Addition of Metastasis-Directed Therapy to Systemic Therapy for Oligometastatic Pancreatic Ductal Adenocarcinoma (EXTEND): A Multicenter, Randomized Phase II Trial.

PURPOSE: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC). METHODS: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures. RESULTS: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy (P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS. CONCLUSION: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Phase I trial of single-photon emission computed tomography-guided liver-directed radiotherapy for patients with low functional liver volume.

BACKGROUND: Traditional constraints specify that 700 cc of liver should be spared a hepatotoxic dose when delivering liver-directed radiotherapy to reduce the risk of inducing liver failure. We investigated the role of single-photon emission computed tomography (SPECT) to identify and preferentially avoid functional liver during liver-directed radiation treatment planning in patients with preserved liver function but limited functional liver volume after receiving prior hepatotoxic chemotherapy or surgical resection. METHODS: This phase I trial with a 3 + 3 design evaluated the safety of liver-directed radiotherapy using escalating functional liver radiation dose constraints in patients with liver metastases. Dose-limiting toxicities were assessed 6-8 weeks and 6 months after completing radiotherapy. RESULTS: All 12 patients had colorectal liver metastases and received prior hepatotoxic chemotherapy; 8 patients underwent prior liver resection. Median computed tomography anatomical nontumor liver volume was 1584 cc (range = 764-2699 cc). Median SPECT functional liver volume was 1117 cc (range = 570-1928 cc). Median nontarget computed tomography and SPECT liver volumes below the volumetric dose constraint were 997 cc (range = 544-1576 cc) and 684 cc (range = 429-1244 cc), respectively. The prescription dose was 67.5-75 Gy in 15 fractions or 75-100 Gy in 25 fractions. No dose-limiting toxicities were observed during follow-up. One-year in-field control was 57%. One-year overall survival was 73%. CONCLUSION: Liver-directed radiotherapy can be safely delivered to high doses when incorporating functional SPECT into the radiation treatment planning process, which may enable sparing of lower volumes of liver than traditionally accepted in patients with preserved liver function. TRIAL REGISTRATION: NCT02626312.

PTCOG Gastrointestinal Subcommittee Lower Gastrointestinal Tract Malignancies Consensus Statement.

Purpose: Radiotherapy delivery in the definitive management of lower gastrointestinal (LGI) tract malignancies is associated with substantial risk of acute and late gastrointestinal (GI), genitourinary, dermatologic, and hematologic toxicities. Advanced radiation therapy techniques such as proton beam therapy (PBT) offer optimal dosimetric sparing of critical organs at risk, achieving a more favorable therapeutic ratio compared with photon therapy. Materials and Methods: The international Particle Therapy Cooperative Group GI Subcommittee conducted a systematic literature review, from which consensus recommendations were developed on the application of PBT for LGI malignancies. Results: Eleven recommendations on clinical indications for which PBT should be considered are presented with supporting literature, and each recommendation was assessed for level of evidence and strength of recommendation. Detailed technical guidelines pertaining to simulation, treatment planning and delivery, and image guidance are also provided. Conclusion: PBT may be of significant value in select patients with LGI malignancies. Additional clinical data are needed to further elucidate the potential benefits of PBT for patients with anal cancer and rectal cancer.

Dosimetric Uncertainties Resulting From Interfractional Anatomic Variations for Patients Receiving Pancreas Stereotactic Body Radiation Therapy and Cone Beam Computed Tomography Image Guidance.

PURPOSE: To estimate the effects of interfractional anatomic changes on dose to organs at risk (OARs) and tumors, as measured with cone beam computed tomography (CBCT) image guidance for pancreatic stereotactic body radiation therapy. METHODS AND MATERIALS: We evaluated 11 patients with pancreatic cancer whom were treated with stereotactic body radiation therapy (33-40 Gy in 5 fractions) using daily CT-on-rails (CTOR) image guidance immediately before treatment with breath-hold motion management. CBCT alignment was simulated in the treatment planning software by aligning the original planning CT to each fractional CTOR image set via fiducial markers. CTOR data sets were used to calculate fractional doses after alignment by applying the rigid shift of the planning CT and CTOR image sets to the planning treatment isocenter and recalculating the fractional dose. Accumulated dose to the gross tumor volume (GTV), tumor vessel interface, duodenum, small bowel, and stomach were calculated by summing the 5 fractional absolute dose-volume histograms into a single dose-volume histogram for comparison with the original planned dose. RESULTS: Four patients had a GTV D100% of at least 1.5 Gy less than the fractional planned value in several fractions; 4 patients had fractional underestimation of duodenum dose by 1.0 Gy per fraction. The D1.0 cm3 <35 Gy constraint was violated for at least 1 OAR in 3 patients, with either the duodenum (n = 2) or small bowel (n = 1) D1.0 cm3 being higher on the accumulated dose distribution (P = .01). D100% was significantly lower according to accumulated dose GTV (P = .01) and tumor vessel interface (P = .02), with 4 and 2 patients having accumulated D100%  ≥4 Gy lower than the planned value for the GTV and tumor vessel interface, respectively. CONCLUSIONS: For some patients, CBCT image guidance based on fiducial alignment may cause large dosimetric uncertainties for OARs and target structures, according to accumulated dose.

Adjustment of the lateral and longitudinal size of scanned proton beam spots using a pre-absorber to optimize penumbrae and delivery efficiency.

In scanned-beam proton therapy, the beam spot properties, such as the lateral and longitudinal size and the minimum achievable range, are influenced by beam optics, scattering media and drift spaces in the treatment unit. Currently available spot scanning systems offer few options for adjusting these properties. We investigated a method for adjusting the lateral and longitudinal spot size that utilizes downstream plastic pre-absorbers located near a water phantom. The spot size adjustment was characterized using Monte Carlo simulations of a modified commercial scanned-beam treatment head. Our results revealed that the pre-absorbers can be used to reduce the lateral full width at half maximum (FWHM) of dose spots in water by up to 14 mm, and to increase the longitudinal extent from about 1 mm to 5 mm at residual ranges of 4 cm and less. A large factor in manipulating the lateral spot sizes is the drift space between the pre-absorber and the water phantom. Increasing the drift space from 0 cm to 15 cm leads to an increase in the lateral FWHM from 2.15 cm to 2.87 cm, at a water-equivalent depth of 1 cm. These findings suggest that this spot adjustment method may improve the quality of spot-scanned proton treatments.

An MCNPX Monte Carlo model of a discrete spot scanning proton beam therapy nozzle.

PURPOSE: The purposes of this study were to validate a discrete spot scanning proton beam nozzle using the Monte Carlo (MC) code MCNPX and use the MC validated model to investigate the effects of a low-dose envelope, which surrounds the beam's central axis, on measurements of integral depth dose (IDD) profiles. METHODS: An accurate model of the discrete spot scanning beam nozzle from The University of Texas M. D. Anderson Cancer Center (Houston, Texas) was developed on the basis of blueprints provided by the manufacturer of the nozzle. The authors performed simulations of single proton pencil beams of various energies using the standard multiple Coulomb scattering (MCS) algorithm within the MCNPX source code and a new MCS algorithm, which was implemented in the MCNPX source code. The MC models were validated by comparing calculated in-air and in-water lateral profiles and percentage depth dose profiles for single pencil beams with their corresponding measured values. The models were then further tested by comparing the calculated and measured three-dimensional (3-D) dose distributions. Finally, an IDD profile was calculated with different scoring radii to determine the limitations on the use of commercially available plane-parallel ionization chambers to measure IDD. RESULTS: The distance to agreement, defined as the distance between the nearest positions of two equivalent distributions with the same value of dose, between measured and simulated ranges was within 0.13 cm for both MCS algorithms. For low and intermediate pencil beam energies, the MC simulations using the standard MCS algorithm were in better agreement with measurements. Conversely, the new MCS algorithm produced better results for high-energy single pencil beams. The IDD profile calculated with cylindrical tallies with an area equivalent to the area of the largest commercially available ionization chamber showed up to 7.8% underestimation of the integral dose in certain depths of the IDD profile. CONCLUSIONS: The authors conclude that a combination of MCS algorithms is required to accurately reproduce experimental data of single pencil beams and 3-D dose distributions for the scanning beam nozzle. In addition, the MC simulations showed that because of the low-dose envelope, ionization chambers with radii as large as 4.08 cm are insufficient to accurately measure IDD profiles for a 221.8 MeV pencil beam in the scanning beam nozzle.