Rosalind Perrin

Exploratory prospective trial of hypoxia-specific PET imaging during radiochemotherapy in patients with locally advanced head-and-neck cancer

PURPOSE To explore in a prospective trial the prognostic value of hypoxia imaging before and during radiochemotherapy in patients with locally advanced head and neck cancer. PATIENTS AND METHODS Twenty-five patients with stage III/IV head and neck cancer were investigated with [(18)F]-fluoromisonidazole (FMISO) PET/CT at four time points during radiochemotherapy (baseline, 8-10 Gy, 18-20 Gy,50-60 Gy). FMISO PET/CT image parameters were extracted including maximum-tumour-to-background (TBR(max)) and thresholded volume at different TBR ratios. CT volume and baseline FDG-PET/CT image parameters were also included. Parameters at all time points were investigated for their prognostic value with the local-progression-free-survival endpoint (LPFS). Significance was evaluated with multivariate Cox (including clinical parameters) and Log-rank tests. RESULTS FMISO-image parameters were found to have a strong association with the LPFS endpoint, and were strongest at the week 1 and 2 time points (p = 0.023-0.048 and 0.042-0.061 respectively on multivariate Cox). Parameters measured at baseline were only significant on univariate analysis. None of the clinical parameters, and also FDG- or CT-delineated volumes, were significantly associated with LPFS. CONCLUSION This prospective, exploratory study demonstrated that FMISO-PET/CT imaging during the initial phase of treatment carries strong prognostic value. FMISO-PET/CT imaging at 1 or 2 weeks during treatment could be promising way to select patients that would benefit from hypoxia modification or dose-escalated treatment. A validation study is on-going.

Hypoxia as a biomarker for radioresistant cancer stem cells

Abstract Background: Tumor initiation, growth and relapse after therapy are thought to be driven by a population of cells with stem cell characteristics, named cancer stem cells (CSC). The regulation of their radiation resistance and their maintenance is poorly understood. CSC are believed to reside preferentially in special microenvironmental niches located within tumor tissues. The features of these niches are of crucial importance for CSC self-renewal, metastatic potential and therapy resistance. One of the characteristics of solid tumors is occurrence of less oxygenated (hypoxic regions), which are believed to serve as so-called hypoxic niches for CSC. Purpose: The purpose of this review was the critical discussion of the supportive role of hypoxia and hypoxia-related pathways during cancer progression and radiotherapy resistance and the relevance for therapeutic implications in the clinic. Conclusion: It is generally known since decades that hypoxia inside solid tumors impedes chemo- and radiotherapy. However, there is limited evidence to date that targeting hypoxic regions during conventional therapy is effective. Nonetheless improved hypoxia-imaging technologies and image guided individualized hypoxia targeted therapy in conjunction with the development of novel molecular targets may be able to challenge the protective effect on the tumor provided by hypoxia.

Identification of Patient Benefit From Proton Therapy for Advanced Head and Neck Cancer Patients Based on Individual and Subgroup Normal Tissue Complication Probability Analysis

PURPOSE The purpose of this study was to determine, by treatment plan comparison along with normal tissue complication probability (NTCP) modeling, whether a subpopulation of patients with head and neck squamous cell carcinoma (HNSCC) could be identified that would gain substantial benefit from proton therapy in terms of NTCP. METHODS AND MATERIALS For 45 HNSCC patients, intensity modulated radiation therapy (IMRT) was compared to intensity modulated proton therapy (IMPT). Physical dose distributions were evaluated as well as the resulting NTCP values, using modern models for acute mucositis, xerostomia, aspiration, dysphagia, laryngeal edema, and trismus. Patient subgroups were defined based on primary tumor location. RESULTS Generally, IMPT reduced the NTCP values while keeping similar target coverage for all patients. Subgroup analyses revealed a higher individual reduction of swallowing-related side effects by IMPT for patients with tumors in the upper head and neck area, whereas the risk reduction of acute mucositis was more pronounced in patients with tumors in the larynx region. More patients with tumors in the upper head and neck area had a reduction in NTCP of more than 10%. CONCLUSIONS Subgrouping can help to identify patients who may benefit more than others from the use of IMPT and, thus, can be a useful tool for a preselection of patients in the clinic where there are limited PT resources. Because the individual benefit differs within a subgroup, the relative merits should additionally be evaluated by individual treatment plan comparisons.

Spatial distribution of FMISO in head and neck squamous cell carcinomas during radio-chemotherapy and its correlation to pattern of failure

ABSTRACT Background. Tumour hypoxia can be measured by FMISO-PET and negatively impacts local tumour control in patients with head and neck squamous cell carcinoma (HNSCC) undergoing radiotherapy. The aim of this post hoc analysis of a prospective clinical trial was to investigate the spatial variability of FMISO hypoxic subvolumes during radio-chemotherapy and the co-localisation of these volumes with later recurrences as a basis for individualised dose prescription trials with dose escalation defined by FMISO-PET. Methods. Sequential FMISO scans of 12 (of 25) patients presenting residual hypoxia taken before (FMISOpre) and during (FMISOw1–FMISOw5) radio-chemotherapy were analysed regarding the stability of the FMISO subvolumes and, in case of local failure, their correlation to local relapse. Results. Consecutive FMISO-PET positive volumes could be classified as moderately stable with Dice conformity indices of 62% and 58% up to the second week of treatment. Substantial volumetric variation during treatment was observed, with more than 20% geographic miss in all patients and more than 40% in half of the patients. The localisation of the maximum standardised uptake value (SUVmax) differed with a mean distance of 7.0 mm and 13.5 mm between the pre-therapeutic and first or second FMISO-PET during treatment. A stable hypoxic consensual volume (i.e. overlap of pre-therapeutic FMISO and intra-treatment FMISO subvolumes up to week two, generated by different contouring methods) was determined for six patients with imaging information of local recurrence. Three of these six local recurrences were located within this consensual volume. Conclusions. Our data suggest that selective dose painting to hypoxic tumour subvolumes requires adaptation during treatment and sufficient margins. An alternative strategy is to escalate the dose to the gross tumour volume, accepting lesser escalation of dose outside hypoxic areas if indicated by constraints for organs at risk.

NTCP reduction for advanced head and neck cancer patients using proton therapy for complete or sequential boost treatment versus photon therapy.

ABSTRACT Background. To determine by treatment plan comparison differences in toxicity risk reduction for patients with head and neck squamous cell carcinoma (HNSCC) from proton therapy either used for complete treatment or sequential boost treatment only. Materials and methods. For 45 HNSCC patients, intensity-modulated photon (IMXT) and proton (IMPT) treatment plans were created including a dose escalation via simultaneous integrated boost with a one-step adaptation strategy after 25 fractions for sequential boost treatment. Dose accumulation was performed for pure IMXT treatment, pure IMPT treatment and for a mixed modality treatment with IMXT for the elective target followed by a sequential boost with IMPT. Treatment plan evaluation was based on modern normal tissue complication probability (NTCP) models for mucositis, xerostomia, aspiration, dysphagia, larynx edema and trismus. Individual NTCP differences between IMXT and IMPT (∆NTCPIMXT-IMPT) as well as between IMXT and the mixed modality treatment (∆NTCPIMXT-Mix) were calculated. Results. Target coverage was similar in all three scenarios. NTCP values could be reduced in all patients using IMPT treatment. However, ∆NTCPIMXT-Mix values were a factor 2–10 smaller than ∆NTCPIMXT-IMPT. Assuming a threshold of ≥ 10% NTCP reduction in xerostomia or dysphagia risk as criterion for patient assignment to IMPT, less than 15% of the patients would be selected for a proton boost, while about 50% would be assigned to pure IMPT treatment. For mucositis and trismus, ∆NTCP ≥ 10% occurred in six and four patients, respectively, with pure IMPT treatment, while no such difference was identified with the proton boost. Conclusions. The use of IMPT generally reduces the expected toxicity risk while maintaining good tumor coverage in the examined HNSCC patients. A mixed modality treatment using IMPT solely for a sequential boost reduces the risk by 10% only in rare cases. In contrast, pure IMPT treatment may be reasonable for about half of the examined patient cohort considering the toxicities xerostomia and dysphagia, if a feasible strategy for patient anatomy changes is implemented.

Required transition from research to clinical application: Report on the 4D treatment planning workshops 2014 and 2015

Since 2009, a 4D treatment planning workshop has taken place annually, gathering researchers working on the treatment of moving targets, mainly with scanned ion beams. Topics discussed during the workshops range from problems of time resolved imaging, the challenges of motion modelling, the implementation of 4D capabilities for treatment planning, up to different aspects related to 4D dosimetry and treatment verification. This report gives an overview on topics discussed at the 4D workshops in 2014 and 2015. It summarizes recent findings, developments and challenges in the field and discusses the relevant literature of the recent years. The report is structured in three parts pointing out developments in the context of understanding moving geometries, of treating moving targets and of 4D quality assurance (QA) and 4D dosimetry. The community represented at the 4D workshops agrees that research in the context of treating moving targets with scanned ion beams faces a crucial phase of clinical translation. In the coming years it will be important to define standards for motion monitoring, to establish 4D treatment planning guidelines and to develop 4D QA tools. These basic requirements for the clinical application of scanned ion beams to moving targets could e.g. be determined by a dedicated ESTRO task group. Besides reviewing recent research results and pointing out urgent needs when treating moving targets with scanned ion beams, the report also gives an outlook on the upcoming 4D workshop organized at the University Medical Center Groningen (UMCG) in the Netherlands at the end of 2016.

Residual tumour hypoxia in head-and-neck cancer patients undergoing primary radiochemotherapy, final results of a prospective trial on repeat FMISO-PET imaging

BACKGROUND Hypoxia is a well recognised parameter of tumour resistance to radiotherapy, a number of anticancer drugs and potentially immunotherapy. In a previously published exploration cohort of 25 head and neck squamous cell carcinoma (HNSCC) patients on [18F]fluoromisonidazole positron emission tomography (FMISO-PET) we identified residual tumour hypoxia during radiochemotherapy, not before start of treatment, as the driving mechanism of hypoxia-mediated therapy resistance. Several quantitative FMISO-PET parameters were identified as potential prognostic biomarkers. Here we present the results of the prospective validation cohort, and the overall results of the study. METHODS FMISO-PET/CT images of further 25 HNSCC patients were acquired at four time-points before and during radiochemotherapy (RCHT). Peak standardised uptake value, tumour-to-background ratio, and hypoxic volume were analysed. The impact of the potential prognostic parameters on loco-regional tumour control (LRC) was validated by the concordance index (ci) using univariable and multivariable Cox models based on the exploration cohort. Log-rank tests were employed to compare the endpoint between risk groups. RESULTS The two cohorts differed significantly in several baseline parameters, e.g., tumour volume, hypoxic volume, HPV status, and intercurrent death. Validation was successful for several FMISO-PET parameters and showed the highest performance (ci=0.77-0.81) after weeks 1 and 2 of treatment. Cut-off values for the FMISO-PET parameters could be validated after week 2 of RCHT. Median values for the residual hypoxic volume, defined as the ratio of the hypoxic volume in week 2 of RCHT and at baseline, stratified patients into groups of significantly different LRC when applied to the respective other cohort. CONCLUSION Our study validates that residual tumour hypoxia during radiochemotherapy is a major driver of therapy resistance of HNSCC, and that hypoxia after the second week of treatment measured by FMISO-PET may serve as biomarker for selection of patients at high risk of loco-regional recurrence after state-of-the art radiochemotherapy.

Respiratory motion-management in stereotactic body radiation therapy for lung cancer – A dosimetric comparison in an anthropomorphic lung phantom (LuCa)

BACKGROUND AND PURPOSE The objective of this study was to compare the latest respiratory motion-management strategies, namely the internal-target-volume (ITV) concept, the mid-ventilation (MidV) principle, respiratory gating and dynamic couch tracking. MATERIALS AND METHODS An anthropomorphic, deformable and dynamic lung phantom was used for the dosimetric validation of these techniques. Stereotactic treatments were adapted to match the techniques and five distinct respiration patterns, and delivered to the phantom while radiographic film measurements were taken inside the tumor. To report on tumor coverage, these dose distributions were used to calculate mean doses (Dmean), changes in homogeneity indices (ΔH2-98), gamma agreement, and areas covered by the planned minimum dose (A>Dmin). RESULTS All techniques achieved good tumor coverage (A>Dmin>99.0%) and minor changes in Dmean (±3.2%). Gating and tracking strategies showed superior results in gamma agreement and ΔH2-98 compared to ITV and MidV concepts, which seem to be more influenced by the interplay and the gradient effect. For lung, heart and spinal cord, significant dose differences between the four techniques were found (p<0.05), with lowest doses for gating and tracking strategies. CONCLUSION Active motion-management techniques, such as gating or tracking, showed superior tumor dose coverage and better organ dose sparing than the passive techniques based on tumor margins.

Increase in Tumor Control and Normal Tissue Complication Probabilities in Advanced Head-and-Neck Cancer for Dose-Escalated Intensity-Modulated Photon and Proton Therapy

Introduction Presently used radiochemotherapy regimens result in moderate local control rates for patients with advanced head-and-neck squamous cell carcinoma (HNSCC). Dose escalation (DE) may be an option to improve patient outcome, but may also increase the risk of toxicities in healthy tissue. The presented treatment planning study evaluated the feasibility of two DE levels for advanced HNSCC patients, planned with either intensity-modulated photon therapy (IMXT) or proton therapy (IMPT). Materials and methods For 45 HNSCC patients, IMXT and IMPT treatment plans were created including DE via a simultaneous integrated boost (SIB) in the high-risk volume, while maintaining standard fractionation with 2 Gy per fraction in the remaining target volume. Two DE levels for the SIB were compared: 2.3 and 2.6 Gy. Treatment plan evaluation included assessment of tumor control probabilities (TCP) and normal tissue complication probabilities (NTCP). Results An increase of approximately 10% in TCP was estimated between the DE levels. A pronounced high-dose rim surrounding the SIB volume was identified in IMXT treatment. Compared to IMPT, this extra dose slightly increased the TCP values and to a larger extent the NTCP values. For both modalities, the higher DE level led only to a small increase in NTCP values (mean differences <2%) in all models, except for the risk of aspiration, which increased on average by 8 and 6% with IMXT and IMPT, respectively, but showed a considerable patient dependence. Conclusion Both DE levels appear applicable to patients with IMXT and IMPT since all calculated NTCP values, except for one, increased only little for the higher DE level. The estimated TCP increase is of relevant magnitude. The higher DE schedule needs to be investigated carefully in the setting of a prospective clinical trial, especially regarding toxicities caused by high local doses that lack a sound dose–response description, e.g., ulcers.

Liquid fiducial marker applicability in proton therapy of locally advanced lung cancer

BACKGROUND AND PURPOSE We investigated the clinical applicability of a novel liquid fiducial marker (LFM) for image-guided pencil beam scanned (PBS) proton therapy (PBSPT) of locally advanced lung cancer (LALC). MATERIALS AND METHODS The relative proton stopping power (RSP) of the LFM was calculated and measured. Dose perturbations of the LFM and three solid markers, in a phantom, were measured. PBSPT treatment planning on computer tomography scans of five patients with LALC with the LFM implanted was performed with 1-3 fields. RESULTS The RSP was experimentally determined to be 1.164 for the LFM. Phantom measurements revealed a maximum relative deviation in dose of 4.8% for the LFM in the spread-out Bragg Peak, compared to 12-67% for the solid markers. Using the experimentally determined RSP, the maximum proton range error introduced by the LFM is about 1mm. If the marker was displaced at PBSPT, the maximum dosimetric error was limited to 2 percentage points for 3-field plans. CONCLUSION The dose perturbations introduced by the LFM were considerably smaller than the solid markers investigated. The RSP of the fiducial marker should be corrected in the treatment planning system to avoid errors. The investigated LFM introduced clinically acceptable dose perturbations for image-guided PBSPT of LALC.