Michael C. Dobelbower

Impact of intensity-modulated radiation therapy technique for locally advanced non-small-cell lung cancer: A secondary analysis of the NRG oncology RTOG 0617 randomized clinical trial

Purpose Although intensity-modulated radiation therapy (IMRT) is increasingly used to treat locally advanced non-small-cell lung cancer (NSCLC), IMRT and three-dimensional conformal external beam radiation therapy (3D-CRT) have not been compared prospectively. This study compares 3D-CRT and IMRT outcomes for locally advanced NSCLC in a large prospective clinical trial. Patients and Methods A secondary analysis was performed to compare IMRT with 3D-CRT in NRG Oncology clinical trial RTOG 0617, in which patients received concurrent chemotherapy of carboplatin and paclitaxel with or without cetuximab, and 60- versus 74-Gy radiation doses. Comparisons included 2-year overall survival (OS), progression-free survival, local failure, distant metastasis, and selected Common Terminology Criteria for Adverse Events (version 3) ≥ grade 3 toxicities. Results The median follow-up was 21.3 months. Of 482 patients, 53% were treated with 3D-CRT and 47% with IMRT. The IMRT group had larger planning treatment volumes (median, 427 v 486 mL; P = .005); a larger planning treatment volume/volume of lung ratio (median, 0.13 v 0.15; P = .013); and more stage IIIB disease (30.3% v 38.6%, P = .056). Two-year OS, progression-free survival, local failure, and distant metastasis-free survival were not different between IMRT and 3D-CRT. IMRT was associated with less ≥ grade 3 pneumonitis (7.9% v 3.5%, P = .039) and a reduced risk in adjusted analyses (odds ratio, 0.41; 95% CI, 0.171 to 0.986; P = .046). IMRT also produced lower heart doses ( P < .05), and the volume of heart receiving 40 Gy (V40) was significantly associated with OS on adjusted analysis ( P < .05). The lung V5 was not associated with any ≥ grade 3 toxicity, whereas the lung V20 was associated with increased ≥ grade 3 pneumonitis risk on multivariable analysis ( P = .026). Conclusion IMRT was associated with lower rates of severe pneumonitis and cardiac doses in NRG Oncology clinical trial RTOG 0617, which supports routine use of IMRT for locally advanced NSCLC.

Comparison of Plan Quality and Delivery Time between Volumetric Arc Therapy (RapidArc) and Gamma Knife Radiosurgery for Multiple Cranial Metastases

BACKGROUND Volumetric modulated arc therapy (VMAT) has been shown to be feasible for radiosurgical treatment of multiple cranial lesions with a single isocenter. OBJECTIVE To investigate whether equivalent radiosurgical plan quality and reduced delivery time could be achieved in VMAT for patients with multiple intracranial targets previously treated with Gamma Knife (GK) radiosurgery. METHODS We identified 28 GK treatments of multiple metastases. These were replanned for multiarc and single-arc, single-isocenter VMAT (RapidArc) in Eclipse. The prescription for all targets was standardized to 18 Gy. Each plan was normalized for 100% prescription dose to 99% to 100% of target volume. Plan quality was analyzed by target conformity (Radiation Therapy Oncology Group and Paddick conformity indices [CIs]), dose falloff (area under the dose-volume histogram curve), as well as the V4.5, V9, V12, and V18 isodose volumes. Other end points included beam-on and treatment time. RESULTS Compared with GK, multiarc VMAT improved median plan conformity (CIVMAT = 1.14, CIGK = 1.65; P < .001) with no significant difference in median dose falloff (P = .269), 12 Gy isodose volume (P = .500), or low isodose spill (P = .49). Multiarc VMAT plans were associated with markedly reduced treatment time. A predictive model of the 12 Gy isodose volume as a function of tumor number and volume was also developed. CONCLUSION For multiple target stereotactic radiosurgery, 4-arc VMAT produced clinically equivalent conformity, dose falloff, 12 Gy isodose volume, and low isodose spill, and reduced treatment time compared with GK. Because of its similar plan quality and increased delivery efficiency, single-isocenter VMAT radiosurgery may constitute an attractive alternative to multi-isocenter radiosurgery for some patients.

Cetuximab augments cytotoxicity with poly (adp-ribose) polymerase inhibition in head and neck cancer.

Overexpression of the epidermal growth factor receptor (EGFR) is a hallmark of head and neck cancers and confers increased resistance and inferior survival rates. Despite targeted agents against EGFR, such as cetuximab (C225), almost half of treated patients fail this therapy, necessitating novel therapeutic strategies. Poly (ADP-Ribose) polymerase (PARP) inhibitors (PARPi) have gained recent attention due to their unique selectivity in killing tumors with defective DNA repair. In this study, we demonstrate that C225 enhances cytotoxicity with the PARPi ABT-888 in UM-SCC1, UM-SCC6, and FaDu head and neck cancer cells. The mechanism of increased susceptibility to C225 and PARPi involves C225-mediated reduction of non-homologous end-joining (NHEJ)- and homologous recombination (HR)-mediated DNA double strand break (DSB) repair, the subsequent persistence of DNA damage, and activation of the intrinsic apoptotic pathway. By generating a DSB repair deficiency, C225 can render head and neck tumor cells susceptible to PARP inhibition. The combination of C225 and the PARPi ABT-888 can thus be an innovative treatment strategy to potentially improve outcomes in head and neck cancer patients. Furthermore, this strategy may also be feasible for other EGFR overexpressing tumors, including lung and brain cancers.

Patterns of failure for glioblastoma multiforme following concurrent radiation and temozolomide

Purpose: To analyse patterns of failure in patients with glioblastoma multiforme treated with concurrent radiation and temozolomide.

Flattening filter-free linac improves treatment delivery efficiency in stereotactic body radiation therapy

Stereotactic body radiation therapy (SBRT) employs precision target tracking and image‐guidance techniques to deliver ablative doses of radiation to localized malignancies; however, treatment with conventional photon beams requires lengthy treatment and immobilization times. The use of flattening filter‐free (FFF) beams operating at higher dose rates can shorten beam‐on time, and we hypothesize that it will shorten overall treatment delivery time. A total of 111 lung and liver SBRT cases treated at our institution from July 2008 to July 2011 were reviewed and 99 cases with complete data were identified. Treatment delivery times for cases treated with a FFF linac versus a conventional dose rate linac were compared. The frequency and type of intrafraction image guidance was also collected and compared between groups. Three hundred and ninety‐one individual SBRT fractions from 99 treatment plans were examined; 36 plans were treated with a FFF linac. In the FFF cohort, the mean (± standard deviation) treatment time (time elapsed from beam‐on until treatment end) and patients immobilization time (time from first alignment image until treatment end) was 11.44 (± 6.3) and 21.08 (± 6.8) minutes compared to 32.94 (± 14.8) and 47.05 (± 17.6) minutes for the conventional cohort (p<0.01 for all values). Intrafraction‐computed tomography (CT) was used more often in the conventional cohort (84% vs. 25%; p<0.05), but use of orthogonal X‐ray imaging remained the same (16% vs. 19%). For lung and liver SBRT, a FFF linac reduces treatment and immobilization time by more than 50% compared to a conventional linac. In addition, treatment with a FFF linac is associated with less physician‐ordered image guidance, which contributes to further improvement in treatment delivery efficiency. PACS number: 87.55.‐x

Effects of flattening filter-free and volumetric-modulated arc therapy delivery on treatment efficiency

Flattening filter‐free (FFF) beams are available on an increasing number of commercial linear accelerators. FFF beams have higher dose rates than flattened beams of equivalent energy which can lead to increased efficiency of treatment delivery, especially in conjunction with increased FFF beam energy and arc‐based delivery configurations. The purpose of this study is to quantify and assess the implications of improved treatment efficiency for several FFF delivery options on common types of linac applicable radiotherapy. Eleven characteristic cases representative of a variety of clinical treatment sites and prescription doses were selected from our patient population. Treatment plans were generated for a Varian TrueBeam linear accelerator. For each case, a reference plan was created using DMLC IMRT with 6 MV flat beams. From the same initial objectives, plans were generated using DMLC IMRT and volumetric‐modulated arc therapy (VMAT) with 6 MV FFF and 10 MV FFF beams (max. dose rates of 1400 and 2400 MU/min, respectively). The plans were delivered to a phantom; beam‐on time, total treatment delivery time, monitor units (MUs), and integral dose were recorded. For plans with low dose fractionations (1.8–2.0 & 3.85 Gy/fraction), mean beam‐on time difference between reference plan and most efficient FFF plan was 0.56 min (41.09% decrease); mean treatment delivery time difference between the reference plan and most efficient FFF plan was 1.54 min (range: 0.31–3.56 min), a relative improvement of 46.1% (range: 29.2%‐59.2%). For plans with high dose fractionations (16–20 Gy/fraction), mean beam‐on time difference was 6.79 min (74.9% decrease); mean treatment delivery time difference was 8.99 min (range: 5.40–13.05 min), a relative improvement of 71.1% (range: 53.4%‐82.4%). 10 MV FFF VMAT beams generated the most efficient plan, except in the spine SBRT case. The distribution of monitor unit counts did not vary by plan type. In cases where respiratory motion management would be applicable, 10 MV FFF DMLC IMRT reduced beam‐on time/field to less than 12 sec. FFF beams significantly reduced treatment delivery time. For radiosurgical doses, the efficiency improvement for FFF beams was clinically significant. For conventional fractionation, a large improvement in relative treatment delivery time was observed, but the absolute time savings were not likely to be of clinical value. In cases that benefit from respiratory motion management, beamon/field was reduced to a time for which most patients can comfortably maintain deep inspiratory breath hold. PACS numbers: 87.55.D‐, 87.55.de, 87.56.bd, 87.56.N‐

Safety and Outcome Measures of First-in-human Intraperitoneal α Radioimmunotherapy With 212pb-tcmc-trastuzumab

Purpose: One-year monitoring of patients receiving intraperitoneal (IP) 212Pb-TCMC-trastuzumab to provide long-term safety and outcome data. A secondary objective was to study 7 tumor markers for correlation with outcome. Methods: Eighteen patients with relapsed intra-abdominal human epidermal growth factor receptor-2 expressing peritoneal metastases were treated with a single IP infusion of 212Pb-TCMC-trastuzumab, delivered <4 h after 4 mg/kg IV trastuzumab. Seven tumor markers were studied for correlation with outcome. Results: Six dose levels (7.4, 9.6, 12.6, 16.3, 21.1, 27.4 MBq/m2) were well tolerated with early possibly agent-related adverse events being mild, transient, and not dose dependent. These included asymptomatic, abnormal laboratory values. No late renal, liver, cardiac, or other toxicity was noted up to 1 year. There were no clinical signs or symptoms of an immune response to 212Pb-TCMC-trastuzumab, and assays to detect an immune response to this conjugate were negative for all tested. Tumor marker studies in ovarian cancer patients showed a trend of decreasing Cancer antigen 72-4 (CA 72-4) aka tumor-associated glycoprotein 72 (TAG-72) and tumor growth with increasing administered radioactivity. Other tumor markers, including carbohydrate antigen (CA125), human epididymis protein 4 (HE-4), serum amyloid A (SAA), mesothelin, interleukin-6 (IL-6), and carcinoembryonic antigen (CEA) did not correlate with imaging outcome. Conclusions: IP 212Pb-TCMC-trastuzumab up to 27 MBq/m2 seems safe for patients with peritoneal carcinomatosis who have failed standard therapies. Serum TAG-72 levels better correlated to imaging changes in ovarian cancer patients than the more common tumor marker, CA125.

Optimal Planning Target Volume Margins for Elective Pelvic Lymphatic Radiotherapy in High-Risk Prostate Cancer Patients

Purpose. High-risk prostate cancer patients often receive radiotherapy (RT) to pelvic lymphatics (PLs). The aim of this study was to determine the safety margin around clinical target volume for PL (PL-CTV) to construct planning target volume for PL (PL-PTV) and for planning elective PL irradiation. Methods and Materials. Six patients who received RT to PL as part of prostate cancer treatment were identified. To determine average daily shifts of PL, the right and left IVs were contoured at 3 predetermined slices on the daily MV scans and their daily shifts were measured at these 3 levels using a measuring tool. Results. A total of 1,932 observations were made. Daily shifts of IV were random in distribution, and the largest observed shift was 13.6 mm in lateral and 15.4 mm in AP directions. The mean lateral and AP shifts of IV were 2.1 mm (±2.2) and 3.5 mm (±2.7), respectively. The data suggest that AP and lateral margins of 8.9 mm and 6.5 mm are necessary. Conclusions. With daily alignment to the prostate, we recommend an additional PL-CTV to PL-PTV conversion margin of 9 mm (AP) and 7 mm (lateral) to account for daily displacement of PL relative to the prostate.

Retention Rate of Electromagnetic Navigation Bronchoscopic Placed Fiducial Markers for Lung Radiosurgery

BACKGROUND Radiosurgery is becoming an increasingly used modality for the medically inoperable early stage lung cancer patient. The optimal fiducial marker with respect to retention rate has yet to be identified. METHODS We retrospectively reviewed our experience with electromagnetic navigational bronchoscopic fiducial marker placement in preparation for stereotactic radiosurgery. RESULTS Forty-eight patients, treated between 2010 and January 2013, were retrospectively reviewed. All patients had a diagnosis of early stage lung cancer. Comparison of initial fiducial placement procedure data with imaging at the time of treatment was accomplished for all patients in this data set. Fiducial retention rates were as follow: VortX coil fiducials were retained in 59 of 61 (96.7%) cases; two-band fiducials were retained in 24 of 33 (72.7%) of instances; and gold seed fiducials were retained in 23 of 33 (69.7%) of cases. Retention was statistically superior when comparing the VortX coil with the two-band fiducial or the gold seed (p = 0.004 and p = 0.0001). Anatomic location by lobe was analyzed, but no statistically significant differences were observed. CONCLUSIONS The VortX coil fiducial marker showed a statistically significant increase in retention rate compared with gold seeds or two-band fiducials. This may translate to cost savings through placing fewer markers per patient as retention is high.

Efficacy and toxicity of conventionally fractionated pelvic radiation with a hypofractionated simultaneous versus conventionally fractionated sequential boost for patients with high-risk prostate cancer.

Abstract Purpose. To determine if high-risk prostate cancer responds differently to hypofractionation. Material and methods. One hundred and fifty-seven men with NCCN high-risk (T3, PSA > 20, or Gleason ≥ 8) clinically localized prostate cancer treated between 1998 and 2010 met the inclusion criteria for the analysis. Eighty-two were treated with conventional WPRT with a conventionally fractionated sequential boost to the prostate (cRT), with the prostate receiving 75–77 Gy in 1.8–2.0 Gy fractions. Seventy-five were treated with pelvic IMRT with a hypofractionated simultaneous boost to the prostate (hRT), with the prostate receiving 70 Gy in 2.5 Gy fractions. The dose to the pelvic lymph nodes was 45 Gy in the cRT group and 50.4 Gy in the hRT group, both at 1.8 Gy per fraction. Ninety-two percent received neoadjuvant hormonal ablation therapy, typically beginning two months prior to the start of RT. Results. Median follow-up was 6.5 years for men receiving cRT and 3.7 years for those receiving hRT. The actuarial rate of biochemical control at four years was 88% for cRT and 94% for hRT (p = 0.82). The rates of early rectal and urinary grade ≥ 2 toxicities were 35% (29 of 82) and 49% (40 of 82) for the cRT group and 36% (27 of 75) and 44% (33 of 75) for the hRT group. The actuarial rate of late grade ≥ 2 rectal toxicity at four years was 25% for the cRT group and 13% for the hRT group (p = 0.037). The rate of late grade 3 rectal complications was 4% (3 of 82) for patients receiving cRT and 1% (1 of 75) for patients receiving hRT. Conclusion. Initial follow-up indicates equivalent biochemical control between regimens. Patients receiving hRT experienced fewer late rectal complications.