PET-CT for response assessment and treatment adaptation in head and neck cancer

doi:10.1016/S1470-2045(09)70353-5

The Lancet Oncology

Volume 11, Issue 7, July 2010, Pages 661-669

https://doi.org/10.1016/S1470-2045(09)70353-5 Get rights and content

Summary

Preferred treatment strategies for advanced-stage squamous cell carcinoma of the head and neck have shifted from surgery to organ-preservation approaches such as radiotherapy, which can be combined with chemotherapy or giving of biologically modifying molecules. Preclinical and clinical researchers aim to customise these treatments on the basis of biological tumour characteristics, including tumour cell proliferation, hypoxia, and apoptosis—important resistance mechanisms for cytotoxic antitumour therapy. Monitoring of these biologically relevant variables before and early during treatment could improve patient selection for specific treatment strategies and guide adaptation of treatment at an early stage. PET provides a non-invasive molecular imaging method with the potential ability to undertake repetitive non-invasive quantification of relevant tumour characteristics. We discuss the role of PET scanning and available radiopharmaceutical tracers for treatment selection, early response monitoring, and treatment adaptation in head and neck cancer.

Introduction

In the past few decades, preferred treatment strategies for advanced-stage squamous cell carcinoma of the head and neck have gradually shifted from surgery to radiotherapy, which is often combined with chemotherapy and sometimes with biologically modifying molecules.¹ The response of a tumour to chemoradiotherapy or radiotherapy greatly depends on tumour biology and microenvironmental characteristics. Tumour cell hypoxia and accelerated tumour cell proliferation counteract these treatment methods. However, data from preclinical studies have shown that many treatments, including radiotherapy, have a notable effect on tumour characteristics.² For example, radiotherapy can stimulate tumour cell proliferation after several weeks of treatment—ie, accelerated proliferation—with the result that extension of the overall treatment time beyond 5–6 weeks leads to reduced tumour control.³

Monitoring of changes in biologically relevant resistance variables early in the course of treatment might enable patients to be selected on an individual basis. However, most assays that could be helpful in this selection procedure need invasive sampling and can be subject to sampling error, hampering their introduction to routine clinical practice.

Molecular imaging techniques can visualise and quantify several aspects of tumour microenvironment relevant to radiation resistance. PET is a molecular imaging method that has emerged as a non-invasive alternative to biopsy, allowing repeat assessment to be done and prospective visualisation of the primary tumour and potentially metastatic lymph nodes, before and during treatment (figure 1).

In this review, we discuss the role of molecular imaging by PET scanning for treatment selection, early response monitoring, and treatment adaptation in head and neck cancer treated with radiotherapy and chemotherapy or biologically modifying drugs. Monitoring of early response will allow treatment modification or adaptation, on the basis of the patient's treatment response. Ultimately, the aim is to improve outcomes and reduce acute and late treatment-related side-effects, to achieve the best possible therapeutic gain and quality of life.

Section snippets

Treatment resistance mechanisms

About two-thirds of patients with squamous cell carcinoma of the head and neck present with locally advanced disease (stage III or IV without distant metastases). The main reason that radiotherapy is preferred to surgery, especially for advanced disease, is its potential for organ preservation. The effectiveness of radiotherapy can be increased by counteraction of the three most important mechanisms of radiation resistance: accelerated tumour cell repopulation, tumour cell hypoxia, and

Molecular markers for biological imaging

Patient selection for treatment is mostly based on pretreatment clinical characteristics rather than individual patient response during treatment. Preclinical studies have shown that treatment itself can upregulate resistance mechanisms to an extent that varies between tumours. Apart from the commonly used [¹⁸F]-fluorodeoxyglucose (FDG), a range of PET tracers are becoming available for analysis of specific tumour microenvironmental characteristics (table).

[¹⁸F]FDG-PET is routinely used for

PET-CT for diagnostic tests

After review of the published work, an expert panel⁴³ concluded that [¹⁸F]FDG-PET has no added benefit compared with conventional anatomical imaging in routine diagnostic investigation of primary head and neck tumours. Whether [¹⁸F]FDG-PET can establish the anatomical extent of the primary tumour more accurately than can CT or MRI was inconclusive. For the neck, a dedicated PET-CT protocol might aid the detection of small lymph node metastases.43, 44 However, [¹⁸F]FDG frequently accumulates in

PET-CT for treatment planning and adaptive radiotherapy

For planning of radiation treatment, PET might be of use to measure accuracy of delineation of gross tumour volume. A reduction of the gross tumour volume with [¹⁸F]FDG-PET was shown in a key study⁴⁷ of laryngectomy patients. [¹⁸F]FDG-PET was able to depict the tumour volume more accurately than were CT and MRI, although exact discrimination of the PET signal (ie, tumour) from the background (ie, healthy tissues) is an important issue. In a study of 78 patients with head and neck cancer, the

Monitoring of early response with [¹⁸F]FDG

Several PET tracers have been used successfully during treatment in many cancers such as head and neck cancer.⁵³ Geets and co-workers⁵³ investigated whether [¹⁸F]FDG-PET imaging every week during radiotherapy could be used to modify or reduce the treated volume of pharyngolaryngeal tumours. In ten patients given a 7-week course of concomitant chemoradiation, investigators obtained a CT, T2-MRI, fat-suppressed T2-MRI, and static and dynamic [¹⁸F]FDG-PET before and during radiotherapy. All

PET-CT after treatment

In head and neck cancer, the main methods to assess tumour response after completion of treatment are physical examination and CT or MR imaging. Interest is increasing in the use of [¹⁸F]FDG-PET imaging to assess treatment outcomes after chemoradiotherapy, to assess the metabolic status of the tumour, and supplement the static anatomical information acquired by CT and MR imaging.

Concomitant chemoradiotherapy is very cytotoxic and results in massive necrosis in the tumour as treatment

Conclusion

Developments in molecular imaging have shown that repetitive visualisation of tumour characteristics is now possible, and can be decisive for treatment response. Several of these tumour characteristics represent crucial resistance mechanisms, not only for the traditional treatment methods such as radiotherapy and chemotherapy, but also for newer biologically modifying molecules. The potential applications of PET imaging have been shown in preclinical and clinical studies. PET imaging can assist

Search strategy and selection criteria

Data for this review were identified by searches of Medline and PubMed. We searched for publications with “hypoxia”, “proliferation”, or “growth factor receptor” and “PET”, including the different spellings of [¹⁸F]FDG-PET. We specifically added the publications related to “head and neck cancer” and “chemoradiation” or “radiotherapy”. Only papers published in English between January, 1997 and August, 2009 were used.

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La valeur pronostique de la tomographie par émission de positons/tomodensitométrie (TEP/TDM) au fluorodésoxyglucose F-18, effectuée immédiatement après la fin de la radiothérapie chez les patients atteints d’un cancer du poumon, n’est pas bien connue. L’objectif de cette étude était d’évaluer la valeur pronostique de la TEP/TDM réalisée immédiatement après la fin de la radiothérapie chez les patients atteints d’un cancer du poumon.
Les patients atteints d’un cancer primitif du poumon devant recevoir une chimioradiothérapie concomitante ont été inclus. Les patients ont eu une TEP/TDM à trois moments : avant la radiothérapie, dans les 24 heures suivant la fin de la radiothérapie (im-PET/TDM) et deux à neuf mois après la radiothérapie (post-PET/TDM). La valeur d’absorption standardisée maximale (SUVmax) a été obtenue. Un seuil de post-PET/TDM-SUVmax de 2,5 a été déterminé comme le succès de la radiothérapie.
Dix-neuf patients ont été inclus. L’im-PET/CT-SUVmax pour les patients du groupe avec une post-PET/CT-SUVmax élevée était significativement plus élevée que celle du groupe avec une valeur faible (p = 0,004). L’analyse de la courbe Receiver-Operating Characteristic (ROC) de l’opérateur récepteur a indiqué que l’im-PET/CT-SUVmax de 4,35 était une valeur seuil optimale pour discriminer les deux groupes. L’analyse multifactorielle a montré qu’une im-PET/TDM-SUVmax élevée était significativement associée à une post-PET/TDM-SUVmax élevée (p = 0,003).
La TEP/TDL-SUVmax prise immédiatement après la radiothérapie était associée à celle évaluée deux à neuf mois après la radiothérapie.
PET/CT: Radiation Therapy Planning in Head and Neck Cancer
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Nasopharyngeal carcinoma (NPC) is an aggressive head and neck malignancy, and radiotherapy (with or without chemotherapy) is the primary treatment modality. Reliable tumour assessment during the treatment phase, which can portend the efficacy of radiotherapy and early identification of potential treatment failure in radioresistant disease, has been implicit for better cancer management. Technological advancement in the last decade has fostered the development of functional magnetic resonance imaging (fMRI) techniques into a promising tool for diagnostic and therapeutic assessments in head and neck cancer. Apart from conventional morphological assessment, early detection of the physiological environment by fMRI allows a more thorough investigation in monitoring tumour response. This article discusses the relevant fMRI utilities in NPC as an early prognostic and monitoring tool for treatment. Challenges and future developments of fMRI in radiation oncology are also discussed.
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We investigated the relationship between genetic alterations and ¹⁸F-FDG PET/CT findings in head and neck squamous cell carcinoma (HNSC).
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¹⁸FMISO-PET/CT images were acquired at three time points (before treatment start, in weeks two and five) for twenty-eight HNSCC patients treated with radiochemotherapy. The images were converted into pO₂ maps and corresponding pO₂-HTVs (pO₂-HTV₁, pO₂-HTV₂, pO₂-HTV₃) were contoured at 10 mmHg. Different parameters describing the pO₂-HTV time evolution were considered, such as the percent and absolute difference between the pO₂-HTVs (%HTV_i,j and HTV_i-HTV_j with i,j = 1, 2, 3, respectively) and the slope of the linear regression curve fitting the pO₂-HTVs in time. Correlations were sought between the pO₂-HTV evolution parameters and loco-regional recurrence (LRR) using the Receiver Operating Characteristic method.
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ReviewPET-CT for response assessment and treatment adaptation in head and neck cancer

Summary

Introduction

Section snippets

Treatment resistance mechanisms

Molecular markers for biological imaging

PET-CT for diagnostic tests

PET-CT for treatment planning and adaptive radiotherapy

Monitoring of early response with [18F]FDG

PET-CT after treatment

Conclusion

Search strategy and selection criteria

Lancet

Lancet

Radiother Oncol

Radiother Oncol

Lancet Oncol

Radiother Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Radiother Oncol

Int J Radiat Oncol Biol Phys

Semin Radiat Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Radiother Oncol

Radiother Oncol

Lancet Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Dynamics of hypoxia, proliferation and apoptosis after irradiation in a murine tumor model

Radiat Res

The hazard of accelerated tumor clonogen repopulation during radiotherapy

Acta Oncol

Hypoxic radiosensitization: adored and ignored

J Clin Oncol

Phase III study of tirapazamine, cisplatin and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck

J Clin Oncol

Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck

N Engl J Med

B3-deoxy-3-[(18)F]fluorothymidine-positron emission tomography for noninvasive assessment of proliferation in pulmonary nodules

Cancer Res

Hypoxia and glucose metabolism in malignant tumors: evaluation by [18F]fluoromisonidazole and [18F]fluorodeoxyglucose positron emission tomography imaging

Clin Cancer Res

Prognostic relevance of response evaluation using [18F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer

J Clin Oncol

Louis Pasteur; achievements and disappointments, 1861

Bacteriol Rev

On respiratory impairment in cancer cells

Science

Cellular uptake of PET tracers of glucose metabolism and hypoxia and their linkage

Eur J Nucl Med Mol Imaging

Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy

J Nucl Med

Prognostic significance of [18F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02

J Clin Oncol

A kinetic model for dynamic [18F]-FMISO PET data to analyse tumour hypoxia

Phys Med Biol

Hypoxia-specific tumor imaging with 18F-fluoroazomycin arabinoside

J Nucl Med

Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells

J Nucl Med

Review
PET-CT for response assessment and treatment adaptation in head and neck cancer

Monitoring of early response with [¹⁸F]FDG

Hypoxia and glucose metabolism in malignant tumors: evaluation by [¹⁸F]fluoromisonidazole and [¹⁸F]fluorodeoxyglucose positron emission tomography imaging

Prognostic relevance of response evaluation using [¹⁸F]-2-fluoro-2-deoxy-D-glucose positron emission tomography in patients with locally advanced non-small-cell lung cancer

Prognostic impact of hypoxia imaging with ¹⁸F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy

Prognostic significance of [¹⁸F]-misonidazole positron emission tomography-detected tumor hypoxia in patients with advanced head and neck cancer randomly assigned to chemoradiation with or without tirapazamine: a substudy of Trans-Tasman Radiation Oncology Group Study 98.02

A kinetic model for dynamic [¹⁸F]-FMISO PET data to analyse tumour hypoxia

Hypoxia-specific tumor imaging with ¹⁸F-fluoroazomycin arabinoside