Stereotactic radiotherapy for bone oligometastases

About 60–90% of cancer patients are estimated to develop bone metastases, particularly in the spine.Bone scintigraphy, computed tomography (CT ) and magnetic resonance imaging (MRI ) are currently used to assess metastatic bone disease; positron emission tomography/computed tomography (PET-CT ) has become more widespread in clinical practice because of its high sensitivity and specificity with about 95% diagnostic accuracy. The most common and well-known radiotracer is 18F-fluorodeoxyglucose (¹⁸FDG); several other PET-radiotracers are currently under investigation for different solid tumors, such as ¹¹C or ¹⁸FDG-choline and prostate specific membrane antigen (PSMA)-PET/CT for prostate cancer. In treatment planning, standard and investigational imaging modalities should be registered with the planning CT so as to best define the bone target volume. For target volume delineation of spine metastases, the International Spine Radiosurgery Consortium (ISRC ) of North American experts provided consensus guidelines. Single fraction stereotactic radiotherapy (SRT ) doses ranged from 12 to 24 Gy; fractionated SRT administered 21–27 Gy in 3 fractions or 20–35 Gy in 5 fractions. After spine SRT, less than 5% of patients experienced grade ≥ 3 acute toxicity. Late toxicity included the extremely rare radiation-induced myelopathy and a 14% risk of de novo vertebral compression fractures.     

Stereotactic radiotherapy for adrenal oligometastases

Approximately 50% of melanomas, 30–40% of lung and breast cancers and 10–20% of renal and gastrointestinal tumors metastasize to the adrenal gland.Metastatic adrenal involvement is diagnosed by computed tomography (CT ) with contrast medium, ultrasound (which does not explore the left adrenal gland well), magnetic resonance imaging (MRI) with contrast medium and 18F-fluorodeoxyglucose positron emission tomography-computed tomography (¹⁸FDGPET-CT ) which also evaluates lesion uptake. The simulation CT should be performed with contrast medium; an oral bolus of contrast medium is useful, given adrenal gland proximity to the duodenum. The simulation CT may be merged with PET-CT images with ¹⁸FDG in order to evaluate uptaking areas. In contouring, the radiologically visible and/or uptaking lesion provides the gross tumor volume (GTV ). Appropriate techniques are needed to overcome target motion. Single fraction stereotactic radiotherapy (SRT ) with median doses of 16–23 Gy is rarely used. More common are doses of 25–48 Gy in 3–10 fractions although 3 or 5 fractions are preferred. Local control at 1 and 2 years ranges from 44 to 100% and from 27 to 100%, respectively. The local control rate is as high as 90%, remaining stable during follow-up when BED_10Gy is equal to or greater than 100 Gy. SRT-related toxicity is mild, consisting mainly of gastrointestinal disorders, local pain and fatigue. Adrenal insufficiency is rare.     

Stereotactic radiotherapy for lung oligometastases

30–60% of cancer patients develop lung metastases, mostly from primary tumors in the colon-rectum, lung, head and neck area, breast and kidney. Nowadays, stereotactic radiotherapy (SRT ) is considered the ideal modality for treating pulmonary metastases.When lung metastases are suspected, complete disease staging includes a total body computed tomography (CT ) and/or positron emission tomography-computed tomography (PET -CT ) scan. PET -CT has higher specificity and sensitivity than a CT scan when investigating mediastinal lymph nodes, diagnosing a solitary lung lesion and detecting distant metastases. For treatment planning, a multi-detector planning CT scan of the entire chest is usually performed, with or without intravenous contrast media or esophageal lumen opacification, especially when central lesions have to be irradiated. Respiratory management is recommended in lung SRT, taking the breath cycle into account in planning and delivery. For contouring, co-registration and/or matching planning CT and diagnostic images (as provided by contrast enhanced CT or PET-CT ) are useful, particularly for central tumors. Doses and fractionation schedules are heterogeneous, ranging from 33 to 60 Gy in 3–6 fractions. Independently of fractionation schedule, a BED₁₀ > 100 Gy is recommended for high local control rates. Single fraction SRT (ranges 15–30 Gy) is occasionally administered, particularly for small lesions. SRT provides tumor control rates of up to 91% at 3 years, with limited toxicities.The present overview focuses on technical and clinical aspects related to treatment planning, dose constraints, outcome and toxicity of SRT for lung metastases.     

Stereotactic radiotherapy for brain oligometastases

Brain metastases, the most common metastases in adults, will develop in up to 40% of cancer patients, accounting for more than one-half of all intracranial tumors. They are most associated with breast and lung cancer, melanoma and, less frequently, colorectal and kidney carcinoma.Magnetic resonance imaging (MRI) is the gold standard for diagnosis. For the treatment plan, computed tomography (CT ) images are co-registered and fused with a gadolinium-enhanced T1-weighted MRI where tumor volume and organs at risk are contoured. Alternatively, plain and contrast-enhanced CT scans are co-registered. Single-fraction stereotactic radiotherapy (SRT ) is used to treat patients with good performance status and up to 4 lesions with a diameter of 30 mm or less that are distant from crucial brain function areas. Fractionated SRT (2–5 fractions) is used for larger lesions, in eloquent areas or in proximity to crucial or surgically inaccessible areas and to reduce treatment-related neurotoxicity. The single-fraction SRT dose, which depends on tumor diameter, impacts local control. Fractionated SRT may encompass different schedules. No randomized trial data compared the safety and efficacy of single and multiple fractions. Both single-fraction and fractionated SRT provide satisfactory local control rates, tolerance, a low risk of transient acute adverse events and of radiation necrosis the incidence of which correlated with the irradiated brain volume.     

Stereotactic radiotherapy for liver oligometastases

The liver is the first metastatic site in 15–25% of colorectal cancer patients and one of the first metastatic sites for lung and breast cancer patients.A computed tomography (CT ) scan with contrast medium is a standard procedure for assessing liver lesions but magnetic resonance imaging (MRI) characterizes small lesions better thanks to its high soft-tissue contrast. Positron emission tomography with computed tomography (PET-CT ) plays a complementary role in the diagnosis of liver metastases. Triphasic (arterial, venous and time-delayed) acquisition of contrast-medium CT images is the first step in treatment planning. Since the liver exhibits a relatively wide mobility due to respiratory movements and bowel filling, appropriate techniques are needed for target identification and motion management. Contouring requires precise recognition of target lesion edges. Information from contrast MRI and/or PET-CT is crucial as they best visualize metastatic disease in the parenchyma. Even though different fractionation schedules were reported, doses and fractionation schedules for liver stereotactic radiotherapy (SRT ) have not yet been established. The best local control rates were obtained with BED₁₀ values over 100 Gy. Local control rates from most retrospective studies, which were limited by short follow-ups and included different primary tumors with intrinsic heterogeneity, ranged from 60% to 90% at 1 and 2 years. The most common SRT-related toxicities are increases in liver enzymes, hyperbilirubinemia and hypoalbuminemia. Overall, late toxicity is mild even in long-term follow-ups.     

Stereotactic radiotherapy for oligometastases in the lymph nodes

Even though systemic therapy is standard treatment for lymph node metastases, metastasis-directed stereotactic radiotherapy (SRT ) seems to be a valid option in oligometastatic patients with a low disease burden.Positron emission tomography-computed tomography (PET-CT ) is the gold standard for assessing metastases to the lymph nodes; co-registration of PET-CT images and planning CT images are the basis for gross tumor volume (GTV ) delineation. Appropriate techniques are needed to overcome target motion. SRT schedules depend on the irradiation site, target volume and dose constraints to the organs at risk (OARs) of toxicity. Although several fractionation schemes were reported, total doses of 48–60 Gy in 4–8 fractions were proposed for mediastinal lymph node SRT, with the spinal cord, esophagus, heart and proximal bronchial tree being the dose limiting OAR s. Total doses ranged from 30 to 45 Gy, with daily fractions of 7–12 Gy for abdominal lymph nodes, with dose limiting OARs being the liver, kidneys, bowel and bladder. SRT on lymph node metastases is safe; late side effects, particularly severe, are rare.     

Deep architecture neural network-based real-time image processing for image-guided radiotherapy

IntroductionTo develop real-time image processing for image-guided radiotherapy, we evaluated several neural network models for use with different imaging modalities, including X-ray fluoroscopic image denoising.Methods & materialsSetup images of prostate cancer patients were acquired with two oblique X-ray fluoroscopic units. Two types of residual network were designed: a convolutional autoencoder (rCAE) and a convolutional neural network (rCNN). We changed the convolutional kernel size and number of convolutional layers for both networks, and the number of pooling and upsampling layers for rCAE. The ground-truth image was applied to the contrast-limited adaptive histogram equalization (CLAHE) method of image processing. Network models were trained to keep the quality of the output image close to that of the ground-truth image from the input image without image processing. For image denoising evaluation, noisy input images were used for the training.ResultsMore than 6 convolutional layers with convolutional kernels >5 × 5 improved image quality. However, this did not allow real-time imaging. After applying a pair of pooling and upsampling layers to both networks, rCAEs with >3 convolutions each and rCNNs with >12 convolutions with a pair of pooling and upsampling layers achieved real-time processing at 30 frames per second (fps) with acceptable image quality.ConclusionsUse of our suggested network achieved real-time image processing for contrast enhancement and image denoising by the use of a conventional modern personal computer.     

Ultrasound versus Cone-beam CT image-guided radiotherapy for prostate and post-prostatectomy pretreatment localization

PurposeTo evaluate the accuracy of an intra-modality trans-abdominal ultrasound (TA-US) device against soft-tissue based Cone-Beam Computed tomography (CBCT) registration for prostate and post-prostatectomy pre-treatment positioning.MethodsThe differences between CBCT and US shifts were calculated on 25 prostate cancer patients (cohort A) and 11 post-prostatectomy patients (cohort B), resulting in 284 and 106 paired shifts for cohorts A and B, respectively. As a second step, a corrective method was applied to the US registration results to decrease the systematic shifts observed between TA-US and CBCT results. This method consisted of subtracting the mean difference obtained between US and CBCT registration results during the first 3 sessions from the US registration results of the subsequent sessions. Inter-operator registration variability (IOV) was also investigated for both modalities.ResultsAfter initial review, about 20% of the US images were excluded because of insufficient quality. The average differences between US and CBCT were: 2.8 ± 4.1 mm, −0.9 ± 4.2 mm, 0.4 ± 3.4 mm for cohort A and 1.3 ± 5.0 mm, −2.3 ± 4.6 mm, 0.5 ± 2.9 mm for cohort B, in the anterior-posterior (AP), superior-inferior (SI) and lateral (LR) directions, respectively. After applying the corrective method, only the differences in the AP direction remained significant (p < 0.05). The IOV values were between 0.6–2.0 mm and 2.1–3.5 mm for the CBCT and TA-US modalities, respectively.ConclusionsBased on the obtained results and on the image quality, the TA-US imaging modality is not safely interchangeable with CBCT for pre-treatment repositioning. Treatment margins adaptation based on the correction of the systematic shifts should be considered.     

Phase II trial of MVE-II in metastic malignant melanoma

Summary MVE-II, a low molecular weight fraction of pyran copolymer was utilized in a Phase II trial in patients with metastatic malignant melanoma. A total of 15 patients were investigated and no clinical responses or immunologic responses were observed. We concluded that MVE-II is not an active agent in malignant melanoma.     

Scapula alata in early breast cancer patients enrolled in a randomized clinical trial of post-surgery short-course image-guided radiotherapy

ABSTRACT: BACKGROUND: Scapula alata (SA) is a known complication of breast surgery associated with palsy of serratus anterior, but is seldom mentioned. We evaluated the risk factors associated with SA and the relationship of SA with ipsilateral shoulder/arm morbidity in a series of patients enrolled in a trial of post-surgery radiotherapy (RT). METHODS: The trial randomized women with completely resected stage I-II breast cancer to short-course image guided RT, vs. conventional RT. SA, arm volume and shoulder-arm mobility were measured prior to RT and at 1-3 months post-RT. Shoulder/arm morbidities were computed as post-RT percent change relatively to pre-RT measurements. RESULTS: Of 119 evaluable patients, 13 (=10.9%) had pre-RT SA. Age younger than 50 years old, body mass index less than 25 kg/m2, and axillary lymph node dissection, with odds ratios of 4.8 (P=0.009), 6.1 (P=0.016), and 6.1 (P=0.005), respectively. Randomization group was not significant. At 1-3 months post-RT, mean arm volume increased by 4.1% (P=0.036) and abduction decreased by 8.6% (P=0.046) among SA patients, but not among non SA patients. SA resolved in 8, persisted in 5, and appeared in 1 patient. CONCLUSION: Relationship of SA with lower body mass index suggests that SA might have been underestimated in overweight patients. Despite apparent resolution of SA in most patients, pre-RT SA portended an increased risk of shoulder/arm morbidity. We argue that SA warrants further investigation. Incidentally, the observation of SA occurring after RT in one patient represents the second case of post-RT SA reported in the literature.     

Phase II trial of hu14.18-IL2 for patients with metastatic melanoma

Phase I testing of the hu14.18-IL2 immunocytokine in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5?mg/m²/day. In this phase II study, 14 patients with measurable metastatic melanoma were scheduled to receive hu14.18-IL2 at 6?mg/m²/day as 4-h intravenous infusions on Days 1, 2, and 3 of each 28?day cycle. Patients with stable disease (SD) or regression following cycle 2 could receive two additional treatment cycles. The primary objective was to evaluate antitumor activity and response duration. Secondary objectives evaluated adverse events and immunologic activation. All patients received two cycles of treatment. One patient had a partial response (PR) [1 PR of 14 patients?=?response rate of 7.1?%; confidence interval, 0.2?C33.9?%], and 4 patients had SD and received cycles 3 and 4. The PR and SD responses lasted 3?C4?months. All toxicities were reversible and those resulting in dose reduction included grade 3 hypotension (2 patients) and grade 2 renal insufficiency with oliguria (1 patient). Patients had a peripheral blood lymphocytosis on Day 8 and increased C-reactive protein. While one PR in 14 patients met protocol criteria to proceed to stage 2 and enter 16 additional patients, we suspended stage 2 due to limited availability of hu14.18-IL2 at that time and the brief duration of PR and SD. We conclude that subsequent testing of hu14.18-IL2 should involve melanoma patients with minimal residual disease based on compelling preclinical data and the confirmed immune activation with some antitumor activity in this study.     

Feasibility of intensity-modulated and image-guided radiotherapy for functional organ preservation in locally advanced laryngeal cancer

Purpose

The study aims to assess the feasibility of intensity-modulated and image-guided radiotherapy (IMRT, and IGRT, respectively) for functional preservation in locally advanced laryngeal cancer. A retrospective review of 27 patients undergoing concurrent chemoradiation for locally advanced laryngeal cancers (8 IMRT, 19 IGRT) was undertaken. In addition to regular clinical examinations, all patients had PET imaging at 4 months and 10 months after radiotherapy, then yearly. Loco-regional control, speech quality and feeding-tube dependency were assessed during follow-up visits.

Results

At a median follow-up of 20 months (range 6–57 months), four out of 27 patients (14.8%) developed local recurrence and underwent salvage total laryngectomy. One patient developed distant metastases following salvage surgery. Among the 23 patients who conserved their larynx with no sign of recurrence at last follow-up, 22 (95%) reported normal or near normal voice quality, allowing them to communicate adequately. Four patients (14.8%) had long-term tube feeding-dependency because of severe dysphagia (2 patients) and chronic aspiration (2 patients, with ensuing death from aspiration pneumonia in one patient).

Conclusions and Clinical Relevance

Functional laryngeal preservation is feasible with IMRT and IGRT for locally advanced laryngeal cancer. However, dysphagia and aspiration remain serious complications, due most likely to high radiation dose delivery to the pharyngeal musculatures.     

Translational and rotational localization errors in cone-beam CT based image-guided lung stereotactic radiotherapy

PurposeAccurate localization is crucial in delivering safe and effective stereotactic body radiation therapy (SBRT). The aim of this study was to analyse the accuracy of image-guidance using the cone-beam computed tomography (CBCT) of the VERO system in 57 patients treated for lung SBRT and to calculate the treatment margins.Materials and methodsThe internal target volume (ITV) was obtained by contouring the tumor on maximum and mean intensity projection CT images reconstructed from a respiration correlated 4D-CT. Translational and rotational tumor localization errors were identified by comparing the manual registration of the ITV to the motion-blurred tumor on the CBCT and they were corrected by means of the robotic couch and the ring rotation. A verification CBCT was acquired after correction in order to evaluate residual errors.ResultsThe mean 3D vector at initial set-up was 6.6 ± 2.3 mm, which was significantly reduced to 1.6 ± 0.8 mm after 6D automatic correction. 94% of the rotational errors were within 3°. The PTV margins used to compensate for residual tumor localization errors were 3.1, 3.5 and 3.3 mm in the LR, SI and AP directions, respectively.ConclusionsOn-line image guidance with the ITV–CBCT matching technique and automatic 6D correction of the VERO system allowed a very accurate tumor localization in lung SBRT.     

First reported case of concurrent sonidegib and radiotherapy for recurrent,advanced basal cell carcinoma

Basal cell carcinoma (BCC ) is the most common human malignancy. Systemic therapy with a sonic hedgehog (SHH) pathway inhibitor plays an important role in the treatment of advanced BCC . Literature on concurrent use of radiation therapy (RT ) with SHH inhibitors has been minimal and has solely been focused on vismodegib. We present a case report of a patient with recurrent basal cell carcinoma involving the high-risk area of the face, who was denied surgery due to comorbidities and difficulty in obtaining complete tumor removal without cosmetic or functional impairment. The patient received combined treatment of fractionated radiation with concurrent sonidegib and had complete clinical response with no significant toxicities. This is the first reported case on the use of concurrent RT with sonidegib for management of recurrent basal cell carcinoma of the head and neck.     

Phase I dose escalation trial of stereotactic radiotherapy prior to robotic prostatectomy in high risk prostate cancer

BackgroundThe aim of the study was to investigate the safety of combining preoperative stereotactic body radiotherapy (SBRT) with robotic radical prostatectomy (RP) for high risk prostate cancer (HRCaP). Many patients with HRCaP will require adjuvant or salvage radiotherapy after RP. The addition of preoperative SBRT before RP may spare patients from subsequent prolonged courses of RT.Materials and methodsEligible patients had NCC N HRCaP and received a total of 25 Gy or 30 Gy in five daily fractions of SBRT to the prostate and seminal vesicles followed by robotic RP with pelvic lymphadenectomy 31–45 days later. The primary endpoint was prevalence of acute genitourinary (GU) and gastrointestinal (GI) toxicity. Secondary endpoints were patient-reported quality of life (QOL) and biochemical recurrence (BcR).ResultsThree patients received preoperative SBRT to 25 Gy and four received 30 Gy. Median follow-up was 18 months. Highest toxicity was grade 2 and 3 in six (85.7%) and one (14.3%) patients, respectively. All patients developed grade 2 erectile dysfunction and 4 of 7 (57%) developed grade 2 urinary incontinence (UI) within a month after surgery. One patient developed acute grade 3 UI, but there was no grade ≥ 4 toxicity. One patient experienced acute grade 2 hemorrhoidal bleeding. On QOL, acute GU complaints were common and peaked within 3 months. Bowel symptoms were mild. Two patients with pN+ experienced BcR.ConclusionsPreoperative SBRT before robotic RP in HRCaP is feasible and safe. The severity of acute GU toxicity with preoperative SBRT may be worse than RP alone, while bowel toxicity was mild.     

Volumetric image-guided conformal radiotherapy for localized prostate cancer: Analysis of dosimetric and clinical factors affecting acute and late toxicity

Aim

To identify factors influencing toxicity in patients affected by localized prostate cancer treated with conformal image-guided radiotherapy.