Variability of treatment of locally advanced cervical cancer: How French multidisciplinary teams follow European guidelines?

INTRODUCTION: Cervical cancer is a global public health concern. Despite ESGO recommendations and FIGO classification changes, management of locally advanced cervical cancer (LACC) remains debated in France. Our study aimed to review LACC treatment practices and assess adherence to ESGO recommendations among different practitioners. METHODS: From February 2021 to August 2022, we conducted a survey among gynecologic oncology surgeons, radiation oncologists, and medical oncologists practicing in France and managing LACC (FIGO stages IB3-IVA) according to the 2018 FIGO classification. We analyzed responses against the 2018 ESGO recommendations as a "gold standard." RESULTS: Among 115 respondents (56% radiation oncologists, 30% surgeons, 13% medical oncologists), 48.6% of gynecologic surgeons didn't perform para-aortic lymphadenectomy (PAL) with significant radiologic pelvic involvement. PAL, when indicated by PET-CT, was more common in university hospitals (66.7% of surgeons). Surgeons in university hospitals also followed ESGO recommendations more closely. Overall, compliance with all ESGO recommendations was low: 5.7% of surgeons, 21.5% of radiation oncologists, and 60% of medical oncologists. Prophylactic para-aortic irradiation, per ESGO, was more frequent in comprehensive cancer centers (52% of radiation oncologists). CONCLUSION: Adherence to ESGO recommendations for LACC treatment appears low in France, particularly in surgery, with limited PAL in cases of lymph node negativity on PET-CT. However, these recommendations are more often followed by surgeons in university hospitals and radiation oncologists in cancer centers. Adherence to these recommendations may impact patient survival and warrants evaluation of care quality, justifying the organization of LACC management in expert centers.

Correlation between peritoneal cancer index and survival in advanced epithelial ovarian cancer with complete resection.

OBJECTIVE: The aim of this study was to investigate the relation between the peritoneal cancer index, overall survival, and recurrence free survival, in patients with epithelial ovarian cancer. METHODS: Patients treated at the Gustave-Roussy Institute between December 2004 and November 2017 for advanced epithelial ovarian cancer in complete resection were included. The correlation between the peritoneal cancer index and survival was studied using statistical modeling. Multivariate analysis was performed with a logistic regression model. RESULTS: Of the 351 patients included, 94 (27%) had initial surgery and 257 (73%) had interval surgery. Median follow-up was 52.7 months (range 47.6-63.9). Median peritoneal cancer index was 10 (range 0-32). The linear model best represented the relationship between peritoneal cancer index and overall survival. Patients with neoadjuvant chemotherapy had a greater instantaneous risk of baseline death than those with initial surgery, as well as a more rapid increase in this risk as the peritoneal cancer index increased. Overall survival and recurrence free survival were better in the initial surgery group (103.4 months (79.1-not reached (NR)) vs 66.5 months (59.1-95.3) and 31.8 months (23.7-48.7) vs 25.9 months (23.2-29), respectively). Risk factors for death were body mass index, peritoneal cancer index, and need for neoadjuvant chemotherapy. CONCLUSION: The peritoneal cancer index is a prognostic indicator, but its linear relationship with survival precluded setting a unique peritoneal cancer index cut-off. Moreover, the prognostic impact of peritoneal cancer index was stronger in the setting of neoadjuvant chemotherapy.

Redefining the role of pulsed-dose-rate brachytherapy in cervical cancer treatment using a preplanned approach.

INTRODUCTION: This study aims to determine predictive factors for cervical cancer patients who would benefit more from high-dose-rate (HDR) or pulsed-dose-rate (PDR) brachytherapy. METHODS: The sample included 50 patients treated with brachytherapy following external radiochemotherapy. PDR plans were compared to HDR preplans, with a focus on patients who may benefit from PDR using preplan metrics and clinical variables. The expected clinical effect was quantified using a tumor control probability model. RESULTS: Results showed PDR plans with 60 pulses to be optimal for achieving target clinical goals for D90CTVHR. A CTVHR volume of >67.5cc and/or D90CTVHR dose on the HDR preplan of <31.1 Gy was the strongest indicator for patient selection who would gain >3% increase in TCP with PDR. The process showed 96% accuracy, 88% sensitivity, and 98% specificity. Only 16% of patients showed a relevant benefit from PDR over HDR, with a mean D90CTVHR of 7 Gy higher and a mean TCP at 3 years of 4.8% higher for PDR. The benefit of PDR is highly influenced by the choice of alpha/beta ratio and repair halftime. CONCLUSION: A small subset of cervical cancer patients may gain from PDR over HDR. CTVHR volume and preplan D90CTVHR doses may be useful in selecting patients for PDR brachytherapy.

Image-guided adaptive brachytherapy for advanced cervical cancer spreading to the bladder and/or rectum: Clinical outcome and prognostic factors.

INTRODUCTION: Refinements of brachytherapy techniques have led to better local control of locally advanced cervical cancer (LACC), especially with the development of image-guided adaptive brachytherapy (IGABT). Data on the efficacy of brachytherapy in cervical cancer spreading to adjacent organs are scarce. We report the experience of our institution in the treatment of these advanced tumors with IGABT. MATERIALS AND METHODS: Medical records of patients treated for a LACC spreading to the bladder and/or rectum between 2006 and 2020 at Gustave Roussy Institute were analyzed. Dosimetric parameters were collected and converted into 2 Gy per fraction equivalent doses, including the minimal dose received by 90% of the high-risk target volume (D90 CTVHR) and intermediate-risk target volume (D90 CTVIR), as well as the dose received by the most exposed 2 cm3 of the organs at risk. A Cox regression model was used to study the potential associations between clinical and dosimetric factors with survival endpoints and fistula formation. RESULTS AND STATISTICAL ANALYSIS: A total of 81 patients were identified. All patients received pelvic+/- para-aortic radiotherapy, 45 Gy in 25 fractions +/- boost to gross lymph nodes. Concomitant platinum-based chemotherapy was administered in 93.8% of cases. The median D90 CTVHR dose was 75.5 GyEQD2 (SD: 10.39 GyEQD2) and median CTVHR volume was 47.6 cm3 (SD: 27.9 cm3). Median bladder and rectal D2cm3 dose were 75.04 GyEQD2 (SD: 8.72 GyEQD2) and 64.07 GyEQD2 (SD: 6.68 GyEQD2). After a median follow-up of 27.62 ± 25.10 months, recurrence was found in 34/81 patients (42%). Metastatic failure was the most common pattern of relapse (n = 25). Use of a combined interstitial/intracavitary technique and D90 CTVHR ≥ 75.1 GyEQD2 were prognostic factors for OS in univariate analysis (HR = 0.24, 95%IC: 0.057-1, p = 0.023; HR = 0.2, 95%IC: 0.059-0.68, p = 0.0025, respectively). In multivariate analysis, a D90 CTVHR ≥ 75.1 GyEQD2 was significant for OS (HR = 0.23; 95%IC: 0.07, 0.78, p = 0.018). The occurrence of vesicovaginal fistula (VVF) was the most frequent pattern of local recurrence (HR = 4.6, 95%CI: 1.5-14, p = 0.01). CONCLUSION: Advances in brachytherapy modalities improved local control and survival while reducing toxicities. Enhancing local control through dose escalation and combined intracavitary/interstitial brachytherapy techniques is a major factor in patients cure probability, together with systemic intensification to better control distant events.

Practice changing data and emerging concepts from recent radiation therapy randomised clinical trials.

INTRODUCTION: Oncology treatments are constantly and rapidly evolving. We aimed at highlighting the latest radiation therapy practice changing trials and emerging concepts, through an overview of recent randomised clinical trials (RCTs). MATERIALS AND METHODS: Requests were performed in the Medline database to identify all publications reporting radiation therapy RCTs from 2018 to 2021. RESULTS: Recent RCTs sustained the role of newer combinatorial strategies through radioimmunotherapy for early stage or metastatic lung cancer, newer pro-apoptotic agents (e.g. debio 1143 in locoregionally advanced head and neck squamous cell carcinoma) or nanoparticles (e.g. NBTXR3 in locally advanced soft-tissue sarcoma). High-tech radiotherapy allows intensifying treatments and gaining ground in some indications through the development of stereotactic body radiotherapy for example. First randomised evidence on personalised radiation therapy through imaging-based (18FDG positron emission tomography-computed tomography for lung cancer or early stage unfavourable Hodgkin lymphoma, PMSA positron emission tomography-computed tomography or magnetic resonance imaging for high-risk prostate cancer) or biological biomarkers (PSA for prostate cancer, HPV for head and neck cancer, etc) were conducted to more tailored treatments, with more favourable outcomes. Patients' quality of life and satisfaction appeared to be increasing aims. RCTs have validated (ultra)hypofractionated schemes in many indications as for breast, prostate or rectal cancer, resulting in equivalent outcomes and toxicities, more convenient for patients and favouring shared decision making. CONCLUSION: Radiation therapy is a dynamic field of research, and many RCTs have greatly impacted therapeutic standards over the last years. Investments in radiotherapy research should facilitate the transfer of innovation to clinic.

Implementation of Image-Guided Brachytherapy for Pediatric Vaginal Cancers: Feasibility and Early Clinical Results.

Background: Brachytherapy (BT) has a major role in pediatric cancers of the lower genital tract, as part of a multimodal organ conservative strategy. Scarce data are available on the location of image-guided BT. Methods: Medical records of all consecutive girls treated in our center between 2005 and 2020 for a vaginal tumor with exclusive image-guided PDR-BT were retrospectively examined, with a focus on treatment parameters, patient compliance, and clinical outcome, including analysis of local control, survival and late toxicity rates. Results: Twenty-six patients were identified, with a median age of 25 months. Histological types were rhabdomyosarcoma, malignant germ cell tumor (MGCT) and clear cell adenocarcinoma in 18 (69%), 7 (27%) and 1 (4%) patients, respectively. Ten (33%) patients had prior surgery and 25 (96%) received chemotherapy prior to BT. The median prescribed dose was 60 Gy through pulses of 0.42 Gy. Global compliance was satisfactory, but three (12%) patients required replanning because of applicator displacement. After a median follow-up of 47.5 months, one patient with MGCT referred for salvage treatment of a local recurrence had a local and metastatic relapse. The local control rate probability was 96% at the last follow-up. Late toxicity rates ≥ grade 2 and ≥ grade 3 were reported in 23% and 11%, respectively, with gynecological toxicities being the most frequent side effect. Two patients required dilatation for vaginal stenosis. Conclusions: PDR-BT allowed similar local control compared to the historical low-dose rate technique. An indirect comparison suggests fewer treatment-related toxicities by integrating image guidance and optimization capabilities, but longer follow-up is necessary. Due to the rarity of the disease and the technical aspects of BT in these very young patients, referral to specialized high-volume centers is recommended.

Providing Patients with Locally Advanced Cervical Cancer Access to Brachytherapy: Experience from a Referral Network for Women Treated in Overseas France.

Image-guided adaptive brachytherapy (IGABT) is part of the standard of care for locally advanced cervical cancer (LACC). Access to IGABT is limited in many regions, thus leading to treatment care disparities. We report the experience of a referral network for women with LACC between radiotherapy facilities in Overseas France and Gustave Roussy. This is a retrospective review of patients with LACC referred to Gustave Roussy, for pulsed-dose-rate (PDR) image-guided adaptive BT after initial radiation therapy in the French overseas between 2014 and 2021. Sixty-four patients were eligible to receive IGABT. Overall treatment time (OTT) was 60.5 days (IQR: 51−68.5). The median follow-up time was 17 months. At two years, estimated probabilities of LC, progression-free survival, and overall survival (OS) were 94.6% (95% CI: 88.9−100.0%), 72.7% (95% CI: 61.1−86.5%), and 82.5% (95% CI: 72.0−94.5%). In multivariable analysis, a D90CTVHR < 85GyEQD2 and a CTVHR volume > 40 cm3 were significant for poorer PFS (p = 0.001 and p = 0.009, respectively) and poorer OS (p = 0.004 and p = 0.004). The centralization of this advanced technique to expert centers requires a well-defined workflow and appropriate dimensioning of resources to minimize OTT.

Current Standards in the Management of Early and Locally Advanced Cervical Cancer: Update on the Benefit of Neoadjuvant/Adjuvant Strategies.

Globally, cervical cancers continue to be one of the leading causes of cancer-related deaths. The primary treatment of patients with early-stage disease includes surgery or radiation therapy with or without chemotherapy. The main challenge in treating these patients is to maintain a curative approach and limit treatment-related morbidity. Traditionally, inoperable patients are treated with radiation therapy solely and operable patients undergo upfront surgery followed by adjuvant (chemo) radiotherapy in cases with poor histopathological prognostic features. Patients with locally advanced cervical cancers are treated with concurrent chemoradiotherapy followed by an image-guided brachytherapy boost. In these patients, the main pattern of failure is distant relapse, encouraging intensification of systemic treatments to improve disease control. Ongoing trials are evaluating immunotherapy in locally advanced tumours following its encouraging efficacy reported in the recurrent and metastatic settings. In this article, clinical evidence of neoadjuvant and adjuvant treatments in cervical cancer patients is reviewed, with a focus on potential strategies to improve patients' outcome and minimize treatment-related morbidity.

Brachytherapy for Pediatric Patients at Gustave Roussy Cancer Campus: A Model of International Cooperation for Highly Specialized Treatments.

PURPOSE: Childhood cancer is rare, and treatment is frequently associated with long-term morbidity. Disparities in survival and long-term side effects encourage the establishment of networks to increase access to complex organ-conservative strategies, such as brachytherapy. We report our experience of an international cooperation model in childhood cancers. METHODS AND MATERIALS: We examined the outcome of all children referred to our center from national or international networks to be treated according to a multimodal organ-conservative approach, including brachytherapy. RESULTS: We identified 305 patients whose median age at diagnosis was 2.2 years (range, 1.4 months to 17.2 years). Among these patients, 99 (32.4%) were treated between 2015 and 2020; 172 (56.4%) were referred from national centers; and 133 (43.6%) were international patients from 31 countries (mainly Europe). Also, 263 patients were referred for primary treatment and 42 patients were referred for salvage treatment. Genitourinary tumors were the most frequent sites, with 56.4% bladder/prostate rhabdomyosarcoma and 28.5% gynecologic tumors. In addition to brachytherapy, local treatment consisted of partial tumor resection in 207 patients (67.9%), and 39 patients (13%) had additional external radiation therapy. Median follow-up was 58 months (range, 1 month to 48 years), 93 months for national patients, and 37 months for international patients (P < .0001). Five-year local control, disease-free survival, and overall survival rates were 90.8% (95% confidence interval [CI], 87.3%-94.4%), 84.4% (95% CI, 80.1%-89.0%), and 93.3% (95% CI, 90.1%-96.5%), respectively. Patients referred for salvage treatment had poorer disease-free survival (P < .01). Implementation of image guided pulse-dose-rate brachytherapy was associated with better local control among patients with rhabdomyosarcoma referred for primary treatment (hazard ratio, 9.72; 95% CI, 1.24-71.0). At last follow-up, 16.7% patients had long-term severe treatment-related complications, and 2 patients (0.7%) had developed second malignancy. CONCLUSIONS: This retrospective series shows the feasibility of a multinational referral network for brachytherapy allowing high patient numbers in rare pediatric cancers. High local control probability and acceptable late severe complication probability could be achieved despite very challenging situations. This cooperation model could serve as a basis for generating international reference networks for high-tech radiation such as brachytherapy to increase treatment care opportunities and cure probability.

Combined modality including novel sensitizers in gynecological cancers.

Standard treatment of locally advanced gynecological cancers relies mainly on platinum-based concurrent chemoradiotherapy followed by brachytherapy. Current chemotherapeutic drugs are only transiently effective and patients with advanced disease often develop resistance and subsequently, distant metastases despite significant initial responses of the primary tumor. In addition, some patients still develop local failure or progression, suggesting that there is still a place for increasing the anti-tumor radiation effect. Several strategies are being developed to increase the probability of curing patients. Vaginal cancer and vulva cancer are rare diseases, which resemble cervical cancer in their histology and pathogenesis. These gynecological cancers are predominantly associated with human papilloma virus infection. Treatment strategies in other unresectable gynecologic cancers are usually derived from evidence in locally advanced cervical cancers. In this review, we discuss mechanisms by which novel therapies could work synergistically with conventional chemoradiotherapy, from pre-clinical and ongoing clinical data. Trimodal, even quadrimodal treatment are currently being tested in clinical trials. Novel combinations derived from a metastatic setting, and being tested in locally advanced tumors, include anti-angiogenic agents, immunotherapy, tumor-infiltrating lymphocytes therapy, adoptive T-cell therapy and apoptosis inducers to enhance chemoradiotherapy efficacy through complementary molecular pathways. In parallel, radiosensitizers, such as nanoparticles and radiosensitizers of hypoxia aim to maximize the effect of radiotherapy locally.

Brachytherapy for the Conservative Treatment of Female Peri-Urethral Carcinoma.

Introduction: Peri-urethral cancers (PUC) are rare tumors. Brachytherapy (BT), either monotherapy or combined with radiation therapy, is a preferred treatment option to spare the morbidity of surgery and achieve organ preservation. We report, to the best of our knowledge, the largest experience of brachytherapy among women with PUC. Patients and Methods: This is a retrospective review of the medical records of female patients with PUC who underwent low- or pulse-dose-rate BT with or without external beam radiotherapy at Gustave Roussy between 1990 and 2018. Patients were categorized according to the treatment intention into a primary and recurrent group. The Kaplan-Meier method was used for survival analysis, and the Cox proportional-hazard model was used for univariate analysis. Brachythewharapy-related adverse events were reported according to Common Terminology Criteria for Adverse Events version 4. Results: We identified 44 patients with PUC who underwent BT. Of the 44 patients, 22 had primary tumors and 22 had recurrent tumors. Histologies were mainly adenocarcinoma (n = 20) and squamous cell carcinoma (n = 14). The median prescribed dose was 60 Gy for the 24 patients treated with BT alone and 20 Gy (IQ range: 15-56.25 Gy) for the 20 patients treated with BT in combination with EBRT. With a median follow-up of 21.5 months (range 7.5-60.8), a total of six patients experienced local relapse (17.5%). The 2-year overall survival probability was 63% (95%CI: 49.2-81.4%). The most common toxicities were acute genito-urinary grade 1-2 toxicities. At the last follow-up, four patients experienced focal necrosis. Conclusions: In this cohort of women with PUC undergoing BT, we observed an 80% probability of local control with acceptable morbidity. Though survival was poor, with high metastatic relapse probability, BT was useful to focally escalate the dose and optimize local control in the context of an organ sparing strategy.

Local treatment in the setting of de novo metastatic rectal cancer: reappraisal of prognostic factors.

BACKGROUND: This retrospective study was conducted to: (1) provide more modern data on real-life local management of metastatic rectal cancer; (2) compare therapeutic strategies; and (3) identify prognostic factors of local failure, overall survival and progression-free survival. METHODS: Data about efficacy and acute toxicity were collected. Patients were diagnosed with metastatic rectal cancer between 2004 and 2015, and were treated at least with radiotherapy. Local failure, overall survival and progression-free survival were correlated with patient, tumour and treatment characteristics using univariate and multivariate analyses. RESULTS: Data of 148 consecutive patients with metastatic rectal cancer were analysed. Median follow-up was 19 months. Median overall survival was 16 months. All patients received local radiotherapy, with a median equivalent 2 Gy per fraction dose of 47.7 Gy. Rectal surgery was performed in 97 patients (65.6%). The majority of patients (86/97, 88.7%) received pre-operative chemoradiation. In multivariate analysis, rectal surgery was found to be the only independent predictor of increased overall survival (24.6 vs 7.1 months, p <0.001). Of the patients undergoing surgical treatment, 22.8% presented with significant complications that required a delay of systemic treatment. Grade 3-4 acute radiation therapy-related toxicities were observed in 6.1% of patients, mainly gastrointestinal toxicities (5.4%). CONCLUSION: Rectal surgery was a key predictive factor of increased progression-free survival and overall survival in patients receiving at least local radiotherapy. In our series of real-life patients, local surgery and radiation seemed as well tolerated as reported in selected phase III non-metastatic rectal cancer patients. These data suggested that local management could be beneficial for metastatic rectal cancer patients.

Pulse-dose-rate interstitial brachytherapy in anal squamous cell carcinoma: clinical outcomes and patients' health quality perception.

PURPOSE: To examine clinical outcomes and quality of life of patients with anal squamous cell carcinoma treated with interstitial pulsed-dose-rate brachytherapy (PDR-BT) with a boost to residual tumor after external radiotherapy. MATERIAL AND METHODS: Medical records of patients receiving a brachytherapy boost after radiotherapy for anal squamous cell carcinoma in our Institute between 2008 and 2019 were retrospectively reviewed. After receiving pelvic irradiation ± concurrent chemotherapy, patients received PDR-BT boost to residual tumor, in order to deliver a minimal total dose of 60 Gy. Patients' outcomes were analyzed, with primary focus on local control, sphincter preservation, morbidity, and quality of life. RESULTS: A total of 42 patients were identified, included 24, 13, and 5 patients with I, II, and III tumor stages, respectively. Median brachytherapy (BT) dose was 20 Gy (range, 10-30 Gy). Median dose per pulse was 42 cGy (range, 37.5-50 cGy). With median follow-up of 60.4 months (range, 5.4-127.4 months), estimated local control and colostomy-free survival rates at 5 years were both 88.7% (95% CI: 67.4-96.4%). The largest axis of residual lesion after external beam radiation therapy (EBRT) and poor tumor shrinkage were associated with more frequent relapses (p = 0.02 and p = 0.007, respectively). Out of 40 patients with more than 6 months follow-up, only one experienced severe delayed toxicity (fecal incontinence). Health quality perception was very good or good in 20 of 22 (91%) patients, according to their replies of quality-of-life surveys. A total dose ≥ 63 Gy was associated with higher number of anorectal grade 1+ toxicities (n = 1.5 vs. n = 0.61, p = 0.02). CONCLUSIONS: In this cohort of 42 patients with mainly I and II tumor stages, PDR-BT boost allowed for local control in 88.7% of patients, with only one grade 3 anorectal toxicity.

Venezia applicator with oblique needles improves clinical target volume coverage in distal parametrial tumor residue compared to parallel needles only.

PURPOSE: Residual distal parametrial involvement after radiochemotherapy is a true challenge for brachytherapists since the width and asymmetry of high-risk clinical target volume (HR-CTV) are difficult to cover properly with a standard implant. MATERIAL AND METHODS: Dosimetric plans of five patients treated with Venezia advanced gynecological applicator at our institution were reviewed. For each patient, we compared the original plan with a new plan where oblique needles were removed and re-optimized manually. Optimization process was halted when EQD210 D90 HR-CTV reached 90 Gy, when one hard constraint to organs at risk (OARs) was reached according to the EMBRACE II protocol, or when dose-rate of one of OARs exceeded 0.6 Gy/h. RESULTS: Tumors were large; median HR-CTV volume was 64 cc and median distance between tandem and outer contour of HR-CTV was 40 mm. For the five patients, HR-CTV EQD210 D90 was superior in the plan using oblique needles, with a median difference of 6.5 Gy (range, 1.7-8.5 Gy). Median D90 HR-CTV and intermediate-risk CTV (IR-CTV) were significantly increased with oblique needles: 85.9 Gy (range, 83.2-90.3 Gy) vs. 81.5 Gy (range, 77.4-84 Gy), and 68.7 Gy (range, 66.3-72.3 Gy) vs. 67 Gy (range, 64.3-69.1 Gy), p = 0.006 for both. There were no significant differences in the dose to OARs. Plans with only parallel needles had less favorable dose distribution, with cold spots on the outer parametria and higher vaginal activation to compensate parametrial coverage in its inferior part. CONCLUSIONS: VeneziaTM applicator permits reproducible application to increase CTV coverage in patients with distal parametrial tumor residue during brachytherapy, while maintaining acceptable dose to OARs.

Combining radiation to EGFR and Bcl-2 blockade: a new approach to target cancer stem cells in head and neck squamous cell carcinoma.

PURPOSE: The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor, partly due to the presence of resistant cancer stem cells (CSCs) which are responsible of recurrences. CSCs have low EGFR expression and, conversely, overexpress the anti-apoptotic Bcl-2 protein, which is involved in resistance to apoptosis and the invasion/migration capacities of tumour cells. METHODS: The combination therapy of ABT-199, a Bcl-2 inhibitor, cetuximab an EGFR inhibitor, and radiation using an HNSCC model (SQ20B cell line) and its corresponding CSC subpopulation were evaluated in vitro (2D/3D cell proliferation; invasion/migration and apoptosis using videomicroscopy) and in vivo. RESULTS: Cetuximab strongly inhibited 2D and 3D cell proliferation, as well as invasion/migration, only in non-CSC-SQ20B cells, whereas ABT-199 selectively inhibited these mechanisms in SQ20B/CSCs. The combination of irradiation + cetuximab + ABT-199 increased the inhibition of the 2D and 3D cell proliferation, invasion/migration, and resistance to apoptosis in both cell sub-populations. In addition, in a nude mouse model with heterotopic tumour xenograft, a treatment combining cetuximab + ABT-199 with fractional irradiation strongly delayed the tumour growth and increased in vivo lifespan without side effects. CONCLUSION: Based on the present results, this triple combination therapy may represent a new opportunity for testing in clinical trials, particularly in locally advanced HNSCC.

Pulsed Dose Rate Brachytherapy of Lip Carcinoma: Clinical Outcome and Quality of Life Analysis.

PURPOSE: Lip carcinoma represents one of the most common types of head and neck cancer. Brachytherapy is a highly effective therapeutic option for all stages of lip cancers. We report our experience of pulsed dose rate brachytherapy (PDR) as treatment of lip carcinoma. METHODS AND MATERIALS: this retrospective single center study included all consecutive patients treated for a lip PDR brachytherapy in our institution from 2010 to 2019. The toxicities and outcomes of the patients were reported, and a retrospective quality of life assessment was conducted by phone interviews (FACT H&N). RESULTS: From October 2010 to December 2019, 38 patients were treated in our institution for a lip carcinoma by PDR brachytherapy. The median age was 73, and the majority of patients presented T1-T2 tumors (79%). The median total dose was 70.14 Gy (range: 60-85 Gy). With a mean follow-up of 35.4 months, two patients (5.6%) presented local failure, and seven patients (19%) had lymph node progression. The Kaplan-Meier estimated probability of local failure was 7.2% (95% CI: 0.84-1) at two and four years. All patients encountered radiomucitis grade II or higher. The rate of late toxicities was low: three patients (8.3%) had grade II fibrosis, and one patient had grade II chronic pain. All patients would highly recommend the treatment. The median FACT H&N total score was 127 out of 148, and the median FACT H&N Trial Outcome Index was 84. CONCLUSIONS: This study confirms that an excellent local control rate is achieved with PDR brachytherapy as treatment of lip carcinoma, with very limited late side effects and satisfactory functional outcomes. A multimodal approach should help to improve regional control.

Image-Guided Brachytherapy for Salvage Reirradiation: A Systematic Review.

BACKGROUND: Local recurrence in gynecological malignancies occurring in a previously irradiated field is a challenging clinical issue. The most frequent curative-intent treatment is salvage surgery. Reirradiation, using three-dimensional image-guided brachytherapy (3D-IGBT), might be a suitable alternative. We reviewed recent literature concerning 3D-IGBT for reirradiation in the context of local recurrences from gynecological malignancies. METHODS: We conducted a large-scale literature research, and 15 original studies, responding to our research criteria, were finally selected. RESULTS: Local control rates ranged from 44% to 71.4% at 2-5 years, and overall survival rates ranged from 39.5% to 78% at 2-5 years. Grade ≥3 toxicities ranged from 1.7% to 50%, with only one study reporting a grade 5 event. Results in terms of outcome and toxicities were highly variable depending on studies. Several studies suggested that local control could be improved with 2 Gy equivalent doses >40 Gy. CONCLUSION: IGBT appears to be a feasible alternative to salvage surgery in inoperable patients or patients refusing surgery, with an acceptable outcome for patients who have no other curative therapeutic options, however at a high cost of long-term grade ≥3 toxicities in some studies. We recommend that patients with local recurrence from gynecologic neoplasm occurring in previously irradiated fields should be referred to highly experienced expert centers. Centralization of data and large-scale multicentric international prospective trials are warranted. Efforts should be made to improve local control while limiting the risk of toxicities.

Analysis of Radiation Dose/Volume Effect Relationship for Anorectal Morbidity in Children Treated for Pelvic Malignancies.

PURPOSE: To examine dose-volume effect relationships for anorectal morbidity in children treated with image-guided brachytherapy for pelvic tumors. METHODS AND MATERIALS: Medical records of all consecutive children with pelvic tumors treated in our center and receiving image-guided pulsed-dose-rate brachytherapy with or without external beam radiation therapy (EBRT) between 2005 and 2019 were reviewed. The effect of the minimal doses to the most exposed 0.5 cm3, 1 cm3, and 2 cm3 of the anorectum (respectively: D0.5cm3, D1cm3, and D2cm3), total reference air kerma (TRAK), and volume of 100% isodose was examined for anorectal toxicities. RESULTS: Seventy-eight consecutive children were included. Median age was 2.9 years (range, 0.8-14.9 years). Most of the tumors were bladder or prostate (67%) or vaginal (22%) rhabdomyosarcoma. Six patients received EBRT in addition to brachytherapy. Median follow-up was 21.3 months. At last follow-up, 30 children (38%) had experienced Common Terminology Criteria for Adverse Events version 5 grade ≥1 acute or late anorectal events: 24% had grade 1 events, 7.7% had grade 2 events, and 6.4% had grade 3 events. No toxicity greater than grade 3 was observed (eg, fistula or stricture). In univariate analysis, the D0.5cm3 and D1cm3 were significant for probability of grade 1 to 3 (P = .009 and P = .017, respectively) and grade 2 to 3 anorectal morbidity (P = .007 and P = .049, respectively). There was no significant correlation for D2cm3 (P = .057 for grade 1-3; P = .407 for grade 2-3). A 10% probability (95% confidence interval, 4%-20%) for anorectal toxicity of grade 2 or greater was reached for a D0.5cm3 = 52 Gy. The age, EBRT use, TRAK, and treated volume values were not significant. CONCLUSIONS: To our knowledge, this study is the first to show a significant dose-volume effect relationships for anorectal morbidity in children undergoing treatment with brachytherapy. Integrating these data into brachytherapy treatment planning could help to optimize the therapeutic index in these young patients.