J. Keith DeWyngaert

Fractionated but Not Single-Dose Radiotherapy Induces an Immune-Mediated Abscopal Effect when Combined with Anti–CTLA-4 Antibody

Purpose: This study tested the hypothesis that the type of dose fractionation regimen determines the ability of radiotherapy to synergize with anti–CTLA-4 antibody. Experimental Design: TSA mouse breast carcinoma cells were injected s.c. into syngeneic mice at two separate sites, defined as a “primary” site that was irradiated and a “secondary” site outside the radiotherapy field. When both tumors were palpable, mice were randomly assigned to eight groups receiving no radiotherapy or three distinct regimens of radiotherapy (20 Gy × 1, 8 Gy × 3, or 6 Gy × 5 fractions in consecutive days) in combination or not with 9H10 monoclonal antibody against CTLA-4. Mice were followed for tumor growth/regression. Similar experiments were conducted in the MCA38 mouse colon carcinoma model. Results: In either of the two models tested, treatment with 9H10 alone had no detectable effect. Each of the radiotherapy regimens caused comparable growth delay of the primary tumors but had no effect on the secondary tumors outside the radiation field. Conversely, the combination of 9H10 and either fractionated radiotherapy regimens achieved enhanced tumor response at the primary site (P < 0.0001). Moreover, an abscopal effect, defined as a significant growth inhibition of the tumor outside the field, occurred only in mice treated with the combination of 9H10 and fractionated radiotherapy (P < 0.01). The frequency of CD8+ T cells showing tumor-specific IFN-γ production was proportional to the inhibition of the secondary tumor. Conclusions: Fractionated but not single-dose radiotherapy induces an abscopal effect when in combination with anti–CTLA-4 antibody in two preclinical carcinoma models. (Clin Cancer Res 2009;15(17):5379–88)

The combination of ionizing radiation and peripheral vaccination produces long-term survival of mice bearing established invasive GL261 gliomas.

Purpose: High-grade glioma treatment includes ionizing radiation therapy. The high invasiveness of glioma cells precludes their eradication and is responsible for the dismal prognosis. Recently, we reported the down-regulation of MHC class I (MHC-I) products in invading tumor cells in human and mouse GL261 gliomas. Here, we tested the hypothesis that whole-brain radiotherapy (WBRT) up-regulates MHC-I expression on GL261 tumors and enhances the effectiveness of immunotherapy. Experimental Design: MHC-I molecule expression on GL261 cells was analyzed in vitro and in vivo by flow cytometry and immunohistochemistry, respectively. To test the response of established GL261 gliomas to treatment, mice with measurable (at CT imaging) brain tumors were randomly assigned to four groups receiving (a) no treatment, (b) WBRT in two fractions of 4 Gy, (c) vaccination with irradiated GL261 cells secreting granulocyte-macrophage colony-stimulating factor, or (d) WBRT and vaccination. Endpoints were tumor response and survival. Results: An ionizing radiation dose of 4 Gy maximally up-regulated MHC-I molecules on GL261 cells in vitro. In vivo, WBRT induced the expression of the β2-microglobulin light chain subunit of the MHC class I complex on glioma cells invading normal brain and increased CD4+ and CD8+ T cell infiltration. However, the survival advantage obtained with WBRT or vaccination alone was minimal. In contrast, WBRT in combination with vaccination increased long-term survival to 40% to 80%, compared with 0% to 10% in the other groups (P < 0.002). Surviving animals showed antitumor immunity by rejecting challenge tumors. Conclusion: Ionizing radiation can be successfully combined with peripheral vaccination for the treatment of established high-grade gliomas.

PRONE ACCELERATED PARTIAL BREAST IRRADIATION AFTER BREAST-CONSERVING SURGERY: FIVE YEAR RESULTS OF 100 PATIENTS

PURPOSE To report the 5-year results of a prospective trial of three-dimensional conformal external beam radiotherapy (3D-CRT) to deliver accelerated partial breast irradiation in the prone position. METHODS AND MATERIALS Postmenopausal patients with Stage I breast cancer with nonpalpable tumors <2 cm, negative margins and negative nodes, positive hormone receptors, and no extensive intraductal component were eligible. The trial was offered only after eligible patients had refused to undergo standard whole-breast radiotherapy. Patients were simulated and treated on a dedicated table for prone setup. 3D-CRT was delivered at a dose of 30 Gy in five 6-Gy/day fractions over 10 days with port film verification at each treatment. Rates of ipsilateral breast failure, ipsilateral nodal failure, contralateral breast failure, and distant failure were estimated using the cumulative incidence method. Rates of disease-free, overall, and cancer-specific survival were recorded. RESULTS One hundred patients were enrolled in this institutional review board-approved prospective trial, one with bilateral breast cancer. One patient withdrew consent after simulation, and another patient elected to interrupt radiotherapy after receiving two treatments. Ninety-eight patients were evaluable for toxicity, and, in 1 case, both breasts were treated with partial breast irradiation. Median patient age was 68 years (range, 53-88 years); in 55% of patients the tumor size was <1 cm. All patients had hormone receptor-positive cancers: 87% of patients underwent adjuvant antihormone therapy. At a median follow-up of 64 months (range, 2-125 months), there was one local recurrence (1% ipsilateral breast failure) and one contralateral breast cancer (1% contralateral breast failure). There were no deaths due to breast cancer by 5 years. Grade 3 late toxicities occurred in 2 patients (one breast edema, one transient breast pain). Cosmesis was rated good/excellent in 89% of patients with at least 36 months follow-up. CONCLUSIONS Five-year efficacy and toxicity of 3D-CRT delivered in prone partial breast irradiation are comparable to other experiences with similar follow-up.

Coverage of Axillary Lymph Nodes in Supine vs. Prone Breast Radiotherapy

PURPOSE To compare the dosimetry of target and normal tissue when tangents with the breast tissue were applied in a subset of breast cancer patients who had undergone computed tomography (CT) planning both supine and prone. METHODS AND MATERIALS The CT images of 20 patients who had undergone simulation in supine and prone positions were used for planning. The axillary lymph node regions (level I-III), breast tissue, tumor bed, heart, and bilateral lungs were manually contoured. Standard tangent fields were designed for the whole breast to deliver a prescribed dose of 50 Gy. Dose-volume histograms were compared between the two sets. RESULTS In each patient, coverage of breast tissue and tumor bed was readily achieved by either technique. In either position, treatment of the nodal regions was inadequate. On average, the mean dose to the nodal regions for levels I-III was approximately 50% less in the prone as compared with the supine position. The mean ipsilateral lung volume receiving 95% of the prescribed dose was 6.3% in the supine position compared to 0.43% in the prone position. When planned supine, the mean heart volume receiving 30 Gy was 0.56% compared with 0.30% in the prone position. CONCLUSIONS Planning in either position was found to achieve adequate coverage of the breast tissue and tumor bed for all patients. Lung was better spared prone. Coverage of axillary nodes was inadequate in either position, but further reduced in the prone vs. supine position. The choice of optimal setup should take into considerations stage and risk of nodal recurrence.

Interfraction and Intrafraction Setup Variability for Prone Breast Radiation Therapy

PURPOSE To report the interfraction and intrafraction setup variation for prone breast radiotherapy and to determine an appropriate clinical tumor volume (CTV) to planning target volume (PTV)_ margin to account for motion and positional uncertainties. METHODS AND MATERIALS Ten consecutive patients were prospectively enrolled in a protocol of accelerated, hypofractionated prone breast irradiation. Portal images were acquired using an electronic portal imaging device in cine mode. Interfraction setup error was determined by comparing the first image from each fraction with the digitally reconstructed radiograph. The intrafraction motion was determined by evaluating every image acquired during each fraction and measuring the maximum displacement of an external fiducial and the breast surface. Mean values and 95% confidence intervals (CI) were calculated. Based on these results, a CTV to PTV expansion was derived using the equation M = 2.5Sigma(tot) + 0.7sigma(tot.) RESULTS The mean interfraction setup variability for the fiducial was 0.08 cm (CI: 0.02-0.14) in the anterior to posterior (AP) direction and -0.04 cm (CI: -0.07-0.00) in the superior to inferior (SI) direction. The mean interfraction variability of the breast surface was -0.14 cm (CI: -0.24 to -0.04) in the AP direction. The mean intrafraction displacements of the fiducial and the breast surface were 0.13 cm (CI: 0.12-0.15) and 0.15 cm (CI: 0.14-0.17), respectively. Using the systematic and random errors for the external fiducial, the calculated CTV to PTV expansion was 1.4 cm. CONCLUSIONS Acceptable interfraction and intrafraction variability were demonstrated. The findings resulted in a CTV to PTV expansion of 1.4 cm.

PROSPECTIVE STUDY OF CONE-BEAM COMPUTED TOMOGRAPHY IMAGE-GUIDED RADIOTHERAPY FOR PRONE ACCELERATED PARTIAL BREAST IRRADIATION

PURPOSE To report setup variations during prone accelerated partial breast irradiation (APBI). METHODS New York University (NYU) 07-582 is an institutional review board-approved protocol of cone-beam computed tomography (CBCT) to deliver image-guided ABPI in the prone position. Eligible are postmenopausal women with pT1 breast cancer excised with negative margins and no nodal involvement. A total dose of 30 Gy in five daily fractions of 6 Gy are delivered to the planning target volume (the tumor cavity with 1.5-cm margin) by image-guided radiotherapy. Patients are set up prone, on a dedicated mattress, used for both simulation and treatment. After positioning with skin marks and lasers, CBCTs are performed and the images are registered to the planning CT. The resulting shifts (setup corrections) are recorded in the three principal directions and applied. Portal images are taken for verification. If they differ from the planning digital reconstructed radiographs, the patient is reset, and a new CBCT is taken. RESULTS 70 consecutive patients have undergone a total of 343 CBCTs: 7 patients had four of five planned CBCTs performed. Seven CBCTs (2%) required to be repeated because of misalignment in the comparison between portal and digital reconstructed radiograph image after the first CBCT. The mean shifts and standard deviations in the anterior-posterior (AP), superior-inferior (SI), and medial-lateral (ML) directions were -0.19 (0.54), -0.02 (0.33), and -0.02 (0.43) cm, respectively. The average root mean squares of the daily shifts were 0.50 (0.28), 0.29 (0.17), and 0.38 (0.20). A conservative margin formula resulted in a recommended margin of 1.26, 0.73, 0.96 cm in the AP, SI, and ML directions. CONCLUSION CBCTs confirmed that the NYU prone APBI setup and treatment technique are reproducible, with interfraction variation comparable to those reported for supine setup. The currently applied margin (1.5 cm) adequately compensates for the setup variation detected.

Comparison of Acute and Late Toxicity of Two Regimens of 3- and 5-Week Concomitant Boost Prone IMRT to Standard 6-Week Breast Radiotherapy

Purpose: Limited information is available comparing toxicity of accelerated radiotherapy (RT) to that of standard fractionation RT for early stage breast cancer. We report early and late toxicities of two prone regimens of accelerated intensity-modulated radiation therapy (IMRT) with a concomitant boost (CB) to the tumor bed delivered over 3 or 5 weeks as compared to standard 6 week RT with a sequential electron boost. Methods: From 2/2003 to 12/2007, 169 consecutive patients with Stage I–II breast cancer were offered the choice to undergo prone RT with either: a 6-week standard RT regimen of 46 Gy/23 fractions (fx) to the whole breast (WB), followed by a14 Gy sequential boost (SB) to the tumor bed (6wSB), a 5-week regimen of 50 Gy to WB with an IMRT CB of 6.25 Gy in 25 fx (5wCB); or a 3-week protocol of 40.5 Gy to WB with an IMRT CB of 7.5 Gy in 15 fx (3wCB). These regimens were estimated as biologically equivalent, based on alpha/beta = 4 for tumor control. Toxicities were reported using RTOG and LENT/SOMA scoring. Results: 51/169 patients chose standard 6wSB, 28 selected 5wCB, and 90 enrolled in 3wCB protocol. Maximum acute toxicity was Grade 3 dermatitis in 4% of the patients in the 6wSB compared 1% in 3wCB. In general, acute complications (breast pain, fatigue, and dermatitis) were significantly less in the 3wCB than in the other schedules (P < 0.05). With a median follow-up of 61 months, the only Grade 3 late toxicity was telangiectasia in two patients: one in 3wCB and one in 5wCB group. Notably, fibrosis was comparable among the three groups (P = NS). Conclusion: These preliminary data suggest that accelerated regimens of breast RT over 3 or 5 weeks in the prone position, with an IMRT tumor bed CB, result in comparable late toxicity to standard fractionation with a sequential tumor boost delivered over 6 weeks. As predicted by radiobiological modeling the shorter regimen was associated with less acute effects.

Prone Accelerated Partial Breast Irradiation After Breast-Conserving Surgery: Compliance to the Dosimetry Requirements of RTOG-0413

PURPOSE The dosimetric results from our institutions trials of prone accelerated partial breast irradiation are compared with the dosimetric requirements of RTOG-0413. METHODS AND MATERIALS Trial 1 and Trial 2 are 2 consecutive trials of prone-accelerated partial breast irradiation. Eligible for both trials were stage I breast cancer patients with negative margins after breast-conserving surgery. The planning target tumor volume (PTV) was created by extending the surgical cavity 2.0 cm for Trial 1 and 1.5 cm for Trial 2, respectively. Contralateral breast, heart, lungs, and thyroid were contoured. Thirty Gray was delivered in five daily fractions of 6 Gy by a three-dimensional conformal radiation therapy technique in Trial 1 and were by image-guided radiation therapy/intensity-modulated radiation therapy in Trial 2. Dosimetric results from the trials are reported and compared with RTOG 0413 requirements. RESULTS One hundred forty-six consecutive plans were analyzed: 67 left and 79 right breast cancers. The plans from the trials complied with the required>90% of prescribed dose covering 90% of PTV_EVAL (=generated from the PTV by cropping 0.5 cm from the skin edge and excluding the chest wall): V90% was 98.1±3.0% (with V100% and V95%, 89.4±12.8%, 96.4±5.1%, respectively). No significant difference between laterality was found (Students t test). The dose constraints criteria of the RTOG-0413 protocol for ipsilateral and contralateral lung (V30<15% and Dmax<3%), heart (V5<40%), and thyroid (Dmax<3%) were satisfied because the plans showed an average V5% of 0.6% (range, 0-13.4) for heart, an average V30% of 0.6% (range, 0-9.1%) for ipsilateral lung, and <2% maximum dose to the thyroid. However, our partial breast irradiation plans demonstrated a higher dose to contralateral breast than that defined by RTOG constraints, with a median value of maximum doses of 4.1% (1.2 Gy), possibly as a result of contouring differences. CONCLUSIONS Our technique for prone accelerated partial breast irradiation generally satisfied RTOG-0413 requirements.

Breast, chest wall, and nodal irradiation with prone set-up: Results of a hypofractionated trial with a median follow-up of 35 months

PURPOSE To test clinical feasibility, safety, and toxicity of prone hypofractionated breast, chest wall, and nodal radiation therapy. METHODS AND MATERIALS Following either segmental or total mastectomy with axillary node dissection, patients were treated in an institutional review board-approved prospective trial of prone radiation therapy to the breast, chest wall, and supraclavicular and level III axillary lymph nodes. A dose of 40.5 Gy/15 fractions with a concomitant daily boost to the tumor bed of 0.5 Gy (total dose, 48 Gy) was prescribed. In postmastectomy patients, the same treatment was prescribed, but without a tumor bed boost. The primary endpoint was incidence of >grade 2 acute skin toxicity. The secondary endpoints were feasibility of treatment using prone set-up, compliance with protocol-defined dosimetric constraints, and incidence of late toxicity. A dosimetric comparison was performed between protocol plans (prone) and nonprotocol plans (supine), targeting the same treatment volumes. RESULTS Sixty-nine patients with stage IB-IIIA breast cancer enrolled in this trial. Surgery was segmental mastectomy (n = 45), mastectomy (n = 23), and bilateral mastectomy (n = 1), resulting in 70 cases. None experienced >grade 2 acute skin toxicity according to the Common Terminology Criteria for Adverse Events, v 3.0, meeting our primary endpoint. Ninety-six percent of patients could be treated with this technique prone. However, 17 plans (24%) exceeded protocol constraints to the brachial plexus. Maximum long-term toxicity was 1 grade 2 arm lymphedema, 1 grade 3 breast retraction, and no occurrence of brachial plexopathy. Dosimetric comparison of protocol with nonprotocol plans demonstrated significantly decreased lung and heart doses in prone plans. CONCLUSIONS Prone hypofractionated breast, chest wall, and nodal radiation therapy is safe and well tolerated in this study. Although the initial pattern of local and regional control is encouraging, longer follow-up is warranted for efficacy and late toxicity assessment, particularly to the brachial plexus.

Decreasing Temporal Lobe Dose With Five-Field Intensity-Modulated Radiotherapy for Treatment of Pituitary Macroadenomas

PURPOSE To compare temporal lobe dose delivered by three pituitary macroadenoma irradiation techniques: three-field three-dimensional conformal radiotherapy (3D-CRT), three-field intensity-modulated radiotherapy (3F IMRT), and a proposed novel alternative of five-field IMRT (5F IMRT). METHODS AND MATERIALS Computed tomography-based external beam radiotherapy planning was performed for 15 pituitary macroadenoma patients treated at New York University between 2002 and 2007 using: 3D-CRT (two lateral, one midline superior anterior oblique [SAO] beams), 3F IMRT (same beam angles), and 5F IMRT (same beam angles with additional right SAO and left SAO beams). Prescription dose was 45 Gy. Target volumes were: gross tumor volume (GTV) = macroadenoma, clinical target volume (CTV) = GTV, and planning target volume = CTV + 0.5 cm. Structure contouring was performed by two radiation oncologists guided by an expert neuroradiologist. RESULTS Five-field IMRT yielded significantly decreased temporal lobe dose delivery compared with 3D-CRT and 3F IMRT. Temporal lobe sparing with 5F IMRT was most pronounced at intermediate doses: mean V25Gy (% of total temporal lobe volume receiving ≥25 Gy) of 13% vs. 28% vs. 29% for right temporal lobe and 14% vs. 29% vs. 30% for left temporal lobe for 5F IMRT, 3D-CRT, and 3F IMRT, respectively (p < 10(-7) for 5F IMRT vs. 3D-CRT and 5F IMRT vs. 3F IMRT). Five-field IMRT plans did not compromise target coverage, exceed normal tissue dose constraints, or increase estimated brain integral dose. CONCLUSIONS Five-field IMRT irradiation technique results in a statistically significant decrease in the dose to the temporal lobes and may thus help prevent neurocognitive sequelae in irradiated pituitary macroadenoma patients.