MRI-guided treatment-planning optimisation in intracavitary or combined intracavitary/interstitial PDR brachytherapy using tandem ovoid applicators in locally advanced cervical cancer

Purpose

To study the impact of MRI-guided treatment planning on dose/volume parameters in pulsed dose rate (PDR) brachytherapy (BT) for cervical cancer. Additionally, we investigated the potential benefit of an intracavitary/interstitial (IC/IS) modification of the classical tandem ovoid applicator.

Material and methods

For 24 patients we compared Standard PDR BT plans, Scaled Standard plans and MRI-guided Optimised plans. The total EBRT/BT prescribed dose to Manchester point A or to 90% of the HR-CTV (D90 HR-CTV) [1] expressed in EQD₂ was 80 Gy_αβ10 in 17 patients (Period I) and 84 Gy_αβ10 in 7 patients (Period II). The constraints to 2 cm³ of the OAR were 90 Gy_αβ3 for bladder and 75 Gy_αβ3 for rectum, sigmoid and bowel. Most cases were treated with a traditional intracavitary tandem ovoid applicator. In 6 patients we used a newly designed combined IC/IS modification for the second PDR fraction and investigated the benefit of the interstitial part.

Results

The average gain of MRI-guided optimisation expressed in D90 HR-CTV was 4 ± 9 Gy_αβ10 (p < 0.001) and 10 ± 7 Gy_αβ10 (p = 0.003) in the two periods. The dose to 2 cm³ of the OAR met the constraints. In the group that was treated with the combined IC/IS approach, we could increase the D90 HR-CTV for the second PDR fraction with 5.4 ± 4.2 Gy_αβ10 (p = 0.005) and the D100 with 4.8 ± 3.1 Gy_αβ10 (p = 0.07).

Conclusions

Three-dimensional MRI-guided treatment planning and optimisation improves the DVH parameters compared to conventional planning strategies. Additional improvement can be achieved by using a combined IC/IS approach.     

The effect of alternative biological modelling parameters (α/β and half time of repair T1/2) on reported EQD2 values in the treatment of advanced cervical cancer

Purpose

To evaluate the effect of different α/β and half-time of repair T_½ on the assessment of clinical treatment plans for patients with cervical cancer.

Materials and methods

We used EBRT and BT treatment plans of five patients, planned with MRI guided BT. We computed 3D EQD2 dose distributions of combined EBRT and BT treatments and calculated D90 of high-risk clinical target volume (HR-CTV) and D_2cc for bladder and rectum, and the ratio D_2cc(bladder)/D90(HR-CTV). BT was modelled as PDR (two applications of 32 × 60 cGy) and HDR (two applications of 2 × 7 Gy). We assumed a low, standard and high value for the biological parameters: HR-CTV α/β = 5/10/15 Gy and T_½ = 0.5/1.5/2.5 h; OAR α/β = 2/3/4 Gy; T_½ = 0.5/1.5/4.5 h.

Results

The chosen variation in modelling parameters had a much larger effect on PDR treatments than on HDR treatments, especially for OAR, thus creating larger uncertainties. The relative mean range of the ratio D_2cc(bladder)/D90(HR-CTV) is 72% for PDR and 25% for HDR. Out of the 125 modelled combinations 48 PDR plans and 23 HDR plans comply with clinical objectives.

Conclusion

For HDR brachytherapy, only α/β has a significant impact on reported EQD2 values, whereas for PDR both α/β and T_1/2 are important.Generally, the ratio D_2cc(bladder)/D90(HR-CTV) is more favourable for PDR, even considering the larger uncertainties in EQD2.     

Determining DVH parameters for combined external beam and brachytherapy treatment: 3D biological dose adding for patients with cervical cancer

Purpose

To compare two methods of DVH parameter determination for combined external beam and brachytherapy treatment of cervical cancer.

Materials and methods

Clinical treatment plans from five patients were used in this study. We simulated two applications given with PDR (32 × 60 cGy per application, given hourly) or HDR (4 × 7 Gy in two applications; each application of two fractions of 7 Gy, given within 17 h) standard and optimised treatment plans, all combined with IMRT (25 × 1.8 Gy). Additionally, we simulated an external beam (EBRT) boost to pathological lymph nodes or the parametrium (7 × 2 Gy).We determined D90 of the high-risk CTV (HR-CTV) and D_2cc of bladder and rectum in EQD2 in two ways. (1) ‘Parameter adding’: assuming a uniform contribution of the EBRT dose distribution and adding the values of DVH parameters for the two brachytherapy insertions, and (2) ‘distributions adding’: summing 3D biological dose distributions of IMRT and brachytherapy plans and subsequently determining the values of the DVH parameters. We took α/β = 10 Gy for HR-CTV, α/β = 3 Gy otherwise and half-time of repair 1.5 h.

Results

Without EBRT boost, ‘parameter adding’ yielded a good approximation. With an EBRT boost to lymph nodes, the total D90 HR-CTV was underestimated by 2.6 (SD 1.3)% for PDR and 2.8 (SD 1.4)% for HDR. This was even worse with a parametrium boost: 9.1 (SD 6.2)% for PDR and 9.9 (SD 6.2)% for HDR.

Conclusion

Without an EBRT boost ‘parameter adding’, as proposed by the GEC-ESTRO, yielded accurate results for the values for DVH parameters. If an EBRT boost is given ‘distributions adding’ should be considered.     

Radiotherapy of malignant gliomas: Comparison of volumetric single arc technique (RapidArc), dynamic intensity-modulated technique and 3D conformal technique

Purpose

The analysis was designed to identify the optimal radiation technique for patients with malignant glioma.

Methods

A volumetric-modulated radiation treatment technique (RapidArc), an IMRT technique and a 3D conformal technique were calculated on computed tomograms of 14 consecutive patients with malignant glioma. The treatment plans were compared with each other using dose-volume histograms.

Results

The 3D conformal technique showed a good PTV coverage, if PTV was distant to organs at risk (OAR). If PTV was nearby OAR, the 3D technique revealed a poor PTV coverage in contrast to both intensity-modulated techniques. The conventional IMRT technique showed a slightly better PTV coverage than RapidArc. The advantages of RapidArc were a shorter treatment time, less monitor units and a small V_107%.

Conclusions

If PTV is distant to OAR, the use of 3D conformal technique is sufficient. Otherwise an intensity-modulated technique should be used. RapidArc was faster than conventional IMRT and should be preferred if PTV coverage is adequate.     

A methodology for incorporating functional bone marrow sparing in IMRT planning for pelvic radiation therapy

Background and purpose

The purpose of this study was to design a radiation therapy treatment planning approach that would spare hematopoietically active bone marrow using [¹⁸F]FLT PET imaging.

Materials and methods

We have developed an IMRT planning methodology to incorporate functional PET imaging using [¹⁸F]FLT scans. Plans were generated for two simulated cervical cancer patients, where pelvic active bone marrow regions were incorporated as avoidance regions based on the ranges: SUV4 ? 4; 4 > SUV3 ? 3; and 3 > SUV2 ? 2. Dose objectives were set to reduce bone marrow volume that received 10 (V₁₀) and 20 (V₂₀) Gy.

Results

Active bone marrow regions identified by [¹⁸F]FLT with an SUV ? 2, SUV ? 3, and SUV ? 4 represented an average of 43.0%, 15.3%, and 5.8%, respectively of the total osseous pelvis for the two cases studied. Improved dose-volume histograms for all identified bone marrow SUV volumes and decreases in V₁₀, and V₂₀ were achieved without clinically significant changes to PTV or OAR doses.

Conclusions

Incorporation of [¹⁸F]FLT PET in IMRT planning provides a methodology to reduce radiation dose to active bone marrow without compromising PTV or OAR dose objectives in pelvic malignancies.     

Applicator reconstruction in MRI 3D image-based dose planning of brachytherapy for cervical cancer

Background and purpose

To elaborate a method for applicator reconstruction for MRI-based brachytherapy for cervical cancer.

Materials and methods

Custom-made plastic catheters with a copper sulphate solution were made for insertion in the source channels of MR-CT compatible applicators: plastic and titanium tandem ring applicators, and titanium needles. The applicators were CT and MR scanned in a phantom for accurate 3D assessment of applicator visibility and geometry. A reconstruction method was developed and evaluated in 19 patient MR examinations with ring applicator (plastic: 14, titanium: 5). MR applicator reconstruction uncertainties related to inter-observer variation were evaluated.

Results

The catheters were visible in the plastic applicator on T1-weighted images in phantom and in 14/14 clinical applications. On T2-weighted images, the catheters appeared weaker but still visible in phantom and in 13/14 MR clinical applications. In the titanium applicator, the catheters could not be separated from the artifacts from the applicator itself. However, these artifacts could be used to localize both titanium ring applicator (5/5 clinical applications) and needles (6/6 clinical applications). Standard deviations of inter-observer differences were below 2 mm in all directions.

Conclusion

3D applicator reconstruction based on MR imaging could be performed for plastic and titanium applicators. Plastic applicators proved well to be suited for MRI-based reconstruction. For improved practicability of titanium applicator reconstruction, development of MR applicator markers is essential. Reconstruction of titanium applicator and needles at 1.5 T MR requires geometric evaluations in phantoms before using the applicator in patients.     

A practical approach to assess clinical planning tradeoffs in the design of individualized IMRT treatment plans

Background and purpose

To investigate the tradeoffs between organ at risk sparing and tumour coverage for IMRT treatment of lung tumours, and to develop a tool for clinical use to graphically represent these tradeoffs.

Material and methods

For 5 patients with inoperable non-small cell lung cancer (NSCLC) different IMRT plans were generated using a standard TPS. The plans were automatically generated for a range of IMRT settings (weights and dose levels of the objective functions) and were systematically evaluated, focusing on the tradeoffs between organ at risk (OAR) dose and target coverage. A method to analyze and visualize planning tradeoffs was developed and evaluated.

Results

Lung and oesophagus were identified as the critical organs at risk for NSCLC, the sparing of which strongly influences PTV coverage. Systematically analyzing the tradeoffs between these organs revealed that the sparing of these organs was approximately linearly related to PTV coverage parameters. Using this property, a tool was developed to graphically present the tradeoffs between the sparing of these organs at risk and the PTV coverage. The tool is an effective method to visualize the tradeoffs.

Conclusions

A tool was developed to assist IMRT plan design and selection. The clear presentation of the tradeoffs between OAR dose and coverage facilitates the optimization process and offers additional information to the clinician for a patient specific choice of the optimal IMRT plan.     

Health-related quality of life after permanent I-125 brachytherapy and conformal external beam radiotherapy for prostate cancer - a matched-pair comparison

Background and purpose

The aim of the study was to compare quality of life after permanent I-125 brachytherapy (BT) and external beam radiotherapy (EBRT) for prostate cancer.

Materials and methods

A group of 104 patients (52 in each group) have been surveyed prospectively before EBRT/BT (time A), at the last day of EBRT (70.2-72.0 Gy) or one month after BT (time B), and a median time of 16 months after EBRT/BT (time C) using a validated questionnaire (Expanded Prostate Cancer Index Composite). Pairs were matched according to the following criteria: age ±5years, prostate volume ±10 cc, use of antiandrogens, and erectile function.

Results

Urinary function/bother scores decreased significantly more after BT both at time B and time C. Bowel function/bother scores tended to be higher after BT, with a lower percentage of patients with painful bowel movements (BT: 12%/27%/15%; EBRT: 19%/52%/35% at time A/B/C; p < 0.05 for differences at times B/C) and rectal bleeding (BT: 12%/12%/12%; EBRT: 8%/14%/17%). No difference concerning erectile dysfunction was found (67% vs. 61% with preserved erections firm enough for intercourse after BT vs. EBRT at time C).

Conclusions

BT was associated with higher urinary, but lower rectal toxicity. The risk of treatment-associated erectile dysfunction did not differ between these methods.     

Applicator reconstruction for HDR cervix treatment planning using images from 0.35 T open MR scanner

Background and purposes

Magnetic resonance (MR) imaging is widely recognised as the modality of choice for imaging soft tissue such as the target volume and critical structures relevant to high dose rate (HDR) brachytherapy of the cervix. This work sets out to assess some of the issues faced when introducing this technique clinically compared to the more widely used computed tomography (CT). MR can be used either as the sole imaging modality, or in conjunction with CT.

Materials and methods

Distortion of the images produced by the MR scanner was assessed with a geometrical phantom. Distortion local to the titanium applicators, introduced by the susceptibility of the applicators themselves, was also measured. The technique used to reconstruct applicators is briefly described. An inter-operator study was performed to assess the variability of applicator reconstruction between operators when MR images are used alone to reconstruct the applicators.

Results

A 14-cm cube within which distortion was less than 2 mm at all points was identified. The inter-operator study showed some variability in applicator reconstruction with both MR and CT (median MR/CT 1.3 mm/0.9 mm, range 0-3.6 mm/0-3.3 mm). Inter-operator variation in planning target volume (PTV) V100% and PTV D90% for MR/CT was 6.1%/3.0% and 7.4%/6.3%, respectively, and D_2cc OAR doses varied by up to 1.0 Gy between operators for both MR and CT.

Conclusions

In this study distortion was minimal within a defined volume and inter-observer errors were comparable on MR and CT when used to define applicators and when applied to dose-volume histograms (DVHs). However this does not assure the technique is appropriate with other scanners and applicator sets without further commissioning.     

Stereotactic body radiotherapy for unresectable cholangiocarcinoma

Purpose

To report outcomes of a single institution study of stereotactic body radiotherapy (SBRT) for unresectable cholangiocarcinoma. The dose-volume dependency of the observed gastrointestinal toxicity is explored.

Methods and materials

Twenty-seven patients with unresectable cholangiocarcinoma (n = 26 Klatskin tumours and one intrahepatic cholangiocarcinoma (IHCC)) were treated by linac-based SBRT. The dose schedule was 45 Gy in three fractions prescribed to the isocenter.

Results

The median progression-free survival and overall survival were 6.7 and 10.6 months, respectively. With a median follow-up of 5.4 years, 6 patients had severe duodenal/pyloric ulceration and 3 patients developed duodenal stenosis. Duodenal radiation exposure was higher in patients developing moderate to high-grade gastrointestinal toxicity with the difference in mean maximum dose to 1 cm³ of duodenum reaching statistical significance. A statistically significant association between grade ? 2 ulceration and volume of duodenum exposed to selected dose levels was not established.

Conclusion

The outcomes of SBRT for unresectable cholangiocarcinoma appear comparable to conventionally fractionated chemoradiotherapy with or without brachytherapy boost. The practical advantages of SBRT are of particular interest for such poor prognosis patients. Patient selection, however, is key in order to avoid compromising such practical gains with excessive gastrointestinal toxicity.     

Accelerated partial-breast irradiation using high-dose-rate interstitial brachytherapy: 12-year update of a prospective clinical study

Background and purpose

To report the 12-year updated results of accelerated partial-breast irradiation (APBI) using multicatheter interstitial high-dose-rate (HDR) brachytherapy (BT).

Patients and methods

Forty-five prospectively selected patients with T1N0-N1mi, nonlobular breast cancer without the presence of an extensive intraductal component and with negative surgical margins were treated with APBI after breast-conserving surgery (BCS) using interstitial HDR BT. A total dose of 30.3 Gy (n = 8) and 36.4 Gy (n = 37) in seven fractions within 4 days was delivered to the tumour bed plus a 1-2 cm margin. The median follow-up time was 133 months for surviving patients. Local and regional control, disease-free (DFS), cancer-specific (CSS), and overall survival (OS), as well as late side effects, and cosmetic results were assessed.

Results

Four (8.9%) ipsilateral breast tumour recurrences were observed, for a 5-, 10-, and 12-year actuarial rate of 4.4%, 9.3%, and 9.3%, respectively. A total of two regional nodal failures were observed for a 12-year actuarial rate of 4.4%. The 12-year DFS, CSS, and OS was 75.3%, 91.1%, and 88.9%, respectively. Grade 3 fibrosis was observed in one patient (2.2%). No patient developed grade 3 teleangiectasia. Fat necrosis requiring surgical intervention occurred in one woman (2.2%). Cosmetic results were rated excellent or good in 35 patients (77.8%).

Conclusions

Twelve-year results with APBI using HDR multicatheter interstitial implants continue to demonstrate excellent long-term local tumour control, survival, and cosmetic results with a low-rate of late side effects.     

Combination therapy of imatinib mesylate and interferon-alpha demonstrates minimal activity and significant toxicity in metastatic renal cell carcinoma: results of a single- institution phase II trial

Background

Renal cell carcinoma (RCC) is characterized by increased expression of vascular endothelial growth factor and platelet-derived growth factor (PDGF)-β, both of which contribute to its angiogenic phenotype. Interferon-α (IFN-α) improves survival in patients with metastatic RCC, perhaps partly because of its antiangiogenic properties. Imatinib mesylate inhibits PDGF-mediated signal transduction and might thus have antiangiogenic activity as well.

Patients and Methods

Patients with metastatic RCC were treated with IFN-α (9 × 10⁶ IU subcutaneously 3 times weekly) and oral imatinib mesylate (600 mg daily starting on day 8). Therapy was continuous, and response was evaluated at 8-week intervals using the Response Evaluation Criteria in Solid Tumors. Baseline plasma PDGF-AA, PDGF-AB, and PDGF-BB levels were obtained.

Results

Between January 2003 and January 2005, 17 patients were treated. One patient (6%) had a partial response, 4 (24%) had stable disease, 7 (41%) had progressive disease, and 5 (29%) were unevaluable because of early withdrawal secondary to toxicity. Median time to progression (TTP) using the Kaplan-Meier method was 8 weeks, and median overall survival was 17.8 months. Six patients (35%) withdrew from therapy because of toxicity, and 9 patients (53%) experienced ≥ 1 grade 3/4 toxicity. Platelet-derived growth factor AA, AB, and BB plasma levels did not correlate with TTP or overall survival.

Conclusion

Based on a response rate of only 6%, a median TTP of 2 months, and significant toxicities, further study of IFN-α in combination with imatinib mesylate is not recommended in patients with metastatic RCC.     

Sigmoid dose using 3D imaging in cervical-cancer brachytherapy

Background and Purpose

To evaluate the proximity, variance, predictors of dose, and complications to the sigmoid in cervical-cancer brachytherapy using 3D planning.

Materials and methods

Over 36 months, 50 patients were treated for cervical cancer with either low-dose-rate (LDR) or high-dose-rate (HDR) brachytherapy. The distance from the central tandem to the sigmoid, the D0.1cc and the D2cc to the sigmoid, rectum and bladder doses, and toxicity were analyzed.

Results

The median sigmoid EQD2 D0.1cc and D2cc were 84 Gy and 68.3 Gy for HDR versus 71.1 Gy and 65.9 Gy for LDR (p = 0.02 and 0.98, respectively). Twenty percent of the HDR fractions required manipulation of the superior dwell positions to decrease the sigmoid dose. The median distance from the sigmoid to the tandem was 1.7 cm (range [rg], 0.1-6.16 cm) for HDR and 2.7 cm (rg, 1.17-4.52 cm) for LDR; from the sigmoid to the 100% isodose region the median distances were −0.1 cm (rg, −1.4 to 2.5 cm) and 0.44 cm (rg. −0.73-5.2 cm), respectively. The proximity of the sigmoid to the tandem is significantly related to sigmoid dose (p < 0.0001). Within-patient (among-fraction) variation in sigmoid-to-tandem distance during HDR was substantial (coefficient of variation =40%). No grade 3-4 sigmoid toxicity was seen after a median 31-month follow-up period.

Conclusions

3D imaging in cervical-cancer brachytherapy shows the sigmoid in close proximity to the tandem. The sigmoid-to-tandem distance varies substantially between fractions, indicating the importance of sigmoid dose-volume evaluation with each fraction.     

Dose-volume thresholds and smoking status for the risk of treatment-related pneumonitis in inoperable non-small cell lung cancer treated with definitive radiotherapy

Purpose

To identify clinical risk factors and dose-volume thresholds for treatment-related pneumonitis (TRP) in patients with non-small cell lung cancer (NSCLC).

Methods and materials

Data were retrospectively collected from patients with inoperable NSCLC treated with radiotherapy with or without chemotherapy. TRP was graded according to Common Terminology Criteria for Adverse Events, version 3.0, with time to grade ?3 TRP calculated from start of radiotherapy. Clinical factors and dose-volume parameters were analyzed for their association with risk of TRP.

Results

Data from 576 patients (75% with stage III NSCLC) were included in this study. The Kaplan-Meier estimate of the incidence of grade ?3 TRP at 12 months was 22%. An analysis of dose-volume parameters identified a threshold dose-volume histogram (DVH) curve defined by V₂₀ ?25%, V₂₅ ?20%, V₃₅ ?15%, and V₅₀ ?10%. Patients with lung DVHs satisfying these constraints had only 2% incidence of grade ?3 TRP. Smoking status was the only clinical factor that affected the risk of TRP independent of dosimetric factors.

Conclusions

The risk of TRP varied significantly, depending on radiation dose-volume parameters and patient smoking status. Further studies are needed to identify biological basis of smoking effect and methods to reduce the incidence of TRP.     

A population-based study on the utilisation rate of primary radiotherapy for prostate cancer in 4 regions in the Netherlands, 1997-2008

Aim

The purpose was to study variations in utilisation rates of external beam radiotherapy (EBRT) and brachytherapy (BT) for prostate cancer patients.

Materials and methods

We calculated the proportion and number of EBRT and BT given or planned within 6 months of diagnosis in 4 Dutch regions, according to stage and age in a population-based setting including 47,259 prostate cancer patients diagnosed from 1997 until 2008.

Results

During this study period, the overall utilisation rate of EBRT remained stable at around 25%, while the rate of BT for non-metastasized patients increased from 1% (95% CI:0-1%) to 12% (11-13%) in 2006 and slightly decreased towards 10% (9-11%) in 2008. From 2001 on, the overall utilisation rate of EBRT decreased significantly in one region (p < 0.05). In this region, a sharp rise in the utilisation rate of BT for non-metastatic patients was noted to 17% (14-20%) in 2008 after a peak of 24% (21-27%) in 2006. For localised disease, BT was used more often at the expense of EBRT while for locally advanced disease the utilisation rate of EBRT increased. In the multivariate analysis, regional differences in the utilisation rate of EBRT persisted with odds ratios ranging from 0.7 to 0.9 compared to the reference region. Moreover, low rates of EBRT were associated with high BT rates. The regional differences could not be explained by differences in risk profiles.

Conclusions

The utilisation rate of EBRT remained stable with limited variation between regions while BT was used increasingly with clear regional differences. To cope with this and in view of the increasing incidence of prostate cancer, adequate resources have to be planned for the optimal care of these patients.     

Identification of residual metabolic-active areas within individual NSCLC tumours using a pre-radiotherapy Fluorodeoxyglucose-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 ¹⁸F-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.