Both genome-wide genetic and epigenetic alterations are fundamentally important for the development of cancers, but the interdependence of these aberrations is poorly understood. Glioblastomas and ...other cancers with the CpG island methylator phenotype (CIMP) constitute a subset of tumours with extensive epigenomic aberrations and a distinct biology. Glioma CIMP (G-CIMP) is a powerful determinant of tumour pathogenicity, but the molecular basis of G-CIMP remains unresolved. Here we show that mutation of a single gene, isocitrate dehydrogenase 1 (IDH1), establishes G-CIMP by remodelling the methylome. This remodelling results in reorganization of the methylome and transcriptome. Examination of the epigenome of a large set of intermediate-grade gliomas demonstrates a distinct G-CIMP phenotype that is highly dependent on the presence of IDH mutation. Introduction of mutant IDH1 into primary human astrocytes alters specific histone marks, induces extensive DNA hypermethylation, and reshapes the methylome in a fashion that mirrors the changes observed in G-CIMP-positive lower-grade gliomas. Furthermore, the epigenomic alterations resulting from mutant IDH1 activate key gene expression programs, characterize G-CIMP-positive proneural glioblastomas but not other glioblastomas, and are predictive of improved survival. Our findings demonstrate that IDH mutation is the molecular basis of CIMP in gliomas, provide a framework for understanding oncogenesis in these gliomas, and highlight the interplay between genomic and epigenomic changes in human cancers.
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DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To review the impact of high-dose radiotherapy (RT) in the postprostatectomy salvage setting on long-term biochemical control and distant metastases-free survival, and to identify clinical and ...pathologic predictors of outcomes.
During 1988-2007, 285 consecutive patients were treated with salvage RT (SRT) after radical prostatectomy. All patients were treated with either three-dimensional conformal RT or intensity-modulated RT. Two hundred seventy patients (95%) were treated to a dose ≥66 Gy, of whom 205 (72%) received doses ≥70 Gy. Eighty-seven patients (31%) received androgen-deprivation therapy as a component of their salvage treatment. All clinical and pathologic records were reviewed to identify treatment risk factors and response.
The median follow-up time after SRT was 60 months. Seven-year actuarial prostate-specific antigen (PSA) relapse-free survival and distant metastases-free survival were 37% and 77%, respectively. Independent predictors of biochemical recurrence were vascular invasion (p < 0.01), negative surgical margins (p < 0.01), presalvage PSA level >0.4 ng/mL (p < 0.01), androgen-deprivation therapy (p = 0.03), Gleason score ≥7 (p = 0.02), and seminal vesicle involvement (p = 0.05). Salvage RT dose ≥70 Gy was not associated with improvement in biochemical control. A doubling time <3 months was the only independent predictor of metastatic disease (p < 0.01). There was a trend suggesting benefit of SRT dose ≥70 Gy in preventing clinical local failure in patients with radiographically visible local disease at time of SRT (7 years: 90% vs. 79.1%, p = 0.07).
Salvage RT provides effective long-term biochemical control and freedom from metastasis in selected patients presenting with detectable PSA after prostatectomy. Androgen-deprivation therapy was associated with improvement in biochemical progression-free survival. Clinical local failures were rare but occurred most commonly in patients with greater burden of disease at time of SRT as reflected by either radiographic imaging or a greater PSA level. Salvage radiation doses ≥70 Gy may ultimately be most beneficial in these patients, but this needs to be further studied.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
To report dosimetry and early toxicity data in breast cancer patients treated with postoperative proton radiation therapy.
From March 2013 to April 2014, 30 patients with nonmetastatic breast cancer ...and no history of prior radiation were treated with proton therapy at a single proton center. Patient characteristics and dosimetry were obtained through chart review. Patients were seen weekly while on treatment, at 1 month after radiation therapy completion, and at 3- to 6-month intervals thereafter. Toxicity was scored using Common Terminology Criteria for Adverse Events version 4.0. Frequencies of toxicities were tabulated.
Median dose delivered was 50.4 Gy (relative biological equivalent RBE) in 5 weeks. Target volumes included the breast/chest wall and regional lymph nodes including the internal mammary lymph nodes (in 93%). No patients required a treatment break. Among patients with >3 months of follow-up (n=28), grade 2 dermatitis occurred in 20 patients (71.4%), with 8 (28.6%) experiencing moist desquamation. Grade 2 esophagitis occurred in 8 patients (28.6%). Grade 3 reconstructive complications occurred in 1 patient. The median planning target volume V95 was 96.43% (range, 79.39%-99.60%). The median mean heart dose was 0.88 Gy (RBE) range, 0.01-3.20 Gy (RBE) for all patients, and 1.00 Gy (RBE) among patients with left-sided tumors. The median V20 of the ipsilateral lung was 16.50% (range, 6.1%-30.3%). The median contralateral lung V5 was 0.34% (range, 0%-5.30%). The median maximal point dose to the esophagus was 45.65 Gy (RBE) range, 0-65.4 Gy (RBE). The median contralateral breast mean dose was 0.29 Gy (RBE) range, 0.03-3.50 Gy (RBE).
Postoperative proton therapy is well tolerated, with acceptable rates of skin toxicity. Proton therapy favorably spares normal tissue without compromising target coverage. Further follow-up is necessary to assess for clinical outcomes and cardiopulmonary toxicities.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
Concurrent bevacizumab with hypofractionated stereotactic radiation therapy (HSRT) is safe and effective for the treatment of recurrent high-grade gliomas (HGG). The objective of this study was to ...characterize the patterns of failure after this treatment regimen.
Twenty-four patients with recurrent enhancing HGG were previously treated on an institutional review board-approved protocol of concurrent bevacizumab and reirradiation. Patients received 30 Gy in 5 fractions to the recurrent tumor with HSRT. Brain magnetic resonance imaging (MRI) was performed every 2 cycles, and bevacizumab was continued until clinical or radiographic tumor progression according to the criteria of Macdonald et al. MRI at the time of progression was fused to the HSRT treatment plan, and the location of recurrence was classified on the basis of volume within the 95% isodose line. Outcomes based on patient characteristics, tumor grade, recurrence pattern, and best response to treatment were analyzed by the Kaplan-Meier method.
Twenty-two patients experienced either clinical or radiographic progression. Recurrent tumor was enhancing in 15 (71.4%) and nonenhancing in 6 (28.6%) patients. Eleven patients (52.4%) had recurrence within the radiation field, 5 patients (23.8%) had marginal recurrence, and 5 patients had recurrence outside the radiation field. Pattern of enhancement and location of failure did not correlate with overall survival or progression-free survival. Radiographic response was the only variable to significantly correlate with progression-free survival.
Despite the promising initial response seen with the addition of HSRT to bevacizumab as salvage treatment for recurrent HGG, approximately half of patients ultimately still experience failure within the radiation field. The rate of local failure with the addition of HSRT seems to be lower than that seen with bevacizumab alone in the salvage setting. Our data underscore the radioresistance of HGG and the need for better salvage treatments.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
The widespread coronavirus disease 2019 (COVID-19) pandemic has resulted in significant changes in care delivery among radiation oncology practices and has demanded the rapid incorporation of ...telehealth. However, the impact of a large-scale transition to telehealth in radiation oncology on patient access to care and the viability of care delivery are largely unknown. In this manuscript, we review our implementation and report data on patient access to care and billing implications. Because telehealth is likely to continue after COVID-19, we propose a radiation oncology–specific algorithm for telehealth.
In March 2020, our department began to use telehealth for all new consults, posttreatment encounters, and follow-up appointments. Billable encounters from January to April 2020 were reviewed and categorized into 1 of the following visit types: in-person, telephonic, or 2-way audio-video. Logistic regression models tested whether visit type differed by patient age, income, or provider.
There was a 35% decrease in billable activity from January to April. In-person visits decreased from 100% to 21%. Sixty percent of telehealth appointments in April were performed with 2-way audio-video and 40% by telephone only. In-person consultation visits were associated with higher billing codes compared with 2-way audio-video telehealth visits (P < .01). No difference was seen for follow-up visits. Univariate and multivariable analysis identified that older patient age was associated with reduced likelihood of 2-way audio-video encounters (P < .01). The physician conducting the telehealth appointment was also associated with the type of visit (P < .01). Patient income was not associated with the type of telehealth visit.
Since the onset of the COVID-19 pandemic, we have been able to move the majority of patient visits to telehealth but have observed inconsistent utilization of the audio-video telehealth platform. We present guidelines and quality metrics for incorporating telehealth into radiation oncology practice, based on type of encounter and disease subsite.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Our purpose was to evaluate hippocampal doses and target volume coverage with and without hippocampal sparing when treating multiple brain metastases using various stereotactic radiosurgery (SRS) ...platforms.
We selected 10 consecutive patients with 14 separate treatments who had been treated in our department for 3 to 10 brain metastases and added hippocampal avoidance contours. All 14 treatments were planned with GammaPlan for Gamma Knife, Eclipse for single isocenter volumetric modulated arc therapy (VMAT), TomoTherapy Treatment Planning System (TPS) for TomoTherapy, and MultiPlan for CyberKnife. Initial planning was performed with the goal of planning target volume coverage of V100 ≥95% without hippocampal avoidance. If the maximum hippocampal point dose (Dmax) was <6.6 Gy in a single fraction and <40% of the hippocampi received ≤4.5 Gy, no second plan was performed. If either constraint was not met, replanning was performed with these constraints.
There was a median of 6 metastases per plan, with an average total tumor volume of 7.32 mL per plan. The median hippocampal Dmax (in Gy) without sparing averaged 1.65, 9.81, 4.38, and 5.46, respectively (P < .0001). Of 14 plans, 3 Gamma Knife and CyberKnife plans required replanning, whereas 13 VMAT and 8 TomoTherapy plans required replanning. The hippocampal constraints were not achievable in 1 plan on any platform when the tumor was bordering the hippocampus. The mean volume of brain receiving 12 Gy (in mL), which has been associated with symptomatic radionecrosis, was 23.57 with Gamma Knife, 76.77 with VMAT, 40.86 with CyberKnife, and 104.06 with TomoTherapy (P = .01). The overall average conformity indices for all plans ranged from 0.36 to 0.52.
Even with SRS, the hippocampi can receive a considerable dose; however, if the hippocampi are outlined as organs of risk, sparing these structures is feasible in nearly all situations with all 4 platforms, without detriment to target coverage, and should be considered in all patients undergoing SRS for multiple brain metastases.
Hippocampi play an important role in memory, and sparing of these structures in whole brain radiation can improve neurocognitive outcomes. The hippocampi are not routinely spared when using stereotactic radiosurgery. We evaluated the incidental dose to the hippocampi when treating multiple brain metastases and sought to examine if hippocampal sparing is feasible without detriment to target coverage. We found that hippocampal sparing is possible without affecting coverage or conformality in most cases across treatment platforms.
Traditionally, patients treated with chemoradiotherapy for node‐positive oropharyngeal squamous cell carcinoma (N+ OPSCC) have undergone a planned neck dissection (ND) after treatment. Recently, ...negative post‐treatment positron‐emission tomography (PET)/computed tomography (CT) imaging has been found to have a high negative predictive value for the presence of residual disease in the neck. Here, we present the first comprehensive analysis of a large, uniform cohort of N+ OPSCC patients achieving a PET/CT‐based complete response (CR) after chemoradiotherapy, and undergoing observation, rather than ND. From 2002 to 2009, 302 patients with N+ OPSCC treated with 70 Gy intensity‐modulated radiation therapy and concurrent chemotherapy underwent post‐treatment clinical assessment including PET/CT. CR was defined as no evidence of disease on clinical examination and post‐treatment PET/CT. ND was reserved for patients with <CR on either PET/CT, clinical examination, or other imaging. 260 patients (86.1%) had clinical and radiographic CRs, and underwent neck observation (rate of regional control, 97.7%; 5‐year overall survival, 79.8%). The four observed patients experiencing neck recurrence had initial staging of N1 (n = 2), N2b (n = 1), and N2c (n = 1). Three of four were successfully surgically salvaged. There was no association between N stage and rate of neck recurrence (p = 0.74). 52 and 25% of patients undergoing ND had viable tumor in the neck after positive and negative PET/CT, respectively. We conclude that patients achieving CRs after chemoradiation, based on clinical and PET/CT assessment, have a high probability of regional control, with a 2.3% regional failure rate, and may be safely observed without planned ND.
What's new?
Traditionally, most patients with head and neck cancer and nodal metastases who are treated with chemoradiotherapy undergo a neck dissection after treatment in order to remove residual metastatic disease in the neck. However, not all of these patients' necks actually harbor residual disease. In fact, emerging data now reveals that patients who experience a complete response after chemoradiation therapy have a very low rate of residual disease identified in the neck. Furthermore, a PET/CT scan obtained after treatment is a highly accurate predictor of whether there will be any residual disease in neck lymph nodes. These findings have led many to hypothesize that patients achieving a complete response might not require post‐treatment neck dissections. The current study now presents the first comprehensive analysis of a large, uniform cohort of node‐positive head and neck cancer patients undergoing observation of the neck rather than neck dissection, provided that PET/CT indicates that a complete response after chemoradiation has been achieved. The rate of recurrence in these observed patients was very low, indicating that head and neck cancer patients experiencing a PET/CT‐confirmed complete response after chemoradiation therapy can be safely observed, rather than undergoing neck dissection.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
BACKGROUND
Patients with brainstem metastases (BSM) have minimal surgical options due to high-risk anatomy. To review our efficacy treating BSM using Gamma Knife stereotactic radiosurgery ...(GK SRS), we compared results based on the utilization of mask-fixation (MF) or frame-fixation (FF).
METHODS
Data were retrospectively collected for 32 patients. Follow-up data for 49 lesions were analyzed for local control rate (LCR) and objective response rate (ORR).
RESULTS
Primary cancers included lung, breast, and melanoma; most lesions were pontine. MF was used in 18 patients. Average tumor volume was 0.99 cm3 (0.005 – 13.3 cm3). 39 lesions were treated with single fraction 16 Gy. 10 lesions were treated in 3-5 fractions with mean dose of 22.5 Gy. Mean follow-up was 14.2 months (1.2 - 48.2 months). 1-year LCR was 94.7%. ORR at last follow-up did not differ between MF vs. FF (p = .81). Average reduction of lesion volume at 6 and 12 months did not differ between MF vs. FF (64% vs 45%, p = .77; 70% vs 77%, p = .78). Failure occurred in a pontine colorectal cancer metastasis mask-immobilized for treatment with 14 Gy.
CONCLUSIONS
SRS for BSM achieved high LCR despite variability in tumor size and histology with no significant difference between MF vs. FF. Although trials have historically excluded patients with BSM, our data support SRS as a safe and efficacious treatment. This is the first study showing that MF provides equivalent, successful outcomes when compared to FF for patients with BSM.
The present study assessed the effect of prostate gland size on patient-assessed quality of life (QOL) after definitive treatment of prostate adenocarcinoma with proton beam therapy. A larger ...prostate size, despite receiving a greater radiation dose, did not affect QOL at 6 months, providing further support that neoadjuvant cytoreductive treatments are unnecessary.
In the present study, we assessed the effect of prostate gland size on patient-assessed genitourinary and gastrointestinal (GI) quality of life (QOL) after definitive treatment of prostate adenocarcinoma with proton beam therapy.
As a part of a prospective outcome tracking protocol, 81 patients treated at a single center between with proton beam therapy completed the Expanded Prostate Cancer Index Composite (EPIC) questionnaire before treatment and at the follow-up examinations. We reviewed the dosimetric data, reported as Vx (volume of organ receiving x Gy), and patient-reported QOL at 6 months. Genitourinary QOL was assessed using the American Urological Association symptom score and EPIC urinary domain score. GI QOL was assessed using the EPIC GI domain score.
Larger prostate glands were associated with greater bladder V70 (P < .01) and rectal V70 (P < .01). The rectal V70 was < 15% for all patients (range, 4%-13.8%) with the planned treatment volume coverage (percentage of the prescription dose covering 95% of the volume > 95%) maintained. Patients with larger prostates did not have a greater change in their American Urological Association symptom index scores (< 30 cm3, +2.3; 30-49 cm3, +3.2; ≥ 50 cm3, 0.2; P = .06) or urinary domain score (< 30 cm3, −3.6; 30-49 cm3, −3.1; ≥ 50 cm3, +3.8; P = .76) at 6 months after treatment. Also, prostate size was not associated with a change in the EPIC GI domain score at 6 months after treatment (< 30 cm3, −3.7; 30-49 cm3, −1.1; ≥ 50 cm3, −0.55; P = .67).
Definitive proton beam therapy for prostate cancer to a dose of 79.2 Gy resulted in excellent patient-reported urinary and GI QOL, independently of the baseline prostate size. This single-institution finding should be tested further in a multi-institutional study to confirm the potential limited role of androgen deprivation therapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
INTRODUCTION:
When treating oligodendroglioma patients, choosing between temozolomide (TMZ) and procarbazine, lomustine, and vincristine (PCV), with concurrent radiotherapy still poses a challenge. ...Given the commonality of tumor recurrence, optimizing progression-free survival while minimizing adverse effects is crucial to improving quality of life.
METHODS:
87 patients treated for oligodendroglioma between 1994-2022 were retrospectively reviewed. Progression-free survival (PFS) and overall survival (OS) from initial resection were compared between PCV-based or TMZ-based treatment groups using Kaplan-Meier and multi-variable Cox survival analysis.
RESULTS:
The median age at diagnosis was 41 years and 62% were male. After initial resection, 42.8% received PCV-based treatment and 57.2% received TMZ-based treatment. Treatment groups were balanced in the following variables: age, tumor genetic profiling, the extent of resection, and KPS score. However, more patients in the TMZ-based group received concurrent radiation. The entire cohort had a 6.3-year PFS and 21.0-year OS. The median time to recurrence was significantly longer in those treated with PCV (12 years) compared to those treated with TMZ (4.7 years). PFS HR = 0.46, p = 0.04 and OS HR = 0.26, p = 0.04 were significantly longer in those receiving PCV-based treatment compared to TMZ-based treatment. After adjusting for previously mentioned variables, Cox regression analysis revealed no difference in OS between PCV- and TMZ-based treatment. The overall adverse effect rate did not significantly differ between PCV-based and TMZ-based treatment (25% vs. 28.1%, p > 0.99).
CONCLUSIONS:
PCV treatment confers longer progression-free survival than TMZ treatment for oligodendroglioma patients, noting that most patients in our series received concurrent radiation with TMZ, and those receiving PCV not having received upfront radiation. As we anticipate the results of the CODEL trial, our findings suggest PCV-based therapy warrants consideration as the preferred therapeutic option for oligodendroglioma patients.
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