RECIST 1.1 versus clinico-radiological response assessment for locally advanced cervical cancer: implications on interpreting survival outcomes of future trials.

OBJECTIVE: To investigate differences in standard clinico-radiological evaluation versus Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 for reporting survival outcomes in patients with locally advanced cervical cancer treated with chemoradiation and brachytherapy. METHODS: Between November 2017 and March 2020, patients recruited in cervical cancer trials were identified. MRI at diagnosis and at least one follow-up imaging was mandatory. Disease-free survival and progression-free survival were determined using standard evaluation (clinical examination and symptom-directed imaging) and RECIST 1.1. Agreement between criteria was estimated using κ value. Sensitivity analysis was done to test the sensitivity, specificity, and accuracy of RECIST 1.1 in detecting response to treatment. RESULTS: Sixty-nine eligible patients had at least one target lesion. Thirty-three patients (47.8%) had pathological lymph nodes. Of these 33 patients, RECIST 1.1 classified only 18% (6/33) as 'target nodal lesions' and the remaining nodes as 'non-target'. There were 6 (8.7%) and 8 (11.6%) patients with disease events using RECIST 1.1 and standard evaluation, respectively. The disease-free survival at 12, 18, and 24 months using RECIST 1.1 was 94.2%, 91.2%, 91.2%, and with standard evaluation was 94.2%, 89.7%, and 88.2%, respectively (p=0.58). Whereas, progression-free survival at 12, 18, and 24 months using RECIST 1.1 and standard evaluation were same (94.2%, 91.2%, and 91.2%, respectively). The κ value was 0.84, showing strong agreement in assessing disease-free survival, although an absolute difference of 3% between endpoint assessment methodologies. RECIST 1.1 had a sensitivity of 75% (95% CI 34.91% to 96.81%), specificity of 100% (95% CI 94.13% to 100%), and accuracy of 97.1% (95% CI 89.92% to 99.65%). CONCLUSIONS: The study showed 1.5% and 3% difference in disease-free survival at 18 and 24 months and no difference in progression-free survival between RECIST 1.1 and standard evaluation in a patient cohort with low event rate.

Evaluation of liver segmental dose threshold for hepatocyte regeneration following liver stereotactic body radiation therapy.

BACKGROUND OBJECTIVES: There is limited evidence studying the relationship of liver segmental dose and segmental volume changes. The segmental dose thresholds could potentially allow for segmental regeneration after liver stereotactic body radiation therapy (SBRT). Given improved survival in hepatocellular cancer (HCC) and liver metastases and more salvage therapy options, this has become an important clinical question to explore. This study assesses the impact of liver segmental dose on segmental volume changes (gain or loss) after SBRT. METHODS: Liver segmental contours were delineated on baseline and serial follow up triphasic computed tomography scans. The volumes of total liver and doses to total liver, uninvolved liver and individual segments were noted. A correlation was evaluated between liver/segmental volume and dose using Pearson's correlation. Furthermore, receiver operator's curve (ROC) analysis was performed to find the segmental dose, i.e . predictive for liver volume loss. RESULTS: A total of 140 non-tumour liver segments were available for analysis in 21 participants. Overall, 13 participants showed loss of overall liver volume and eight showed gain of overall liver volume. The median dose in segments reporting an increase in volume was 9.1 Gy (7-36 Gy). The median dose in segments losing volume was 15.5 Gy (1-49 Gy). On ROC analysis, segmental dose >11 Gy was associated with volume loss. On univariate analysis, only liver segmental dose contributed to a significant segmental volume loss. INTERPRETATION CONCLUSIONS: We propose from the findings of this study that in SBRT for large hepatocellular cancer or liver metastases, liver segments should be individually delineated. Furthermore, 3-5 liver segments may be preferentially subjected to <9 Gy to facilitate hepatocyte regeneration. Preferential sparing of uninvolved liver segments may improve outcomes in liver stereotaxyas lower segmental doses were associated with liver regeneration. This may have implications on future liver SBRT planning where segmental doses may be as important as the mean dose.

Co-occurrence of symptoms after radiochemotherapy in locally advanced cervix cancer patients: a cluster analysis.

BACKGROUND: State of the art combined radiochemotherapy and image-guided brachytherapy for locally advanced cervical cancer (LACC) has shown improved disease control and survival as well as a significant reduction of organ related morbidity. However, LACC cancer survivors are still experiencing a spectrum of symptoms. The aim of this study was to identify co-occurring symptoms in cervix cancer survivors by using patient-reported outcome and physician assessed morbidity. MATERIALS AND METHOD: EMBRACE I is a multicenter prospective observational study with 1416 LACC patients (2008-2015). Information on physician-assessed morbidity and patient-reported outcome was assessed at baseline and at regular follow-ups up with the CTCAE v.3 and EORTC-C30/CX24, respectively. Patients with at least 2 years of follow-up were included and data from 3 months to 2 years was used in the analysis. Factor analysis was used on both EORTC and CTCAE data with symptoms and follow-ups as observations. The extracted factors represent clusters of symptoms. Subsequently, regression models were built to investigate associations between the symptom clusters and QOL. RESULTS: The analysis included 742 patients. Despite the differences in the definition of physician-assessed and patient-reported symptoms, similar clusters are identified by the two assessment methods. Three main organ-related clusters are recognized for urinary, gastro-intestinal and vaginal morbidity. Furthermore, a general symptoms cluster where fatigue, pain, insomnia, neuropathy, and hot flashes have large weights is found. Lastly, a cluster with nausea, vomit and lack of appetite is also identified. The general, gastrointestinal and nausea clusters show significant associations with general QOL. CONCLUSIONS: This analysis on both PRO and physician-assessed morbidity found a cluster associated with general symptoms and organ-related symptom clusters (urinary, gastrointestinal, vaginal). This shows that LACC survivors experience a variety of co-occurring symptoms. Our analysis also shows that the cluster of general symptoms is associated with a decrease in QOL.

Postoperative adjuvant radiation for cervix cancer: reflections on the evidence and a peep into the future.

Early stage cervical cancer, stages IB1-2 and IIA1, can be treated with (chemo)radiation and brachytherapy or radical hysterectomy with or without further adjuvant (chemo)radiation. In a carefully selected cohort for surgery, traditionally a small proportion of patients would need adjuvant (chemo)radiation so that the therapeutic ratio is maximized. However, advances in radiation technology, specifically intensity modulated radiotherapy, have led to a reduction in treatment related adverse events. Also, recent developments in risk stratification suggest using a lower threshold to offer adjuvant treatment to minimize pelvic relapse. These developments together present opportunities of not only re-examining the therapeutic ratio but also of further evolving postoperative risk stratification. This review article summarizes the current evidence on adjuvant treatment strategies and summarizes the key areas where research should be focused.

Drug repurposing as a potential source of innovative therapies in cervical cancer.

OBJECTIVE: Drug repurposing is an alternative development pathway that utilizes the properties of drugs approved for other diseases and builds on available safety and pharmacological data to develop the drug as a potential treatment for other diseases. A literature-based approach was performed to identify drug repurposing opportunities in cervical cancer to inform future research and trials. METHODS: We queried PubMed for each drug included in two databases (ReDO_DB and CDcervix_DB, which include 300+ non-cancer drugs and 200+ cancer drugs not used in cervical cancer, respectively) and manually assessed all abstracts for relevance and activity in cervix cancer, and type of evidence. Subsequently, we also performed a search of clinical trial databases where we generated a list of registered trials in cervical cancer with all drugs from our databases. RESULTS: Of the 534 drugs from both databases, 174 (33%) had at least one relevant abstract or registered trial in cervical cancer. 94 (18%) drugs had at least human data available, and 52 (10%) drugs were evaluated in registered trials. To prioritize drugs to consider for future trials, all 174 drugs were further assessed for strength of scientific rationale, feasibility for integration in cervical cancer standard of care, evidence of radiosensitization, and potential mechanism of action. Out of the 174 drugs, 38 (22%) potential drug candidates were selected. CONCLUSION: This study resulted in a list of candidate drugs for potential evaluation in cervical cancer. Many drugs might warrant additional (pre)clinical investigation, which could be done in a coordinated manner using platform trials.

Towards standardization of management of gallbladder carcinoma with obstructive jaundice: Analysis of 113 cases over 10 years at a single institution.

BACKGROUND: Presence of jaundice in gallbladder carcinoma (GBC) is considered a sign of inoperability with no defined treatment pathways. METHODS: Retrospective analysis of all surgically treated GBC patients from January 2010 to December 2019 was performed for evaluating etiology of obstructive jaundice, resectability, postoperative morbidity, mortality, disease-free survival (DFS) and overall survival (OS). RESULTS: Out of 954 patients, 521 patients (54.61%) were locally advanced gallbladder carcinoma (LAGBC: Stage III and IV) and 113 patients (11.84%) had jaundice at presentation. Thirty-four (30%) patients had benign cause of obstructive jaundice. Median OS of the whole cohort (n=113) was 22 months (16.5-27.49 months) with resectability rate of 62% (70/113). Median OS of curative resection group (n=70) was 32 months and DFS was 25 months. Treatment completion was achieved in 30% (n= 21/70) patients with median OS of 46 months and median DFS of 27 months. Isolated bile duct infiltration subgroup fared the best with median OS of 74 months with a 5-year survival of 66.7%. CONCLUSION: Surgical resection as a part of multimodality treatment improves survival in carefully selected locally advanced gallbladder cancer patients with jaundice. Early introduction of systemic therapy is the key in the management of this disease with aggressive tumor biology.

Contribution of Tata Memorial Centre, India, to cervical cancer care: Journey of two decades.

Cervical cancer continues to be a major public health concern in India and other low- and middle-income countries. Tata Memorial Centre, India, has been at the forefront in providing treatment, developing best practice guidelines for low-cost efficacious interventions, conducting practice-changing randomized trials and engaging in regional and international collaborations for education and research in cervical cancer. This review summarizes how cervical cancer research and clinical care has evolved over the past two decades at the Tata Memorial Centre, right from testing low-cost public health screening of cervical cancers to the incorporation of the latest technological advancements and providing high-quality evidence for therapeutic management of cervical cancer. The various ongoing strategies for improving survival, toxicity reduction, translational research studies, educational activities and teaching programmes initiated by the Tata Memorial Centre at both national and international levels are discussed.

Defining the role of high-dose radiation in oligometastatic & oligorecurrent cervical cancer.

Around 5-8 per cent of women diagnosed with cervical cancer present with metastatic disease at presentation and 16-25 per cent of patients fail at either within irradiated fields or at distant sites post-curative therapy in advanced cervical cancers. Conventionally, chemotherapy with palliative intent constituted the mainstay of treatment with modest survival outcomes and radiation therapy was reserved for symptomatic benefit only. While targeted therapies and immunotherapy have been added in therapeutic armamentarium, the impact on the outcomes is modest. In limited metastatic disease, radiation therapy to metastatic sites from different primary cancers has shown survival benefits; however, the data are scarce in cervical cancer. With a better understanding of the molecular biology of the metastases and recurrence pattern, emphasis is laid upon total eradication of the disease rather than offering relief from symptoms. This article summarizes the role of radiation therapy in limited metastatic disease and recurrent cervical cancer.

Temporal course of late rectal toxicity & impact of intervention in patients undergoing radiation for cervical cancer.

BACKGROUND & OBJECTIVES: : There is limited information available on the temporal course of late stage radiotherapy adverse effects. The present study reports on the temporal course of late toxicities after chemoradiation and brachytherapy. METHODS: : Women with cervical cancer who presented with late toxicity after (chemo) radiation were included in the study. Grade of toxicity (Clinical Toxicity Criteria for Adverse Events version 4.03) and type of intervention were recorded at three-monthly interval for the first year and then six monthly until 24 months. Direct cost for the management of toxicity was calculated. Univariate analysis was performed to understand the impact of various factors on persistence of toxicity. RESULTS: : Ninety two patients were included in this study. Grades I, II, III and IV toxicities were observed in 50 (54%), 33 (36%), 7 (8%) and 2 (2%) patients, respectively, at first reporting. Patients spent a median of 12 (3-27) months with toxicity. At 12 months, 48/92 (52.2%) patients had a complete resolution of toxicity, whereas 27/92 (29.3%) patients had low grade (I-II) persistent toxicity. Only 6/92 (6.5%) patients who had grade III-IV toxicity had resolution to a lower grade. Four (4.3%) patients died due to toxicity. At 24 months, 9 (10%) patients continued to have grade ≥ III toxicity. On an average, 7 (2-24) interventions were required for the clinical management of late toxicity and median direct cost incurred was ₹ 50,625 (1,125-303,750). INTERPRETATION & CONCLUSIONS: : In this study late radiation toxicity resolved within 12 months in more than half of patients. However, others are likely to have had persistent lower grade toxicity or progression to higher grade. Structured strategies are hence needed for the effective management of late toxicities.

Evaluation of outcomes in patients of cervical Cancer with lower one third vaginal involvement: A single institutional experience.

OBJECTIVE(S): The objective of this study was to evaluate the clinical outcomes and prognostic factors affecting survival of cervical cancer patients presenting with lower third vaginal involvement. MATERIALS/METHODS: The patients with histologically proven invasive cervical cancer with clinical FIGO-2009 stage IIIA and IIIB with lower one-third vaginal involvement, treated with radio (chemo) therapy between 2010 and 2016 at our institution were retrospectively analyzed. RESULTS: There were 118 cervical cancer patients with lower third vaginal involvement with median age of 56.5 years (Range: 33-77 years). Forty-five patients were of FIGO stage IIIA, 73 patients staged as stage IIIB at diagnosis with predominant squamous histology. At a median follow up of 30 months, 12 patients (10.1%) developed local vaginal recurrences and 4 patients (3.3%) had developed loco regional recurrences, 27 patients (23%) developed distant and 2 patients developed loco-regional and distant relapses. The 3- year DFS and OS rates were 61.5% and 69.8% respectively. The 3-year DFS and OS of patients with IIIA was significantly better than IIIB patients (71% vs 56%, p: 0.02 and 76% vs 66%, p: 0.01 respectively) on univariate analysis. Concurrent chemotherapy and absence of persistent disease emerged as independent predictors of survival on multi-variate analysis. CONCLUSION: The outcome of patients with FIGO IIIA is better than IIIB with lower vaginal involvement. Elderly patients, patients not receiving concomitant chemotherapy and presence of residual disease at BT are associated with poorer outcomes.

Radiation therapy for gynecologic malignancies during the COVID-19 pandemic: International expert consensus recommendations.

OBJECTIVE: To develop expert consensus recommendations regarding radiation therapy for gynecologic malignancies during the COVID-19 pandemic. METHODS: An international committee of ten experts in gynecologic radiation oncology convened to provide consensus recommendations for patients with gynecologic malignancies referred for radiation therapy. Treatment priority groups were established. A review of the relevant literature was performed and different clinical scenarios were categorized into three priority groups. For each stage and clinical scenario in cervical, endometrial, vulvar, vaginal and ovarian cancer, specific recommendations regarding dose, technique, and timing were provided by the panel. RESULTS: Expert review and discussion generated consensus recommendations to guide radiation oncologists treating gynecologic malignancies during the COVID-19 pandemic. Priority scales for cervical, endometrial, vulvar, vaginal, and ovarian cancers are presented. Both radical and palliative treatments are discussed. Management of COVID-19 positive patients is considered. Hypofractionated radiation therapy should be used when feasible and recommendations regarding radiation dose, timing, and technique have been provided for external beam and brachytherapy treatments. Concurrent chemotherapy may be limited in some countries, and consideration of radiation alone is recommended. CONCLUSIONS: The expert consensus recommendations provide guidance for delivering radiation therapy during the COVID-19 pandemic. Specific recommendations have been provided for common clinical scenarios encountered in gynecologic radiation oncology with a focus on strategies to reduce patient and staff exposure to COVID-19.

Clinicopathological features of 50 mismatch repair (MMR)-deficient endometrial carcinomas, tested by immunohistochemistry: A single institutional feasibility study, India.

There are few comprehensive studies from Asia on clinicopathologic features of mismatch repair (MMR)-deficient endometrial carcinomas, including rarely from our country. One hundred and four cases of endometrial carcinomas were tested for four MMR proteins by immunohistochemistry. Among 50 MMR-deficient (MMRd) tumors(48%), age-range was 27-68 years(median = 53) and tumor size(n = 34) varied from 1.2-10 cm(average = 4.6). Lower uterine segment(LUS) was involved in 21/31 cases(67.7%). Histopathologically, all cases were endometrioid adenocarcinomas(EMACs), of FIGO grade 2(low-grade)(18 cases) and 3(high-grade)(32 cases), displaying de-differentiated, undifferentiated and lymphoepithelioma(LE)-like patterns, in 24 cases(48%). Tumor infiltration ≥ half of myometrium was seen in 30/44 cases (68.1%); lymphovascular emboli in 19/43 cases(44.1%); and lymph node metastasis in 7/22(31.8%) cases. Uncommonly, clear cell component(n = 2) and focal neuroendocrine differentiation (n = 2) were observed. Immunohistochemically, tumor cells showed paired loss of MLH1 and PMS2 in 33(66%) and MSH2 and MSH6 in 14(28%) cases, along with loss of MSH2 and PMS2, in two and a single case, respectively. Nine patients(18%) were treated for another cancer and 9/33(27.2%) disclosed familial history of cancer. MSH2 was the most frequently lost MMR protein in those cases. Additionally, tumor cells displayed ER positivity in 41/50 cases(82%), PR in 38/41cases(92.6%) and wild-type p53 staining in 24/28 cases(85.7%). Tumor with LE-pattern showed PDLI immunoexpression. Certain clinicopathologic features suggestive for MMRd associated ECs, such as relatively large-sized tumors, involving LUS; especially high-grade, infiltrative EMACs, with undifferentiated/de-differentiated, and LE-like patterns; showing deep muscle invasion, frequent PR immunoexpression and invariably, wild-type p53 immunostaining can be useful in screening cases of Lynch syndrome. This constitutes the first report on these tumors from our country.

The management of locally advanced cervical cancer.

PURPOSE OF REVIEW: Cervical cancer is still a major cause of morbidity and mortality among women worldwide. Surgery and chemoradiation are widely utilized treatments for cervical cancer. Despite the available standard treatment of choice, outcome is suboptimal among patients with LACC. It is vital to integrate the evidence generated from high-quality research work for effective management of these cases. This review intends to critically evaluate the latest evidence supporting the available treatment modalities and to provide a comprehensive overview of recent advances and ongoing research in the management of LACC. RECENT FINDINGS: Research advances in imaging and radiotherapy technologies, incorporating imaging into brachytherapy planning, use of newer targeted agents, chemotherapy intensification and immunotherapy are some of the new therapeutic options that have been in the forefront of research to improve the outcome of patients with LACC. SUMMARY: Advanced imaging modalities are increasingly being utilized to tailor treatments. Neoadjuvant chemotherapy followed by surgery does not improve outcomes in FIGO Stage IB2-IIB. Although cisplatin-based concurrent chemoradiation is the standard of care, more aggressive systemic therapies (neoadjuvant or adjuvant chemotherapy and chemoradiation) and use of newer agents, still remains investigational.

Impact of HPV 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy - A prospective observational study.

OBJECTIVE: With an aim to investigate the impact of Human Papilloma Virus (HPV) 16/18 infection on clinical outcomes in locally advanced cervical cancers treated with radical radio (chemo) therapy, we undertook this prospective study. METHODS: Between May 2010 and April 2012, 150 histologically proven cervical cancer patients treated with radio (chemo) therapy were accrued. Cervical biopsies/brushings were collected at pre-treatment, end of treatment and at 3 monthly intervals up to 24months. Quantitative estimation of HPV 16/18 was done using real-time polymerase chain reaction (RT-PCR) and correlated with various clinical end-points. RESULTS: Out of 150 patients accrued, 135 patients were considered for final analysis. Pre-treatment HPV16/18 DNA was detected in 126 (93%) patients, with HPV-16 present in 91%. The mean log (±SD) HPV-16 and HPV-18 viral load at pre-treatment was 4.76 (±2.5) and 0.14 (±2.1) copies/10ng of DNA, respectively. Though significant decline in viral load was observed on follow-ups (p<0.0001); by 9-month follow-up, 89 (66%) patients had persistence of HPV infection. Patients with persistent HPV 16/18 infection had a significantly higher overall and loco-regional relapses [44/89 (49%) and 29/89 (32%)] as compared to HPV clearance by 9months [12/43 (28%) and 5/43 (11%)] with p=0.024 and p=0.02, respectively. Also, persistent HPV infection by 24-month showed a significant impact on loco-regional control (LRC) and recurrence-free survival (RFS). CONCLUSION: In locally advanced cervical cancers treated with radical radio (chemo) therapy, persistent HPV 16/18 infection is significantly high in immediate post-treatment period and correlated with higher loco-regional, overall relapses and was also associated with early relapses.

Emerging role of multimodality treatment in gall bladder cancer: Outcomes following 510 consecutive resections in a tertiary referral center.

BACKGROUND AND OBJECTIVES: Gall bladder cancer (GBC) is a disease with high incidence in India. We analyzed the outcomes of patients with suspected GBC who underwent surgical exploration. METHODS: Analysis of a prospectively maintained database of patients undergoing surgical exploration for clinic-radiologically suspected GBC from January 2010 to August 2015. Outcomes as well as factors influencing survival were analyzed. RESULTS: Five hundred and ten patients underwent surgery for suspected GBC. Of these 400 had histologically proven malignancy. Eighty patients were deemed inoperable. Radical cholecystectomy was performed in 153 patients, revision surgery for incidental GBC in 160 and port site excision in seven patients. A total of 112 received peri-operative chemotherapy or chemoradiation. Majority were stage III (36%, n = 144) and stage II (31.8% n = 127). At a median follow up of 28.4 months, the median overall survival (OS) was not yet reached. Median disease free survival (DFS) was 33.4 months. Lymph node involvement, stage of the disease and resection status were the main factors influencing outcomes (P = 0.0001). CONCLUSION: Surgery alone is curative only for early GBC (Stage I). Combination of surgery and peri-operative systemic therapy results in favorable outcomes even in stage II/III disease. Potentially, multimodality treatment may add meaningful survival for this disease with inherently aggressive tumor biology.

Neoadjuvant Chemoradiation Followed by Surgery for Locally Advanced Gallbladder Cancers: A New Paradigm.

PURPOSE: Locally advanced (T3/T4) gallbladder cancers with large fixed portal nodes have a dismal prognosis. If undertaken, surgery entails extensive resections with high morbidity; therefore, in many centers, patients are offered palliative chemotherapy. In this prospective study, we used neoadjuvant concurrent chemoradiation with the intention of downstaging and facilitating R0 resection of these tumors. PATIENTS AND METHODS: Twenty-eight patients with locally advanced carcinoma gallbladder (stage III, having deep liver infiltrations and/or large portal nodes) underwent prior positron emission tomography/computed tomography to rule out metastatic disease. All were treated with concomitant chemoradiation using helical tomotherapy (dose of 57 Gy over 25 fractions to the gross tumor and 45 Gy over 25 fractions to the surrounding nodes) with injectable gemcitabine (300 mg/m(2)/week × 5 weeks). RESULTS: Of the 28 patients, 25 (89 %) successfully completed planned chemoradiation and 20 (71 %) achieved partial or complete radiologic response. Eighteen (64 %) patients were surgically explored, of whom 14 (56 %) achieved R0 resection. At the median follow-up of 37 months for the surviving patients, the median overall survival (OS) was 20 months for all patients. Only one patient recurred in the common bile duct postsurgery, whereas six patients had distant metastasis. The 5-year OS was 24 % for all patients and 47 % for patients with R0 resection. Biliary leak was seen in 6 (43 %) patients, of whom two required interventions. CONCLUSION: Locally advanced unresectable cancers may benefit from neoadjuvant chemoradiation to facilitate a curative resection with a good survival.

Targeting the AKT pathway: Repositioning HIV protease inhibitors as radiosensitizers.

Cellular resistance in tumour cells to different therapeutic approaches has been a limiting factor in the curative treatment of cancer. Resistance to therapeutic radiation is a common phenomenon which significantly reduces treatment options and impacts survival. One of the mechanisms of acquiring resistance to ionizing radiation is the overexpression or activation of various oncogenes like the EGFR (epidermal growth factor receptor), RAS (rat sarcoma) oncogene or loss of PTEN (phosphatase and tensin homologue) which in turn activates the phosphatidyl inositol 3-kinase/protein kinase B (PI3-K)/AKT pathway responsible for radiation resistance in various tumours. Blocking the pathway enhances the radiation response both in vitro and in vivo. Due to the differential activation of this pathway (constitutively activated in tumour cells and not in the normal host cells), it is an excellent candidate target for molecular targeted therapy to enhance radiation sensitivity. In this regard, HIV protease inhibitors (HPIs) known to interfere with PI3-K/AKT signaling in tumour cells, have been shown to sensitize various tumour cells to radiation both in vitro and in vivo. As a result, HPIs are now being investigated as possible radiosensitizers along with various chemotherapeutic drugs. This review describes the mechanisms by which PI3-K/AKT pathway causes radioresistance and the role of HIV protease inhibitors especially nelfinavir as a potential candidate drug to target the AKT pathway for overcoming radioresistance and its use in various clinical trials for different malignancies.

Longitudinal Costs of Image-Guided Intensity-Modulated Radiation Therapy Versus Three-Dimensional Conformal Radiation: Lessons From Phase III PARCER Trial for Shaping Resource-Stratified Guidelines in Low- and Middle-Income Countries.

PURPOSE: The PARCER trial provided level I evidence for image-guided intensity-modulated radiation therapy (IG-IMRT) in patients with cervical cancer. Further information regarding long-term financial impact is imperative for adoption into the National Cancer Grid of India cervical cancer resource-stratified guidelines. METHODS: Patient data from the PARCER trial were analyzed to evaluate the cost implications of transitioning to IG-IMRT. Lacking differences in outcomes between the three-dimensional conformal radiation (3D-CRT) and IG-IMRT, differences in treatment costs, adverse event incidence, and toxicity management costs were examined. The overall financial impact was estimated by adding the treatment costs, toxicity management, and wage loss. This was extrapolated nationally to determine if a transition to IG-IMRT would be feasible for the Indian health care system. RESULTS: Of the 300 patients in the PARCER trial, 93 faced grades ≥2 adverse events (3D-CRT = 59, IG-IMRT = 34). Patients in the 3D-CRT and IG-IMRT arms spent an average of 2.39 years and 1.96 years in toxicity, respectively. The average toxicity management and the yearly financial impact per patient were, respectively, 1.50 and 1.44 times higher for 3D-CRT patients compared with IG-IMRT patients. Extrapolation to the national level showed that treatment with 3D-CRT led to a 2.88 times higher cost ratio when compared with treatment with IG-IMRT. CONCLUSION: Although the initial costs of IG-IMRT are high, on the basis of longitudinal data, it is financially inefficient to treat with 3D-CRT. Resource-stratified guidelines should include longitudinal health intervention costs rather than solely initial costs for policy decisions to implement advanced radiation technology.

Personalized strategies for brachytherapy of cervix cancer.

Among most tailored approaches in radiation oncology, the development of brachytherapy for the treatment of cervical cancer patients has benefited from various technological innovations. The development of 3D image-guided treatments was the first step for treatment personalization. This breakthrough preceded practice homogenization and validation of predictive dose and volume parameters and prognostic factors. We review some of the most significant strategies that emerged from the ongoing research in order to increase personalization in uterovaginal brachytherapy. A better stratification based on patients and tumors characteristics may lead to better discriminate candidates for intensification or de-escalation strategies, in order to still improve patient outcome while minimizing the risk of treatment-related side effects.