Angela van Baardwijk

Identification of residual metabolic-active areas within individual NSCLC tumours using a pre-radiotherapy 18Fluorodeoxyglucose-PET-CT scan

BACKGROUND AND PURPOSE Non-small cell lung cancer (NSCLC) tumours are mostly heterogeneous. We hypothesized that areas within the tumour with a high pre-radiation (18)F-deoxyglucose (FDG) uptake, could identify residual metabolic-active areas, ultimately enabling selective-boosting of tumour sub-volumes. MATERIAL AND METHODS Fifty-five patients with inoperable stage I-III NSCLC treated with chemo-radiation or with radiotherapy alone were included. For each patient one pre-radiotherapy and one post-radiotherapy FDG-PET-CT scans were available. Twenty-two patients showing persistent FDG uptake in the primary tumour after radiotherapy were analyzed. Overlap fractions (OFs) were calculated between standardized uptake value (SUV) threshold-based auto-delineations on the pre- and post-radiotherapy scan. RESULTS Patients with residual metabolic-active areas within the tumour had a significantly worse survival compared to individuals with a complete metabolic response (p=0.002). The residual metabolic-active areas within the tumour largely corresponded (OF>70%) with the 50%SUV high FDG uptake area of the pre-radiotherapy scan. The hotspot within the residual area (90%SUV) was completely within the GTV (OF=100%), and had a high overlap with the pre-radiotherapy 50%SUV threshold (OF>84%). CONCLUSIONS The location of residual metabolic-active areas within the primary tumour after therapy corresponded with the original high FDG uptake areas pre-radiotherapy. Therefore, a single pre-treatment FDG-PET-CT scan allows for the identification of residual metabolic-active areas.

Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non-Small-Cell Lung Cancer

PURPOSE We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach. PATIENTS AND METHODS In total, 166 patients with stage III or medically inoperable stage I to II non-small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide >or= 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0. RESULTS The median prescribed TTD was 64.8 Gy (standard deviation, +/- 11.4 Gy) delivered in 25 +/- 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable. CONCLUSION Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

Radical Treatment of Non-Small-Cell Lung Cancer Patients with Synchronous Oligometastases Long-Term Results of a Prospective Phase II Trial (Nct01282450)

Background: Stage IV non–small-cell lung cancer (NSCLC) patients with oligometastases (< 5 metastatic lesions) may experience long-term survival when all macroscopic tumor sites are treated radically, but no prospective data on NSCLCs with synchronous oligometastases are available. Methods: A prospective single-arm phase II trial was conducted. The main inclusion criteria were pathologically proven NSCLC stage IV with less than five metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov, number NCT01282450. Results: Forty patients were enrolled, 39 of whom were evaluable (18 men, 21 women); mean age was 62.1 ± 9.2 years (range, 44–81). Twenty-nine (74%) had local stage III; 17 (44%) brain, seven (18%) bone, and four (10%) adrenal gland metastases. Thirty-five (87%) had a single metastatic lesion. Thirty-seven (95%) of the patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95% confidence interval 7.6–19.4); 1-, 2-, and 3-year OS was 56.4%, 23.3%, and 17.5%, respectively. Median progression-free survival (PFS) was 12.1 months (95% confidence interval 9.6–14.3); 1-year PFS was 51.3%, and both 2- and 3-year PFS was 13.6%. Only two patients (5%) had a local recurrence. No patient or tumor parameter, including volume and 18F-deoxyglucose uptake was significantly correlated with OS or PFS. The treatment was well tolerated. Conclusion: In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favorable subgroup before therapy is needed.

Is high-dose stereotactic body radiotherapy (SBRT) for stage I non-small cell lung cancer (NSCLC) overkill? A systematic review

BACKGROUND AND PURPOSE For stereotactic body radiotherapy (SBRT), typically a scheme of 60 Gy in 3-8 fractions is applied, producing local tumour control rates around 90%. The dose specification is in one point only and ignores possible underdosages at the edge of the planning target volume (PTV). We investigated the doses at the edge of the PTV and correlated this with local tumour control with the aim to shed light on the radiation dose needed to eradicate stage I NSCLC. MATERIALS AND METHODS Published data on the freedom from local progression (FFLP) data from SBRT and accelerated high-dose conventional radiotherapy series for stage I NSCLC with a follow up of at least 30 months were included. The EQD(2,T) was calculated from the dose at the periphery of the PTV. RESULTS Fifteen studies for SBRT (1076 patients) showed a median FFLP of 88.0±10.4% with a median EQD(2,T) of 76.9±17.4 Gy. The median FFLP was 87.6±6.0% for the accelerated schedules with an EQD(2,T) of 86.9±39.1 Gy, respectively. No significant relation was found between FFLP and the EQD(2,T) (p=0.23). CONCLUSIONS Several fractionated and accelerated schedules with equal biological doses achieve the same tumour control rates as SBRT. Lower, but more uniform doses to the whole PTV may be sufficient to achieve similar control rates, with the possibility to deliver SBRT in adapted schedules, beneficial to centrally located tumours in the vicinity of critical structures like the oesophagus and great vessels.

Stability of 18F-deoxyglucose uptake locations within tumor during radiotherapy for NSCLC: a prospective study.

PURPOSE Because individual tumors are heterogeneous, including for (18)F-deoxyglucose (FDG) uptake and, most likely, for radioresistance, selective boosting of high FDG uptake zones within the tumor has been suggested. To do this, it is critical to know whether the location of these high FDG uptake patterns within the tumor remain stable during radiotherapy (RT). METHODS AND MATERIALS Twenty-three patients with Stage I-III non-small-cell lung cancer underwent repeated FDG positron emission tomography computed tomography scans before radical RT (Day 0) and at Days 7 and 14 of RT. On all scans, the high and low FDG uptake regions were autodelineated using several standardized uptake value thresholds, varying from 34% to 80% of the maximal standardized uptake value. The volumes and overlap fractions of these delineations were calculated to demonstrate the stability of the high FDG uptake regions during RT. RESULTS The mean overlap fraction of the 34% uptake zones at Day 0 with Days 7 and 14 was 82.8% +/- 8.1% and 84.3% +/- 7.6%, respectively. The mean overlap fraction of the high uptake zones (60%) was 72.3% +/- 15.0% and 71.3% +/- 19.7% at Day 0 with Days 7 and 14, respectively. The volumes of the thresholds varied markedly (e.g., at Day 0, the volume of the 60% zone was 16.8 +/- 20.3 cm(3)). In contrast, although the location of the high FDG uptake patterns within the tumor during RT remained stable, the delineated volumes varied markedly. CONCLUSION The location of the low and high FDG uptake areas within the tumor remained stable during RT. This knowledge may enable selective boosting of high FDG uptake areas within the tumor.

18FDG-PET based radiation planning of mediastinal lymph nodes in limited disease small cell lung cancer changes radiotherapy fields: A planning study

BACKGROUND AND PURPOSE To investigate the influence of selective irradiation of 18FDG-PET positive mediastinal nodes on radiation fields and normal tissue exposure in limited disease small cell lung cancer (LD-SCLC). MATERIAL AND METHODS Twenty-one patients with LD-SCLC, of whom both CT and PET images were available, were studied. For each patient, two three-dimensional conformal treatment plans were made with selective irradiation of involved lymph nodes, based on CT and on PET, respectively. Changes in treatment plans as well as dosimetric factors associated with lung and esophageal toxicity were analyzed and compared. RESULTS FDG-PET information changed the treatment field in 5 patients (24%). In 3 patients, this was due to a decrease and in 2 patients to an increase in the number of involved nodal areas. However, there were no significant differences in gross tumor volume (GTV), lung, and esophageal parameters between CT- and PET-based plans. CONCLUSIONS Incorporating FDG-PET information in radiotherapy planning for patients with LD-SCLC changed the treatment plan in 24% of patients compared to CT. Both increases and decreases of the GTV were observed, theoretically leading to the avoidance of geographical miss or a decrease of radiation exposure of normal tissues, respectively. Based on these findings, a phase II trial, evaluating PET-scan based selective nodal irradiation, is ongoing in our department.

The importance of patient characteristics for the prediction of radiation-induced lung toxicity

PURPOSE Extensive research has led to the identification of numerous dosimetric parameters as well as patient characteristics, associated with lung toxicity, but their clinical usefulness remains largely unknown. We investigated the predictive value of patient characteristics in combination with established dosimetric parameters. PATIENTS AND METHODS Data from 438 lung cancer patients treated with (chemo)radiation were used. Lung toxicity was scored using the Common Toxicity Criteria version 3.0. A multivariate model as well as two single parameter models, including either V(20) or MLD, was built. Performance of the models was expressed as the AUC (Area Under the Curve). RESULTS The mean MLD was 13.5 Gy (SD 4.5 Gy), while the mean V(20) was 21.0% (SD 7.3%). Univariate models with V(20) or MLD both yielded an AUC of 0.47. The final multivariate model, which included WHO-performance status, smoking status, forced expiratory volume (FEV(1)), age and MLD, yielded an AUC of 0.62 (95% CI: 0.55-0.69). CONCLUSIONS Within the range of radiation doses used in our clinic, dosimetric parameters play a less important role than patient characteristics for the prediction of lung toxicity. Future research should focus more on patient-related factors, as opposed to dosimetric parameters, in order to identify patients at high risk for developing radiation-induced lung toxicity more accurately.

Radiation Dose Prescription for Non–Small-Cell Lung Cancer According to Normal Tissue Dose Constraints: An In Silico Clinical Trial

PURPOSE Local tumor recurrence remains a major problem in patients with inoperable non-small-cell lung cancer undergoing radiotherapy. We investigated the theoretical gain in the estimated tumor control probability (TCP) using an individualized maximal tolerable dose (MTD) prescription, for both conventional and accelerated fractionation schemes. METHODS AND MATERIALS For 64 non-small-cell lung cancer patients, five treatment plans were compared, dependent on the normal tissue dose constraints for the lung and spinal cord. The first two used a classic fractionation (2 Gy/d, 5 d/wk) to a total dose of 60 Gy (QD(classic)) or determined by the individualized MTD (QD(MTD)). The third scheme assumed a hypofractionated schedule of 2.75-Gy fractions (QD(hypofr)). The fourth and fifth assumed hyperfractionation and acceleration (1.8 Gy twice daily, either BID(classic) or BID(MTD)). The TCPs for the groups of patients were estimated. RESULTS The mean biologic equivalent dose in 2-Gy fractions for tumor, corrected for accelerated repopulation was significantly greater for the BID(MTD) scheme (62.1 Gy) than for any other scheme (QD(classic), 47.5 Gy; QD(MTD), 52.0 Gy; QD(hypofr), 56.9 Gy; and BID(classic), 56.9 Gy; p < 0.001). Although both dose-escalation (QD(MTD)) and hypofractionation (QD(hypofr)) resulted in an increase in the mean estimated TCP of 5.6% (p < 0.001) and 14.6% (p < 0.001), respectively, compared with QD(classic), the combination of escalation and acceleration (BID(MTD)) improved the mean estimated TCP by 26.4% (p < 0.001). CONCLUSION The results of this planning study showed a large gain in the estimated TCP using an MTD scheme with 1.8-Gy fractions BID compared with other fractionation schedules. Clinical studies implementing this concept are ongoing.

Can an FDG-PET/CT predict tumor clearance of the mesorectal fascia after preoperative chemoradiation of locally advanced rectal cancer?

Background and Purpose:More effective preoperative treatment in locally advanced rectal cancer gives rise to a more individualized, conservative surgical treatment strategy. This, however, requires accurate information on tumor response after chemoradiation (CRT). So far, MRI and CT have failed to provide such information. Therefore, the value of a combined FDG-PET/CT in predicting tumor clearance of the mesorectal fascia (MRF) was determined.Patients and Methods:20 rectal cancer patients with MRF tumor invasion underwent preoperative PET/CT before and on average 6.3 weeks after CRT. The SUVmax(maximal standard uptake value) on sequential PET/CT and the shortest distance between the outlined tumor volume and the MRF measured by using autocontouring software on post-CRT PET/CT were registered. The surgical specimen was evaluated for tumor clearance of the MRF and the tumor regression grade (TRG).Results:The TRG significantly corresponded with the SUVmaxchanges induced by CRT (p = 0.025), and showed a trend with the post-CRT SUVmax(TRG 1–2 vs. TRG 3–5: SUVmax= 3.0 vs. 5.0; p = 0.06). However, the pathologically verified tumor clearance of the MRF was not correlated with any of the tested SUV parameters nor with the shortest distance between the residual tumor and the MRF.Conclusion:Post-CRT PET/CT is not a useful tool for evaluating anatomic tumor changes and, therefore, not accurate in predicting tumor clearance of the MRF. However, it might be a useful tool in predicting pathologic tumor response after CRT.Hintergrund und Ziel:Die immer effektivere präoperative Behandlung bei lokal fortgeschrittenem Rektumkarzinom verstärkt den Wunsch nach einer individuelleren, eher konservativen chirurgischen Behandlungsstrategie. Dies setzt jedoch exakte Informationen bezüglich der anatomischen Tumorantwort nach Radiochemotherapie voraus. In dieser Studie wurde der Wert der kombinierten FDG-PET/CT für die Vorhersage einer Tumorrückbildung an der mesorektalen Faszie (MRF) untersucht.Patienten und Methodik:20 Patienten mit Rektumkarzinom und MRT-bestätigter Tumorinvasion der MRF wurden präoperativ mit einer kombinierten FDG-PET/CT vor und im Mittel 6,3 Wochen nach Radiochemotherapie untersucht. Die Tumorvolumina wurden bei beiden PETs/CTs mit Hilfe einer Autokonturierungssoftware eingezeichnet. Der SUVmax(„maximal standard uptake value“) und der kürzeste Abstand zwischen dem eingezeichneten Tumorvolumen und der MRF wurden ermittelt. Das chirurgisch exzidierte Präparat wurde auf eine Tumorrückbildung an der mesorektalen Faszie und den Tumorregressionsgrad (TRG) untersucht.Ergebnisse:Der TRG korrespondierte signifikant mit den durch die Radiochemotherapie induzierten Veränderungen des SUVmax(p = 0,025) und annähernd signifikant mit dem SUVmaxnach Radiochemotherapie (TRG 1–2 vs. TRG 3–5: SUVmax= 3,0 vs. 5,0; p = 0,06). Es ließ sich jedoch keine Korrelation zwischen der pathologisch verifizierten Tumorrückbildung an der MRF und den untersuchten SUV-Parametern sowie dem kürzesten Abstand zwischen Resttumor und MRF feststellen.Schlussfolgerung:Diese Daten legen den Schluss nahe, dass eine wiederholte PET/CT-Untersuchung nach Radiochemotherapie beim Rektumkarzinom nicht in der Lage ist, anatomische Veränderungen so sicher zu ermitteln, dass eine konservativere operative Vorgehensweise zu verantworten wäre. Jedoch erweist sich die PET/CT als sinnvolle Untersuchung zur Vorhersage der pathologischen Tumorantwort nach Radiochemotherapie.

The Use of FDG-PET to Target Tumors by Radiotherapy

Fluorodeoxyglucose positron emission tomography (FDG-PET) plays an increasingly important role in radiotherapy, beyond staging and selection of patients. Especially for non-small cell lung cancer, FDG-PET has, in the majority of the patients, led to the safe decrease of radiotherapy volumes, enabling radiation dose escalation and, experimentally, redistribution of radiation doses within the tumor. In limited-disease small cell lung cancer, the role of FDG-PET is emerging. For primary brain tumors, PET based on amino acid tracers is currently the best choice, including high-grade glioma. This is especially true for low-grade gliomas, where most data are available for the use of 11C-MET (methionine) in radiation treatment planning. For esophageal cancer, the main advantage of FDG-PET is the detection of otherwise unrecognized lymph node metastases. In Hodgkin’s disease, FDG-PET is essential for involved-node irradiation and leads to decreased irradiation volumes while also decreasing geographic miss. FDG-PET’s major role in the treatment of cervical cancer with radiation lies in the detection of para-aortic nodes that can be encompassed in radiation fields. Besides for staging purposes, FDG-PET is not recommended for routine radiotherapy delineation purposes. It should be emphasized that using PET is only safe when adhering to strictly standardized protocols.ZusammenfassungDie Fluordesoxyglucose-Positronenemissionstomographie (FDG-PET) spielt eine zunehmende Bedeutung in der Strahlentherapie, neben der bereits etablierten Bedeutung für Tumorstaging und Patientenselektion. Insbesondere bei nichtkleinzelligen Lungenkarzinomen führt der Einsatz der FDG-PET in der Mehrzahl der Fälle zu einer unbedenklichen Abnahme des Strahlenvolumens, wodurch Dosiseskalationen und auf experimenteller Ebene selbst Dosisumverteilungen der Strahlendosis im Zielvolumen möglich werden. Bei kleinzelligen Lungenkarzinomen nimmt die Bedeutung der FDG-PET ebenfalls zu. Bei primären Hirntumoren stellt die Aminosäure-PET derzeit die beste Wahl dar, auch bei den hochgradigen Gliomen. Für die niedriggradigen Gliome favorisieren die meisten Daten den Einsatz von 11C-MET (Methionin) in der Strahlentherapieplanung. Beim Ösophaguskarzinom liegt der wesentliche Vorteil der FDG-PET in der Detektion von unerkannten Lymphknotenmetastasen. Beim Morbus Hodgkin ist die FDG-PET essentiell für die „involved-field“-Bestrahlung und führt zu einem reduzierten Strahlenvolumen bei gleichzeitig vermindertem Risko der geographischen Fehlbehandlung. Die bedeutendste Rolle der FDG-PET bei der Behandlung des Zervixkarzinoms liegt in der Detektion von paraaortalen Lymphknoten, die in das Bestrahlungsgebiet mit aufgenommen werden. Zusammenfassend wird die FDG-PET neben dem Einsatz beim primären Tumorstaging derzeit nicht für den Routineeinsatz bei der Einzeichnung des Zielvolumens in der Strahlentherapie empfohlen. Der Einsatz der FDG-PET sollte nur nach streng standardisierten Protokollen erfolgen.