Control charts for evaluation of quality of low-dose-rate brachytherapy for prostate cancer.

Purpose: Variations in dosimetric outcomes among patients treated with low-dose-rate brachytherapy for prostate cancer exist, even when implants are within dose constraints. Here, we used control charts to investigate reasons for intra-patient dosimetric variability. Material and methods: Univariate and multivariate control charts for prostate V100 (percentage of prostate volume that received 100% of prescribed radiation dose), D90 (radiation dose to 90% of prostate volume), and RV100 (rectal wall volume that received 100% of prescribed radiation dose) were generated for 212 consecutive prostate cancer patients implanted with iodine-125 (125I) radioactive seeds at the Princess Margaret Cancer Centre. Control limits were calculated based on the first fifty implants. Data points that were out of control were identified, and their pre-treatment and post-treatment dosimetric and clinical parameters were compared to data points that were in-control, using Student's t-test. Results: All implants were clinically acceptable. Twelve data points exceeded multivariate control limits. Ten of those points fell below the lower control limit of V100 control chart. Average prostate edema in the 10 out-of-control patients on both multivariate and V100 charts was 8.3%, as compared to 0.4% for in-control patients (p < 0.04). Two patients were observed to be out-of-control on multivariate control chart, but not on V100 control chart, and were found to have a reduction in prostate volume of 19.1% and 20.1% at one month after seed implant, compared to prostate volumes of pre-implantation evaluations. Conclusions: Control charts helped in identifying cases with out-of-control variability in post-plan prostate dosimetry. Post-treatment prostatic edema and contraction are important factors predicting variability in patients treated with 125I permanent seed brachytherapy.

Androgen Flare after LHRH Initiation Is the Side Effect That Makes Most of the Beneficial Effect When It Coincides with Radiation Therapy for Prostate Cancer.

Treatment of metastatic prostate cancer was historically performed via bilateral orchiectomy to achieve castration. An alternative to surgical castration is the administration of subcutaneous recombinant luteinizing hormone-releasing hormone (LHRH). LHRH causes the pituitary gland to produce luteinizing hormone (LH), which results in synthesis and secretion of testosterone from the testicles. When LHRH levels are continuously high, the pituitary gland stops producing LH, which results in reduced testosterone production by the testicles. Long-acting formulations of LHRH were developed, and its use replaced surgical orchiectomy in the vast majority of patients. Combining LHRH and radiation therapy was shown to increase survival of prostate cancer patients with locally advanced disease. Here, we present a hypothesis, and preliminary evidence based on previous randomized controlled trials, that androgen surge during radiation, rather than its suppression, could be responsible for the enhanced prostate cancer cell kill during radiation. Starting LHRH agonist on the first day of radiation therapy, as in the EORTC 22863 study, should be the standard of care when treating locally advanced prostate cancer. We are developing formulations of short-acting LHRH agonists that induce androgen flare, without subsequent androgen deprivation, which could open the door for an era in which locally advanced prostate cancer could be cured while patients maintain potency.

Administering Docetaxel for Metastatic Hormone-Sensitive Prostate Cancer 1-6 Days Compared to More Than 14 Days after the Start of LHRH Agonist Is Associated with Better Clinical Outcomes Due to Androgen Flare.

Docetaxel, when given at the beginning of androgen deprivation therapy (ADT) for patients with metastatic hormone-sensitive prostate cancer (MHSPC), results in significantly longer overall survival than ADT alone. We aimed to investigate if the delivery of the first dose of docetaxel during the testosterone flare associated with LHRH initiation results in better clinical outcomes, as testosterone induces mitosis of prostate cancer cells, and docetaxel specifically targets cells in mitosis. We analyzed data from the CHAARTED trial which randomized MHSPC patients to ADT alone or ADT plus docetaxel. We included only patients treated with LHRH agonist and docetaxel (n = 379). The only cutoff that resulted in differences in treatment outcomes was between patients who started docetaxel 1-6 days (n = 18) compared to more than 14 days from LHRH initiation (n = 297). Actuarial median overall survival was 72 versus 57 months (p = 0.2); progression-free survival was 49 versus 17 months (p = 0.06), and freedom from castrate-resistant prostate cancer was 51 versus 18 months (p = 0.04) for patients who started docetaxel 1-6 days compared to more than 14 days from LHRH initiation, respectively. Administering docetaxel 1-6 days from the initiation of LHRH agonist for patients with MHSPC could be associated with improved clinical outcomes.

Applicator for cervical brachytherapy for MRI or CT guided therapy.

Cervical cancer is the second leading cause of cancer death in women aged 20 to 39 years in the USA. Radiation therapy for cervical cancer in the definitive setting is delivered by combining external beam radiation and brachytherapy. The procedure of cervical brachytherapy could be associated with significant discomfort and pain to the patient. Here we describe a novel cervical applicator, that can be inserted bedside, with local anesthesia only. The device is similar to intrauterine device and vaginal ring used for contraception, albeit with channels for high dose rate brachytherapy.

Automatic localization of the prostatic urethra for image guided radiation therapy.

Treatment of prostate cancer with radiation therapy (RT) requires image guided RT (IGRT) to focus the radiation on the target volumes while minimizing doses to organs at risk. Here we describe a urinary catheter that allows imaging of the prostatic urethra and uses it for automatic localization of the prostate for IGRT. The catheter has a contrast lumen that can be empty or full with contrast. Computerized tomography is performed twice, with contrast lumen empty and full, allowing urethral autosegmentation using digital subtraction. Under ultrasound, continuous urethral visualization is possible by pumping aerated gel in- and out of the contrast lumen.

Maintaining consistent bladder filling during external beam radiotherapy for prostate cancer.

Radiation therapy for patients with prostate cancer is preferably provided with a full urinary bladder. Full bladder can potentially move the small intestine out of the radiation treatment regions, and results in decreased small bowel radiation dose and gastrointestinal toxicity. Maintaining consistent bladder filling during computerized tomography simulation scan used for treatment planning and at daily radiation treatments is challenging. Here we present an in-development urinary catheter with a floating balloon that drains the bladder only when urine reaches to a prespecified level, and review current methods used in clinic to ensure consistent bladder filling. These includes bladder filling protocols, ultrasound scanning and biofeedback techniques.

Markers of Toxicity and Response to Radiation Therapy in Patients With Prostate Cancer.

The main treatment modalities for localized prostate cancer are surgery and radiation. Surgery removes the whole prostate gland, whereas with radiation therapy the irradiated prostate remains within the patient's body. Biomarkers specific to the prostate gland should become undetectable after surgery, but this is not the case when radiation therapy is used, as residual prostate cells may still be metabolically active. Here, we review the role of tumor markers of toxicity and response to radiation therapy in patients with prostate cancer, including prostate specific antigen, human kallikrein 2, osteopontin, prostate cancer associated 3, citrulline, and others.

Predictors of prostate bed recurrence on magnetic resonance imaging in patients with rising prostate-specific antigen after radical prostatectomy.

INTRODUCTION: Radical prostatectomy (RP) is a standard treatment modality for localized prostate cancer. Biochemical failure after RP is usually evaluated with whole-body imaging to exclude distant metastatic disease, and pelvic magnetic resonance imaging (MRI) to detect local recurrence in the prostatectomy bed. The goal of this study is to correlate disease characteristics and demographic data in patients with rising prostate-specific antigen (PSA) after RP to determine association with MRI-detected cancer recurrence. METHODS: Sixty-four patients who underwent pelvic MRI for rising PSA after RP and had complete clinical and pathological data available were included. Using Chi-squared testing, we analyzed PSA levels, pathological disease characteristics (prostate cancer risk group, Gleason score, extracapsular extension, positive surgical margin, seminal vesicle involvement, perineural invasion, lymphovascular invasion, and PSA level before MRI), time from surgery to biochemical failure, and patient demographic characteristics as potential predictors of MRI-detected local recurrence. RESULTS: Definite MRI-detected local recurrence was observed in 17/64 patients (27%). Eleven (17%) patients had a suspicious lesion with the differential of scarring, retained seminal vesicle, or recurrent cancer. Thirty-six (56%) patients had no evidence of tumor in the prostate bed or pelvis on MRI. Patient race was associated with likelihood of detecting a prostate nodule on MRI (p=0.04), with African American patients having 82% lower odds of MRI-detected tumor recurrence compared with white patients (p=0.045). No other tumor or patient characteristic was significantly associated with MRI-detected recurrence. CONCLUSIONS: African American patients with biochemical failure after RP are less likely to have MRI-detectable recurrence in the prostate bed compared with white patients.

First line Immunotherapy for Non-Small Cell Lung Cancer.

Immunotherapy for non-small cell lung cancer (NSCLC) is incorporated increasingly in first line treatments protocols. Multiple phase 3 studies have tested different medications targeting programmed death receptor 1 (PD-1), programmed death-ligand 1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), with or without chemotherapy. The inclusion criteria differ between the various clinical trials, including the cut-off levels of PD-L1 expression on tumor cells, and the tumor histology (squamous or non-squamous). Patients with tumor expression levels of PD-L1 ≥ 50% are candidates for treatment with single agent Pembrolizumab or Atezolizumab. Patients with PD-L1 < 50% are candidates for immunotherapy with pembrolizumab as a single agent if PL-1 > 1%; immunotherapy doublet, Nivolumab and Ipilimumab, or single agent immunotherapy combined with chemotherapy. Here we review phase 3 clinical trials utilizing immunotherapy in the first line for treatment of NSCLC, including Pembrolizumab in KEYNOTE-024, KEYNOTE-042, KEYNOTE-189 and KEYNOTE-407; Nivolumab and Ipilimumab in CHECKMATE-227 and CHECKMATE 9LA; and Atezolizumab in IMpower110, IMpower130 and IMpower150.

[MANAGING LUNG CANCER PATIENTS' CARE DURING THE COVID-19 PANDEMIC].

BACKGROUND: Lung cancer patients who contract the new coronavirus, appear to have a greater risk for severe COVID-19 illness along with early deterioration and death. However, the prognosis may depend on the cancer stage and the type of treatment administered. OBJECTIVES: Establishing updated treatments and care management regulations for lung cancer patients during the COVID-19 pandemic, based on worldwide clinical experience. METHODS: This article reviews the main recommendations described by the American and European Oncology Societies managing lung cancer patients infected by COVID-19. RESULTS: In the current pandemic setting, attempts should be made to avoid jeopardizing the prognosis of lung cancer patients, by maintaining current guidelines in oncology practice. In cases of patients with active infection, the recommendation is to hold treatment until recovery. For other patients, due to the aggressive nature of lung cancer, the guidelines suggest not to delay curative treatments in non-metastatic disease and provide palliative treatment in shortened protocols. CONCLUSIONS: The present summary of guideline recommendations provides different management strategies for patients with lung cancer. These care approaches attempt to solve new challenges raised by the COVID-19 pandemic. Each specific case must be considered individually.

Cloning of two splice variants of Spalax heparanase encoding for truncated proteins.

Heparanase is an endoglycosidase that degrades heparan sulfate side chains of heparan sulfate-proteoglycans. It liberates heparan sulfate-bound growth factors and thereby promotes blood vessel sprouting and angiogenesis. The subterranean blind mole rat, Spalax, is a wild mammal that lives most of its life in underground tunnels where it experiences sharp fluctuations in oxygen and carbon dioxide levels. We described two splice variants of heparanase from Spalax, Splice 7 and splice 36, both devoid of heparanase enzymatic activity. Splice 7 increases tumor growth, while splice 36 functions as a dominant negative to wild-type heparanase and decreases tumor growth and metastasis. Here, we describe two novel splice variants of Spalax heparanase, splice 67 and splice 612. These splice variants result in production of a shorter heparanase proteins that are similar to the wild-type native heparanase in their N-terminal but have unique C-terminals. Both splice 67 and 612 lack heparan sulfate degradation activity.

Potential Mechanisms of Cancer-Related Hypercoagulability.

The association between cancer and thrombosis has been known for over a century and a half. However, the mechanisms that underlie this correlation are not fully characterized. Hypercoagulability in cancer patients can be classified into two main categories: Type I and Type II. Type I occurs when the balance of endogenous heparin production and degradation is disturbed, with increased degradation of endogenous heparin by tumor-secreted heparanase. Type II hypercoagulability includes all the other etiologies, with factors related to the patient, the tumor, and/or the treatment. Patients with poor performance status are at higher risk of venous thromboembolism (VTE). Tumors can result in VTE through direct pressure on blood vessels, resulting in stasis. Several medications for cancer are correlated with a high risk of thrombosis. These include hormonal therapy (e.g., tamoxifen), chemotherapy (e.g., cisplatin, thalidomide and asparaginase), molecular targeted therapy (e.g., lenvatinib, osimertinib), and anti-angiogenesis monoclonal antibodies (e.g., bevacizumab and ramucirumab).

Inter-institutional analysis demonstrates the importance of lower than previously anticipated dose regions to prevent late rectal bleeding following prostate radiotherapy.

PURPOSE: To investigate whether inter-institutional cohort analysis uncovers more reliable dose-response relationships exemplified for late rectal bleeding (LRB) following prostate radiotherapy. MATERIAL AND METHODS: Data from five institutions were used. Rectal dose-volume histograms (DVHs) for 989 patients treated with 3DCRT or IMRT to 70-86.4 Gy@1.8-2.0 Gy/fraction were obtained, and corrected for fractionation effects (α/ß = 3 Gy). Cohorts with best-fit Lyman-Kutcher-Burman volume-effect parameter a were pooled after calibration adjustments of the available LRB definitions. In the pooled cohort, dose-response modeling (incorporating rectal dose and geometry, and patient characteristics) was conducted on a training cohort (70%) followed by final testing on the remaining 30%. Multivariate logistic regression was performed to build models with bootstrap stability. RESULTS: Two cohorts with low bleeding rates (2%) were judged to be inconsistent with the remaining data, and were excluded. In the remaining pooled cohorts (n = 690; LRB rate = 12%), an optimal model was generated for 3DCRT using the minimum rectal dose and the absolute rectal volume receiving less than 55 Gy (AUC = 0.67; p = 0.0002; Hosmer-Lemeshow p-value, pHL = 0.59). The model performed nearly as well in the hold-out testing data (AUC = 0.71; p < 0.0001; pHL = 0.63), indicating a logistically shaped dose-response. CONCLUSION: We have demonstrated the importance of integrating datasets from multiple institutions, thereby reducing the impact of intra-institutional dose-volume parameters explicitly correlated with prescription dose levels. This uncovered an unexpected emphasis on sparing of the low to intermediate rectal dose range in the etiology of late rectal bleeding following prostate radiotherapy.

Molecular Predictors of Response to Neoadjuvant Chemoradiation for Rectal Cancer.

OBJECTIVES: To determine whether the expression of specific molecular markers in the rectal cancer biopsies prior to treatment, can correlate with complete tumor response to chemoradiotherapy (CRT) as determined by the pathology of the surgical specimen. METHODS: We retrospectively examined pretreatment rectal biopsies of patients aged 18 years or older with locally advanced rectal cancer who had been treated with neoadjuvant CRT and surgical resection in our tertiary-care, university-affiliated medical center, between January 2001 and December 2011. Samples were analyzed for expression of B-cell lymphoma 2, P53, Ki67, epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, and the tumor regression grade after CRT and radical surgery. RESULTS: Forty-seven patients were included in the final analysis. Main outcome measures were the correlation between the expression of the molecular markers tested in the pretreatment biopsy, and complete tumor response. Complete pathologic response after CRT was attained in 27% of the patients. Percentage of cells expressing EGFR in the pretreated biopsies of patients having complete pathologic response after CRT and surgery was 33.08±7.87% compared to 19±15.36% (P=0.38), 6.66±2.83% (P<0.003), and 12.5±4.93% (P=0.033) in patients with partial response and tumor regression grades of 2, 3, and 4, respectively. The other molecular markers tested in the pretreatment biopsy did not corresponded with complete pathologic response. CONCLUSIONS: EGFR expression pattern in the pretreatment biopsies of rectal tumors can assist in identifying patients who will benefit from neoadjuvant CRT.

Vitamin D ointment for prevention of radiation dermatitis in breast cancer patients.

Radiation dermatitis occurs frequently during adjuvant radiation therapy for breast cancer. Prevention of radiation dermatitis by applying various creams and ointments has a limited success, and Aqua cream which has urea as one of its active ingredients is used in many institutions as a preventive treatment. The primary goal of this study is to assess the effect of vitamin D (calcipotriol) ointment in prevention of radiodermatitis in breast cancer patients compared to Aqua cream. Twenty-three women with localized breast cancer who underwent breast-conserving surgery and opted to receive adjuvant radiotherapy to breast only were enrolled in this study. A cream containing an active vitamin D analog, calcipotriol (Daivonex), was randomly applied either to the medial or to the lateral half of the irradiated breast, while Aqua cream was applied to the complimentary half of the same breast along the whole treatment days, each day, after the delivery of radiation. Skin reaction was recorded and compared between the two halves of the breast. Vitamin D was well tolerated by patients with no local or systemic allergic reactions. Radiation dermatitis was not significantly different between both treatment arms. Topical vitamin D ointment is not superior to Aqua cream for prevention of radiation-induced dermatitis in women treated with adjuvant radiation for breast cancer.

Human tissue Kallikreins: Blood levels and response to radiotherapy in intermediate risk prostate cancer.

OBJECTIVES: Kallikreins are serine proteases over expressed in many malignancies. In this study, we measure changes in serum kallikrein (KLKs) levels during intensity-modulated radiotherapy (IMRT) in prostate cancer patients, and find potential correlations between serum kallikrein level and normal tissues toxicity during radiation. METHODS: Forty-nine patients with prostate cancer were recruited as follows: group 1, definitive standard fractionation IMRT (78Gy in 39 fractions, n=15); group 2, definitive hypofractionated IMRT (60Gy in 20 fractions, n=15); and group 3, IMRT postprostatectomy (66Gy in 33 fractions, n=19). Patients treated with definitive radiation therapy were intermediate risk. Blood samples were collected at baseline and quarterly during IMRT and at each follow-up visit. Acute toxicity was graded weekly during radiotherapy using CTC-AE v4.0 criteria. Multiplexed immunoassays were used to quantify total, free, and intact Prostate Specific Antigen (PSA), as well as Kallikreins 2, 4, 6, and 11. RESULTS: The serum kallikreins, PSA (total, free and intact), KLK2, 6, and 11 change significantly after definitive radiotherapy. KLK2 and intact PSA decrease as fast as two weeks after initiation of radiation, while the first significant decrease in total and free PSA is noted only at the completion of radiation. KLK6 and KLK11 surge temporarily during radiation therapy and decrease below baseline levels at 8weeks and 12months, respectively after completion of radiation. KLK4 levels did not change with radiation. There was no correlation between GU or GI toxicities and serum kallikreins. CONCLUSIONS: PSA, KLK2, 6, and 11, change significantly after definitive prostate radiotherapy, though KLK2 and PSA decrease by the end of the radiation course while KLK6 and KLK11 decrease significantly starting at 2 and 12months, respectively, after radiation. There was no correlation between GU or GI toxicities and serum kallikreins.

Radiation safety of receptive anal intercourse with prostate cancer patients treated with low-dose-rate brachytherapy.

PURPOSE: Prostate low-dose-rate (LDR) brachytherapy involves implantation of radioactive seeds permanently into the prostate gland. During receptive anal intercourse, the penis of the partner may come in close proximity to the implanted prostate gland. We estimate the potential intrarectal dose rates and suggest guidance on radiation precautions. METHODS AND MATERIALS: One hundred two patients were included in the study. After implantation, with patients under anesthesia in the dorsal lithotomy position, a new set of ultrasound (US) images and a CT scan were obtained. The images were fused, radioactive seeds and US probe locations were determined on the CT, and prostate, bladder, and rectal contours were drawn on the US. Dose rates (cGy/h) were calculated for the portion of the US probe spanning the prostate for several dose-volume histogram parameters. RESULTS: Twenty patients were treated with (125)I and 82 patients with (103)Pd. Average dose rates at Day 0 to the portion of the US probe spanning the prostate were 2.1 ± 1.3 cGy/h and 2.5 ± 0.8 cGy/h for patients treated with (125)I and (103)Pd, respectively. After 60 days, average calculated probe dose drops to 1.0 ± 0.6 cGy/h and 0.2 ± 0.1 cGy/h for (125)I and (103)Pd, respectively. CONCLUSIONS: During the immediate weeks after prostate seed implant, the estimated intrarectal dose rates are higher in (103)Pd compared to (125)I. As (103)Pd decays faster than (125)I, 2 months after the implant, radiation exposure from (103)Pd becomes lower than (125)I. Receptive anal intercourse time should be kept as low as possible during 2 and 6 months after low-dose-rate brachytherapy of the prostate with (103)Pd and (125)I, respectively.

Long-term outcome of magnetic resonance spectroscopic image-directed dose escalation for prostate brachytherapy.

PURPOSE: To report the long-term control and toxicity outcomes of patients with clinically localized prostate cancer, who underwent low-dose-rate prostate brachytherapy with magnetic resonance spectroscopic image (MRSI)-directed dose escalation to intraprostatic regions. METHODS AND MATERIALS: Forty-seven consecutive patients between May 2000 and December 2003 were analyzed retrospectively. Each patient underwent a preprocedural MRSI, and MRS-positive voxels suspicious for malignancy were identified. Intraoperative planning was used to determine the optimal seed distribution to deliver a standard prescription dose to the entire prostate, while escalating the dose to MRS-positive voxels to 150% of prescription. Each patient underwent transperineal implantation of radioactive seeds followed by same-day CT for postimplant dosimetry. RESULTS: The median prostate D90 (minimum dose received by 90% of the prostate) was 125.7% (interquartile range [IQR], 110.3-136.5%) of prescription. The median value for the MRS-positive mean dose was 229.9% (IQR, 200.0-251.9%). Median urethra D30 and rectal D30 values were 142.2% (137.5-168.2%) and 56.1% (40.1-63.4%), respectively. Median followup was 86.4 months (IQR, 49.8-117.6). The 10-year actuarial prostate-specific antigen relapse-free survival was 98% (95% confidence interval, 93-100%). Five patients (11%) experienced late Grade 3 urinary toxicity (e.g., urethral stricture), which improved after operative intervention. Four of these patients had dose-escalated voxels less than 1.0 cm from the urethra. CONCLUSIONS: Low-dose-rate brachytherapy with MRSI-directed dose escalation to suspicious intraprostatic regions exhibits excellent long-term biochemical control. Patients with dose-escalated voxels close to the urethra were at higher risk of late urinary stricture.

Evaluation of the dosimetric impact of loss and displacement of seeds in prostate low-dose-rate brachytherapy.

PURPOSE: To analyze the seed loss and displacement and their dosimetric impact in prostate low-dose-rate (LDR) brachytherapy while utilizing the combination of loose and stranded seeds. MATERIAL AND METHODS: Two hundred and seventeen prostate cancer patients have been treated with LDR brachytherapy. Loose seeds were implanted in the prostate center and stranded seeds in the periphery of the gland. Patients were imaged with transrectal ultrasound before implant and with computerized tomography/magnetic resonance imaging (CT/MR) one month after implant. The seed loss and displacement had been analyzed. Their impact on prostate dosimetry had been examined. The seed distribution beyond the prostate inferior boundary had been studied. RESULTS: The mean number of seeds per patient that were lost to lung, pelvis/abdomen, urine, or unknown destinations was 0.21, 0.13, 0.03, and 0.29, respectively. Overall, 40.1% of patients had seed loss. Seed migration to lung and pelvis/abdomen occurred in 15.5% and 10.5% of the patients, respectively. Documented seed loss to urine was found in 3% of the patients while 20% of patients had seed loss to unknown destinations. Prostate length difference between pre-plan and post-implant images was within 6 mm in more than 98% of cases. The difference in number of seeds inferior to prostate between pre-plan and post-implant dosimetry was within 7 seeds for 93% of patients. At time of implant, 98% of seeds, inferior to prostate, were within 5 mm and 100% within 15 mm, and in one month post-implant 83% within 9 mm and 96.3% within 15 mm. Prostate post-implant V100, D90, and rectal wall RV100 for patients without seed loss were 94.6%, 113.9%, and 0.98 cm(3), respectively, as compared to 95.0%, 114.8%, and 0.95 cm(3) for the group with seed loss. CONCLUSIONS: Seed loss and displacement have been observed to be frequent. No correlation between seed loss and displacement and post-plan dosimetry has been reported.