Additional PET/CT in week 5-6 of radiotherapy for patients with stage III non-small cell lung cancer as a means of dose escalation planning?

BACKGROUND AND PURPOSE Loco-regional failure after radiotherapy with total doses of 60-70 Gy for non-small cell lung cancer (NSCLC) remains a major clinical problem. Escalation of radiation dose is often limited because of exceeding normal tissue constraints. The present study was designed to test the hypothesis that a reduction in disease volume during radiotherapy detected by FDG PET/CT would facilitate radiation dose escalation, whilst remaining within normal tissue constraints. MATERIALS AND METHODS Ten patients with localised inoperable NSCLC were prospectively enrolled. Each received standard 3D-conformally planned radiotherapy to a dose of 66 Gy in 33 fractions over 6.5 weeks. FDG PET/CT imaging in the treatment position was performed prior to treatment and repeated following 50 or 60 Gy. CT and PET-delineated gross tumour volumes were generated and a composite created. A margin of 15mm was added in all planes to form the planning target volume (PTV). Treatment planning was performed to compare two dose escalation strategies: 78 Gy delivered to the initial PTV with treatment in two phases (shrinking field), i.e., 66 Gy to the initial PTV with a 12 Gy-boost to the PTV after 50/60 Gy. As an alternative planning approach the maximal dose without exceeding normal tissue constraints was evaluated for each patient (individualized dose prescription). RESULTS There was a median PTV reduction after 50/60 Gy of 20%. Delivering 78 Gy to the initial PTV could have been achieved in 4/10 patients. Of the remaining 6, delivering 78 Gy to the initial PTV would have exceeded normal tissue constraints and no benefit was seen when delivered in two phases. The results from the individualized dose prescription indicated a higher median maximal dose when treatment would be given in two phases compared to one phase resulting in a modest increase of calculated tumour control probability. CONCLUSIONS Our data suggest that despite tumour shrinkage determined by subsequent FDG PET/CT during treatment the tested adaptive targeting strategy would result only in a modest improvement in the context of dose escalation. Further studies on the optimal use of FDG PET/CT and other approaches for dose escalation in loco-regionally advanced NSCLC are warranted.

[1]  O. Holmberg,et al.  Escalated dose for non-small-cell lung cancer with accelerated hypofractionated three-dimensional conformal radiation therapy. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[2]  M. Martel,et al.  Results following treatment to doses of 92.4 or 102.9 Gy on a phase I dose escalation study for non-small cell lung cancer. , 2004, Lung cancer.

[3]  R K Ten Haken,et al.  Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. , 1999, Lung cancer.

[4]  Sadek Nehmeh,et al.  Does registration of PET and planning CT images decrease interobserver and intraobserver variation in delineating tumor volumes for non-small-cell lung cancer? , 2005, International journal of radiation oncology, biology, physics.

[5]  Ursula Nestle,et al.  Practical integration of [18F]-FDG-PET and PET-CT in the planning of radiotherapy for non-small cell lung cancer (NSCLC): the technical basis, ICRU-target volumes, problems, perspectives. , 2006, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[6]  Suresh Senan,et al.  Time trends in target volumes for stage I non-small-cell lung cancer after stereotactic radiotherapy. , 2006, International journal of radiation oncology, biology, physics.

[7]  C B Caldwell,et al.  Observer variation in contouring gross tumor volume in patients with poorly defined non-small-cell lung tumors on CT: the impact of 18FDG-hybrid PET fusion. , 2001, International journal of radiation oncology, biology, physics.

[8]  Jeffrey Bradley,et al.  Toxicity and outcome results of RTOG 9311: a phase I-II dose-escalation study using three-dimensional conformal radiotherapy in patients with inoperable non-small-cell lung carcinoma. , 2005, International journal of radiation oncology, biology, physics.

[9]  Gerald J. Kutcher,et al.  The impact of 18F-fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer , 2000 .

[10]  M. Krause,et al.  Molecular targeting in radiotherapy of lung cancer. , 2004, Lung cancer.

[11]  Joos V Lebesque,et al.  Portal imaging to assess set-up errors, tumor motion and tumor shrinkage during conformal radiotherapy of non-small cell lung cancer. , 2001, Radiotherapy and Oncology.

[12]  Tae Hyun Kim,et al.  Dose-volumetric parameters of acute esophageal toxicity in patients with lung cancer treated with three-dimensional conformal radiotherapy. , 2005, International journal of radiation oncology, biology, physics.

[13]  C. Ling,et al.  Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer. , 2004, International journal of radiation oncology, biology, physics.

[14]  Kurt Baier,et al.  Dose, volume, and tumor control prediction in primary radiotherapy of non-small-cell lung cancer. , 2002, International journal of radiation oncology, biology, physics.

[15]  Philippe Lambin,et al.  PET-CT-based auto-contouring in non-small-cell lung cancer correlates with pathology and reduces interobserver variability in the delineation of the primary tumor and involved nodal volumes. , 2007, International journal of radiation oncology, biology, physics.

[16]  Joos V Lebesque,et al.  Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. , 2003, International journal of radiation oncology, biology, physics.

[17]  M. Socinski,et al.  Bronchial stenosis: an underreported complication of high-dose external beam radiotherapy for lung cancer? , 2005, International journal of radiation oncology, biology, physics.

[18]  G J Kutcher,et al.  The impact of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) lymph node staging on the radiation treatment volumes in patients with non-small cell lung cancer. , 2000, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[19]  M. Socinski,et al.  High-dose conformal radiotherapy for treatment of stage IIIA/IIIB non-small-cell lung cancer: technical issues and results of a phase I/II trial. , 2002, International journal of radiation oncology, biology, physics.

[20]  Radhe Mohan,et al.  Significant reduction of normal tissue dose by proton radiotherapy compared with three-dimensional conformal or intensity-modulated radiation therapy in Stage I or Stage III non-small-cell lung cancer. , 2006, International journal of radiation oncology, biology, physics.

[21]  Patrick A Kupelian,et al.  Serial megavoltage CT imaging during external beam radiotherapy for non-small-cell lung cancer: observations on tumor regression during treatment. , 2005, International journal of radiation oncology, biology, physics.

[22]  Marcel van Herk,et al.  Reduction of observer variation using matched CT-PET for lung cancer delineation: a three-dimensional analysis. , 2006, International Journal of Radiation Oncology, Biology, Physics.

[23]  Branislav Jeremic,et al.  Positron Emission Tomography for Radiation Treatment Planning , 2005, Strahlentherapie und Onkologie.

[24]  Wolfgang A Tomé,et al.  Tumor volume changes on serial imaging with megavoltage CT for non-small-cell lung cancer during intensity-modulated radiotherapy: how reliable, consistent, and meaningful is the effect? , 2006, International journal of radiation oncology, biology, physics.

[25]  R. T. Ten Haken,et al.  High-dose radiation improved local tumor control and overall survival in patients with inoperable/unresectable non-small-cell lung cancer: long-term results of a radiation dose escalation study. , 2005, International journal of radiation oncology, biology, physics.

[26]  M. Socinski,et al.  Induction and concurrent chemotherapy with high-dose thoracic conformal radiation therapy in unresectable stage IIIA and IIIB non-small-cell lung cancer: a dose-escalation phase I trial. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  J. Lebesque,et al.  Final results of a Phase I/II dose escalation trial in non-small-cell lung cancer using three-dimensional conformal radiotherapy. , 2006, International journal of radiation oncology, biology, physics.

[28]  José Belderbos,et al.  Biology contributionComparing different NTCP models that predict the incidence of radiation pneumonitis , 2003 .

[29]  Philippe Lambin,et al.  Effects of radiotherapy planning with a dedicated combined PET-CT-simulator of patients with non-small cell lung cancer on dose limiting normal tissues and radiation dose-escalation: a planning study. , 2005, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[30]  P. Lambin,et al.  Time trends in the maximal uptake of FDG on PET scan during thoracic radiotherapy. A prospective study in locally advanced non-small cell lung cancer (NSCLC) patients , 2007 .

[31]  M. Goitein,et al.  Tolerance of normal tissue to therapeutic irradiation. , 1991, International journal of radiation oncology, biology, physics.

[32]  R K Ten Haken,et al.  Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  H. Dittmann,et al.  Repeat 18F-FDG PET for monitoring neoadjuvant chemotherapy in patients with stage III non-small cell lung cancer. , 2007, Lung Cancer.

[34]  P. Lambin,et al.  HI-CHART: a phase I/II study on the feasibility of high-dose continuous hyperfractionated accelerated radiotherapy in patients with inoperable non-small-cell lung cancer. , 2008, International journal of radiation oncology, biology, physics.

[35]  G. Cook,et al.  Positron emission tomography for target volume definition in the treatment of non-small cell lung cancer. , 2005, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[36]  Barbara Vanderstraeten,et al.  Positron emission tomography-guided, focal-dose escalation using intensity-modulated radiotherapy for head and neck cancer. , 2007, International journal of radiation oncology, biology, physics.

[37]  Philippe Lambin,et al.  Intra-patient variability of tumor volume and tumor motion during conventionally fractionated radiotherapy for locally advanced non-small-cell lung cancer: a prospective clinical study. , 2006, International journal of radiation oncology, biology, physics.

[38]  J. Steinbach,et al.  Effect of increase of radiation dose on local control relates to pre-treatment FDG uptake in FaDu tumours in nude mice. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[39]  E. Yorke,et al.  Involved-field radiation therapy for inoperable non small-cell lung cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  M. V. van Herk,et al.  Anatomy changes in radiotherapy detected using portal imaging. , 2006, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[41]  Radhe Mohan,et al.  Initial evaluation of treatment-related pneumonitis in advanced-stage non-small-cell lung cancer patients treated with concurrent chemotherapy and intensity-modulated radiotherapy. , 2007, International journal of radiation oncology, biology, physics.

[42]  Matthias Guckenberger,et al.  Intra-fractional uncertainties in cone-beam CT based image-guided radiotherapy (IGRT) of pulmonary tumors. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[43]  A Harvey,et al.  Continuous, hyperfractionated, accelerated radiotherapy (CHART) versus conventional radiotherapy in non-small cell lung cancer: mature data from the randomised multicentre trial. CHART Steering committee. , 1999, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[44]  J. Bedford,et al.  A potential to reduce pulmonary toxicity: the use of perfusion SPECT with IMRT for functional lung avoidance in radiotherapy of non-small cell lung cancer. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[45]  Philippe Lambin,et al.  Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study. , 2005, International journal of radiation oncology, biology, physics.

[46]  George Starkschall,et al.  Assessment of gross tumor volume regression and motion changes during radiotherapy for non-small-cell lung cancer as measured by four-dimensional computed tomography. , 2007, International journal of radiation oncology, biology, physics.

[47]  Suresh Senan,et al.  Literature-based recommendations for treatment planning and execution in high-dose radiotherapy for lung cancer. , 2004, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[48]  R K Ten Haken,et al.  Radiation pneumonitis as a function of mean lung dose: an analysis of pooled data of 540 patients. , 1998, International journal of radiation oncology, biology, physics.

[49]  O. Brodin,et al.  Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials , 1995 .

[50]  M. Baumann,et al.  Dose and fractionation concepts in the primary radiotherapy of non-small cell lung cancer. , 2001, Lung cancer.