Combined External Beam Radiotherapy Research Articles

Pattern of care and clinical outcome of patients with carcinoma endometrium and the impact of central histopathological review on management: A tertiary cancer centre experience.

Endometrial carcinoma (EC) is the third most common gynecological malignancy in India. Recent PORTEC-3 analysis emphasized the role of central histopathological review. We aimed to retrospectively analyze the demographic and histopathological characteristics of EC patients treated at our institute and assess the impact of the central histopathological review on management and also analyze clinical outcomes in this cohort of patients. Data of 75 EC patients treated at our center between 2013 and 2022 were retrieved from our departmental archives. Patients were analyzed for demographic details, histopathological findings, details of surgery and histopathology (HPE), results of a review of HPE, adjuvant treatment details, and clinical outcomes. All patients with HPE outside of our institute were reviewed at our center prior to initiation of treatment. In cases of discordance, patients were discussed in the multidisciplinary tumor board for the final treatment decisions. Patients were staged as per International Federation of Gynaecology and Obstetrics 2018. The median age was 57 years (range: 37-74 years). Twenty-seven patients with HPE reported from the outside center were reviewed at our institute and changes were observed in 26 patients (96.3%). HPE review changes were observed in terms of histological grade, histological type, myometrial invasion, and lymph node involvement in five (18.5%), three (11.1%), seven (25.9%), and three (42.8%), respectively. HPE review leads to changes in the management of 19/26 patients. Stage distribution was I: II: III in 48 (64%): 9 (13.3%): 18 (24%) patients, respectively. The median external beam radiotherapy dose was 50 Gray (range: 45-50.4 Gray at 1.8-2 Gray per fraction). The median brachytherapy dose for patients treated with brachytherapy alone was 7 Gray each for three sessions and in combination with EBRT was 6 Gray each in two sessions. At a median follow-up of 51 months (range: 6-116 months), seven (9.3%) patients developed distant metastasis, two (2.7%) patients had local plus distant metastasis, and two (2.7%) patients had local recurrence. The overall survival and disease-free survival rates at 3 years were 93.5% and 86.7%, respectively. EC patients treated at our center have excellent local control rates with a combination of external beam radiotherapy and brachytherapy. The central histopathological review may result in changes impacting patient management and should be routinely done prior to initiation of treatment in EC.

Primary Malignant Melanoma of the Cervix with Rapidly Progressing Metastases

Introduction: Mucosal melanomas only account for 0.03% of newly diagnosed cancer cases. Female genital tract melanomas account for only 3% of all melanomas, with melanoma of the cervix accounting for less than 3% of all female genital tract melanomas. It is difficult to understand how mucosal melanomas arise as the pathogenesis is still unknown. The incidence of cutaneous melanoma has greatly increased over the years whereas the incidence of mucosal melanomas has stayed relatively steady. Given the rarity of melanoma of the cervix, a standard of care treatment has not been established. Based on the limited cases that have previously been treated, the first option is surgery for early stage melanomas with adjuvant radiation therapy indicated in some cases. The use of systemic chemotherapy is still controversial as it has not been shown to prevent metastases. Case Report: A 66-year-old postmenopausal female presented with heavy vaginal bleeding. A transvaginal ultrasound showed a complex cystic structure in the cervix and she was referred to gynecologic oncology. She was up to date on her pap smears, and they have always been normal. Patient was found to have a fungating 4 x 5 cm mass in the upper vagina and pathology demonstrated poorly differentiated malignant neoplasm. The patient was diagnosed with FIGO Stage IIA2 cervical cancer. Patient’s initial PET/CT demonstrated hypermetabolic area in the cervix consistent with known cervical carcinoma with no other uptake in the uterus. Weekly chemosensitization with cisplatin and external beam radiation was initiated. On clinical examination after treatment by the gynecologic oncologist, visible disease was seen confined to the cervix. An MRI of the pelvis showed response with the suspected tumor limited to the cervical stroma in the anterior and lateral portion of the cervix with no definitive parametrial tumor and no evidence of nodal metastasis. Second opinion from pathology review was received and results showed poorly differentiated malignant neoplasm immunohistochemically consistent with “melanoma”. After 25 fractions of daily radiotherapy with weekly cisplatin, patient underwent exploratory laparotomy for radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling. Final pathology of the uterus and cervix showed invasive poorly differentiated melanoma with deepest invasion of melanoma measuring 8mm and negative surgical margins. All lymph nodes removed during surgery were negative for malignancy. Adjuvant Pembrolizumab was started at this time. Two months postoperatively, the patient underwent CT surveillance again due to new onset chest wall and axillary nodules varying in size from 2-4 cm. Right chest wall axilla biopsy pathology was consistent with melanoma. At this time Pembrolizumab was discontinued and the patient was transitioned to Nivolumab and Ipilimumab 19 days after discontinuing Pembrolizumab. Four months postoperatively, additional CT scans were performed showing widespread metastatic disease in the lungs, chest wall, liver, peritoneum, retroperitoneum and left eye. Patient underwent left frontal craniotomy with tumor resection, and pathology was consistent with metastatic melanoma. Subsequent to craniotomy, the patient underwent three treatments with stereotactic radiosurgery. Despite treatment, six months postoperatively, the patient’s symptoms continued to progress with slurred speech, generalized weakness and abdominal pain. Ultimately, the patient passed away nine months after the diagnosis and four months after a combination of external beam radiotherapy, surgery, and vaginal brachytherapy. Discussion: Melanoma of the cervix is a rare type of cervical cancer with poor prognosis. Globally, 5-year survival is 18.8% for stage I, 11.1% for stage II, and 0% for stages III–IV. It has been shown that median overall survival time decreases with increasing FIGO stage. Risk factors have not been identified for gynecologic melanomas or most other mucosal melanomas. Pembrolizumab is most effective for cutaneous melanomas, however, has been shown to prolong progression free survival in mucosal melanomas. The median overall survival is significantly shorter for patients with mucosal melanoma (11.3 months) as compared to patients with a cutaneous primary (23.5 months). Primary malignant melanoma of the cervix (PMMC) remains a rare tumor and the prognosis is generally poor. Radical hysterectomy, chemoradiation, and immunotherapy have all been utilized in the treatment of PMMC. Further investigation of primary melanoma of the cervix is necessary to formulate a standard of care treatment.

Primary Malignant Melanoma of the Cervix with Rapidly Progressing Metastases

Introduction: Mucosal melanomas only account for 0.03% of newly diagnosed cancer cases. Female genital tract melanomas account for only 3% of all melanomas, with melanoma of the cervix accounting for less than 3% of all female genital tract melanomas. It is difficult to understand how mucosal melanomas arise as the pathogenesis is still unknown. The incidence of cutaneous melanoma has greatly increased over the years whereas the incidence of mucosal melanomas has stayed relatively steady. Given the rarity of melanoma of the cervix, a standard of care treatment has not been established. Based on the limited cases that have previously been treated, the first option is surgery for early stage melanomas with adjuvant radiation therapy indicated in some cases. The use of systemic chemotherapy is still controversial as it has not been shown to prevent metastases. Case Report: A 66-year-old postmenopausal female presented with heavy vaginal bleeding. A transvaginal ultrasound showed a complex cystic structure in the cervix and she was referred to gynecologic oncology. She was up to date on her pap smears, and they have always been normal. Patient was found to have a fungating 4 x 5 cm mass in the upper vagina and pathology demonstrated poorly differentiated malignant neoplasm. The patient was diagnosed with FIGO Stage IIA2 cervical cancer. Patient’s initial PET/CT demonstrated hypermetabolic area in the cervix consistent with known cervical carcinoma with no other uptake in the uterus. Weekly chemosensitization with cisplatin and external beam radiation was initiated. On clinical examination after treatment by the gynecologic oncologist, visible disease was seen confined to the cervix. An MRI of the pelvis showed response with the suspected tumor limited to the cervical stroma in the anterior and lateral portion of the cervix with no definitive parametrial tumor and no evidence of nodal metastasis. Second opinion from pathology review was received and results showed poorly differentiated malignant neoplasm immunohistochemically consistent with “melanoma”. After 25 fractions of daily radiotherapy with weekly cisplatin, patient underwent exploratory laparotomy for radical hysterectomy, bilateral salpingo-oophorectomy, and pelvic lymph node sampling. Final pathology of the uterus and cervix showed invasive poorly differentiated melanoma with deepest invasion of melanoma measuring 8mm and negative surgical margins. All lymph nodes removed during surgery were negative for malignancy. Adjuvant Pembrolizumab was started at this time. Two months postoperatively, the patient underwent CT surveillance again due to new onset chest wall and axillary nodules varying in size from 2-4 cm. Right chest wall axilla biopsy pathology was consistent with melanoma. At this time Pembrolizumab was discontinued and the patient was transitioned to Nivolumab and Ipilimumab 19 days after discontinuing Pembrolizumab. Four months postoperatively, additional CT scans were performed showing widespread metastatic disease in the lungs, chest wall, liver, peritoneum, retroperitoneum and left eye. Patient underwent left frontal craniotomy with tumor resection, and pathology was consistent with metastatic melanoma. Subsequent to craniotomy, the patient underwent three treatments with stereotactic radiosurgery. Despite treatment, six months postoperatively, the patient’s symptoms continued to progress with slurred speech, generalized weakness and abdominal pain. Ultimately, the patient passed away nine months after the diagnosis and four months after a combination of external beam radiotherapy, surgery, and vaginal brachytherapy. Discussion: Melanoma of the cervix is a rare type of cervical cancer with poor prognosis. Globally, 5-year survival is 18.8% for stage I, 11.1% for stage II, and 0% for stages III–IV. It has been shown that median overall survival time decreases with increasing FIGO stage. Risk factors have not been identified for gynecologic melanomas or most other mucosal melanomas. Pembrolizumab is most effective for cutaneous melanomas, however, has been shown to prolong progression free survival in mucosal melanomas. The median overall survival is significantly shorter for patients with mucosal melanoma (11.3 months) as compared to patients with a cutaneous primary (23.5 months). Primary malignant melanoma of the cervix (PMMC) remains a rare tumor and the prognosis is generally poor. Radical hysterectomy, chemoradiation, and immunotherapy have all been utilized in the treatment of PMMC. Further investigation of primary melanoma of the cervix is necessary to formulate a standard of care treatment.

Outcomes of patients with localized prostate cancer treated with combined external beam radiotherapy and high-dose-rate brachytherapy boost: A single-center retrospective study

Abstract Background Temporary prostate brachytherapy, in combination with external beam radiotherapy (EBRT), is an established and evolving treatment technique for non-metastatic, intermediate and high-risk prostate cancer. This study aimed to evaluate the outcomes of patients with localized intermediate and high-risk prostate cancer treated with combined EBRT and high-dose-rate brachytherapy boost (HDR-BT) at a single centre. Patients & Methods A retrospective review of patients who underwent EBRT and HDR-BT treatment between January 2015 and December 2020. Patient and tumor characteristics, treatment outcomes (Kaplan-Meier analysis), and toxicities were analysed. Results 127 patients with intermediate (28.3%) or high-risk (71.7%) prostate cancer were included. Median follow-up was 42 months. Five-year bDFS, CSS and OS rate was 77.5%, 98.1% and 93.0%, respectively, with no significant difference between risk groups. The most frequent toxicity was acute grade 1 urinary obstruction (7.9%). One patient experienced acute and late grade 3 urinary obstruction. No grade ≥4 were observed. Conclusions Combined EBRT and HDR-BT demonstrated favourable disease control rates and manageable toxicities in patients with localized intermediate and high-risk prostate cancer. The 5-year bDFS rate was consistent with previous studies, supporting the effectiveness of this treatment approach. The low incidence of toxicities highlights the conformality and biological efficiency of HDR-BT boost. This treatment strategy provides an effective, safe and convenient option for this group of patients. To the best of our knowledge, this is the first report of the use of helical tomotherapy based intensity-modulated radiation therapy in combination with prostate HDR-BT (81.1% of cases).

Radiation proctitis after iodine-125 low-dose-rate prostate brachytherapy utilizing SpaceOAR hydrogel.

We retrospectively evaluated the efficacy of combining the SpaceOAR (SOAR) hydrogel with prostate brachytherapy, using colonoscopy findings to assess for radiation proctitis. Among 731 patients undergoing iodine-125 low-dose-rate prostate brachytherapy (LDR-BT), SOAR was utilized in 394 patients (53.9%). Colonoscopy was performed for 97 patients (13.3%) to assess the presence, location, condition, and treatment of radiation proctitis. We also investigated treatment factors associated with the occurrence of radiation proctitis. Radiation proctitis was observed in 57 patients (7.8%) and 17 (2.3%) were treated with argon plasma coagulation (APC). The incidence of radiation proctitis was 12.2% in the non-SOAR and 4.1% in the SOAR group (p < 0.001). In the non-SOAR group, the incidence of radiation proctitis was 6.6% for LDR-BT monotherapy and increased to 22.0% when combined with external beam radiation therapy (EBRT) (p = 0.001). However, in the SOAR group, these rates significantly decreased to 3.3% and 5.7% for monotherapy and combination therapy, respectively (p = 0.035, p < 0.001). With SOAR, inflammation was observed directly above the DL in most patients (87.5%), and only one patient (6.3%) required APC. The absence of SOAR (p < 0.001, HR = 0.29) and the concurrent use of EBRT (p = 0.018, HR = 2.87) were identified as significant risk factors for the occurrence of radiation proctitis. The use of SOAR significantly reduced the incidence of radiation proctitis in patients undergoing LDR-BT monotherapy and combined EBRT. Inflammation primarily occurred directly above the DL; further examination is necessary to clarify its cause.

The prognostic effect of tumor volume, reduction ratio, and cumulative doses on external beam radiotherapy with central-shielding method and image-guided adaptive brachytherapy for cervical cancer.

To evaluate the prognostic effect of tumor volume at diagnosis, tumor reduction ratio during external beam radiotherapy (EBRT) with central-shielding method, and cumulative minimal dose to 90% of the high-risk clinical target volume (CTVHR D90) on combined EBRT and image-guided adaptive brachytherapy (IGABT) for cervical cancer. Consecutive patients who underwent definitive radiotherapy or concurrent chemoradiotherapy for cervical cancer at Gunma University Hospital between January 2010 and December 2019 were retrospectively reviewed. Tumor volume at diagnosis and reduction ratio were calculated using magnetic resonance imaging at diagnosis and before the first IGABT session. The cumulative dose of EBRT and IGABT was calculated as an equivalent dose in 2 Gy fractions (EQD2). Optimal cutoff values were determined according to a receiver operating characteristic curve. Treatment outcomes were evaluated using the Kaplan-Meier method and compared using the log-rank test and Cox proportional hazards regression. A total of 254 patients were included in the analysis. The median follow-up for all patients was 57 (2-134) months. The 5-year overall survival (OS) was 81.9%, progression-free survival (PFS) was 71.3%, and local control (LC) was 94.5%. The patients were divided into four groups according to tumor volume at diagnosis and reduction ratio. The group with tumor volume at diagnosis ≥ 34.1 cm3 and reduction ratio < 68.8% showed significantly worse OS, PFS, and LC than the other three groups (All p < 0.05). In this group, the patients with a cumulative CTVHR D90 < 69.6 GyEQD2 showed significantly worse PFS and LC (p = 0.042 and p = 0.027, respectively). In the multivariate analysis of OS, adenocarcinoma/adenosquamous carcinoma, International Federation of Gynecology and Obstetrics 2009 stage III/IV, and a reduction ratio of < 68.8% were independent significant poor prognostic factors (p = 0.045, p = 0.009 and p = 0.001, respectively). In the univariate analysis of LC, a reduction ratio of < 68.8% was the only poor prognostic factor (p = 0.041). The patients with large and poorly responding tumors had significantly worse prognoses in terms of OS, PFS, and LC, suggesting that dose escalation should be considered for such tumors.

Results of Definitive (Chemo)radiotherapy Using Computed Tomography-based Brachytherapy for Cervical Cancer.

Concurrent cisplatin-based chemoradiotherapy (CCRT) is the standard treatment for locally advanced cervical cancer. Especially, CCRT with magnetic resonance imaging (MRI) or computed tomography-based image-guided brachytherapy (CT-based 3D-IGBT) for cervical cancer has resulted in good LC rates. However, progression-free survival (PFS) and overall survival (OS) rates for locally advanced cervical cancer are still low and could be improved. The aim of the study was to evaluate treatment efficacy and late toxicity of external beam radiotherapy (EBRT) and CT-based IGBT with or without concurrent chemotherapy in patients with squamous cell carcinoma of the uterine cervix and investigate patterns of failure. We retrospectively analyzed clinical data of cervical squamous cell carcinoma patients treated with definitive radiotherapy with or without concurrent chemotherapy at Saitama Medical University International Medical Center. Local control (LC), PFS, patterns of failure, and late toxicity were the evaluated outcomes. Overall, 290 patients were enrolled in the study. Median follow-up was 51.5 months. During follow-up, 74 patients developed recurrence: 10 patients with intra-pelvic failure only, 45 with extra-pelvic failure only, and 19 with both. The 3-year LC was 100% for T1b-T2a, 96.8% for T2b, 89.5% for T3b, and 88.5% for T4 disease. The 3-year PFS was 100% for stage IB-IIA, 89.0% for stage IIB, 70.7% for stage IIIB, 72.6% for stage IIIC1r, and 40.1% for stage IVA. The incidence of grade 3-4 gastrointestinal and genitourinary toxicities was 3.0% and 1.7%, respectively. Combination of EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC with acceptable rates of late toxicities. However, extra-pelvic failures frequently occurred and PFS was less satisfactory in patients with stage III-IVA disease, which indicated the need for additional treatment in these patients.

A Randomized Trial Comparing Quality of Life After Low-Dose Rate or High-Dose Rate Prostate Brachytherapy Boost With Pelvic External Beam Radiation Therapy

Purpose/ObjectivesTo compare health-related Quality of Life (QoL) in urinary, bowel and sexual domains after combined external beam radiotherapy (EBRT) and either low dose rate (LDR) or high dose rate (HDR) prostate brachytherapy (BT). Materials/MethodsEligible men with intermediate or high-risk prostate cancer, treated with combined pelvic EBRT and BT were randomly assigned to either HDR (15 Gy) or LDR (110 Gy) boost. International Prostate Symptom Score (IPSS), Index of Erectile Function (IIEF), Expanded Prostate Cancer Composite (EPIC-26) were collected at baseline, 1,3,6 and 12 months, q6 months to 3 years and then annually along with PSA/testosterone. Fisher's exact test compared categorical variables and the Mann Whitney U test EPIC domain scores. ResultsFrom 01/2014 to 12/2019, a random number generator assigned 195 men: 108 to HDR and 87 to LDR. Median age was 71 years. Risk group was high in 57% and unfavorable intermediate in 43%. Androgen deprivation (used in 74%) began with 3 months neoadjuvant and continued for median 12 months. Baseline EPIC scores were similar for the LDR/HDR cohorts: 89/88 for GU and 92/93 for GI. EPIC urinary scores decreased at one month for HDR but recovered promptly to a steady state by 6 months. LDR scores reached a nadir at 3 months with slow recovery to 18 months, after which urinary QoL was similar for HDR and LDR. Bowel QOL scores fell in both cohorts reaching respective nadirs at 12 months. HDR patients recovered close to baseline and maintained higher scores than LDR patients to 5 years. The decline for LDR patients remained > the MCID out to 5 years. ConclusionsPatient experience for combined EBRT and prostate BT is improved with HDR BT. Urinary QoL improves over time to be equivalent between the 2 modalities after 18 months, but LDR patients report lasting bowel symptoms.

Treatment intensification strategies for men undergoing definitive radiotherapy for high-risk prostate cancer.

Treatment intensification of external beam radiotherapy (EBRT) plays a crucial role in the treatment of high-risk prostate cancer. We performed a critical narrative review of the relevant literature and present new developments in evidence-based treatment intensification strategies. For men with high-risk prostate cancer, there is strong evidence to support prolonging androgen deprivation therapy (ADT) to 18-36months and escalating the dose to the prostate using a brachytherapy boost. A potentially less toxic alternative to a brachytherapy boost is delivering a focal boost to dominant intraprostatic lesions using EBRT. In patients who meet STAMPEDE high-risk criteria, there is evidence to support adding a second-generation anti-androgen agent, such as abiraterone acetate, to long-term ADT. Elective pelvic lymph node irradiation may be beneficial in select patients, though more prospective data is needed to elucidate the group of patients who may benefit the most. Tumor genomic classifier (GC) testing and advanced molecular imaging will likely play a role in improving patient selection for treatment intensification as well as contribute to the evolution of treatment intensification strategies for future patients. Treatment intensification using a combination of EBRT, advanced hormonal therapies, and brachytherapy may improve patient outcomes and survival in men with high-risk prostate cancer. Shared decision-making between patients and multidisciplinary teams of radiation oncologists, urologists, and medical oncologists is essential for personalizing care in this setting and deciding which strategies make sense for individual patients.

External beam radiation therapy for recurrent or residual thyroid cancer: What is the best treatment time and the best candidate for long-term local disease control?

Cervical disease control might be challenging in advanced thyroid cancer (DTC). Indications for cervical external beam radiation therapy (EBRT) are controversial. To identify clinical and molecular factors associated with control of cervical disease with EBRT. Retrospective evaluation and molecular analysis of the primary tumor DTC patients who underwent cervical EBRT between 1995 and 2022 was performed. Eighty adults, median age of 61 years, were included. T4 disease was present in 43.7%, lymph node involvement in 42.5%, and distant metastasis in 47.5%. Those with cervical progression were older (62.5 vs. 57.3, p = 0.04) with more nodes affected (12.1 vs. 2.8, p = 0.04) and had EBRT performed later following surgery (76.6 vs. 64 months, p = 0.05). EBRT associated with multikinase inhibitors showed longer overall survival than EBRT alone (64.3 vs. 37.9, p = 0.018) and better local disease control. Performing EBRT before radioiodine (RAI) was associated with longer cervical progression-free survival (CPFS) than was RAI before (67.5 vs. 34.5, p < 0.01). EBRT ≥2 years after surgery was associated with worse CPFS (4.9 vs. 34, p = 0.04). The most common molecular alterations were ERBB2, BRAF, FAT1, RET and ROS1 and TERT mutation was predictive of worse disease control after EBRT (p = 0.04). Younger patients, with fewer affected nodes and treated earlier after surgery had better cervical disease control. Combination of EBRT with MKI improved OS. TERT mutation might indicate worse responders to EBRT; however, further studies are necessary to clarify the role of molecular testing in selecting candidates for cervical EBRT.

Comparative Study between Two Fractions of 9Gy &amp; Three Fractions of 7Gy High Dose Rate Brachytherapy Following Concurrent Chemo Radiotherapy in Patients with Locally Advanced Carcinoma of Uterine Cervix

Introduction: Traditionally, a judicious combination of external beam radiotherapy (EBRT) and intracavitary brachytherapy (ICBT) is the widely accepted primary modality of treatment for locally advanced carcinoma of the cervix. Although the recommendation ofAmerican Brachytherapy Society is &lt;7.5 Gyfor individual fraction and four to eight should be the range of fractions; however, literature showed high dose rate (HDR) brachytherapy of two fractions of 9Gyresults in acceptable toxicity without compromising the local control. Methods: This was a Prospective Quasi-Experimental study, conducted in Department of Radiation Oncology, National Institute of Cancer Research and Hospital, Mohakhali, Dhaka from July 2018 to June 2019. Patients with Clinically diagnosed and histopathologically proven squamous cell carcinoma of uterine cervix in locally advanced stage (FIGO stage IIB to IVA) were selected. Total 60 patients were enrolled according to selection criteria and allocated in to group. Both arm was received 50Gy EBRT in 25 fractions with concurrent inj.Cisplatin 40 mg/m2 weekly. Then Arm A was given HDR Brachytherapy 9Gy in each fraction for 2 fractions and Arm B was given HDR Brachytherapy 7Gy in each fraction for 3 fractions. Then treatment responses, locoregional control of disease and acute toxicities were compared between groups. Result:Follow up at 6 months after completion of treatment, complete remission was 90% and 86% respectively for arm A and arm B. The overall complete response was 88%. The common toxicities associated with treatment were bladder and rectal toxicities, skin reaction, small bowel toxicity and haematologic complications which were managed well. During follow up after 6 months, 3 patients in arm A and 2 patients in arm B developed grade II bladder toxicities and only 2 patients in arm A developed rectal grade II toxicities, but there was no rectal toxicity in arm B. Conclusions: Present study showed that a total dose of 18 Gy ICRT in two fractions of 9 Gy over 2 weeks is equally effective in short term local control with acceptable toxicities in comparison with a total dose of 21 Gy in three fractions of 7 Gy ICRT. J Bangladesh Coll Phys Surg 2024; 42: 49-56

Exploring the role of combined external beam radiotherapy and targeted radioligand therapy with [177Lu]Lu-PSMA-617 for prostate cancer - from bench to bedside.

Management of prostate cancer (PC) might be improved by combining external beam radiotherapy (EBRT) and prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) with lutetium-177 (177Lu)-labeled PSMA inhibitors. We hypothesized a higher efficacy of the combination due to augmentation of the radiation dose to the tumor and interactions of EBRT with PSMA expression potentially increasing radiopharmaceutical uptake. Therefore, this study analyzed the influence of radiation on PSMA expression levels in vitro. The results were translated to evaluate the efficacy of the combination of photon EBRT and [177Lu]Lu-PSMA-617 in a murine PC xenograft model. Finally, a clinical case report on a combined elective field EBRT with RLT dose escalation illustrates a proof-of-concept. Methods: PSMA gene and protein expression were assessed in human PSMA-overexpressing LNCaP cells after irradiation using reverse transcription quantitative polymerase chain reaction (RT-qPCR), flow cytometry and On-Cell Western assays. In the in vivo therapy study, LNCaP tumor-bearing BALB/c nu/nu mice were irradiated once with 2 Gy X-ray EBRT and injected with 40 MBq [177Lu]Lu-PSMA-617 after 4 h or received single or no treatment (n = 10 each). Tumor-absorbed doses by [177Lu]Lu-PSMA-617 were calculated according to the Medical Internal Radiation Dosimetry (MIRD) formalism after deriving time-activity curves using a gamma probe. An exemplified patient case is demonstrated where fractionated EBRT (54 Gy to prostate; 45 Gy to pelvic lymphatics) and three cycles of [177Lu]Lu-PSMA-617 (3.4-6.0 GBq per cycle) were sequentially combined under concurrent androgen deprivation for treating locally advanced PC. Results: At 4 h following irradiation with 2-8 Gy, LNCaP cells displayed a PSMA protein upregulation by around 18% relative to non-irradiated cells, and a stronger upregulation on mRNA level (up to 2.6-fold). This effect was reversed by 24 h when PSMA protein levels were downregulated by up to 22%. Mice treated with the combination therapy showed significantly improved outcomes regarding tumor control and median survival (p < 0.0001) as compared to single or no treatment. Relative to monotherapy with PSMA-RLT or EBRT, the tumor doubling time was prolonged 1.7- or 2.7-fold and the median survival was extended by 24% or 60% with the combination, respectively. Additionally, tumors treated with EBRT exhibited a 14% higher uptake of the radiopharmaceutical as evident from the calculated tumor-absorbed dose, albeit with high variability in the data. Concerning the patient case, the tri-modality treatment was well tolerated and the patient responded with a long-lasting complete biochemical remission for five years following end of PSMA-RLT. The patient then developed a biochemical relapse with oligo-recurrent disease on follow-up imaging. Conclusion: The present preclinical and clinical data demonstrate that the combination of EBRT with dose escalation by PSMA-RLT improves tumor control and potentially prolongs survival. This may pave the way for further clinical investigations of this approach to explore the curative potential of the combination therapy.

Concurrent nivolumab and external beam radiation therapy for hepatocellular carcinoma with macrovascular invasion: A phase II study

Nivolumab was the first immune checkpoint inhibitor approved for hepatocellular carcinoma (HCC). External beam radiation therapy (EBRT) is locally effective and may enhance the effectiveness of immunotherapy. This study investigated the efficacy and safety of concurrent nivolumab and EBRT in HCC with macrovascular invasion. In this phase II multicenter trial, patients with HCC and macrovascular invasion were concurrently treated with intravenous nivolumab (3mg/kg every 2 weeks) and EBRT, followed by maintenance nivolumab until progression or unacceptable toxicity. Primary endpoints were progression-free survival (PFS) and safety, and secondary endpoints were overall survival, time-to-progression, objective response rate, and disease control rate. Between January 2020 and June 2021, 50 patients (male 84%, median age 62.5) were enrolled; 47 (94.0%) and 13 (26.0%) with portal (Vp1/2, n= 21; Vp3, n= 23; Vp4, n= 3) and hepatic vein invasion, respectively. Patients received EBRT (median dose: 50 [IQR 43-50] Gy) after the first nivolumab dose. The median number of nivolumab doses was 8.5. Median PFS was 5.6 (90% CI 3.6-9.9) months. Median overall survival and time-to-progression were 15.2 (90% CI 10.8-19.6) and 5.6 (90% CI 3.6-9.9) months, respectively. The objective response rate and disease control rate were 36.0% and 74.0%, respectively. The median duration of response was 9.9 months. Of 35 patients with follow-up data, 23 received subsequent systemic treatment, including atezolizumab-bevacizumab, sorafenib, lenvatinib, and regorafenib. Treatment-related any grade adverse events (AEs) and grade 3/4 AEs occurred in 40 (80.0%) and 6 (12.0%) patients, respectively. Common treatment-related AEs included pruritus (38.0%) and rash (16.0%), with no treatment-related deaths. Concurrent nivolumab therapy and EBRT showed encouraging PFS with acceptable safety in patients with advanced HCC and macrovascular invasion. Immune checkpoint inhibitors, the standard care for advanced hepatocellular carcinoma (HCC), show relatively poor therapeutic effects in patients with advanced HCC and macrovascular invasion. In this investigator-initiated phase II study, we, for the first time, show that concurrent external beam radiation therapy with nivolumab, an immune checkpoint inhibitor, led to encouraging progression-free survival in patients with HCC and macrovascular invasion. The concurrent treatment was tolerable without significant safety concerns. Further randomized studies investigating the combination of immunotherapy and external beam radiation therapy are required. NCT04611165.

A potential biomarker of radiosensitivity in metastatic hormone sensitive prostate cancer patients treated with combination external beam radiotherapy and radium-223

PurposeThe ADRRAD trial reported the safety and feasibility of the combination of external beam radiotherapy and radium-223 in the treatment of de novo bone metastatic prostate. This study aimed to determine if any biomarkers predictive of response to these treatments could be identified. Experimental design30 patients with newly diagnosed bone metastatic hormone sensitive prostate cancer were recruited to the ADRRAD trial. Blood samples were taken pre-treatment, before cycles 2 to 6 of radium-223, and 8 weeks and 6 months after treatment. Mononuclear cells were isolated and DNA damage was assessed at all timepoints. ResultsDNA damage was increased in all patients during treatment, with bigger increases in foci observed in patients who relapsed late compared to those who relapsed early. Increases in DNA damage during the radium-223 only cycles of treatment were specifically related to response in these patients. Analysis of hematology counts also showed bigger decreases in red blood cell and hemoglobin counts in patients who experienced later biochemical relapse. ConclusionsWhile some patients responded to this combination treatment, others relapsed within one year of treatment initiation. This study identifies a biomarker based approach that may be useful in predicting which patients will respond to treatment, by monitoring both increases in DNA damage above baseline levels in circulating lymphocytes and decreases in red blood cell and hemoglobin counts during treatment.

Prospective study of HDR brachytherapy (BT), external beam radiotherapy (EBRT) and androgen deprivation therapy (ADT): 10-years experience of an MRI-guided approach

ObjectivesTo evaluate the predictive factors for biochemical failure and distant metastases in a prospective cohort of patients with localized prostate cancer treated with the combination of HDR BT and EBRT. Methods and materialsPatients with intermediate (IR) or high-risk (HR) prostate adenocarcinoma received a single fraction of HDR of 15 Gy combined with RT of 37.5 Gy in 15 fractions. ADT duration was used depending on risk-group. Descriptive analyses were performed. Univariate and multivariate Hazard Ratios were obtained. Finally, the Kaplan-Meier model was used to describe the survival of the events of interest. Results309 patients were treated prospectively (199 were IR and 110 HR). Median age was 72 years; 58.3 % were MRI stage ≤ T2c, 34.1 % T3a and 7.6 % T3b; ISUP-grade 1–3 in 78.9 % and ISUP 4–5 in 21.1 %. 71.8 % of patients had ≤ 50 % positive-cores in biopsy and 28.2 % had > 50 %. Median pre-treatment PSA was 9.9 ng/mL. After a median follow-up of 88 months, 41 patients presented biochemical failure and 18 developed distant metastases. Multivariate cox-regression analyses found that MR-T3b Stage (HR 3.88, p = 0.001) and ADT use (HR 3.99, p = 0.03) were the only predictive factors for biochemical failure and the number of positive cores (>50 %) the only independent predictive factor of distant metastases (HR 4.36, p = 0.002). ConclusionsPatients with mpMRI evidence of invasion of the SV and involvement of more than 50% of the cores in the prostate biopsy are patients with a higher risk of presenting a biochemical recurrence or developing metastasis due to their prostate cancer, respectively.

Vaginal Dose Reduction by Changing the Ovoid Loading Pattern in Image Guided Intracavitary Brachytherapy of Cervix.

Locally advanced cervical cancer is frequently treated using a combination of external beam radiotherapy and brachytherapy. Radiotherapy often leads to vaginal morbidity, which poses a significant problem. This study aims to analyze the impact of reducing ovoid loading on dosimetry. We analyzed forty-five CT-based intracavitary brachytherapy plans from fifteen patients. Three plan sets were created for the 45 applications: a standard loading plan (A), a plan with reduced ovoid loading (B), and a tandem-only loading plan (C). We generated Dose-Volume Histograms and recorded dose volume parameters for the three plan sets. The D90 for the Clinical Target Volume (CTV) did not show significant differences among the three plan sets (p = 0.20). The average D90 values for plans A, B, and C were 8.15Gy, 8.16Gy, and 7.4Gy, respectively. No statistically significant differences were observed in D2cc bladder (p = 0.09) (average values: 6.8Gy, 6.5Gy, and 5.9Gy for plans A, B, and C, respectively) and D2cc sigmoid (p = 0.43) (average values: 2.8Gy, 2.6Gy, and 2.4Gy, respectively) among the three plan sets. However, there was a statistically significant difference in D2cc rectum (p < 0.001) (average values: 4Gy, 3.3Gy, and 1.8Gy, respectively), as well as in vaginal dose points (p < 0.001). Reducing ovoid loading significantly decreased the doses to vaginal dose points and the rectum without compromising the dose to the Clinical Target Volume (CTV). Therefore, in carefully selected cases, the adoption of tandem-only loading or reduced ovoid loading could be considered to minimize vaginal morbidity following high dose rate intracavitary brachytherapy.

Retrospective analysis of tooth extraction and osteoradionecrosis after low-dose rate brachytherapy for patients with tongue cancer.

This study aimed to investigate the incidence of osteonecrosis of the jawbones (ORN) after tooth extraction in patients undergoing low-dose rate brachytherapy (LDR-BT) and assess its safety. This study retrospectively analyzed 145 patients with tongue cancer treated at Hiroshima University Hospital from 2007 to 2021 with LDR-BT using 192Ir or 198Au alone, LDR-BT and external beam radiotherapy (EBRT) with or without chemotherapy, and LDR-BT with chemotherapy. Patients' mandible and maxilla were protected with spacers. Forty-seven patients underwent tooth extraction, and the incidence, site, and relationship of ORN with tooth extraction were recorded. A subgroup of 26 patients received additional EBRT to the neck after dissection for late cervical lymph node metastases. Of 145 patients, six (4.1%) developed ORN on the same side of the mandible as LDR-BT, and EBRT was performed before and/or after LDR-BT on the sites where ORNs developed. Five of 47 (10.6%) patients who underwent tooth extraction after LDR-BT developed ORN. ORN incidence was 1.8% (2/109) in the LDR-BT and/or chemotherapy group and 11.1% (4/36) in the combination LDR-BT and EBRT and/or chemotherapy group for primary tongue cancer. Different irradiation methods (LDR-BT and/or chemotherapy and combination LDR-BT and EBRT and/or chemotherapy) and the presence or absence of tooth extraction showed significant differences (p = 0.0335 and p = 0.0139, respectively) with or without ORN. Mandibular tooth extraction should be avoided on the side of LDR-BT in combined EBRT cases. However, tooth extraction is feasible using a spacer in LDR-BT and/or chemotherapy.

Long-Term Urinary Toxicity Follow-Up of Combined External Beam Radiation and Cs-131 LDR Brachytherapy Boost for Prostate Cancer

To evaluate and update our institutional data on chronic patient-reported urinary symptoms in patients with prostate cancer treated with combined external beam radiation therapy (EBRT) and Cesium-131 (Cs-131) LDR brachytherapy boost. Patients treated from September 2006-July 2022 and with at least 6 months of follow-up were analyzed. Patients filled out the Expanded Prostate Cancer Index Composite (EPIC) questionnaire pre-treatment and at each scheduled follow-up. Mean EPIC urinary scores were calculated for urinary summary, urinary function, urinary bother, urinary incontinence, and urinary irritative/obstructive domains. Changes of 7-points or more in mean domain scores were deemed clinically significant. The prevalence of urinary bleeding was calculated and bleeding occurring more than "about once a week" ("more than once a week", "about once a day", and "more than once a day") was deemed clinically significant. Outcomes were analyzed at each follow-up timepoint using paired t-test. A total of 341 patients with prostate cancer were included in the analysis of which 183 were intermediate-risk and 158 high-risk. 174 patients were treated with tri-modality therapy, and SpaceOAR was used in 108 patients. Long-term statistically significant decreases in mean EPIC QOL scores were seen in urinary summary, urinary function, urinary bother, urinary incontinence, and urinary irritative/obstructive domains at 6 months, with clinically and statistically significant decreases in urinary function and urinary incontinence at 6 months (86±17.4, 83.4±22.2 respectively) and up to 18 months post-treatment (84.8±17.4, 83.6±20.7 respectively) compared with pre-treatment scores (93.1±10.7, 90.8±14.8 respectively), with both domains returning to clinical baseline at 24 months. Urinary irritative/obstructive mean scores clinically and significantly decreased at 9 months (77±17.4) compared to pre-treatment (84.7±13.5), returning to clinical baseline at 12 months. The prevalence of clinically significant urinary bleeding at 6, 12, 24, 36, 48, and 60 months was 1.3%, 2.6%, 3.7%, 0.7%, 0.9%, and 2.3% respectively. At the median follow-up of 42 months (IQR 54, 18-72), mean EPIC scores were clinically improved (≥7-point increase) from pre-treatment baseline in 15-30% of patients across the analyzed urinary domains. Long-term patient-reported clinically significant decreases in urinary function and urinary incontinence mean EPIC scores occurred up to 18 months following combined external beam radiation and Cs-131 prostate brachytherapy and returned to baseline at 24 months, while clinically significant decrease in urinary irritability/obstructive mean scores occurred at 9 months and returned to baseline at 12 months. At 42 months follow-up, mean urinary domain scores improved from pre-treatment baseline in 15-30% of patients.

Health-Related Quality of Life after Combined External Beam and Either High Dose Rate (HDR) or Low Dose Rate (LDR) Brachytherapy: Does the Rectal Dose from the LDR Brachytherapy Make a Difference?

The recently reported randomized Phase III trial comparing health related quality of life (HRQOL) after combined external beam radiation therapy (EBRT) and either HDR or LDR brachytherapy (BT) found a significant decline in the EPIC Bowel domain HRQOL score at 24- 48 months after treatment in the LDR arm of the trial. As all patients in the trial received the same EBRT dose, and HDR rectal dose was strictly controlled to be <9.5 Gy to 1cc of rectal wall (RD1cc), we investigated whether the variable rectal dose from the LDR component of treatment was related to the decline in Bowel HRQOL for these patients. A total of 195 men with upper tier intermediate or high-risk prostate cancer were assigned by a random number generator to receive either an HDR (15 Gy, n = 108) or LDR (110Gy, n = 87) brachytherapy boost combined with 46Gy/23 fractions EBRT. All LDR patients had 1 month post implant quality assurance using CT-MRI fusion. The Expanded Prostate Cancer Composite (EPIC) questionnaire was used to evaluate HRQOL at baseline, q3 mo for 1 year, q6mo for 3 yr and then annually. A multivariate linear regression model was used to investigate the dose-response relationship between EPIC bowel domain score at 24- 48 months and RD1cc. With a median follow up of 48 months, the previous analysis confirmed the expected time course of acute bowel/urinary symptoms, with LDR showing more prolonged decline in HRQOL bowel domain at 3 and 6 months, but equivalence to HDR by 12 months. HRQOL urinary domain remained equivalent from 12-60 mo. The decline in the HRQOL bowel domain observed for LDR patients from 24-48 mo was analyzed for the 79 patients with sufficient data. The mean baseline HRQOL bowel domain score was 92 and fell on average to 85 at 24-48 mo. Mean RD1cc for the LDR patients was 82Gy (SD 22 Gy), with a maximum value of 129 Gy. In this range of rectal doses, a 20Gy increase in RD1cc, was associated on average with a 1.5-point decrease in EPIC HRQOL bowel domain score (p = 0.21). The rectal dose received by the LDR patients showed a non-significant dose-response with the EPIC Bowel domain HRQOL score. This confirms the accepted rectal dose constraints for LDR brachytherapy but does not explain the observed decline in bowel scores from 24-48 months.

Assessing the Sexual Health of Female Survivors of Pelvic Malignancies after Radiotherapy

To assess patient-reported sexual health outcomes of female survivors of pelvic malignancies after radiotherapy (RT). Female patients treated with curative intent RT for pelvic malignancies between 2013 and 2019 were surveyed electronically post-RT using the PROMIS Sexual Function and Satisfaction Full Profile and Female Sexual Distress Scale-Revised questionnaires. Cervical and vaginal cancers were grouped together due to the similar treatment characteristics. Surveys were sent to 544 patients, and 53 (10%) completed the questionnaires. Respondents included survivors of anal canal (N = 11), cervical or vaginal (N = 10), uterine (N = 30), and vulvar cancers (N = 2). The median age of patients at the time of treatment was 60 years (range 31,77). The median time between RT and survey completion was 6 years (range 3,9). A total of 22 (42%), 17 (32%), and 14 patients (26%) were treated with brachytherapy (BT), external beam RT (EBRT), or a combination of EBRT and BT, respectively. Of respondents, 96% were free of disease recurrence. Sexually active was defined as partaking in sexual activity within 30 days of survey response. Patients were stratified by age greater than or less than 52 at time of RT, representing the average age of menopause. A total of 30 patients (57%) had at least somewhat interest in sex. There was no difference in the proportion of patients who had at least somewhat interest in sex over 52 years compared to those 52 and (54% vs 67%, p = 0.424). A total of 39 patients (74%) were sexually active, and of those 30 (77%) were over the age of 52 at the time of RT. Of sexually active patients, 28 (72%) reported some, quite a bit, or a lot of satisfaction with their sex lives, whereas the remaining 11 (28%) reported having none or a little bit of satisfaction with their sex lives; the proportion of those with at least some satisfaction with their sex lives did not differ between those who were over or under 52 years at the time of RT (73% vs 67%, p = 0.697). Satisfaction with sex life differed by site of malignancy with 71% cervical or vaginal, 44% anal canal, 86% uterine, and 0% vulvar patients reporting at least some satisfaction (p = 0.043). Patients treated for anal canal cancer tended to have quite a bit or a lot of vaginal discomfort during sex (78%), compared to those treated for cervical/vaginal (29%), or endometrial (18%) cancers (p = 0.006). There was no difference in patients feeling frequently or always stressed about sex between those who were sexually active compared to those who were not (13% vs 14%, p = 0.890). Patients 52 or under at the time of RT were more likely to feel frequently or always stressed about sex compared to those receiving RT over the age of 52 (42% vs 5%, p<0.001). In our cohort, the majority of female survivors of pelvic malignancies were sexually active post-RT, and this important topic warrants further investigation.