 12 and 24 months were evaluated only if preceding interval scans were negative. Of 1114 identified patients, 284 had 3‐month scans, 175 had 3‐ and 12‐month scans, and 77 had 3‐, 12‐, and 24‐month scans.

RESULTS:

PET/CT detection rates in clinically occult patients were 9% (15 of 175) at 12 months, and 4% (3 of 77) at 24 months. No difference in outcomes was identified between PET/CT‐detected and clinically detected recurrences, with similar 3‐year disease‐free survival (41% vs 46%, P = .91) and 3‐year overall survival (60% vs 54%, P = .70) rates. Compared with 3‐month PET/CT, 12‐month PET/CT demonstrated fewer equivocal reads (26% vs 10%, P < .001). Of scans deemed equivocal, 6% (5 of 89) were ultimately found to be positive.

CONCLUSIONS:

HNC patients with negative 3‐month imaging appear to derive limited benefit from subsequent PET/CT surveillance. No survival differences were observed between PET/CT‐detected and clinically detected recurrences, although larger prospective studies are needed for further investigation. Cancer 2013. © 2012 American Cancer Society.     

Recurrence in region of spared parotid gland after definitive intensity-modulated radiotherapy for head and neck cancer

PURPOSE: To discuss the implications of three examples of periparotid recurrence after definitive intensity-modulated radiotherapy (IMRT) for head and neck cancer (HNC). METHODS AND MATERIALS: We present 3 patients with HNC who underwent definitive IMRT with concurrent chemotherapy and later had treatment failure in or near a spared parotid gland. Two patients had bilateral multilevel nodal disease, and all had Level II nodal disease ipsilateral to the site of recurrence. The patients were treated using dose-painting IMRT with a dose of 70 Gy to the gross tumor volume and 59.4 Gy or 54 Gy to the high-risk or low-risk clinical tumor volume, respectively. The parotid glands were spared bilaterally. The patients had not undergone any surgical treatment for HNC before radiotherapy. RESULTS: All patients had treatment failure in the region of a spared parotid gland. Failure in the 2 patients with bilateral multilevel nodal involvement occurred in the periparotid lymph nodes. The third patient developed a dermal metastasis near the tail of a spared parotid gland. On pretreatment imaging, the 2 patients with nodal failure had small nonspecific periparotid nodules that showed no hypermetabolic activity on positron emission tomography. CONCLUSION: For HNC patients receiving definitive IMRT, nonspecific positron emission tomography-negative periparotid nodules on pretreatment imaging should raise the index of suspicion for subclinical disease in the presence of multilevel or Level II nodal metastases. Additional evaluation of such nodules might be indicated before sparing the ipsilateral parotid gland.