Comparison between the ICRU rectal point and modern volumetric parameters in brachytherapy for locally advanced cervical cancer

PurposeThe implementation of image-guided brachytherapy in cervical cancer raises the problem of adapting the experience acquired with 2D brachytherapy to this technique. The GEC-ESTRO (Groupe européen de curiethérapie – European Society for Radiotherapy and Oncology) has recommended reporting the dose delivered to the rectum in the maximally exposed 2 cm³ volume, but so far, the recommended dose constraints still rely on 2D data. The aim of this study was to evaluate the relationship between the doses evaluated at the ICRU rectal point and modern dosimetric parameters.Material and methodsFor each patient, dosimetric parameters were generated prospectively at the time of dosimetry and were reported. For analysis, they were converted in 2 Gy equivalent doses using an α/β ratio of 3 with a half-time of repair of 1.5 hours.ResultsThe dosimetric data from 229 consecutive patients treated for locally advanced cervical cancer was analyzed. The mean dose calculated at ICRU point (DICRU) was 55.75 Gy ± 4.15, while it was 59.27 Gy ± 6.16 in the maximally exposed 2 cm³ of the rectum (P = 0.0003). The D2 cm³ was higher than the DICRU in 78% of the cases. The mean difference between D2 cm³ and DICRU was 3.53 Gy ± 4.91. This difference represented 5.41% ± 7.40 of the total dose delivered to the rectum (EBRT and BT), and 15.49% ± 24.30 of the dose delivered when considering brachytherapy alone. The two parameters were significantly correlated (P = 0.000001), and related by the equation: D2 cm³ = 0.902 × DICRU + 0.984. The r² coefficient was 0.369.ConclusionIn this large cohort of patients, the DICRU significantly underestimates the D2 cm³. This difference probably results from the optimization process itself, which consists in increasing dwell times above the ICRU point in the cervix. Considering these findings, caution must be taken while implementing image-guided brachytherapy and dose escalation.     

Cervix cancer brachytherapy: High dose rate

Cervical cancer, although less common in industrialized countries, is the fourth most common cancer affecting women worldwide and the fourth leading cause of cancer death. In developing countries, these cancers are often discovered at a later stage in the form of locally advanced tumour with a poor prognosis. Depending on the stage of the disease, treatment is mainly based on a chemoradiotherapy followed by uterovaginal brachytherapy ending by a potential remaining tumour surgery or in principle for some teams. The role of irradiation is crucial to ensure a better local control. It has been shown that the more the delivered dose is important, the better the local results are. In order to preserve the maximum of organs at risk and to allow this dose escalation, brachytherapy (intracavitary and/or interstitial) has been progressively introduced. Its evolution and its progressive improvement have led to the development of high dose rate brachytherapy, the advantages of which are especially based on the possibility of outpatient treatment while maintaining the effectiveness of other brachytherapy forms (i.e., low dose rate or pulsed dose rate). Numerous innovations have also been completed in the field of imaging, leading to a progress in treatment planning systems by switching from two-dimensional form to a three-dimensional one. Image-guided brachytherapy allows more precise target volume delineation as well as an optimized dosimetry permitting a better coverage of target volumes.     

Outcomes and treatments of IB1 cervical cancers with high recurrence risk: A 13 years’ experience

Purpose

The aim of the present study was to identify management strategies and outcomes of patients with stage IB1 cervical cancer with high recurrence risk.

(18F)-FDG PET/CT parameters to predict survival and recurrence in patients with locally advanced cervical cancer treated with chemoradiotherapy

Purpose

To identify predictive (¹⁸F)-fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT)-based parameters for locoregional control, disease-free survival and overall survival, by testing different thresholds of metabolic tumor volume and total lesion glycolysis in patients with locally-advanced cervical cancer.

3D brachytherapy for cervical cancer: New optimization ways

Brachytherapy has known major improvements in recent decades. It represents an essential component of local treatment of cervix cancers. One major breakthrough was the advent of 3D imaging for image-guided brachytherapy. Doses could be prescribed to volumes. This allows better delineation and coverage of target volumes, as well as organs at risk (bladder, rectum, sigmoid) protection. Local recurrences have been consequently reduced and survival has been improved. In addition, improvement and development of new applicators have facilitated the delivery of interstitial treatments. Afterloading applicators, associated with 3D imaging, allow dosimetry optimization in order to improve the coverage of the target volumes (dose in 90% of the high risk clinical target volume) and to limit dose to the organs at risk. In the future, more personalized treatments will be achieved through more advanced applicators and/or by improving the accuracy of imaging at the time of brachytherapy.     

Evaluation of adjuvant vaginal vault brachytherapy in early stage cervical cancer patients

PurposeAdjuvant external beam radiotherapy (EBRT) was shown to decrease pelvic relapses in patients with an early stage cervical cancer and intermediate-risk histopathological prognostic factors, at the cost of increased bowel morbidity. We examined the feasibility and results of adjuvant brachytherapy alone as an alternative to EBRT in this situation.Patients and methodsMedical records of consecutive patients receiving adjuvant brachytherapy between 1991 and 2018 for an early stage cervical cancer were examined. Patients were included if they presented a pT1a2N0 or pT1b1N0 disease following radical colpohysterectomy. Adjuvant vaginal wall brachytherapy (without EBRT) was indicated because of a tumor size ≥ 2 cm and/or presence of lymphovascular space invasion (LVSI). Patients received 60 Gy to 5 mm of the vaginal wall, through low-dose or pulse-dose rate technique. Patients’ outcome was examined for disease control, toxicities and prognostic factors.ResultsA total of 40 patients were included. Eight patients (20%) had LVSI, 26 patients (65%) had a tumor size ≥ 2 cm. With median follow-up time of 42.0 months, 90% of patients were in complete remission and four patients (10%) experienced tumor relapse, all in the peritoneal cavity, and associated with synchronous pelvic lymph node failure in 2/4 patients. No vaginal or isolated pelvic nodal failure was reported. At 5 year, overall survival was 83.6% (CI95%: 67.8–100%) and disease-free survival was 85.1% (CI95%: 72.6–99.9%). In univariate analysis, probability of relapse correlated with tumor size ≥ 3 cm (P = 0.004). No acute or late toxicity grade more than 2 was reported.ConclusionBrachytherapy alone was a well-tolerated adjuvant treatment for selected patients with intermediate risk factors. The risk of relapse in patients with tumor size ≥ 3 cm was however high, suggesting that EBRT is more appropriate in this situation.     

Glassy cell carcinoma of the uterine cervix: 20-year experience from a comprehensive cancer center

PurposeGlassy cell carcinoma (GCC) of the uterine cervix is a rare entity. This study aims at describing the clinical characteristics and outcomes of cervical GCC patients treated in a comprehensive cancer center.Material and methodsWe retrospectively reported patients and tumors characteristics, therapeutic management, overall survival (OS), progression-free progression (PFS), relapse rates, and toxicities.ResultsBetween 1994 and 2014, 55 patients were treated with curative intent. The median age at diagnosis was 41 years (range, 20–68). Among 22 patients with early stage tumors (IA2-IB1-IIA1), 17 had preoperative brachytherapy, followed by radical hysterectomy. Among 33 patients with locally advanced disease (≥IB2), 32 underwent chemoradiation ± brachytherapy boost. After a median follow-up of 5.4 years (range, 0.15–21.7 years), 18/55 (33%) patients experienced tumor relapse. Local recurrence occurred in 2/22 (9%) patients with early disease (treated with upfront surgery) and in 3/32 (9%) patients with locally advanced disease. Most frequent relapses were distant, occurring in a total of 11/55 patients (20%). PFS rates at 5-year were 86.4% (95% CI: 63.4–95.4) for early stage versus 75.9% (95% CI: 55.2–89.2) for locally advanced stages, respectively (P = 0.18).ConclusionLarge cohort data are warranted to guide the optimal management of GCC. From this retrospective analysis, a multimodal approach yielded to good disease control in early stages tumors. Given the high-risk of distant failure, consideration should be given to adjuvant chemotherapy in locally advanced disease.     

Integration of functional imaging in brachytherapy

Functional imaging allows the evaluation of numerous biological properties that could be considered at all steps of the therapeutic management of patients treated with brachytherapy. Indeed, it enables better initial staging of the disease, and some parameters may also be used as predictive biomarkers for treatment response, allowing better selection of patients eligible for brachytherapy. It may also improve the definition of target volumes with the aim of dose escalations by dose-painting. Finally, it could be useful during the follow-up to assess response to treatment. In this review, we report how functional imaging is integrated at the present time during the brachytherapy procedure, and what are its potential future contributions in the main tumour locations where brachytherapy is recommended. Functional imaging has great potential in the contact of brachytherapy, but still, several issues remain to be resolved before integrating it into clinical practice, especially as a biomarker or in dose painting strategies.     

Volumetric modulated arctherapy for locally advanced nasopharyngeal carcinoma: Clinical efficacy and late toxicity

PurposeWe report our experience of 86 consecutive patients with locally advanced nasopharyngeal carcinoma who were treated with volumetric modulated arc therapy.Materials and methodsWe retrospectively reviewed the medical records of 86 patients with histologically proven primary nasopharyngeal carcinoma treated with volumetric modulated arctherapy technique radiotherapy. Primary endpoints were local, regional, distant control, and overall survival, second endpoint was late toxicity.ResultsThe median age was 47.5 years (range: 13–79 years) with sex ratio 1.09. At diagnosis, rhinologic symptoms represented the most common clinical presentation, reported by 61 patients (70.9%). Almost 88.4% of patients presented non-keratinizing undifferentiated carcinoma histology (n = 76). Most of the patients presented a locally advanced disease defined by stage III and IVa (95.3%). Therefore, 31 patients were treated by concurrent chemoradiation (36%), 52 patients received induction chemotherapy followed by concurrent chemoradiotherapy (57%), three patients received induction chemotherapy followed by exclusive radiotherapy (3.5%). and three patients treated with exclusive irradiation (3.5%). With a median follow up of 15.7 months (range: 4–33.3 months), nine patients died (10.4%), three presented local or locoregional relapse (3.4%), while nine patients presented distant recurrences (10.4%). The two years overall and disease-free survival rates were 88.7% and 83.1% respectively, locoregional control was 100% at 12 months and 96.2% at 24 months, and the two years distant failure-free survival was 86.7%. Time to relapse was the only prognostic factor in univariate analysis for overall survival in our study. The therapeutic tolerance was good with 61.7% of grade 3 and 2.3% grade 4 hyposialia respectively, 46.5% of otological disorders and no radionecrosis was noted.ConclusionVolumetric modulated arctherapy technique with concurrent chemoradiotherapy is an effective treatment for nasopharyngeal carcinoma with excellent overall and locoregional control without severe toxicity. Distant metastasis is the major site of failure, so induction chemotherapy added to chemoradiotherapy must be discussed in multidisciplinary consultation meeting because it significantly improved recurrence-free survival and overall survival, as compared with chemoradiotherapy alone.     

Cancers du col utérin : nouveautés dans la prise en charge en oncologie radiothérapie

During the recent past years, the therapeutic management of locally advanced cervical cancer patients has consistently improved, with the integration of image guided brachytherapy and dose escalation strategies leading to an improvement of local control rates. In parallel, the evolution of external beam radiotherapy techniques and the better control of organs at risk doses in brachytherapy have contributed to decrease the probability of severe normal tissue complication. In case of advanced disease, patients prognosis remains however marked by a high risk of distant failure, and this finding has encouraged the assessment of various research pathways in order to better predict and/or prevent tumor relapse. Major studies are being conducted or have been published, and the place of chemoradiation and brachytherapy has been confirmed as first intent treatment in case of locally advanced disease. Numerous prospective or retrospective data, few of which are reviewed there, have been integrated as part of a strategy aimed at being more and more personalized. Next steps of therapeutic optimization will include the assessment of multiparameters radiological tools, but will also rely on a better understanding of radiobiological pathways involved in local or systemic response to irradiation, and the most promising of those is probably the anti-tumor immune response.     

FIGO stage IB1 cervical carcinoma: Place and principles of brachytherapy

The treatment of cervical cancers according to FIGO staging is well defined. For FIGO stage IB2 or more, chemoradiotherapy followed by uterovaginal brachytherapy boost is the standard treatment. Surgery is the preferred choice for less advanced tumors. However, most French institutions propose preoperative brachytherapy followed by hysterectomy with pelvic lymphadenectomy for FIGO stage IB1 tumors over 2 cm. Brachytherapy is also used for the boost after adjuvant pelvic external beam radiotherapy. Tridimensional dosimetry with optimization allows better treatment planning, delivering high doses to target volumes with limited irradiation to the organs at risk. We will discuss the indications of brachytherapy for FIGO stage IB1 tumors and the principles of pulsed-dose rate and high-dose rate techniques.     

TPF induction chemotherapy followed by concurrent chemoradiotherapy for locally advanced nasopharyngeal carcinoma: Long term results of a Tunisian series

Purpose

We represent in this study the long term results of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy followed by concurrent chemoradiotherapy in Tunisian patients with locally advanced nasopharyngeal carcinoma. The objective of our study is to analyse the efficacy as well as the toxicity of this therapeutic protocol.

What to expect from immediate salvage hysterectomy following concomitant chemoradiation and image-guided adaptive brachytherapy in locally advanced cervical cancer

PurposeConcomitant chemoradiation followed by brachytherapy is the standard treatment for locally advanced cervical cancers. The place of adjuvant hysterectomy remains unclear but tends to be limited to incomplete responses to radiotherapy or local relapse. The aim was to analyse the benefit from immediate salvage surgery following radiation therapy in incomplete responders.MethodsAmong the patients with locally advanced cervical cancer treated with concomitant chemoradiation followed by 3D image-guided adaptive brachytherapy and hysterectomy, cases with genuine macroscopic remnant, defined as at least 1 cm in width, were identified. Their clinical data and outcomes were retrospectively reviewed and compared to the patients treated with the same modalities.ResultsFifty-eight patients were included, with a median follow-up of 4.2 years. After hysterectomy, 9 patients had macroscopic residual disease, 10 microscopic and the remaining 39 patients were considered in complete histological response. The 4-year overall survival and disease-free survival rates were significantly decreased in patients with macroscopic residual disease: 50 and 51% versus 92% and 93%, respectively. Intestinal grades 3–4 toxicities were reported in 10.4% and urinary grades 3–4 in 8.6% in the whole population without distinctive histological features. Planning aims were reached in only one patient with macroscopic residuum (11.1%). In univariate analysis, overall treatment time (> 55 days) and histological subtype (adenocarcinomas or adenosquamous carcinomas) appeared to be significant predictive factors for macroscopic remnant after treatment completion (P = 0.021 and P = 0.017, respectively). In multivariate analysis, treatment time was the only independent factor (P = 0.046, odds ratio = 7.0).ConclusionsAlthough immediate salvage hysterectomy in incomplete responders provided a 4-year disease-free survival of 51%, its impact on late morbidity is significant. Efforts should focus on respect of treatment time and dose escalation. Adenocarcinoma might require higher high-risk clinical target volume planning aims.     

Correlation between changes in the number of peripheral blood lymphocytes and survival rate in patients with cervical cancer after radio-chemotherapy

PurposeThis study aimed to compare the absolute numbers of various types of lymphocytes in the peripheral blood before and after chemotherapy following radio-chemotherapy in patients with cervical cancer, so as to explore the correlation between the changes in the absolute numbers of peripheral various types of lymphocytes and the overall survival rate of patients.MethodsData of 205 patients with cervical cancer admitted to the hospital from June 2014 to August 2016 were retrospectively analyzed. These patients underwent concurrent radio-chemotherapy, followed by chemotherapy. The absolute numbers of peripheral blood lymphocytes and subtypes were compared before and after re-chemotherapy.ResultsFor patients with a good prognosis, the number of lymphocytes, T cells, and cytotoxic T cells (Tc) significantly decreased (P < 0.05) after re-chemotherapy, while this phenomenon was not observed in patients with poor prognosis. Kaplan–Meier univariate analysis showed that patients with cervical cancer who had an advanced FIGO stage before treatment, presence of lymph node metastasis, and increased numbers of Tc and T helper cells after re-chemotherapy showed a low 30-month survival rate; the overall log-rank analysis showed significant differences (P < 0.05). Multivariate Cox proportional hazards regression analysis, presence of lymph node metastasis: HR = 9.718, P = 0.002, 95% CI = 0.183–0.679; Tc grouping: HR = 3.239, P = 0.0.072, 95% CI = 0.950–03.347; Th group: HR = 3.197, P = 0.074, 95% CI = 0.943–3.564.ConclusionsAfter radio-chemotherapy, in patients with advanced cervical cancer, the change in the numbers of peripheral blood Tc and Th before and after re-chemotherapy was associated with the 30-month overall survival rate of patients. It can be considered as a predictor of the survival of patients with advanced cervical cancer.     

Dose rate in brachytherapy using after-loading machine: Pulsed or high-dose rate?

Since February 2014, it is no longer possible to use low-dose rate 192 iridium wires due to the end of industrial production of IRF1 and IRF2 sources. The Brachytherapy Group of the French society of radiation oncology (GC-SFRO) has recommended switching from iridium wires to after-loading machines. Two types of after-loading machines are currently available, based on the dose rate used: pulsed-dose rate or high-dose rate. In this article, we propose a comparative analysis between pulsed-dose rate and high-dose rate brachytherapy, based on biological, technological, organizational and financial considerations.     

Comparison of dosimetric parameters and acute toxicity of intensity-modulated and three-dimensional radiotherapy in patients with cervix carcinoma: A randomized prospective study

PurposeThe use of intensity-modulated radiotherapy (IMRT) to treat cervix carcinoma has increased, however prospective randomized trials are still lacking.AimTo compare the dosimetric parameters and associated acute toxicity in patients with cervix carcinoma treated with three-dimensional (3D) conformal radiotherapy and IMRT.Patients and methodsForty patients were randomized in two arms each consisting of 20 patients. Patients in both arms received concurrent chemoradiation (cisplatin 40 mg/m² weekly; 50 Gy/25 fractions). Patients were treated with 3D conformal radiotherapy in one arm and with IMRT in another arm. After external beam radiotherapy, all patients received brachytherapy (21 Gy/3 fractions at weekly interval). For dosimetric comparison, both kinds of the plans were done for all the patients. All patients were assessed throughout and until 90 days after completion of treatment for acute gastrointestinal, genitourinary and hematologic toxicities.ResultsBoth plans achieved adequate planning target volume coverage, while mean conformity index was found significantly better in IMRT plans (P-value = 0.001). D₃₅ (dose to 35% volume) and D₅₀ for bladder was reduced by 14.62 and 32.57% and for rectum by 23.82 and 43.68% in IMRT. For IMRT, V₄₅ (volume receiving 45 Gy) of bowel were found significantly lesser (P-value = 0.0001), non-tumour integral dose was found significantly higher (P-value = 0.0240) and V₂₀ of bone marrow was found significantly reduced (P-value = 0.019) in comparison to that in 3D conformal radiotherapy. Significant reduction of grade 2 or more (20 vs 45%; P-value = 0.058) and grade ≥ 3 (5 vs 15%, P-value = 0.004) acute genitourinary toxicity and grade 2 or more (20 vs 45%, P-value = 0.003) and grade 3 or more (5 vs. 20%, P-value = 0.004) acute gastrointestinal toxicity while no significant difference for grade 2 and 3 or more haematological toxicity was noted in patients treated with IMRT compared to 3D conformal radiotherapy.ConclusionIMRT provide a good alternative for treatment of cervix carcinoma with lower acute gastrointestinal and acute genitourinary toxicity with similar target coverage compared to 3D conformal radiotherapy.     

Predictive factors associated with complete pathological response after neoadjuvant treatment for rectal cancer

PurposeA proportion of 10 to 30% of patients treated by chemoradiotherapy followed by total mesorectal excision surgery for a locally advanced rectal cancer can achieve a complete pathological response. We aimed to identify predictive factors associated with complete pathological response or no response and to assess the impact of each response on survival rates.Patients and methodsPatients treated with long course chemoradiotherapy for locally advanced and/or node positive rectal cancer from 2010 to 2016 were retrospectively reviewed. Statistical analysis was carried out to determine predictors of tumor regression and treatment outcomes.ResultsRecords were available on 70 patients. In the univariate analysis, clinical factors associated with complete tumor response were tumor mobility in digital rectal examination (P = 0.047), a limited parietal invasion (P = 0.001), clinically negative lymph node (P < 0.001) and a circumferential extent greater than 50% (P = 0.001). On the other hand, a T4 classification and an endoscopic tumor size greater than 6 cm were associated with no response to treatment (P = 0.049 and P = 0.017 respectively). On multivariate analysis, T2 clinical classification and N0 statement before treatment were independent predictive factors of pathologic complete response (P < 0.001 and P = 0.001) and a delayed surgery after 12 weeks was associated with no response to treatment (P = 0.001).ConclusionThe identification of predictive factors of histological response may help clinicians to predict the prognosis and to propose organ preservation for good responders.     

The inverse square law: A basic principle in brachytherapy

The purpose of this article is to remind the importance of the inverse square law in radiotherapy and especially in brachytherapy. Indeed, beyond the impact in radiation therapy with high energy beam, there is the use of radionuclides and low energy photons with short FSD where it is still more important. Comparisons between Iridium Brachytherapy and low energy X-rays brachytherapy show equivalent dose distributions in the first few centimeters. If the inverse square law is not the only element influencing the dose distributions calculations, it must not be forgotten. And it is playing a major role in brachytherapy with short FSD (< 6 cm).     

Intensity-modulated whole pelvic radiotherapy provides effective dosimetric outcomes for cervical cancer treatment with lower toxicities

PurposeTo compare the efficacy of intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, and conventional radiotherapy for cervical cancer treatment.Materials and methodsWhole pelvis intensity-modulated radiotherapy, three-dimensional conformal radiotherapy, and conventional radiotherapy plans were designed for 16 patients with stage IIB cervical cancer, each using the prescribed dose of 50.4 Gy/28 fractions. Dose–volume histograms of the target volume and organs at risk were evaluated.ResultsCompared to the 3D conformal and conventional radiotherapy plans, the intensity-modulated radiotherapy plan demonstrated superior conformal treatment. The mean planning target volume dose of all three plans reached the target effective therapeutic dose. The planning target volume dose of the intensity-modulated radiotherapy plan was significantly higher than that of either the three-dimensional conformal radiotherapy or conventional radiotherapy plan (P < 0.05). When more than 30 Gy was administered in intensity-modulated radiotherapy, organs at risk including the small intestine, rectum, bladder, and bone marrow received a significantly reduced volume of radiation. In comparison of the average planning target volume doses, significant volume reductions in irradiation of organs at risk were obtained with full bladders.ConclusionsAn intensity-modulated radiotherapy plan with appropriate margins encompassing the primary tumour and potential microscopic pelvic disease reduces the dose to organs at risk without compromising target coverage. Intensity-modulated radiotherapy is an appropriate definitive treatment for patients with cervical cancer.     

Toxicity and early clinical outcomes in cervical cancer following extended field helical tomotherapy to para-aortic lymph nodes

PurposeTo evaluate toxicity and early disease outcome among patients treated for cervical cancer with extended-field helical tomotherapy to the para-aortic nodes.Patients and methodsThirty-eight patients (International Federation of Gynecology and Obstetrics [FIGO] stage IB2–IVA) from four institutions received extended-field helical tomotherapy and were retrospectively evaluated. All had nodal disease. Para-aortic lymph nodes were involved in 31 patients. Patients were assessed for toxicity using version 4 of the National Cancer Institute's common terminology criteria for adverse events. Survival curves were plotted using Kaplan-Meier estimates.ResultsAll patients underwent radiation to the tumor region (median dose: 45 Gy; range: 44–66 Gy), pelvic lymph nodes and para-aortic lymph nodes (median dose: 45 Gy; range: 44–60 Gy). The median dose to positive lymph nodes was 55 Gy (range: 45–65 Gy). All received platinum-based chemotherapy (31 concurrently). The median follow-up was 15 months. Acute toxicity events observed included one patient with grade 5 febrile neutropenia, 11 patients (29%) with grade 3 hematologic complications. Grades 3–4 gastrointestinal and genitourinary toxicities occurred in six (16%) and four (11%) patients, respectively. Three patients had grade 3 pelvic pain (8%). The 6- and 18-month overall survival rates were 94.7 and 63.9%, respectively. The 18-month locoregional control, disease-free survival, and late grade 3 toxicity rates were 60.2, 43.3 and 7.3%, respectively.ConclusionExtended-field helical tomotherapy was associated with low rates of acute gastrointestinal and genitourinary toxicities with early survival and locoregional control similar to other published series.