Multiparametric MRI as a Predictor of PSA Response in Patients Undergoing Stereotactic Body Radiation Therapy for Prostate Cancer.

Purpose: To maximize the therapeutic ratio, it is important to identify adverse prognostic features in men with prostate cancer, especially among those with intermediate risk disease, which represents a heterogeneous group. These men may benefit from treatment intensification. Prior studies have shown pretreatment mpMRI may predict biochemical failure in patients with intermediate and/or high-risk prostate cancer undergoing conventionally fractionated external beam radiation therapy and/or brachytherapy. This study aims to evaluate pretreatment mpMRI findings as a marker for outcome in patients undergoing stereotactic body radiation therapy (SBRT). Methods and Materials: We identified all patients treated at our institution with linear accelerator based SBRT to 3625 cGy in 5 fractions, with or without androgen deprivation therapy (ADT) from November 2015 to March 2021. All patients underwent pretreatment Magnetic Resonance Imaging (MRI). Posttreatment Prostate Specific Imaging (PSA) measurements were typically obtained 4 months after SBRT, followed by every 3 to 6 months thereafter. A 2 sample t test was used to compare preoperative mpMRI features with clinical outcomes. Results: One hundred twenty-three men were included in the study. Pretreatment MRI variables including median diameter of the largest intraprostatic lesion, median number of prostate lesions, and median maximal PI-RADS score, were each predictive of PSA nadir and time to PSA nadir (P < .0001). When separated by ADT treatment, this association remained for patients who were not treated with ADT (P < .001). In patients who received ADT, the pretreatment MRI variables were each significantly associated with time to PSA nadir (P < .01) but not with PSA nadir (P > 0.30). With a median follow-up time of 15.9 months (IQR: 8.5-23.3), only 3 patients (2.4%) experienced biochemical recurrence as defined by the Phoenix criteria. Conclusions: Our experience shows the significant ability of mpMRI for predicting PSA outcome in prostate cancer patients treated with SBRT with or without ADT. Since PSA nadir has been shown to correlate with biochemical failure, this information may help radiation oncologists better counsel their patients regarding outcome after SBRT and can help inform future studies regarding who may benefit from treatment intensification with, for example, ADT and/or boosts to dominant intraprostatic lesions.

Risk of corticosteroid treatment and hospitalization after checkpoint inhibitor and radiation therapy in patients with cancer.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are potent new cancer therapies but can cause serious immune-related adverse events. ICIs have contributed significantly to improved survival and thereby provide more opportunity for the development of local disease symptomatology requiring palliative radiation. Radiation therapy (RT) has also recently shown benefit in the oligometastatic setting. Data on the interaction and safety of concurrent ICIs and RT are limited. METHODS: In this retrospective cohort study using a large medical claims database from 2010 to 2017, the need for corticosteroid therapy and the risk of hospitalization within 180 days of treatment with an ICI were determined for patients with a diagnosis of malignant melanoma or lung cancer. Patients were stratified by the use of RT within the 30 days before and after ICI therapy. RESULTS: In all, 2020 patients (218 with RT and 1802 without RT) met the inclusion criteria for prednisone analysis, whereas 3519 patients (361 with RT and 3158 without RT) met the inclusion criteria for all other analyses. In a univariable analysis, RT was not associated with the need for prednisone (relative risk [RR], 1.2; 95% confidence interval [CI], 0.8-1.9) or methylprednisolone (RR, 1.1; 95% CI, 0.7-2.0). When the end point was hospitalization, RT was significantly associated with hospitalization after ICI therapy for certain cancer/drug combinations (RR for lung cancer/programmed death 1 receptor inhibitors, 1.4; 95% CI, 1.2-1.6; P < .001; RR for melanoma/ipilimumab, 2.0; 95% CI, 1.0-3.5; P = .03). CONCLUSIONS: In patients treated with ICIs, receiving RT was not associated with a higher risk of requiring corticosteroid therapy in comparison with not receiving RT. However, RT was associated with a higher risk of hospitalization, although this finding may be a result of differences in the underlying patient illness severity or oncologic disease burden at the baseline. LAY SUMMARY: Data on the interaction of immunotherapy (immune checkpoint inhibitors) and radiation therapy and the safety of combining them are limited. Using a large database, this study has found that patients treated concurrently with immune checkpoint inhibitors and radiation therapy are not at increased risk for requiring corticosteroid therapy (which is used as a proxy for immune-related adverse events). However, concurrent therapy is associated with a higher risk of hospitalization, although this finding may be due to differences in the underlying patient illness severity (sicker patients may require both immunotherapy and radiation therapy).

3D treatment planning on helical tomotherapy delivery system.

The helical tomotherapy is a technologically advanced radiation dose delivery system designed to perform intensity-modulated radiation therapy (IMRT). It is mechanistically unique, based on a small 6-MV linear accelerator mounted on a ring gantry that rotates around the patient while the patient moves through a bore, ultimately yielding a helical path of radiation dose delivery. The helical pattern of dose delivery differentiated tomotherapy from other contemporary radiation therapy systems at the time of its inception. The accompanying 3-dimensional (3D) treatment planning system has been developed to solely support this specific type of dose delivery system. The treatment planning system has 2 modules identified as TomoHelical and TomoDirect to perform IMRT and conformal radiation therapy, respectively. The focus of this work within the scope of this special issue on 3D treatment planning systems is to assess the use of planning tools to generate treatment plans for helical tomotherapy. Clinical examples are used throughout to demonstrate the quality and differences of various clinical scenarios planned with tomotherapy.

Clinical implementation of radiosurgery using the Helical TomoTherapy unit.

The American Society of Radiation Oncology has recently recommended the use of radiosurgery to manage brain metastases. For such a recommendation to be implemented in a widespread manner, radiosurgery must be accessible at community radiation therapy facilities. The work presented here describes our clinical experience in the implementation of radiosurgery using a Helical TomoTherapy unit. Helical TomoTherapy is a unique dose-delivery system designed to perform intensity-modulated radiation therapy (IMRT). The system built on the ring-based gantry has the tight machine tolerances required for radiosurgery. A frameless system consisting of a thermoplastic mask and a noninvasive "stereotactic radiosurgery (SRS)-stereotactic radiotherapy (SRT)" fixation device is used for patient immobilization. Treatment planning is performed using the TomoHD treatment planning system designed for IMRT. The image-guidance system on the Helical TomoTherapy is used for patient localization. Our clinical experience demonstrated that the radiosurgery procedure can be streamlined as we do for IMRT patients. The treatment time of about 10 minutes is comparable with that for IMRT patients. The same patient-specific quality assurance for IMRT is used for radiosurgery. As demonstrated, SRS using Helical TomoTherapy is not a whole-day event, unlike SRS using other dose-delivery systems or SRS performed in the past.

Concurrent Chemoradiotherapy With Cisplatin Versus Cetuximab for Squamous Cell Carcinoma of the Head and Neck.

OBJECTIVES: We previously reported inferior outcomes for locally advanced head and neck cancer treated with cetuximab (C225) versus cisplatin (CDDP). We now examine if this difference persists when accounting for HPV status and update outcomes on the entire cohort. MATERIALS AND METHODS: From 3/106 to 4/1/08, 174 locally advanced head and neck cancer patients received definitive treatment with RT and CDDP (n=125) or RT and C225 (n=49). Of these, 62 patients had tissue available for HPV analysis. RESULTS: The median follow-up was 47 months. The 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.7% versus 40.2% (P<0.0001), 85.1% versus 35.4% (P<0.0001), and 90.0% versus 56.6% (P<0.0001), respectively. In the subset with tissue, there was no difference in rates of HPV or p16 positivity between the 2 groups. In this subset, the 3-year loco-regional failure, disease-free survival, and overall survival for CDDP versus C225 were 5.3% versus 32.0% (P=0.01), 86.8% versus 43.2% (P=0.002), and 86.7% versus 76.9% (P=0.09), respectively. Multivariate analysis continued to show a benefit for CDDP. CONCLUSIONS: With longer follow-up and the inclusion of HPV and p16 status for about one third of patients where tissue was available, we continued to find superior outcomes with concurrent CDDP versus C225.

Efficacy of concurrent cetuximab vs. 5-fluorouracil/carboplatin or high-dose cisplatin with intensity-modulated radiation therapy (IMRT) for locally-advanced head and neck cancer (LAHNSCC).

OBJECTIVES: We previously reported inferior outcomes for locally-advanced head and neck squamous cell carcinoma (LAHNSCC) patients treated with concurrent cetuximab vs. high-dose cisplatin with intensity-modulated radiation therapy (IMRT). Prior to FDA approval of cetuximab for LAHNSCC, non-cisplatin eligible patients at our institution received 5-fluorouracil (5FU)/carboplatin. We sought to compare concurrent cetuximab vs. 5FU/carboplatin vs. high-dose cisplatin with IMRT for LAHNSCC. MATERIALS AND METHODS: Retrospective review was performed for LAHNSCC patients treated at Memorial Sloan-Kettering Cancer Center from 11/02 to 04/08 with concurrent cetuximab (n=49), 5FU/carboplatin (n=52), or cisplatin (n=259) and IMRT. Overall survival (OS), locoregional failure (LRF), distant metastasis-free survival, and late toxicity were analyzed using univariate and multivariate analyses. OS analysis was confirmed by propensity score adjustment. RESULTS: Treatment groups were similar with regard to primary tumor site, overall stage, and alcohol and tobacco history. Cetuximab and 5FU/carboplatin patients were older, with lower performance status, more comorbidities, higher T classification, and worse renal function. On multivariate analysis, compared with cisplatin and 5FU/carboplatin, cetuximab was associated with inferior 4-year OS (86.9% vs. 70.2% vs. 40.9%; P<.0001) and 4-year LRF (6.3% vs. 9.7% vs. 40.2%; P<.0001). Late toxicity was highest with 5FU/carboplatin (25.0%) vs. cisplatin (8.0%) vs. cetuximab (7.7%). CONCLUSIONS: Although 5FU/carboplatin patients were sicker and experienced greater toxicity than cisplatin patients, no significant difference was found in all endpoints. In contrast, despite similar pretreatment characteristics, outcomes for cetuximab vs. 5FU/carboplatin were significantly worse. We feel that caution should be used with routine use of cetuximab in the management of LAHNSCC.

Intensity-modulated radiotherapy in the treatment of oropharyngeal cancer: an update of the Memorial Sloan-Kettering Cancer Center experience.

PURPOSE: To update the Memorial Sloan-Kettering Cancer Center's experience with intensity-modulated radiotherapy (IMRT) in the treatment of oropharyngeal cancer (OPC). METHODS AND MATERIALS: Between September 1998 and April 2009, 442 patients with histologically confirmed OPC underwent IMRT at our center. There were 379 men and 63 women with a median age of 57 years (range, 27-91). The disease was Stage I in 2%, Stage II in 4%, Stage III in 21%, and Stage IV in 73% of patients. The primary tumor subsite was tonsil in 50%, base of tongue in 46%, pharyngeal wall in 3%, and soft palate in 2%. The median prescription dose to the planning target volume of the gross tumor was 70 Gy for definitive (n = 412) cases and 66 Gy for postoperative cases (n = 30). A total 404 patients (91%) received chemotherapy, including 389 (88%) who received concurrent chemotherapy, the majority of which was platinum-based. RESULTS: Median follow-up among surviving patients was 36.8 months (range, 3-135). The 3-year cumulative incidence of local failure, regional failure, and distant metastasis was 5.4%, 5.6%, and 12.5%, respectively. The 3-year OS rate was 84.9%. The incidence of late dysphagia and late xerostomia ≥Grade 2 was 11% and 29%, respectively. CONCLUSIONS: Our results confirm the feasibility of IMRT in achieving excellent locoregional control and low rates of xerostomia. According to our knowledge, this study is the largest report of patients treated with IMRT for OPC.

Concurrent cisplatin and radiation versus cetuximab and radiation for locally advanced head-and-neck cancer.

PURPOSE: To compare concurrent cisplatin (CDDP) and radiation (RT) with cetuximab (C225) and RT for locally advanced head-and-neck cancer (LAHNC). METHODS AND MATERIALS: This study retrospectively compared 174 consecutive, newly diagnosed LAHNC patients definitively treated from March 1, 2006, to April 1, 2008, with single-agent CDDP/RT (n = 125) or C225/RT (n = 49). We excluded patients who received additional concurrent, induction, or adjuvant systemic therapy; weekly cisplatin; prior head-and-neck radiotherapy; or primary surgical resection. Outcomes were analyzed by the Kaplan-Meier method, Cox model, and competing-risks analysis tools. RESULTS: The C225/RT patients were older and had decreased creatinine clearance. At a median follow-up of 22.5 months for living patients, the 2-year locoregional failure rate was 5.7% for CDDP/RT and 39.9% for C225/RT (p < 0.0001). The 2-year failure-free survival (FFS) and overall survival (OS) rates were 87.4% vs. 44.5% (p < 0.0001) and 92.8% vs. 66.6% (p = 0.0003), respectively, in favor of CDDP/RT. When the Cox proportional hazards model was used for multivariate analysis, treatment with CDDP/RT predicted for improved locoregional control (p < 0.0001), FFS (p < 0.0001), and OS (p = 0.01). Late Grade 3 or 4 toxicity or feeding tube dependence 9 months after completion of RT was observed in 21% of patients in the CDDP/RT cohort and 24% in the C225/RT cohort (p = 0.66). CONCLUSIONS: In this study of LAHNC patients, CDDP/RT achieved better locoregional control, FFS, and OS than C225/RT. Although the results were upheld on multivariate analysis, they must be interpreted cautiously because of the retrospective nature of the study and significant differences in patient selection. There was no statistically significant difference in late Grade 3 or 4 effects or feeding tube dependence.

Postmastectomy intensity modulated radiation therapy following immediate expander-implant reconstruction.

BACKGROUND/PURPOSE: To evaluate radiation plans of patients undergoing mastectomy with immediate expander-implant reconstruction followed by postmastectomy radiation therapy (PMRT). MATERIALS/METHODS: We identified 41 patients from June 2004 to May 2007 who underwent mastectomy, immediate expander-implant reconstruction, and PMRT with intensity-modulated radiation therapy. We assessed chest wall (CW) coverage and volume of heart and lung irradiated. RESULTS: In 73% of patients, all CW borders were adequately covered, and in 22%, all but 1 border were adequately covered. The total lung V(20) was<20% in 39/41 patients. The mean lung V(20) was 13% (range, 3-23%), and the mean heart D(mean) was 2.81 Gy (range, 0.53-9.60 Gy). In patients with left-sided lesions without internal mammary nodes (IMNs) treatment (n=22), the mean lung V(20) was 12.6% and the mean heart D(mean) was 3.90 Gy, and in the patient with IMN treatment, the lung V(20) was 18% and heart D(mean) was 8.04 Gy. For right-sided lesions without IMN treatment (n=12), the mean lung V(20) was 12.4% and the mean heart D(mean) was 0.90 Gy, and in patients with IMN treatment (n=6), these numbers were 17.8% and 1.76 Gy. At a median follow-up of 29 months, the 30-month actuarial local control was 97%. CONCLUSIONS: In women undergoing immediate expander-implant reconstruction, PMRT can achieve excellent local control with acceptable heart and lung doses. These results can be achieved even when the IMN are being treated, although doses to the heart and lungs will be higher.

Reirradiation of locally recurrent nasopharynx cancer with external beam radiotherapy with or without brachytherapy.

PURPOSE: To determine survival rates of patients with locally recurrent nasopharynx cancer (LRNPC) treated with modern therapeutic modalities. METHODS AND MATERIALS: From July 1996 to March 2008, 29 patients were reirradiated for LRNPC. Thirteen patients received combined-modality treatment (CMT), consisting of external beam radiotherapy (EBRT) followed by intracavitary brachytherapy, whereas 16 received EBRT alone. The median age was 50 years, 59% were male, 38% were Asian, 69% had World Health Organization Class III histology, and 86% were treated for their first recurrence. Nine, 6, 8, and 6 patients had recurrent Stage I, II, III, and IV disease, respectively. Patients in the EBRT-alone group had more advanced disease. Median time to reirradiation was 3.9 years. In total, 93% underwent imaging with positron emission tomography and/or magnetic resonance imaging before reirradiation, 83% received intensity-modulated radiotherapy, and 93% received chemotherapy, which was platinum-based in 85% of cases. RESULTS: The median follow-up for all patients was 45 months and for surviving patients was 54 months. Five-year actuarial local control, event-free survival, and overall survival rates were 52%, 44%, and 60%, respectively. No difference was observed between patients treated with EBRT or CMT. Overall survival was superior in patients who achieved local control (p = 0.0003). The incidence of late Grade > or =3 events in patients re-treated with EBRT alone was significantly increased compared with those receiving CMT (73% vs. 8%; p = 0.005). CONCLUSIONS: In this modern reirradiation series of patients with LRNPC, favorable overall survival compared with historical series was achieved. Patients treated with CMT experienced significantly fewer severe late effects compared with those treated with EBRT.

Severe radiation dermatitis in patients with locally advanced head and neck cancer treated with concurrent radiation and cetuximab.

OBJECTIVES: A phase III trial has shown the superiority of concurrent cetuximab and radiotherapy versus radiotherapy alone for the treatment of locally advanced head and neck cancer (HNC). We evaluated our institution's experience of patients treated with concurrent cetuximab and radiotherapy to determine the rate of serious (≥ grade 3) radiation dermatitis. We also sought to more fully describe and characterize the grade 4 dermatitis that these patients develop. METHODS: We performed a retrospective review of HNC patients who were treated with concurrent cetuximab and radiation. We included patients treated in either the definitive or loco-regionally recurrent setting with nonmetastatic disease who received their first dose of cetuximab from March 1, 2006 to January 1, 2008. We found 115 patients who fit our search. RESULTS: Serious radiation dermatitis was noted in 26 (23%) patients, with 22 patients developing grade 3 dermatitis and 4 patients developing grade 4 dermatitis. All 4 patients who developed grade 4 dermatitis did so within the radiation field. The dermatitis was manifested by spontaneous bleeding from the involved skin, and in 1 case, skin necrosis. These toxicities developed during the fifth week of treatment. CONCLUSIONS: Treatment with concurrent radiation and cetuximab for locally advanced HNC is a relatively new treatment modality, and the toxicities of this regimen are becoming better understood. We believe that the serious skin toxicities that these patients develop when treated with concomitant cetuximab occur more frequently than when patients are treated with concurrent cisplatin, although further study is needed to confirm this.

Improved local control with higher doses of radiation in large-volume stage III non-small-cell lung cancer.

PURPOSE: It has been suggested that larger tumor volume is associated with poor survival in patients with non-small-cell lung cancer (NSCLC). We investigated whether high-dose radiation improved local control in patients with large-volume Stage III NSCLC. METHODS AND MATERIALS: Seventy-two patients with Stage III NSCLC and gross tumor volumes (GTV) of greater than 100 cc were treated with three-dimensional conformal radiotherapy (3D-CRT). Patients were divided into two groups: those treated to less than 64 Gy (37 patients) and those treated to 64 Gy or higher (35 patients). RESULTS: The 1-year and 2-year local failure rates were 27% and 47%, respectively, for Stage III patients treated to 64 Gy or higher, and 61% and 76%, respectively, for those treated to less than 64 Gy (p = 0.024). The median survival time for patients treated to 64 Gy or higher was 20 months vs. 15 months for those treated to less than 64 Gy (p = 0.068). Multivariate analysis revealed that dose and GTV are predictors of local failure-free survival. A 10 Gy increase in dose resulted in a 36.4% decreased risk of local failure. CONCLUSIONS: Our data suggest that administration of higher doses using 3D-CRT improves local control in Stage III NSCLC patients with large GTVs.

Reactivity of the B-H Bond in tris(pyrazolyl)hydroborato zinc complexes: unexpected example of zinc hydride formation in a protic solvent and its relevance towards hydrogen transfer to NAD(+) mimics by tris(pyrazolyl)hydroborato zinc complexes in alcoholic media.

Solutions of the zinc hydroxide complex [Tp(Bu(t),Me)]ZnOH in alcohols (ROH; R = Me, Et, Pr(i)) achieve hydride transfer to the NAD(+) model, 10-methylacridinium perchlorate. Deuterium labeling studies, however, demonstrate that the source of the hydride is not the alcohol but, rather, the B [bond] H group of the [Tp(Bu(t),Me)] ligand. A further example in which a [Tp(Bu(t),Me)] ligand acts as a hydride donor is provided by the reaction of the aqua complex [[Tp(Bu(t),Me)]Zn(OH(2))][HOB(C(6)F(5))(3)] with MeOH to generate the zinc hydride complex [Tp(Bu(t),Me)]ZnH. The present study therefore provides a caveat for the often assumed inertness of the B [bond] H group in tris(pyrazolyl)hydroborato ligands, especially in the presence of reactive cationic species.