Cyrus Chargari

PHYSICS CONTRIBUTIONS AND CLINICAL OUTCOME WITH 3D-MRI-BASED PULSED-DOSE-RATE INTRACAVITARY BRACHYTHERAPY IN CERVICAL CANCER PATIENTS

PURPOSE To assess the physics contributions and clinical outcome with three-dimensional magnetic resonance imaging-guided pulsed-dose-rate (PDR) intracavitary brachytherapy in cervical cancer patients. METHODS AND MATERIALS The data from 45 patients with primary locally advanced cervical carcinoma were analyzed. The median tumor cervical volume was 64.0 cm(3) (range, 3-178). Of the 45 patients, 24 (53%) had histologic and/or radiologic pelvic involvement. After pelvic with or without para-aortic concomitant chemoradiotherapy, a PDR brachytherapy boost was delivered to a three-dimensional magnetic resonance imaging-based clinical target volume, taking into account the dose-volume constraints for critical organs and optimization of the target volume coverage. RESULTS At a median follow-up of 26 months (range, 9-47), the 2-year overall survival and disease-free survival rate was 78% and 73%, respectively. At the last follow-up visit, the disease of all patients remained locally controlled. Adding external beam radiotherapy and PDR using the equivalent dose in 2-Gy fractions model, the median dose received by 100% and 90% of the target was 54.4 Gy(alpha/beta10) and 63.5 Gy(alpha/beta10) for the intermediate-risk clinical target volume and 61.6 Gy(alpha/beta10) and 74.9 Gy(alpha/beta10) for the high-risk clinical target volume, respectively. Of the 45 patients, 23 and 2 developed acute Grade 1-2 and Grade 3 complications, respectively; 21 patients presented with delayed Grade 1-2 complications. One other patient presented with Grade 3 vesicovaginal fistula. No Grade 4 or greater complications, whether acute or delayed, were observed. CONCLUSION Magnetic resonance imaging-guided PDR brachytherapy with optimization integrating the limits of tolerance to critical organs allows for excellent local control rates. Moreover, the present results have confirmed that the ability to optimize dwell times can contribute to an improvement in local control rates with a low level of late side effects.

Targeting a cornerstone of radiation resistance: cancer stem cell.

In radiation oncology, cancer stem cells (CSCs) have become an important research field. In fact, it appears that most cancer types contain populations of cells that exhibit stem-cell properties. CSCs have the ability to renew indefinitely, which can drive tumor development and metastatic invasion. As those cells are classically resistant to conventional chemotherapy and to radiation therapy, they may contribute to treatment failure and relapse. Over past decades, preclinical research has highlighted that variations in the CSCs content within tumor could affect their radiocurability by interfering with mechanisms of DNA repair, redistribution in the cell cycle, tumor cells repopulation, and hypoxia. It is now possible to isolate particular cells expressing specific surface markers and thus better investigating CSCs pathways. Numerous inhibitory agents targeting these specific signaling pathways, such as Notch and Wnt/B-catenin, are currently evaluated in early clinical trials. By targeting CSCs, tumor radioresistance could be potentially overcome to improve outcome for patients with solid malignancies. Radiation therapy using ion particles (proton and carbon) may be also more effective than classic photon on CSCs. This review presents the major pathophysiological mechanisms involved in CSCs radioresistance and recent developments for targeted strategies.

Nutritional support during oncologic treatment of patients with gastrointestinal cancer: Who could benefit?

INTRODUCTION In patients with gastrointestinal (GI) cancer, severe malnutrition is associated with increased morbidity and mortality, reduction of treatment efficacy, and increased length of hospital stay. Therefore, systematic screening and care of malnutrition is mandatory. MATERIALS AND METHODS Data for this review were identified by searches of Medline with and without MeSH database and Cancerlit. Studies were selected only if they were randomised clinical trials or historical reports. References were also identified from reference lists in relevant previously published articles. Recent guidelines and meta-analyses were included. Only articles published in English were taken into consideration. RESULTS For surgical patients, practical information such as weight loss or subjective global assessment would provide a better basis for deciding whether or not to delay surgery. At least 10 days of nutritional support is recommended in severely malnourished patients before major digestive surgery. In non-severely malnourished patients, preoperative oral immunonutrition is associated with a 50% decrease in postoperative complications. The benefit of immune-enhancing diets in severely malnourished patients remains to be proven. For patients undergoing radiochemotherapy, dietary counselling should be proposed to all patients. In cases of severely malnourished patients or if dietary counselling suffers a setback, enteral nutrition should be recommended. Parenteral nutrition should be reserved for patients with severe digestive intolerance when enteral nutrition is not possible. CONCLUSION Propose an adaptive nutritional support at each step of a multimodal GI oncological treatment is essential. These recommendations should be used in daily practice but should also be included in all clinical research protocols.

Impact of treatment time and dose escalation on local control in locally advanced cervical cancer treated by chemoradiation and image-guided pulsed-dose rate adaptive brachytherapy.

PURPOSE To report the prognostic factors for local control in patients treated for locally advanced cervical cancer with image guided pulsed-dose rate brachytherapy. MATERIALS/METHODS Patients treated with curative intent by a combination of external beam radiotherapy and pulsed-dose rate brachytherapy were selected. Local failure was defined as any relapse in the cervix, vagina, parametria, or uterus during follow-up. Prognostic factors were selected based on log rank tests and then analyzed with a Cox model. Dose/effect correlations were performed using the probit model. RESULTS Two hundred and twenty-five patients treated from 2006 to 2011 were included. According to the FIGO classification, 29% were stage IB, 58% stage II, 10% stage III, and 3% stage IVA; 95% received concomitant chemotherapy. Thirty patients were considered having incomplete response or local failure. Among the selected parameters, D90 for HR-CTV, D90 for IR-CTV, the overall treatment time, the TRAK, and the HR-CTV volume appeared significantly correlated with local control in univariate analysis. In multivariate analysis, overall treatment time >55days and HR-CTV volume >30cm(3) appeared as independent. The probit analysis showed significant correlations between the D90 for both CTVs, and the probability of achieving local control (p=0.008 and 0.024). The thresholds to reach to warrant a probability of 90% of local control were 85Gy to the D90 of the HR-CTV and 75Gy to 90% of the IR-CTV (in 2Gy equivalent, α/β=10). To warrant the same local control rate, the D90 HR-CTV should be significantly increased in stage III-IV tumors, in case of HR-CTV >30cm(3), excessive treatment time, or tumor width at diagnosis >5cm (97, 92, 105, and 92Gy respectively). CONCLUSIONS Overall treatment time and HR-CTV volume were independent prognostic factors for local control. The D90 for HR and IR CTV were significantly correlated with local control, and D90 HR-CTV should be adapted to clinical criteria.

MRI-based low dose-rate brachytherapy experience in locally advanced cervical cancer patients initially treated by concomitant chemoradiotherapy.

PURPOSE To retrospectively assess the physics contributions and the clinical outcome with preliminary 3D MRI-guided low dose-rate (LDR) intracavitary brachytherapy (BT) experience in locally advanced cervical cancer patients. PATIENTS AND METHODS Eighty-four patients with primary locally advanced cervical carcinoma were analyzed. The median tumoral cervical volume was 48.0 cc (range 1-468 cc). Twenty-four patients (53%) had histological and/or radiological pelvic involvement. After pelvic+/-paraaortic concomitant chemoradiation, a LDR BT boost was delivered to a 3D MRI-based clinical target volume taking into account dose volume constraints for critical organs and optimization of target volume coverage. RESULTS With a median follow-up of 53 months (range 31-79 months), the 4-year overall survival and disease-free survival rates were 57 (95%CI, 43-69) and 52% (95%CI, 40-64), respectively. Adding EBRT and LDR using EQD2 model, the median D(100) and D(90) for the IR-CTV were 56.5 Gy(alpha/beta10) (range 37-83 Gy(alpha/beta10)) and 69 Gy(alpha/beta10) (range 52-113 Gy(alpha/beta10)), respectively. For HR-CTV, the median D(100) and D(90) were 67 Gy(alpha/beta10) (range 47-119 Gy(alpha/beta10)) and 79 Gy(alpha/beta10) (range 53-122 Gy(alpha/beta10)), respectively. Thirty-nine late complications were observed in 28 patients (33.3%): 13 bladder, 7 rectal, 5 small bowel, 4 urethral, 3 colic, 2 vaginal, 1 pelvic fibrosis, and 4 others. Four grade 3 delayed complications were observed and no grade 4 complication occurred. CONCLUSIONS Applying an individual treatment planning with 3D MRI-guided LDR brachytherapy appears to be feasible and efficient for patients with locally advanced cervical cancer in routine clinical practice.

DVH parameters and outcome for patients with early-stage cervical cancer treated with preoperative MRI-based low dose rate brachytherapy followed by surgery

BACKGROUND To our knowledge no DVH data have so far been reported for MRI-guided BT in the preoperative setting of early-stage cervical cancer. We assessed DVH parameters and clinical outcome using 3D MRI-guided preoperative intracavitary LDR BT. PATIENTS AND METHODS Thirty-nine patients with primary early cervical carcinoma (IB1 37, IIA 1 and IIB 1) were treated with preoperative MRI-based LDR BT, consisting of uterovaginal BT to a total dose of 60 Gy to the intermediate-risk CTV, followed 6 weeks later by bilateral salpingo-oophorectomy and extrafascial hysterectomy plus pelvic node dissection. Adjuvant chemoradiation was delivered to patients with pelvic lymph node involvement. RESULTS With a median follow-up of 4.4 years (range 2.6-6.6 years), local recurrence occurred in 1 patient (a lateropelvic relapse) (2.6%). The 4-year actuarial overall survival and disease-free survival were 94% (95% CI, 82-98), and 86% (95% CI, 67-95), respectively. The 2- and 4-year actuarial local relapse-free survival were 94 (95% CI, 86-100) and 91% (95% CI, 81-100), respectively. For intermediate-risk CTV, median D(100) and D(90) were 43 Gy(alpha)(/)(beta)(10) (range 2-74 Gy(alpha)(/)(beta)(10)) and 75 Gy(alpha/beta)(10), respectively (range 29-129 Gy(alpha/beta)(10)). For high-risk CTV, the median D(100) and D(90) were 69 Gy(alpha/beta)(10) (range 24-137 Gy(alpha/beta)(10)) and 109 Gy(alpha/beta)(10) (range 37-198 Gy(alpha/beta)(10)), respectively. Twenty grade 1-2 late complications were observed in 13 patients (33.3%): 10 bladder, 3 ureteral, 1 rectal, 1 small bowel, 1 vaginal, 1 pelvic fibrosis, 1 peripheral nerve, and 2 others. No grade 3 or 4 complication occurred. CONCLUSION MRI-guided brachytherapy with adaptation of the time duration and/or the length of each radioactive source allows both high local control and low toxicity in the preoperative settings of early-stage cervical cancers.

Can immunostimulatory agents enhance the abscopal effect of radiotherapy

Ionising radiation (IR) may harm cancer cells through a rare indirect out-of-field phenomenon described as the abscopal effect. Increasing evidence demonstrates that radiotherapy could be capable of generating tumour-specific immune responses. On the other hand, effects of IR also include inhibitory immune signals on the tumour microenvironment. Following these observations, and in the context of newly available immunostimulatory agents in metastatic cancers (anti-cytotoxic T lymphocyte-associated antigen 4 and programmed cell death protein-1 or -ligand 1 [PD1 or PDL-1]), there is a remarkable potential for synergistic combinations of IR with such agents that act through the reactivation of immune surveillance. Here, we present and discuss the pre-clinical and clinical rationale supporting the enhancement of the abscopal effect of IR on the blockade of immune checkpoints and discuss the evolving potential of immunoradiotherapy.

Oncological outcomes after fertility-sparing surgery for cervical cancer: a systematic review

Fertility preservation in young patients with cervical cancer is suitable only for patients with good prognostic factors and disease amenable to surgery without adjuvant therapy. Consequently, it is only offered to patients with early-stage disease (stage IB tumours <4 cm), negative nodes, and non-aggressive histological subtypes. To determine whether fertility preservation is suitable, the first step is pelvic-node dissection to establish nodal spread. Tumour size (≤2 cm vs >2 cm) and lymphovascular space invasion status are two main factors to determine the best fertility-sparing surgical technique. In this systematic Review, we assess six different techniques that are available to preserve fertility (Dargents procedure, simple trachelectomy or cone resection, neoadjuvant chemotherapy with conservative surgery, and laparotomic, laparoscopic and robot-assisted abdominal radical trachelectomy). The choice between the six different fertility preservation techniques should be based on the experience of the team, discussion with the patient or couple, and, above all, objective oncological data to balance the best chance for cure with optimum fertility results for each procedure.

Concurrent hormone and radiation therapy in patients with breast cancer: what is the rationale?

Endocrine therapy is often given together with postoperative radiotherapy in patients with breast cancer and positive hormone-receptor status. However, few experimental or clinical studies address the combined effects of hormone and radiation therapy. Preclinical models have shown changes in tumour cell kinetics with the addition of tamoxifen, and some show reduced tumour cell death with concurrent anti-oestrogen treatment and radiotherapy. Although data from in-vitro studies support the notion of antagonistic effects of concurrent tamoxifen and radiotherapy on tumour cells, in-vivo research suggests a synergistic effect that could be attributable to micro-environmental changes in tumour responsiveness to ionising radiation and hormone therapy. Retrospective studies suggest that in practical application, concurrent administration of tamoxifen with radiotherapy does not compromise local control but might increase toxicity. Preliminary results from simultaneous treatment with aromatase inhibitors and radiation indicate that this combination of endocrine and radiation therapy could enhance cytotoxicity and improve tumour response. Further studies are needed to clarify the physiological mechanisms activated by oestrogens, which will allow a more thorough understanding of the complex interactions between 17beta-oestradiol and P53/P21(WAF1/CIP1)/Rb pathways and of the interaction between endocrine therapy and radiotherapy.

Technical aspects and perspectives of the vaginal mold applicator for brachytherapy of gynecologic malignancies

PURPOSE The importance of the quality of cervical cancer brachytherapy applicators has been reported, suggesting a direct influence of competent technical implant performance on outcome. In our institute, an original brachytherapy technique based on the use of a molded applicator for genital tract brachytherapy has been applied routinely in clinical practice. Here, we report the technical aspects of this customized applicator and perspectives on its use. TECHNICAL ASPECTS The first step consists of a vaginal impression that accurately shows the topography and extension of the tumor as well as the anatomy of the vagina and cervix. From this impression, an acrylic applicator is made. Then, the intended positions of the vaginal catheters are drawn on the surface of the mold by the radiation oncologist. Two plastic vaginal catheters are introduced and fixed on the internal surface of the molded applicator. A hole for the cervical os is made through which the uterine probe will be positioned. PERSPECTIVES This method allows for high specificity within the framework of a modern brachytherapy procedure, integrating the tumor topography, anatomy of the patient, and internal movements of target and critical volumes. This technique has been successfully extended to other tumor locations, such as genital tract rhabdomyosarcoma in children and postoperative endocavitary brachytherapy in patients with endometrial cancer. CONCLUSION Customization of a vaginal brachytherapy applicator allows for the maintenance of morphologic optimization throughout the treatment course, which better takes into account a fourth dimension: internal organ motion during the course of brachytherapy.