Possibility Of Dose Escalation Research Articles

Stereotactic Body Radiation Therapy in Prostate Cancer: Where Do We Stand?

Stereotactic body radiotherapy (SBRT) is an important option for prostate cancer treatment. It involves the delivery of a high dose of radiation to the malignant tissue without affecting the neighboring healthy tissue to achieve a high therapeutic index. As the cells of prostate cancer are radiobiologically similar to a late-responding tissue with a low 𝛼/𝛽 ratio, the dose escalation approach has a better disease control probability than conventional dose fractionation. Therefore, considering the availability of intensity-modulated RT and possibility of dose escalation (>70 Gy), ultrahypofractionated SBRT is now being recommended in select patients with prostate cancers of low and intermediate risk. Although adverse events following SBRT are a concern, acute toxicity can be limited to a certain extent by adjusting the overall length of treatment time by spacing out RT over multiple fractions. Modern radiation planning and delivery methods used in conjunction with cutting-edge imaging techniques have led to the increased adoption of SBRT in prostate cancer. Thus, from a practical standpoint, it is noninvasive and effective for treating prostate cancer, leading to increased access and higher patient satisfaction.

Naxitamab Activity in Neuroblastoma Cells Is Enhanced by Nanofenretinide and Nanospermidine

Neuroblastoma cells highly express the disialoganglioside GD2, a tumor-associated carbohydrate antigen, which is also expressed in neurons, skin melanocytes, and peripheral nerve fibers. Immunotherapy with monoclonal anti-GD2 antibodies has a proven efficacy in clinical trials and is included in the standard treatment for children with high-risk neuroblastoma. However, the strong neuro-toxicity associated with anti-GD2 antibodies administration has hindered, until now, the possibility for dose-escalation and protracted use, thus restraining their therapeutic potential. Strategies to increase the efficacy of anti-GD2 antibodies are actively sought, with the aim to enable chronic treatments that could eradicate minimal residual disease and subsequent relapses, often occurring after treatment. Here, we report that Nanofenretinide and Nanospermidine improved the expression of GD2 in neuroblastoma cells (CHP-134) and provided different effects in combination with the anti-GD2 antibody naxitamab. In particular, Nanofenretinide significantly increased the cytotoxic effect of naxitamab while Nanospermidine inhibited cell motility at extents proportional to naxitamab concentration. In neuroblastoma cells characterized by a low and heterogeneous basal expression of GD2, such as SH-SY5Y, which may represent the cell heterogeneity in tumors after chemotherapy, both Nanofenretinide and Nanospermidine increased GD2 expression in approximately 50% of cells, thus shifting the tumor population towards improved sensitivity to anti-GD2 antibodies.

Intraoperative radiotherapy (IORT) for surgically resected brain metastases: outcome analysis of an international cooperative study.

The ideal delivery of radiation to the surgical cavity of brain metastases (BMs) remains the subject of debate. Risks of local failure (LF) and radiation necrosis (RN) have prompted a reappraisal of the timing and/or modality of this critical component of BM management. IORT delivered at the time of resection for BMs requiring surgery offers the potential for improved local control (LC) afforded by the elimination of delay in time to initiation of radiation following surgery, decreased uncertainty in target delineation, and the possibility of dose escalation beyond that seen in stereotactic radiosurgery (SRS). This study provides a retrospective analysis with identification of potential predictors of outcomes. Retrospective data was collected on patients treated with IORT immediately following surgical resection of BMs at three institutions according to the approval of individual IRBs. All patients were treated with 50kV portable linear accelerator using spherical applicators ranging from 1.5 to 4.0 cm. Statistical analyses were performed using IBM SPSS with endpoints of LC, DBC, incidence of RN, and overall survival (OS) and p < 0.05 considered significant. 54 patients were treated with IORT with a median age of 64 years. The most common primary diagnosis was non-small cell lung cancer (40%) with the most common location in the frontal lobe (38%). Median follow-up was 7.2 months and 1-year LC, DBC, and OS were 88%, 58%, and 73%, respectively. LMD was identified in 2 patients (3%) and RN present in 4 patients (7%). The only predictor of LC was extent of resection with 1-year LC of 94% for GTR versus 62% for STR (p = 0.049). IORT is a safe and effective means of delivering adjuvant radiation to the BM resection cavities with high rates of LC and low incidence of RN. Further studies are warranted directly comparing LC outcomes to SRS.

RADI-20. RETROSPECTIVE OUTCOME ANALYSIS OF INTRAOPERATIVE RADIOTHERAPY (IORT) FOR SURGICALLY RESECTED BRAIN METASTASES: AN INTERNATIONAL COOPERATIVE STUDY.

BACKGROUND & OBJECTIVE: The ideal delivery of adjuvant radiation to the surgical cavity of brain metastases (BMs) remains the subject of debate. Risks of leptomeningeal dissemination (LMD), local failure (LF) and radiation necrosis (RN) have prompted a reappraisal of the timing and/or modality of this critical component of BM management. IORT delivered at the time of resection for BMs requiring surgery offers the potential for improved LC and decreased LMD afforded by the elimination of delay in time to initiation of radiation following surgery and the possibility of dose escalation beyond that seen in stereotactic radiosurgery (SRS). This study provides a retrospective analysis with identification of potential predictors of outcomes. METHODS: Retrospective data was collected on patients treated with IORT immediately following surgical resection of BMs at three institutions according to the approval of individual IRBs. All patients were treated with the Zeiss Intrabeam device (Carl Zeiss Meditech, Germany) using spherical applicators ranging from 1.5 to 4.0cm with 50kV output. Statistical analyses were performed using SPSS (IBM) with endpoints of LF, DBF, incidence of RN, and overall survival (OS) and p< 0.05 considered significant. RESULTS: 54 patients were treated with IORT with a median age of 64 years. The most common primary diagnosis was non-small cell lung cancer (40%) with the most common location in the frontal lobe (38%). Median follow-up was 7.2 months and 1-year LC, DBF, and OS were 88%, 58%, and 73%, respectively. LMD was identified in 2 patients (3%) and RN present in 4 patients (7%). The only predictor of LC was extent of resection with 1-yr LC of 94% for GTR vs 62% for STR (p=0.049). CONCLUSIONS: IORT is a safe and effective means of delivering adjuvant radiation to the BM resection cavities with high rates of LC and low incidence of RN.

46. Real-time MR image guided radiotherapy: The time is near!

Introduction Despite the fact that several studies has shown that dose escalation improves treatment outcome, there are currently very limited clinical indications treated with high dose-high precision radiotherapy. Due to the inability to visualize tumor and critical organs sufficiently during delivery, a normal tissue margin around the tumor needs to be included in the target volume, which leads to toxicity and thereby limiting the maximum dose. If high quality (contrast) real-time MRI images of the tumor and surroundings are available during treatment, it is expected that smaller normal tissue margins are necessary (what you see is what you treat), and consequently increasing the possibility for dose escalation. Methods MR guided radiotherapy is rapidly evolving from research feasibilities towards real clinical treatment machines. Cobalt systems are currently on the market and soon the first clinical MR-linac based on a 7 MV linear accelerator and a 1.5T MRI scanner will become operational. It is a misconception to consider the MR-guided radiotherapy systems as the next generation CBCT-linacs. The combination of a radiotherapy device with an MRI scanner enables high dose-high precision radiotherapy for many complex indications, bringing a new paradigm for radiotherapy. This enables new possibilities of on-line treatment plan adaptation, including gating and tumor tracking. However, the implications on reference dosimetry, machine QA and treatment planning due to the changed dose deposition by the magnetic field must be taken into account. This opens a whole new field of radiotherapy physics. In this talk the different MR radiotherapy solutions currently clinically available or under development will be discussed. Furthermore, a short description of the clinical MR guided workflow is given. The impact of the magnetic field on dose deposition is large due to the Lorentz force on the electrons released in matter. This results in skewed dose distributions and different build-up and exit doses compared to distributions in conventional radiotherapy. Since the trajectories of the electrons are now curved, readings in ionization chambers will also differ. My talk will address these effects on dose based on the Utrecht experience but these implications also apply to the other MR radiotherapy solutions. Conclusions The use of MRI in radiotherapy is fast growing. To explore the patient benefits of MR guided radiotherapy almost all conventional aspects of current radiotherapy needs an overhaul, from the clinical workflow to dosimetry physics and machine QA. A short overview will be given.

Complément d’irradiation dans le cancer du col de l’utérus localement évolué : curiethérapie utérovaginale ou radiothérapie conformationnelle avec modulation d’intensité ?

Intensity-modulated conformal radiotherapy (IMRT) is booming as treatment of locally advanced cervical cancer. This technique reduces the doses delivered to organs at risk and, by analogy to the irradiation of prostate cancer, opens the door to the possibility of dose escalation to levels close or similar to those achieved by brachytherapy. To date, several studies comparing IMRT with brachytherapy have been published, often methodologically flawed, concluding sometimes that both techniques are comparable. These results should be taken with extreme caution and should not overshadow the recent advances in brachytherapy with the use of 3D imaging and optimization. Preliminary works also showed that the combination of 3D optimized brachytherapy with IMRT could improve the management of the local disease especially for lesions poorly covered by intracavitary techniques.

Dosimetric Benefit of Incorporating Active Breath Control in Image-guided Radiotherapy for Gastric Cancer Treatment

Radiotherapy for gastric cancer is generally delivered with patients in free breathing and a large margin is needed to compensate for the respiratory related organ motion. We have investigated the dosimetric benefit and possibility of dose escalation using the Active Breath Control (ABC) in image-guided radiotherapy (IGRT).

A phase III trial of carboplatin, paclitaxel, and thoracic radiation therapy with or without thalidomide in patients with stage III non-small cell carcinoma of the lung (NSCLC): E3598

7503 Background: Thalidomide (T) is an oral angiogenesis inhibitor with anti-tumor activity in hematological malignancies. Given that antiangiogenic drugs such as bevacizumab have proven activity in advanced NSCLC, ECOG conducted a phase III study to compare the effects of the addition of thalidomide to paclitaxel/carboplatin/radiation therapy (PC/RT) on overall survival (OS) in pts with newly diagnosed stage III NSCLC. Secondary endpoints included time to progression (PFS) and toxicity. Methods: Pts were required to have inoperable stage IIIA or IIIB (no pleural effusion) NSCLC and a PS of 0 or 1. Pts were randomized to receive 2 cycles of P (225 mg/m2)+ C (AUC=6) every 3 wks or PC + thalidomide starting at 200 mg daily with the possibility of dose escalation. This was followed by weekly C (AUC=2), P (45 mg/m2) and concurrent RT (60 Gy) ± T. Pts on PC/RT + T continued thalidomide for 24 mo. or until disease progression. Results: 277 eligible pts were randomized to PC/RT and 272 pts to PC/RT + T. Median age was 63; 61% of pts had stage IIIB disease, 35% had squamous histology, and 46% were PS 0. The third planned interim analysis was conducted with 403 of 506 planned deaths (73.9%) for full analysis and the trial was stopped early by the ECOG Data Monitoring Committee for futility. The median overall survival for the no T arm was 15.3 mo. (12.4–20.2 mo.) compared to 16.0 mo for the T arm (14.4–18.3 mo.); hazard ratio = 0.985 (0.81–1.19); p = 0.88. Median PFS for the no T arm was 7.6 mo. (6.6–8.7 mo.) compared to 8.0 mo. for the T arm (7.1–9.1 mo.), p&gt;0.05. The most common toxicity on both arms was myelosuppression. 11% of pts on the T arm had a grade 3–5 thrombosis/embolism, compared to &lt;3% on the no T arm. Conclusions: The addition of thalidomide to PC/RT in pts with stage III NSCLC does not provide a clinically significant benefit. [Table: see text]

Potential for reduced toxicity and dose escalation in the treatment of inoperable non–small-cell lung cancer: A comparison of intensity-modulated radiation therapy (IMRT), 3D conformal radiation, and elective nodal irradiation

Purpose To systematically evaluate four different techniques of radiation therapy (RT) used to treat non–small-cell lung cancer and to determine their efficacy in meeting multiple normal-tissue constraints while maximizing tumor coverage and achieving dose escalation. Methods and materials Treatment planning was performed for 18 patients with Stage I to IIIB inoperable non–small-cell lung cancer using four different RT techniques to treat the primary lung tumor ± the hilar/mediastinal lymph nodes: ( 1) Intensity-modulated radiation therapy (IMRT), ( 2) Optimized three-dimensional conformal RT (3D-CRT) using multiple beam angles, ( 3) Limited 3D-CRT using only 2 to 3 beams, and ( 4) Traditional RT using elective nodal irradiation (ENI) to treat the mediastinum. All patients underwent virtual simulation, including a CT scan and 18fluorodeoxyglucose positron emission tomography scan, fused to the CT to create a composite tumor volume. For IMRT and 3D-CRT, the target included the primary tumor and regional nodes either ≥1.0 cm in short-axis dimension on CT or with increased uptake on PET. For ENI, the target included the primary tumor plus the ipsilateral hilum and mediastinum from the inferior head of the clavicle to at least 5.0 cm below the carina. The goal was to deliver 70 Gy to ≥99% of the planning target volume (PTV) in 35 daily fractions (46 Gy to electively treated mediastinum) while meeting multiple normal-tissue dose constraints. Heterogeneity correction was applied to all dose calculations (maximum allowable heterogeneity within PTV 30%). Pulmonary and esophageal constraints were as follows: lung V 20 ≤25%, mean lung dose ≤15 Gy, esophagus V 50 ≤25%, mean esophageal dose ≤25 Gy. At the completion of all planning, the four techniques were contrasted for their ability to achieve the set dose constraints and deliver tumoricidal RT doses. Results Requiring a minimum dose of 70 Gy within the PTV, we found that IMRT was associated with a greater degree of heterogeneity within the target and, correspondingly, higher mean doses and tumor control probabilities (TCPs), 7%–8% greater than 3D-CRT and 14%–16% greater than ENI. Comparing the treatment techniques in this manner, we found only minor differences between 3D-CRT and IMRT, but clearly greater risks of pulmonary and esophageal toxicity with ENI. The mean lung V 20 was 36% with ENI vs. 23%–25% with the three other techniques, whereas the average mean lung dose was approximately 21.5 Gy (ENI) vs. 15.5 Gy (others). Similarly, the mean esophagus V 50 was doubled with ENI, to 34% rather than 15%–18%. To account for differences in heterogeneity, we also compared the techniques giving each plan a tumor control probability equivalent to that of the optimized 3D-CRT plan delivering 70 Gy. Using this method, IMRT and 3D-CRT offered similar results in node-negative cases (mean lung and esophageal normal-tissue complication probability [NTCP] of approximately 10% and 2%–7%, respectively), but ENI was distinctly worse (mean NTCPs of 29% and 20%). In node-positive cases, however, IMRT reduced the lung V 20 and mean dose by approximately 15% and lung NTCP by 30%, compared to 3D-CRT. Compared to ENI, the reductions were 50% and >100%. Again, for node-positive cases, especially where the gross tumor volume was close to the esophagus, IMRT reduced the mean esophagus V 50 by 40% (vs. 3D-CRT) to 145% (vs. ENI). The esophageal NTCP was at least doubled converting from IMRT to 3D-CRT and tripled converting from IMRT to ENI. Finally, the total number of fractions for each plan was increased or decreased until all outlined normal-tissue constraints were reached/satisfied. While meeting all constraints, IMRT or 3D-CRT increased the deliverable dose in node-negative patients by >200% over ENI. In node-positive patients, IMRT increased the deliverable dose 25%–30% over 3D-CRT and 130%–140% over ENI. The use of 3D-CRT without IMRT increased the deliverable RT dose >80% over ENI. Using a limited number of 3D-CRT beams decreased the lung V 20, mean dose, and NTCP in node-positive patients. Conclusions The use of 3D-CRT, particularly with only 3 to 4 beam angles, has the ability to reduce normal-tissue toxicity, but has limited potential for dose escalation beyond the current standard in node-positive patients. IMRT is of limited additional value (compared to 3D-CRT) in node-negative cases, but is beneficial in node-positive cases and in cases with target volumes close to the esophagus. When meeting all normal-tissue constraints in node-positive patients, IMRT can deliver RT doses 25%–30% greater than 3D-CRT and 130%–140% greater than ENI. Whereas the possibility of dose escalation is severely limited with ENI, the potential for pulmonary and esophageal toxicity is clearly increased.

Curative radiotherapy of localized prostate cancer. Treatment methods and results

Radiation oncology has undergone rapid technical development during the last few years. The further development of treatment planning systems and treatment machines had a major impact on the improvement of radiation therapy results in prostate cancer. This paper presents different treatment modalities and results. Currently available are three-dimensional conformal radiation, intensity modulated radiation therapy (IMRT), high dose rate brachytherapy, and low dose rate brachytherapy (seed implantation). All modalities offer the possibility for dose escalation, which is essential for curative treatment. Dose escalation using these techniques makes it possible to reduce the dose for the surrounding organs at risk. Three-dimensional conformal radiation therapy can be delivered with doses up to 78 Gy. The biochemical control rate is up to 90% depending on the risk factors T stage, initial PSA, and Gleason score. The incidence of late side effects is <10%. IMRT is a newer modality for percutaneous radiotherapy. By individual dose modification in the treatment fields, doses >80 Gy can be delivered in small treatment volumes. Treatment has to be highly precise to avoid dose peaks in the organs at risk, i.e., rectum and bladder. The preliminary data for remission and toxicity rates are promising, but it is too early for final conclusions. For cases with high-risk factors such as PSA >10 ng/ml, Gleason score >6, and stage T3, percutaneous radiation can be combined with neoadjuvant or adjuvant hormonal treatment. Randomized trials showed an improvement of the results in favor of combined treatment. HDR brachytherapy in combination with external radiation is a good option for dose escalation in patients with locally advanced tumors and/or other high-risk factors. The biochemical control rates are between 60 and 84%, late effects occur in less than 10%. Seed implantation (LDR brachytherapy) as sole treatment is indicated for prognostically favorable situations (PSA <10 ng/ml, Gleason score < or =6, and T1c or T2a tumors). The biochemical control rates are between 80 and 90%. Toxicity consists of urine retention and proctitis, occurring in 10-20% of the patients.

PDEPT: polymer-directed enzyme prodrug therapy

Polymer Directed Enzyme Prodrug Therapy (PDEPT) was proposed as a novel two-step antitumour approach. Combination of N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer prodrug and an HPMA copolymer-enzyme conjugate was suggested as a means of generating a potent cytotoxic agent rapidly and selectively at the tumour site. To test the feasibility of PDEPT, two HPMA copolymer-enzyme conjugates were synthesised (containing (β-lactamase and cathepsin B as model enzymes) and their in vitro and in vivo properties were evaluated. HPMA copolymer-Gly-Phe-Leu-Gly-doxorubicin (PKl) was used as a substrate for HPMA copolymer-cathepsin B to test the PDEPT combination in vitro and in vivo. Following polymer conjugation (yield of 30-35%) both enzymes retained 20- 25% of their enzymatic activity. To investigate their pharmacokinetics in vivo, 125I-labelled HPMA copolymer-enzyme conjugates were administered intravenously (i.v.) to B16F10 tumour-bearing mice. Due to selective tumour tissue accumulation by the enhanced permeability and retention (EPR) effect, the HPMA copolymer-enzyme conjugates showed a 2-3 fold increase in tumour accumulation compared to the native enzyme, and they also exhibited a longer plasma half-life. The ability of HPMA copolymer-cathepsin B to access and degrade the prodrug in vivo was determined by HPLC evaluation of doxombicin release. PKl was injected i.v. to B16F10-bearing mice and after 5 h HPMA copolymer-cathepsin B was administered. This enzyme led to a rapid increase in the rate of doxorubicin release intratumourally (3.6-fold faster than seen for PKl alone). Moreover, when the antitumour activity (doxorubicin-equivalent dose of 10 mg/Kg) was measured using this tumour model, the combination (PDEPT) had the highest activity (T/C = 168%) compared to that seen for PKl alone (T/C = 152%) or free doxorubicin (T/C = 144%). No animal weight loss or other toxicity was observed indicating the possibility of dose escalation. As conjugation of proteins to HPMA copolymers is known to reduce their immunogenicity, and antitumour activity has been demonstrated, further development of PDEPT is warranted.

Deep inspiration breath-hold technique for lung tumors: the potential value of target immobilization and reduced lung density in dose escalation

Purpose/Objective: This study evaluates the dosimetric benefits and feasibility of a deep inspiration breath-hold (DIBH) technique in the treatment of lung tumors. The technique has two distinct features—deep inspiration, which reduces lung density, and breath-hold, which immobilizes lung tumors, thereby allowing for reduced margins. Both of these properties can potentially reduce the amount of normal lung tissue in the high-dose region, thus reducing morbidity and improving the possibility of dose escalation. Methods and Materials: Five patients treated for non-small cell lung carcinoma (Stage IIA-IIIB) received computed tomography (CT) scans under 4 respiration conditions: free-breathing, DIBH, shallow inspiration breath-hold, and shallow expiration breath-hold. The free-breathing and DIBH scans were used to generate 3-dimensional conformal treatment plans for comparison, while the shallow inspiration and expiration scans determined the extent of tumor motion under free-breathing conditions. To acquire the breath-hold scans, the patients are brought to reproducible respiration levels using spirometry, and for DIBH, modified slow vital capacity maneuvers. Planning target volumes (PTVs) for free-breathing plans included a margin for setup error (0.75 cm) plus a margin equal to the extent of tumor motion due to respiration (1–2 cm). Planning target volumes for DIBH plans included the same margin for setup error, with a reduced margin for residual uncertainty in tumor position (0.2–0.5 cm) as determined from repeat fluoroscopic movies. To simulate the effects of respiration-gated treatments and estimate the role of target immobilization alone (i.e., without the benefit of reduced lung density), a third plan is generated from the free-breathing scan using a PTV with the same margins as for DIBH plans. Results: The treatment plan comparison suggests that, on average, the DIBH technique can reduce the volume of lung receiving more than 25 Gy by 30% compared to free-breathing plans, while respiration gating can reduce the volume by 18%. The DIBH maneuver was found to be highly reproducible, with intra breath-hold reproducibility of 1.0 (± 0.9) mm and inter breath-hold reproducibility of 2.5 (± 1.6) mm, as determined from diaphragm position. Patients were able to perform 10–13 breath-holds in one session, with a comfortable breath-hold duration of 12–16 s. Conclusion: Patients tolerate DIBH maneuvers well and can perform them in a highly reproducible fashion. Compared to conventional free-breathing treatment, the DIBH technique benefits from reduced margins, as a result of the suppressed target motion, as well as a decreased lung density; both contribute to moving normal lung tissue out of the high-dose region. Because less normal lung tissue is irradiated to high dose, the possibility for dose escalation is significantly improved.