The Effect of Radium-223 Therapy in Agent Orange-Related Prostate Carcinoma.

BACKGROUND: Radium-223 (Ra-223) radioisotope has been reported to increase median survival in bone metastatic prostate carcinoma. The addition of Ra-223 to abiraterone was associated with an increased risk of bone fractures. There has been no comprehensive data for using Ra-223 in veterans who were exposed to Agent Orange (AO+). METHODS: We present a retrospective study of veterans with bone metastatic castration-resistant prostate cancer (CRPC) who received standard doses of Ra-223 and other sequential therapies at US Department of Veterans Affairs Pittsburgh Healthcare System in Pennsylvania from January 2014 to January 2019. Veterans were divided into 2 groups: those who were exposed to Agent Orange (AO+) and those who had no exposure (AO-). Time to study was calculated from the initiation of Ra-223. Time to skeletal-related events (SRE), progression of prostate specific antigen (PSA), bone metastasis, and alkaline phosphatase (ALP) were calculated in months using unpaired t test with 2-tailed P values. Median survival was calculated by Kaplan Meier R log-rank test. RESULTS: There were 34 veterans with bone metastatic CRPC: 17 veterans (50%) were AO+ and 17 veterans (50%) were AO-. The mean age of diagnosis of AO+ veterans was 62 years and 69 years (P = .005) for AO- veterans (the mean Gleason score 8.2 and 8.0, respectively [P = .71]). The median number of Ra-223 cycles was 6 (60%). Ten veterans received Ra-223 as first line (29%) and 24 veterans received Ra-223 later (71%). There were 12 SREs with median survival of 15 months. There was no difference in mean time to SRE between AO+ (8 veterans, 10.6 months) and AO- (4 veterans, 10.3 months) (P = .93). The mean time to PSA progression for AO+ was 5.4 months and AO- was 6.8 months (P = .28). Mean time to bone progression for AO+ was 7.6 months and AO- was 10.1 months (P = .16). Mean time to ALP progression for AO+ and AO- was 6.3 months and 8.7 months, respectively (P = .05). Twenty veterans (58%) had died. Median survival for Ra-223 first was 32 months and for Ra-223 later was 15 months (P = .14; hazard ratio [HR] 0.48; 95% CI, 0.17-1.3). Median survival for AO+ and AO- veterans was 12 months and 18 months, respectively (P = .15; HR, 2.0; 95% CI, 0.77-5.0). CONCLUSIONS: There was no statistical difference between AO+ and AO- veterans in terms of time to SRE, PSA, bone and ALP progression, even though there was a trend of shorter duration in AO+ veterans. There was no median survival difference between Ra-223 first vs Ra-223 later as well as between AO+ and AO- but there is a trend of worse survival in AO+ veterans.

Breast skin doses from brachytherapy using MammoSite HDR, intensity modulated radiation therapy, and tangential fields techniques.

Skin doses from brachytherapy using MammoSite HDR, Intensity Modulated Radiation Therapy (IMRT), and conventional tangential fields techniques were compared. For each treatment technique, skin doses were measured using paired thermoluminescent dosimeters placed on the patient's skin: (i) directly above the balloon catheter during MammoSite HDR brachytherapy treatments and (ii) 4 cm inside the treatment borders during the IMRT and conventional breast treatments. The mean dose measured was about 58% of the prescription dose for the patients treated using the MammoSite technique. On the other hand, for patients treated with IMRT and tangential fields, the mean dose was found to be about 69% and 71% of the corresponding prescription dose. This study suggests that in breast cancer radiation treatments the MammoSite HDR technique reduces skin doses compared to IMRT and tangential field techniques.

Treatment techniques for 3D conformal radiation to breast and chest wall including the internal mammary chain.

Breast, chest wall, and regional nodal irradiation have been associated with an improved outcome in high-risk breast cancer patients. Complex treatment planning is often utilized to ensure complete coverage of the target volume while minimizing the dose to surrounding normal tissues. The 2 techniques evaluated in this report are the partially wide tangent fields (PWTFs) and the 4-field photon/electron combination (the modified "Kuske Technique"). These 2 techniques were evaluated in 10 consecutive breast cancer patients. All patients had computerized tomographic (CT) scans for 3D planning supine on a breast board. The breast was defined clinically by the physician and confirmed radiographically with radiopaque bebes. The resulting dose-volume histograms (DVHs) of normal and target tissues were then compared. The deep tangent field with blocks resulted in optimal coverage of the target and the upper internal mammary chain (IMC) while sparing of critical and nontarget tissues. The wide tangent technique required less treatment planning and delivery time. We compared the 2 techniques and their resultant DVHs and feasibility in a busy clinic.

Interventions to enhance physical and psychological functioning among younger women who are ending nonhormonal adjuvant treatment for early-stage breast cancer.

PURPOSE: To conduct a clinical trial to determine if an educational intervention and a nutritional intervention could enhance physical and psychological functioning among younger women completing treatment for early-stage breast cancer. PATIENTS AND METHODS: Younger women (50 years of age or younger, N = 252), within 2 months of having completed active nonhormonal adjuvant therapy, diagnosed with stage 0, I, or II breast cancer with 10 or fewer positive lymph nodes were randomly assigned to a three-arm clinical trial. Women in the control arm of the trial received standard medical care. Women in the two active arms received either an educational intervention, designed to provide information about their illness and enhance adjustment, or a nutritional intervention, designed to promote a more healthy diet. Primary end points included mental functioning, physical functioning, and depressive symptoms. Women were assessed before random assignment, 4 months later (immediately post-intervention), and 13 months later (9 months post-intervention). RESULTS: Participants assigned to the two active treatment arms had significantly less depressive symptomatology and better physical functioning by 13-month follow-up (differences between the two active arms were nonsignificant). These effects were primarily accounted for by changes in intrusive thoughts, concerns regarding cancer recurrence and mortality, self-concept perceptions, and self-efficacy expectations. CONCLUSION Tailored psychosocial interventions can be effectively designed to enhance adjustment among younger women who are completing nonhormonal adjuvant therapy.

Intensity-modulated radiotherapy for the treatment of vulvar carcinoma: a comparative dosimetric study with early clinical outcome.

OBJECTIVES: To assess early clinical outcome of intensity-modulated radiation therapy (IMRT) in the treatment of vulvar cancer and compare dosimetric parameters with 3D conformal radiotherapy (3D CRT). METHODS: Fifteen patients with vulvar cancer were treated with IMRT. Seven patients were treated with preoperative chemoradiation, and 8 patients were treated with adjuvant postoperative radiation therapy. Median dose was 46 Gy in the preoperative and 50.4 Gy in the postoperative group. RESULTS: The mean volume of small bowel, rectum, and bladder that received doses in excess of 30 Gy with IMRT was reduced when compared with 3D CRT. Treatment was well tolerated, and only 1 patient had acute Grade 3 small-bowel toxicity. Median follow-up was 12 months. In the preoperative group, 5 patients (71%) had clinical complete response and 3 patients (42.8%) had pathologic complete response. In the adjuvant group, 2 patients had recurrences in the treatment field. No patients had late Grade 3 toxicity. The 2-year actuarial disease-specific survival was 100%. CONCLUSIONS: Intensity-modulated RT appears to offer advantages over 3D CRT treatment of vulvar cancer by elimination of dose modulation across overlapping regions and reduction of unnecessary dose to the bladder, rectum, and small bowel. Early results with a small number of patients show promising results, with a low incidence of severe toxicity.

Abdominal organ motion measured using 4D CT.

PURPOSE: To measure respiration-induced abdominal organ motion using four-dimensional computed tomography (4D CT) scanning and to examine the organ paths. METHODS AND MATERIALS: During 4D CT scanning, consecutive CT images are acquired of the patient at each couch position. Simultaneously, the patient's respiratory pattern is recorded using an external marker block taped to the patient's abdomen. This pattern is used to retrospectively organize the CT images into multiple three-dimensional images, each representing one breathing phase. These images are analyzed to measure organ motion between each phase. The displacement from end expiration is compared to a displacement limit that represents acceptable dosimetric results (5 mm). RESULTS: The organs measured in 13 patients were the liver, spleen, and left and right kidneys. Their average superior to inferior absolute displacements were 1.3 cm for the liver, 1.3 cm for the spleen, 1.1 cm for the left kidney, and 1.3 cm for the right kidney. Although the organ paths varied among patients, 5 mm of superior to inferior displacement from end expiration resulted in less than 5 mm of displacement in the other directions for 41 of 43 organs measured. CONCLUSIONS: Four-dimensional CT scanning can accurately measure abdominal organ motion throughout respiration. This information may result in greater organ sparing and planning target volume coverage.

Twice-daily high-dose-rate brachytherapy for medically inoperable uterine cancer.

PURPOSE: Medically inoperable patients with uterine cancer pose a therapeutic challenge. We developed a twice-daily schedule of high-dose-rate brachytherapy (HDRB) after a single insertion procedure that required a hospitalization of 3 days. METHODS AND MATERIALS: Favorable patients were offered brachytherapy alone, and all other patients received HDRB after pelvic external beam radiation therapy (EBRT). The prescribed dose was 7Gyx5 fractions and 4-5Gyx4-5 fractions for those treated after EBRT. HDRB was delivered with a b.i.d. schedule (4-6-h interval). RESULTS: Twenty-two patients (21 Stage I, 1 Stage IIB) were deemed medically inoperable. Sixteen patients received EBRT followed by HDRB, and six received HDRB alone. There were no procedural complications or significant acute toxicity. No thromboembolic events occurred within 30 days of the implant. CONCLUSIONS: This technique allows patients to be treated using a single procedure for insertion, with brief hospitalization for twice-daily HDRB.

High-dose-rate interstitial brachytherapy for gynecologic malignancies.

PURPOSE: The study aimed to assess the outcome of locally advanced cervical and vaginal cancer treated with high-dose-rate interstitial brachytherapy (HDRB). METHODS AND MATERIALS: Between 1998 and 2004, 16 previously unirradiated patients with locally advanced cervical and vaginal cancer not suitable for intracavitary brachytherapy because of distorted anatomy or extensive vaginal disease were treated with HDRB in combination with external beam radiotherapy. All patients received whole pelvis external beam radiation therapy (EBRT) followed by interstitial implantation. The median whole pelvis external beam dose was 45 Gy (range, 39.6-50.4 Gy) with 11 patients receiving parametrial boost to a median dose of 9 Gy. Twelve (75%) of these patients received chemotherapy concurrent with external beam. All patients received a single HDRB procedure using a modified Syed-Neblett template. A CT scan was performed postimplant for needle placement verification and treatment planning purpose. Dose was prescribed to the tumor volume based on the radiographic and clinical examination. All patients received 18.75 Gy in five fractions delivered twice daily. The median followup was 25 months (6-69 months). RESULTS: Median cumulative biologic effective dose (EBRT+HDRB) to tumor volume was 78.9 Gy10 with the range of 72.5-85.2Gy10. Median cumulative biologic effective dose for the rectum and bladder were 99.4 Gy3 (range, 79.6-107.8 Gy3) and 96.4 Gy3 (range, 78.3-105.3 Gy3), respectively. Complete response was achieved in 13 (81%) patients with 3 patients having persistent disease. Five of these 13 patients developed recurrence at a median time of 14 months (distant in 4 and local and distant in 1). The 5-year actuarial local control and cause-specific survival were 75% and 64%, respectively. In subset analysis, 5-year actuarial local control was 63% for cervical cancer patients and 100% for vaginal cancer patients. No patient had acute Grade 3 or 4 morbidity. Grade 3 or 4 delayed morbidity resulting from treatment occurred in 1 patient with 5-year actuarial rate of 7%. Three patients had late Grade 2 rectal morbidity and 1 patient had Grade 2 small bowel morbidity. CONCLUSIONS: Our series suggests that single interstitial implantation procedure with five fractions of 3.75 Gy each to target volume is an effective and safe fractionation schedule. The integration of imaging modality helps in decreasing dose to the critical organs. Additional patients and followup are ongoing to determine the long-term efficacy of this approach.

Determining radiographic outcome after spine radiosurgery--not as straightforward as one might think.

COMMENTARY ON: Spratt DE, Arevalo-Perez J, Leeman JE, Gerber NK, Folkert M, Taunk NK, et al. Early magnetic resonance imaging biomarkers to predict local control after high dose stereotactic body radiotherapy for patients with sarcoma spine metastases. Spine J 2016:16:291-98 (in this issue).

Moderators of interventions designed to enhance physical and psychological functioning among younger women with early-stage breast cancer.

PURPOSE: To identify factors that condition or moderate the impact of a previously described set of interventions on psychological and physical adjustment after diagnosis and treatment for early-stage breast cancer. PATIENTS AND METHODS: Younger women (age < 51 years, N = 252) with early-stage breast cancer within 2 months of having completed active nonhormonal adjuvant therapy were randomly assigned to a three-arm clinical trial, consisting of a control arm, an education arm, and a nutrition arm. Primary end points, assessed before random assignment and 4 and 13 months later, included mental functioning, physical functioning, and depressive symptoms. Four types of moderator variables were identified, including two sets reflecting psychosocial resources, specifically personality factors and factors related to the person's social environment, a set reflecting demographic variables, and a set reflecting treatment and disease variables (including comorbidities). RESULTS: Psychosocial factors were more likely to moderate treatment effects than were demographic and disease-related factors, but the moderating effects of these psychosocial factors were limited to patients receiving the nutrition intervention. Patients with lower psychosocial resources benefited from the nutrition intervention, whereas patients with a greater amount of psychosocial resources did not. CONCLUSION: Future trials of this type should stratify by or select for the moderating variables identified here (ie, dispositional pessimism, unmitigated communion, and negative social interaction) to establish more firmly their role in responses to psychosocial interventions. Effort should also be made to collect data to inform the delivery of interventions to those who might benefit the most.

A single institutional experience with definitive radiotherapy for cervical cancer using both high- and low-dose-rate brachytherapy.

OBJECTIVE: To evaluate outcomes in cervical cancer patients treated with high-dose-rate (HDRB) or low-dose-rate (LDRB) brachytherapy. METHODS: A retrospective chart review compared control rates, survival, and complications in the two groups. RESULTS: All patients received pelvic EBRT (45 Gy/5 weeks). 106 patients receiving LDRB were compared to 107 treated with HDRB. The median point A LDRB and HDRB dose was 42 Gy and 25 Gy/5, respectively. Tumor size and stage (I(B) 23% LDRB, 30% HDRB, II(A) 22% LDRB, 11% HDRB, II(B) 44% LDRB, 48% HDRB, III(B) 11% LDRB and HDRB) were similar, but more HDRB patients received chemosensitization (44% versus 6%). After adjusting for lymph node status with cox regression, no difference in 5-year survival (53% HDRB and 61% LDRB P = 0.088) or 5-year DFS (54% both groups, P = 0.089) was found between the two groups. Local recurrences occurred in 19% of the LDRB and 5% of the HDRB cohort. The time to LR was significantly longer in the HDRB group, and this persisted after adjusting for the increased used of chemotherapy in these patients. There was no significant difference in grade III or IV toxicity (6.6% LDRB and 3.7% HDRB). CONCLUSIONS: This HDRB dose fractionation schedule yielded improved local control but similar survival compared to LDRB.

The potential nephrotoxic effects of intensity modulated radiotherapy delivered to the para-aortic area of women with gynecologic malignancies: preliminary results.

OBJECTIVE: To assess kidney function via creatinine clearance before and after radiotherapy in gynecologic cancer patients treated to the para-aortic (PA) area via Intensity Modulated Radiotherapy (IMRT). METHODS: Twenty-three patients underwent IMRT to the para-aortic area, were followed for at least 5 months, and had the necessary laboratory data to calculate creatinine clearance. Various patient-related factors and radiotherapy-treatment related factors were analyzed to determine their association with changes in CrCl. RESULTS: Median follow-up was 10.9 months (range, 5-19 months). Median patient age was 51.7 years (range, 22-78). The average initial CrCl was noted to be 109.23 mL/min (range, 38.64-188.38) before radiotherapy and decreased to 90.00 mL/min (29.31-175.61) after radiotherapy (P = 0.004). Although 17 patients had a decrease in their CrCl, 6 were found to have a slight elevation. Five factors were associated with a decrement in CrCl greater than the average decrease (17.6%): presence of hydronephrosis, age <50, no history of cisplatin treatment, a BED to gross adenopathy exceeding mean BED, and salvage treatment of PA node recurrence. Subgroup analysis revealed that the only statistically significant change within the group of patient and/or treatment-related factors was between patients who were <50-year-old and patients who were > or =50 years of age (P = 0.03). No patient exhibited clinical signs of radiation-induced nephropathy. CONCLUSION: With a median follow-up of 10.9 months, the estimated CrCl decreased by 17.6% after IMRT to the para-aortic area +/- cisplatin chemotherapy. The greatest decrease in CrCl occurred in patients who had a history of hydronephrosis. Subgroup analysis revealed that the decline in CrCl was significantly greater for patients younger than 50 years of age. Interestingly, a greater decline in CrCl was noted for those patients who did not have a history of cisplatin treatment. Our preliminary results indicate that IMRT +/- cisplatin chemotherapy to the para-aortic area of women is safe and is not associated with any clinical sequelae of renal toxicity despite a small decrement in CrCl in most, but not all patients.

Clinical outcome with adjuvant treatment of endometrial carcinoma using intensity-modulated radiation therapy.

OBJECTIVE: To assess local control and chronic toxicity with IMRT for adjuvant treatment of endometrial carcinoma. METHODS: Forty-seven patients with endometrial cancer were treated with adjuvant IMRT and HDR brachytherapy (HDRB). The external beam dose was between 45 and 50.4 Gy, and all patients received 10 Gy in 2 fractions of HDRB to the vaginal cuff. Eight of these patients were treated with extended field to include the paraaortic region. RESULTS: IMRT dosimetry showed excellent coverage of the planning target volume (PTV) with mean PTV 95, PTV 110 and PTV 120 of 97.8%, 8.2% and 0.9% respectively. At a median follow-up of 20 months, four patients have recurred at extra pelvic sites. No patient had pelvic recurrence. The treatment was well tolerated with late toxicities as follows: small bowel grade 1: 25%, rectal grade 1: 2% and bladder grade 1: 13%. One patient had grade 3 small bowel toxicity. The 3-year actuarial rate of grade 2 or greater toxicity, disease-free survival and overall survival rate were 3.3%, 84% and 90%, respectively. CONCLUSIONS: The preliminary analysis of IMRT for adjuvant treatment of endometrial carcinoma shows excellent local control and low toxicity. However, longer follow-up and more patients are needed to ascertain whether the benefits of IMRT treatment seen here translate into long-term reductions in toxicities and local recurrence.

Feasibility of concurrent cisplatin and extended field radiation therapy (EFRT) using intensity-modulated radiotherapy (IMRT) for carcinoma of the cervix.

OBJECTIVES: To assess the acute tolerance of delivering concurrent cisplatin and extended field radiotherapy (EFRT) using intensity-modulated radiotherapy technique (IMRT) for cancer of the cervix. METHODS: All patients receiving definitive treatment for cervical cancer were treated with EFRT using IMRT technique and concurrent cisplatin. The treatment volume included the cervix, uterus, parametria, presacral space, upper vagina, pelvic, common iliac, and paraaortic nodes to the top of L1. All regions received 45 Gy (25 fractions) with a simultaneous boost to involved nodes (55 Gy/25 fractions). Patients were assessed weekly for toxicity and response. RESULTS: Twenty-two consecutive patients underwent treatment. All patients completed the prescribed course of EFRT. Median treatment length was 39.5 days (range 36-53). Treatment breaks of 2 and 3 days were required for bone marrow toxicity in 2 patients. The final week of chemotherapy was held in 2 patients because of neutropenia. No patient suffered acute or subacute grade 3 or 4 GI or GU toxicity. CONCLUSION: In this clinical study, an IMRT technique was used to successfully deliver EFRT with concurrent chemosensitization for cervical cancer. The technique was associated with an acceptable acute toxicity without significant treatment protraction. This new role for IMRT merits further evaluation with larger patient numbers and longer follow-up.

Preoperative chemoradiation for locally advanced carcinoma of the vulva.

OBJECTIVE: A twice daily (BID) radiation treatment schedule (interval of 4-6 h) delivered concurrent with chemotherapy for advanced or critically located carcinoma of the vulva was modeled on the schema developed by the Gynecology Oncology Group (GOG). Inguinal nodes were included in the treatment fields even if clinically negative. This review analyzed the outcomes using this approach. METHODS: A retrospective review was conducted of the records of 18 patients with vulvar cancer. Patients were treated with a modified GOG schema using 5-fluorouracil (5FU) and cisplatin with BID radiation treatments during the first and last weeks of treatment and seven daily radiation treatments in between. The regional nodes and primary tumor were prescribed 44.6 Gy. Resection of the primary tumor bed and inguinal dissection was planned at 4-6 weeks post-treatment. Clinical and pathological responses as well as locoregional control and toxicity were assessed. RESULTS: All patients responded. There were 13/18 complete clinical responses (cCR), of whom 12 remained NED at 25 months. Of the five partial clinical response (cPR) patients, two have suffered local recurrences, despite surgical resection in one and electron boost in the other. All patients developed a desquamative perineal skin reaction necessitating a mean treatment break of 15 days. No severe hematological toxicity was encountered, and only one patient had grade 3 small bowel toxicity. One patient required surgical debridement for groin wound breakdown. CONCLUSION: The use of BID chemoradiation resulted in complete or partial responses in all cases. Post-treatment groin dissection can be performed without significant post-operative complications.