Fluorine-18-labeled fluoromisonidazole positron emission and computed tomography-guided intensity-modulated radiotherapy for head and neck cancer: a feasibility study

PURPOSE: Hypoxia renders tumor cells radioresistant, limiting locoregional control from radiotherapy (RT). Intensity-modulated RT (IMRT) allows for targeting of the gross tumor volume (GTV) and can potentially deliver a greater dose to hypoxic subvolumes (GTV(h)) while sparing normal tissues. A Monte Carlo model has shown that boosting the GTV(h) increases the tumor control probability. This study examined the feasibility of fluorine-18-labeled fluoromisonidazole positron emission tomography/computed tomography ((18)F-FMISO PET/CT)-guided IMRT with the goal of maximally escalating the dose to radioresistant hypoxic zones in a cohort of head and neck cancer (HNC) patients. METHODS AND MATERIALS: (18)F-FMISO was administered intravenously for PET imaging. The CT simulation, fluorodeoxyglucose PET/CT, and (18)F-FMISO PET/CT scans were co-registered using the same immobilization methods. The tumor boundaries were defined by clinical examination and available imaging studies, including fluorodeoxyglucose PET/CT. Regions of elevated (18)F-FMISO uptake within the fluorodeoxyglucose PET/CT GTV were targeted for an IMRT boost. Additional targets and/or normal structures were contoured or transferred to treatment planning to generate (18)F-FMISO PET/CT-guided IMRT plans. RESULTS: The heterogeneous distribution of (18)F-FMISO within the GTV demonstrated variable levels of hypoxia within the tumor. Plans directed at performing (18)F-FMISO PET/CT-guided IMRT for 10 HNC patients achieved 84 Gy to the GTV(h) and 70 Gy to the GTV, without exceeding the normal tissue tolerance. We also attempted to deliver 105 Gy to the GTV(h) for 2 patients and were successful in 1, with normal tissue sparing. CONCLUSION: It was feasible to dose escalate the GTV(h) to 84 Gy in all 10 patients and in 1 patient to 105 Gy without exceeding the normal tissue tolerance. This information has provided important data for subsequent hypoxia-guided IMRT trials with the goal of further improving locoregional control in HNC patients.     

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.     

Clinical evidence on PET-CT for radiation therapy planning in head and neck tumours

The potential benefits of positron emission tomography (PET) imaging for the management of head and neck tumours are increasingly being recognized. Integrated PET-CT has found its way into the practice of radiation oncology providing both functional and anatomical tumour information for treatment planning and the implications for clinical practice are currently being investigated. First, it has been demonstrated that ¹⁸F-fluorodeoxyglucose (¹⁸FDG)-PET can improve the accuracy of gross tumour volume delineation for radiation therapy planning. Next, PET using ¹⁸FDG or more specific tracers may facilitate dose escalation to radioresistant tumour subvolumes. Finally, PET can provide tumour characterization prior to and during radiotherapy, facilitating adaptive radiotherapy and other tailored treatment strategies. Although these are promising prospects, unresolved issues remain and these applications are not yet ready for introduction into routine clinical practice.     

Impact of combined (18)F-FDG PET/CT in head and neck tumours

To compare the interobserver agreement and degree of confidence in anatomical localisation of lesions using 2-[fluorine-18]fluoro-2-deoxy-D-glucose ((18)F-FDG) positron emission tomography (PET)/computed tomography (CT) and (18)F-FDG PET alone in patients with head and neck tumours. A prospective study of 24 patients (16 male, eight female, median age 59 years) with head and neck tumours was undertaken. (18)F-FDG PET/CT was performed for staging purposes. 2D images were acquired over the head and neck area using a GE Discovery LS PET/CT scanner. (18)F-FDG PET images were interpreted by three independent observers. The observers were asked to localise abnormal (18)F-FDG activity to an anatomical territory and score the degree of confidence in localisation on a scale from 1 to 3 (1=exact region unknown; 2=probable; 3=definite). For all (18)F-FDG-avid lesions, standardised uptake values (SUVs) were also calculated. After 3 weeks, the same exercise was carried out using (18)F-FDG PET/CT images, where CT and fused volume data were made available to observers. The degree of interobserver agreement was measured in both instances. A total of six primary lesions with abnormal (18)F-FDG uptake (SUV range 7.2-22) were identified on (18)F-FDG PET alone and on (18)F-FDG PET/CT. In all, 15 nonprimary tumour sites were identified with (18)F-FDG PET only (SUV range 4.5-11.7), while 17 were identified on (18)F-FDG PET/CT. Using (18)F-FDG PET only, correct localisation was documented in three of six primary lesions, while (18)F-FDG PET/CT correctly identified all primary sites. In nonprimary tumour sites, (18)F-FDG PET/CT improved the degree of confidence in anatomical localisation by 51%. Interobserver agreement in assigning primary and nonprimary lesions to anatomical territories was moderate using (18)F-FDG PET alone (kappa coefficients of 0.45 and 0.54, respectively), but almost perfect with (18)F-FDG PET/CT (kappa coefficients of 0.90 and 0.93, respectively). We conclude that (18)F-FDG PET/CT significantly increases interobserver agreement and confidence in disease localisation of (18)F-FDG-avid lesions in patients with head and neck cancers.     

Maximum tolerated dose in a phase I trial on adaptive dose painting by numbers for head and neck cancer

Purpose

To determine the maximum tolerated dose (MTD) in a phase I trial on adaptive dose-painting-by-numbers (DPBN) for non-metastatic head and neck cancer.

Materials and methods

Adaptive intensity-modulated radiotherapy was based on voxel intensity of pre-treatment and per-treatment [¹⁸F]fluoro-2-deoxy-d-glucose positron emission tomography (¹⁸F-FDG-PET) scans. Dose was escalated to a median total dose of 80.9 Gy in the high-dose clinical target volume (dose level I) and 85.9 Gy in the gross tumor volume (dose level II). The MTD would be reached, if ?33% of patients developed any grade ?4 toxicity (DLT) up to 3 months follow-up.

Results

Between February 2007 and August 2009, seven patients at dose level I and 14 at dose level II were treated. All patients completed treatment without interruption. At a median follow-up for surviving patients of 38 (dose level I) and 22 months (dose level II) there was no grade ?4 toxicity during treatment and follow-up but six cases of mucosal ulcers at latency of 4-10 months, of which five (36%) were observed at dose level II. Mucosal ulcers healed spontaneously in four patients.

Conclusions

Considering late mucosal ulcers as DLT, the MTD of a median dose of 80.9 Gy has been reached in our trial.     

F-FDG-PET imaging in radiotherapy tumor volume delineation in treatment of head and neck cancer

Purpose

To determine the impact of ¹⁸F-fluorodeoxyglucose positron emission tomography (PET) in radiotherapy target delineation and patient management for head and neck squamous cell carcinoma (HNSCC) compared to computed tomography (CT) alone.

Materials and methods

Twenty-nine patients with HNSCC were included. CT and PET/CT obtained for treatment planning purposes were reviewed respectively by a neuroradiologist and a nuclear medicine specialist who were blinded to the findings from each other. The attending radiation oncologist together with the neuroradiologist initially defined all gross tumor volume of the primary (GTVp) and the suspicious lymph nodes (GTVn) on CT. Subsequently, the same radiation oncologist and the nuclear medicine specialist defined the GTVp and GTVn on ¹⁸F-FDG-PET/CT. Upon disagreement between CT and ¹⁸F-FDG-PET on the status of a particular lymph node, an ultrasound-guided fine needle aspiration was performed. Volumes based on CT and ¹⁸F-FDG-PET were compared with a paired Student’s t-test.

Results

For the primary disease, four patients had previous diagnostic tonsillectomy and therefore, FDG uptake occurred in 25 patients. For these patients, GTVp contoured on ¹⁸F-FDG-PET (GTVp-PET) were smaller than the GTVp contoured on CT (GTVp-CT) in 80% of the cases, leading to a statistically significant volume difference (p = 0.001). Of the 60 lymph nodes suspicious on PET, 55 were also detected on CT. No volume change was observed (p = 0.08). Ten biopsies were performed for lymph nodes that were discordant between modalities and all were of benign histology. Distant metastases were found in two patients and one had a newly diagnosed lung adenocarcinoma.

Conclusions

GTVp-CT was significantly larger when compared to GTVp-PET. No such change was observed for the lymph nodes. ¹⁸F-FDG-PET modified treatment management in three patients, including two for which no curative radiotherapy was attempted. Larger multicenter studies are needed to ascertain whether combined ¹⁸F-FDG-PET/CT in target delineation can influence the main clinical outcomes.     

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.     

Radiosensitivity and effect of hypoxia in HPV positive head and neck cancer cells

Background and purpose

HPV associated Head and Neck Squamous Cell Carcinoma (HNSCC) represents a distinct subgroup of HNSCC characterized by a favorable prognosis and a distinct molecular biology. Previous data from the randomized DAHANCA 5 trial indicated that HPV positive tumors did not benefit from hypoxic modifications by Nimorazole during radiotherapy, whereas a significant benefit was observed in the HPV negative tumors. However, more studies have demonstrated equal frequencies of hypoxic tumors among HPV-positive and HPV-negative tumors. The aim of the present study was to determine radiosensitivity, the impact of hypoxia and the effect of Nimorazole in HPV positive and HPV negative cell lines.

Materials and method

The used cell lines were: UDSCC2, UMSCC47 and UPCISCC90 (HPV positive) and FaDu_DD, UTSCC33 and UTSCC5 (HPV negative). Cells were cultured under normoxic or hypoxic conditions, and gene expression levels of previously established hypoxia induced genes were assessed by qPCR. Cells were irradiated with various doses under normoxia, hypoxia or hypoxia +1 mM Nimorazole, and the clonogenic survival was determined.

Results

The HPV positive and HPV negative cell lines exhibited similar patterns of upregulation of hypoxia induced genes in response to hypoxia. The HPV positive cell lines were up to 2.4 times more radiation sensitive than HPV negative cell lines. However, all HPV positive cells displayed the same response to hypoxia in radiosensitivity, with an OER in the range 2.3–2.9, and a sensitizer effect of Nimorazole of 1.13–1.29, similar to HPV negative cells.

Conclusions

Although HPV positive cells had a markedly higher radiosensitivity compared to HPV negative cells, they displayed the same relative radioresistance under hypoxia and the same relative sensitizer effect of Nimorazole. The clinical observation that HPV positive patients do not seem to benefit from Nimorazole treatment is not due to inherent differences in hypoxia sensitivity or response to Nimorazole, but can be accounted for by the overall higher radiosensitivity of HPV positive cells.     

Chemotherapy advances in locally advanced head and neck cancer

The management of locally advanced unresectable head and neck squamous cell cancer (HNSCC) continues to improve. One of the major advances in the treatment of HNSCC was the addition of chemotherapy to radiation in the treatment of non-surgical patients. The majority of the data regarding chemotherapy in HNSCC involve cisplatin chemotherapy with concurrent radiation. However, several new approaches have included targeted therapy against epidermal growth factor receptor and several recent studies have explored the role of induction chemotherapy in the treatment of HNSCC. The purpose of this article is to provide an overview of the role of chemotherapy in the treatment of locally advanced HNSCC.     

光动力治疗消化道和头颈部肿瘤的临床观察

目的　探讨光动力疗法治疗消化道和头颈部肿瘤的疗效和安全性。方法　选取消化道肿瘤９例、头颈部复发转移癌７例行光动力治疗,其中早期４例,晚期１２例。具体治疗：静脉输注血卟啉３～５ｍｇ／ｋｇ,４８～７２ｈ在肿瘤表面或瘤体内行激光照射（输出波长６３０ｎｍ,输出功率６００～８００ｍＷ,能量密度为２００～３００Ｊ／ｃｍ２）。根据治疗后肉眼及内镜观察、Ｂ超和ＣＴ检查肿瘤缩小及症状缓解情况评价疗效。结果　所有患者治疗后随访１０～３９个月。４例早期患者均获ＣＲ,随访期间无复发;１２例晚期患者,获ＳＲ７例,ＭＲ４例,ＮＲ１例。全组患者的总有效率为９３.７％。主要毒副反应为暴露部位皮肤肤色加深,无严重并发症。结论　光动力疗法对于早期病灶局限的恶性肿瘤可达到局部根治的作用,对于晚期病例也能缓解症状并改善生存质量。     

In vivo evaluation of percutaneous carbon dioxide treatment for improving intratumoral hypoxia using 18F-fluoromisonidazole PET-CT

Carbon dioxide (CO₂) treatment is reported to have an antitumor effect owing to the improvement in intratumoral hypoxia. Previous studies were based on histological analysis alone. In the present study, the improvement in intratumoral hypoxia by percutaneous CO₂ treatment in vivo was determined using ¹⁸F-fluoromisonidazole positron emission tomography-computed tomography (¹⁸F-FMISO PET-CT) images. Twelve Japanese nude mice underwent implantation of LM8 tumor cells in the dorsal subcutaneous area 2 weeks before percutaneous CO₂ treatment and ¹⁸F-FMISO PET-CT scans. Immediately after intravenous injection of ¹⁸F-FMISO, CO₂ and room air were administered transcutaneously in the CO₂-treated group (n=6) and a control group (n=6), respectively; each treatment was performed for 10 minutes. PET-CT was performed 2 h after administration of ¹⁸F-FMISO. ¹⁸F-FMISO tumor uptake was quantitatively evaluated using the maximum standardized uptake value (SUV_max), tumor-to-liver ratio (TLR), tumor-to-muscle ratio (TMR), metabolic tumor volume (MTV) and total lesion glycolysis (TLG). Mean ± standard error of the mean (SEM) of the tumor volume was not significantly different between the two groups (CO₂-treated group, 1.178±0.450 cm³; control group, 1.368±0.295 cm3; P=0.485). Mean ± SEM of SUV_max, TLR, MTV (cm3) and TLG were significantly lower in the CO₂-treated group compared with the control group (0.880±0.095 vs. 1.253±0.071, P=0.015; 1.063±0.147361 vs. 1.455±0.078, P=0.041; 0.353±0.139 vs. 1.569±0.438, P=0.015; 0.182±0.070 vs. 1.028±0.338, P=0.015), respectively. TMR was not significantly different between the two groups (4.520±0.503 vs. 5.504±0.310; P=0.240). In conclusion, ¹⁸F-FMISO PET revealed that percutaneous CO₂ treatment improved intratumoral hypoxia in vivo. This technique enables assessment of the therapeutic effect in CO₂ treatment by imaging, and may contribute to its clinical application.     

Twice-daily fractionation schemes for advanced head and neck cancer

Eighty-five patients with advanced squamous cell carcinoma of the head and neck were treated with twice-a-day fractionation schedules between April 1972 and December 1980. Two types of treatment were distinguished: hyperfractionation, by which 65 patients (Group 1) were treated at a weekly dose rate of 1100 to 1200 rad (10 fractions of 110 to 120 rad) in 5 to $\text{6}\text{1}\text{2}$ weeks for either advanced primary disease (Group IA) and/or advanced neck metastases (Group 1B); and accelerated treatment, used to treat 20 patients (Group 2) who had fast-growing and usually massive neck nodes, at a weekly dose rate of 1300 to 1500 rad in 7 to 10 fractions, to a total dose of 6100 to 8000 rad in 4 to 6 weeks. The radiation portals for patients in Group 2 excluded the mucosa of mouth and throat for part of the treatment. The local control rate at 1 year in Groups 1A and 1B was 41 and 54%, respectively; the incidence of complications was 17%, 5% of them fatal. The local control rate in Group 2 was 80%. Seven patients in this group underwent a neck dissection 6 to 8 weeks following irradiation. Four specimens were negative for tumor. In two, only necrotic tumor cells were identified, and in one specimen morphologically intact tumor cells were seen. There were no fatal complications.     

A dose escalation study of hyperfractionated accelerated radiation delivered with integrated neck surgery (HARDWINS) for the management of advanced head and neck cancer

BACKGROUND AND PURPOSE: To determine toxicity and outcome of radiation dose escalation with hyperfractionated accelerated radiation delivered with neck surgery (HARDWINS) for head and neck cancer. PATIENTS AND METHODS: Patients with stage III and IV squamous cell carcinoma of the oropharynx, hypopharynx or larynx were enrolled. Dose levels of 60, 62 and 64Gy were delivered with twice daily fractionation in 40 fractions over 4 weeks. Involved and at-risk nodal regions received microscopic dose (46.5-48Gy) with neck dissection for node positive patients 8 weeks after radiation. RESULTS: One hundred and sixty-nine patients were enrolled (60Gy n=22, 62Gy n=26, 64Gy n=121). No grade 4 acute toxicity was observed. Incidence of acute grade 3 toxicity was: skin (2%), larynx (6%), pharynx and esophagus (66%) and mucous membrane (75%). Feeding tube dependence was observed in 14% of patients receiving 64Gy. Overall survival, and relapse free rate at 5 years were 65% and 63%, respectively. Local, nodal and distant relapse free rates at 5 years were 77%, 94% and 81% (median follow-up 3.8 years). CONCLUSIONS: HARDWINS can be delivered without acute grade 4 toxicity but significant grade 3 acute toxicity. A significant proportion of the patients have prolonged swallowing dysfunction. Outcomes suggest this regimen represents an alternative to chemoradiation.     

The role of FDG PET in the clinical management of head and neck cancer

Positron emission tomography (PET) with fluorodeoxyglucose (FDG) allows the visualization of metabolic tissue activity. Use of FDG in in-vivo cancer imaging is based on enhanced glycolysis in tumor cells. In vivo experiments have demonstrated the potential use of FDG PET in squamous-cell head and neck tumors and the detection of tumor involvement in lymph nodes. Since its introduction in this area, several papers have appeared on the use of this imaging modality. Indications for the use of FDG PET in patients with head and neck cancer are discussed.     

Two- vs three-drug combination chemotherapy in advanced or recurrent head and neck cancer

Head and neck squamous cancer is a major concern in India. The proportion of advanced cases is significantly high, and these patients have dismal survival prospects despite aggressive therapy. Often surgical resection and/or radiotherapy are not feasible in these patients. Hence, we decided to explore the option of neoadjuvant chemotherapy using effective agents like ifosfamide and paclitaxel in combination with cisplatin in these patients. A total of 361 patients were evaluable at the end of study. Of these, 207 had received ifosfamide and cisplatin and 154 had received taxanes (paclitaxel or docetaxel) in addition to ifosfamide and cisplatin. The ifosfamide-cisplatin group had an overall response rate of 66.67% (CR, 16.42%; PR, 50.24%) and the median duration of response was 5.5 mo; whereas the group in which taxanes were added, showed an overall response rate of 73.37% (CR, 7.79%; PR, 65.58%) with a median duration of response of 10 mo. The toxicity in both the groups was acceptable and there was no mortality. We conclude that taxane-based combinations have a significant activity in advanced head and neck squamous cancer and warrant further studies.