A hypoxia biomarker does not predict benefit from giving chemotherapy with radiotherapy in the BC2001 randomised controlled trial.

BACKGROUND: BC2001 showed combining chemotherapy (5-FU + mitomycin-C) with radiotherapy improves loco-regional disease-free survival in patients with muscle-invasive bladder cancer (MIBC). We previously showed a 24-gene hypoxia-associated signature predicted benefit from hypoxia-modifying radiosensitisation in BCON and hypothesised that only patients with low hypoxia scores (HSs) would benefit from chemotherapy in BC2001. BC2001 allowed conventional (64Gy/32 fractions) or hypofractionated (55Gy/20 fractions) radiotherapy. An exploratory analysis tested an additional hypothesis that hypofractionation reduces reoxygenation and would be detrimental for patients with hypoxic tumours. METHODS: RNA was extracted from pre-treatment biopsies (298 BC2001 patients), transcriptomic data generated (Affymetrix Clariom-S arrays), HSs calculated (median expression of 24-signature genes) and patients stratified as hypoxia-high or -low (cut-off: cohort median). PRIMARY ENDPOINT: invasive loco-regional control (ILRC); secondary overall survival. FINDINGS: Hypoxia affected overall survival (HR = 1.30; 95% CI 0.99-1.70; p = 0.062): more uncertainty for ILRC (HR = 1.29; 95% CI 0.82-2.03; p = 0.264). Benefit from chemotherapy was similar for patients with high or low HSs, with no interaction between HS and treatment arm. High HS associated with poor ILRC following hypofractionated (n = 90, HR 1.69; 95% CI 0.99-2.89 p = 0.057) but not conventional (n = 207, HR 0.70; 95% CI 0.28-1.80, p = 0.461) radiotherapy. The finding was confirmed in an independent cohort (BCON) where hypoxia associated with a poor prognosis for patients receiving hypofractionated (n = 51; HR 14.2; 95% CI 1.7-119; p = 0.015) but not conventional (n = 24, HR 1.04; 95% CI 0.07-15.5, p = 0.978) radiotherapy. INTERPRETATION: Tumour hypoxia status does not affect benefit from BC2001 chemotherapy. Hypoxia appears to affect fractionation sensitivity. Use of HSs to personalise treatment needs testing in a biomarker-stratified trial. FUNDING: Cancer Research UK, NIHR, MRC.

Lung Cancer Survival in Sri Lanka.

Nuradh JosephIntroduction Lung cancer is the second commonest cancer among males in Sri Lanka. Real-world survival data are scarce, and we conducted a retrospective survival analysis among patients treated for lung cancer. Methods All patients with primary lung cancer treated at three selected units during 2015-2016 were included in the study. Data on clinicopathological and treatment delivered were extracted from clinic records. Overall survival was considered the primary end-point. Results The study population comprised 349 patients. The median age was 61 years and majority of patients (74%) were males. Adenocarcinoma (56%) was the commonest histological subtype, followed by squamous cell carcinoma (26%), whereas 6% of patients had small cell lung cancer. Only 10% of patients with non-small cell lung cancer were treated with curative intent, whereas 67% presented with systemic metastases. The median overall survival was 12 months in patients treated with curative intent and there was no significant difference between radical surgery and radiotherapy. The median overall survival was 3 months in those treated palliatively. On multivariate analysis, female gender and first-line treatment with tyrosine kinase inhibitors was associated with superior survival. Conclusion More than 90% of lung cancer patients in Sri Lanka are treated with palliative intent. Further work is needed to identify patient and care pathway barriers to ensure diagnosis at an earlier stage.

Outcomes of patients with esophageal and gastric cancer in Sri Lanka: A retrospective survival analysis.

Introduction: Esophageal carcinoma is the fourth most common cancer among males and sixth most common cancer among females in Sri Lanka. Gastric cancer is less common, but its incidence is gradually rising. We conducted a retrospective analysis of survival of esophageal and gastric cancer patients treated at National Cancer Institute, Maharagama, Sri Lanka. Methodology: Patients with esophageal and gastric cancer treated in three selected oncology units of the National Cancer Institute, Maharagama during 2015 and 2016 were included in the study. Data on clinical and pathological factors were extracted from clinical records. Overall survival (OS), defined as time to death or loss to follow-up, was the primary endpoint. Univariate and multivariate analyses of survival were performed using the log-rank test and Cox proportional-hazard model, respectively. Results: The study population comprised 374 patients with a median age of 62 years (interquartile range 55-70). Majority (64%) were male and had squamous cell carcinoma (58%). In the sample, 20% were gastric cancers, while 71% were esophageal cancers, and 9% had gastro-esophageal junction tumors. The 2-year OS was 19% in patients treated with curative intent (95% confidence interval [CI] 14-26 months) with those receiving neoadjuvant chemotherapy, followed by radical surgery having the highest survival (P < 0.001, hazard ratio 0.25 [95% CI 0.11-0.56]). Median OS was 2 months (95% CI 1-2 months) in patients treated with palliative intent. Conclusion: Our results suggest that the outcome of patients with esophageal and gastric cancer is poor in Sri Lanka. Early detection and greater utilization of multimodality treatment could improve outcomes of these patients.

Myths About Bladder Preservation in Muscle-Invasive Bladder Cancer.

Radical cystectomy is long considered as the "gold standard" in the management of localized muscle-invasive bladder cancer (MIBC), and curative intent radiotherapy is relegated to those with either inoperable tumors or with multiple co-morbidities precluding surgery. This is despite a large volume of data showing equal survival between the two modalities of treatment in this setting. In this work we seek to dispel some common myths surrounding curative intent radiotherapy as part of a bladder preservation strategy in MIBC. Baseless claims of inferior outcomes and perceived contraindications for bladder preservation are debunked along with unfounded doubts relating to hypofractionation. Finally, we caution against using response to neoadjuvant chemotherapy as a predictive biomarker for treatment selection and conclude by recommending that trimodality bladder preservation be offered as a therapeutic option that is in clinical equipoise with radical cystectomy.

High weekly integral dose and larger fraction size increase risk of fatigue and worsening of functional outcomes following radiotherapy for localized prostate cancer.

Introduction: We hypothesized that increasing the pelvic integral dose (ID) and a higher dose per fraction correlate with worsening fatigue and functional outcomes in localized prostate cancer (PCa) patients treated with external beam radiotherapy (EBRT). Methods: The study design was a retrospective analysis of two prospective observational cohorts, REQUITE (development, n=543) and DUE-01 (validation, n=228). Data were available for comorbidities, medication, androgen deprivation therapy, previous surgeries, smoking, age, and body mass index. The ID was calculated as the product of the mean body dose and body volume. The weekly ID accounted for differences in fractionation. The worsening (end of radiotherapy versus baseline) of European Organisation for Research and Treatment of Cancer EORTC) Quality of Life Questionnaire (QLQ)-C30 scores in physical/role/social functioning and fatigue symptom scales were evaluated, and two outcome measures were defined as worsening in ≥2 (WS2) or ≥3 (WS3) scales, respectively. The weekly ID and clinical risk factors were tested in multivariable logistic regression analysis. Results: In REQUITE, WS2 was seen in 28% and WS3 in 16% of patients. The median weekly ID was 13.1 L·Gy/week [interquartile (IQ) range 10.2-19.3]. The weekly ID, diabetes, the use of intensity-modulated radiotherapy, and the dose per fraction were significantly associated with WS2 [AUC (area under the receiver operating characteristics curve) =0.59; 95% CI 0.55-0.63] and WS3 (AUC=0.60; 95% CI 0.55-0.64). The prevalence of WS2 (15.3%) and WS3 (6.1%) was lower in DUE-01, but the median weekly ID was higher (15.8 L·Gy/week; IQ range 13.2-19.3). The model for WS2 was validated with reduced discrimination (AUC=0.52 95% CI 0.47-0.61), The AUC for WS3 was 0.58. Conclusion: Increasing the weekly ID and the dose per fraction lead to the worsening of fatigue and functional outcomes in patients with localized PCa treated with EBRT.

Biomarkers in muscle invasive bladder cancer.

Muscle invasive bladder cancer (MIBC) carries a poor prognosis with a 5-year overall survival rate of 40-50%. For localized disease, radical treatment options are cystectomy or radiotherapy with or without a radiosensitiser. Neoadjuvant or adjuvant chemotherapy is often delivered in addition to either. Metastatic disease can be treated with palliative systemic chemotherapy or immunotherapy. Standard clinicopathological information is insufficient to guide treatment decisions in several clinical scenarios in MIBC and there has been substantial effort to identify predictive and prognostic biomarkers. Despite this, no biomarker has been sufficiently qualified in prospective clinical trials to justify routine use. In this chapter we discuss these biomarkers and provide insight into the significant unmet need for robust biomarkers to inform treatment decisions and ultimately improve outcomes for bladder cancer patients.

Clinical Oncology Workload in Sri Lanka: Infrastructure, Supports, and Delivery of Clinical Care.

PURPOSE: Sri Lanka is a lower middle-income country undergoing a demographic transition with an increasing aging population. This has given rise to a higher burden of noncommunicable diseases including cancer. A well-trained oncology workforce is essential to address this growing public health challenge. Understanding the baseline status of the clinical oncology workforce is an essential step to improving cancer care delivery in Sri Lanka. METHODS: In this cross-sectional study, we distributed a web-based survey to all clinical oncologists in Sri Lanka. The survey captured data regarding clinical workload, demographic details, practice setting, and perceived barriers to quality patient care. RESULTS: A total of 41 of 54 oncologists responded to the survey, and all participants had training in clinical oncology. Thirty-seven (90%) of 41 oncologists treated both solid and hematologic malignancies, and the median duration of independent practice was 5 years. Almost two thirds of the oncologists (26 of 41, 63%) work at an academic center, and two thirds of the oncologists (27 of 41, 66%) work in both public and private sectors. A majority of the oncologists (26 of 41, 63%) were on-call 7 days per week. More than half of the oncologists saw over 400 new patient consults per year. With regard to barriers to quality patient care, most of the concerns relate to the scarcity of resources. CONCLUSION: This study sheds significant light about the clinical oncology workload landscape in Sri Lanka. Compared with other low- and middle-income countries, Sri Lankan clinical oncologists are faced with a very high workload, which may affect delivery or care.

Hypofractionation: less is more?

One third of patients with bladder cancer present with muscle invasive bladder cancer (MIBC) which has a poor prognosis. International guidelines for the management of MIBC recommend radical cystectomy or bladder-preserving treatment based on radical radiotherapy with a form of radiosensitisation. In the UK, both conventional fractionation with 64 Gy in 32 fractions and hypofractionation with 55 Gy in 20 fractions are standard of care options with the choice varying between centres. A meta-analysis of individual patients with locally advanced bladder cancer from two UK multicentre phase 3 trials was published recently. This study evaluated the non-inferiority of a hypofractionated schedule compared to a conventional regime. This analysis confirmed the non-inferiority of the hypofractionated regimen, and noted superior locoregional control. We discuss the relevance of these findings to current practice while considering the radiobiology of hypofractionation, the role of systemic therapies and radiosensitisation, as well as the socioeconomic benefits.

Does the choice of care pathways matter in timely breast cancer care in Sri Lanka?

BACKGROUND: An understanding on the use of care pathways facilitates identification of timeliness in breast cancer care. Aims of this study were to describe different breast cancer care pathways used by female breast cancer patients in Sri Lanka and to identify whether they experienced timely breast cancer care. METHODS: We conducted a cross-sectional study among 800 female breast cancer patients with a histological/ cytological confirmation, from four state cancer treatment centers. We conceptualized five different care pathways with essential care points and in-between time intervals to be explored using an interviewer administered tool. Dates were cross-checked with the medical record. The difference of time intervals spent in different care pathways was tested for significance using one-way ANOVA test. RESULTS: Mean (SD) age was 55.5 (10.7) years. A vast majority of 98.4 % (n = 787) self-detected the breast lesion, while only 13 had been detected through screening. Following self-detection, two thirds (n = 473, 59.1 %, 95 % CI = 55.7-62.5) had first consulted a primary healthcare physician, and a third n = 287, 35.8 %, 95 % CI = 32.6-39.3) had consulted an appropriate specialist first. Presentation interval among those who visited an Ayurvedic physician first was significantly longer than other pathways (p < 0.0001). Diagnosis interval for those who consulted an appropriate consultant was significantly shorter than other pathways (p < 0.0001). CONCLUSIONS: Women take up numerous care paths following self-detection of a breast lesion. Empowering women on appropriate care pathways and expanding dedicated breast clinics where women to be first seen by an appropriate specialist are likely to improve timely breast cancer care in Sri Lanka.

Radical External-Beam Radiotherapy in Combination With Intracavitary Brachytherapy for Localized Carcinoma of the Cervix in Sri Lanka: Is Treatment Delayed Treatment Denied?

PURPOSE: Radical external-beam radiotherapy (EBRT) followed by intracavitary brachytherapy is standard of care for patients with localized carcinoma of the cervix unsuitable for radical surgery. However, outcome data are scarce in resource-limited settings. We conducted a retrospective analysis of survival in a cohort of patients treated with this strategy in Sri Lanka. PATIENTS AND METHODS: All patients with localized cervical cancer treated with primary EBRT and intracavitary brachytherapy from 2014 to 2015 were included in the study. Primary end point was disease-free survival (DFS), defined as time to local or systemic recurrence or death. Univariable analysis was performed to determine the prognostic significance of the following variables: age, stage, use of concurrent chemotherapy, EBRT dose, brachytherapy dose, and time to completion of treatment (dichotomized at 60 days). Factors significant on univariable analysis were included in a multivariable model. RESULTS: A total of 113 patients with available data were included in the analysis. Mean age was 58 years (range, 35-85 years), and most patients (n = 103 of 113) presented with stage ≥ IIB disease. Median time to delivery of brachytherapy from commencement of EBRT was 110 days (range, 34-215 days), with only 12 (11%) of 113 patients completing treatment within 60 days. Median follow-up was 28 months (range, 5-60 months), and 2-year DFS was 63.7% (95% CI, 55.4% to 73.2%). Treatment delay was the only significant factor associated with inferior DFS on univariable analysis (log-rank P = .03), and therefore, multivariable analysis was not performed. CONCLUSION: There are significant delays in receiving intracavitary brachytherapy after completing EBRT for cervical cancer in Sri Lanka, which is associated with inferior DFS. Increasing brachytherapy resources is an urgent priority to improve outcomes of patients with cervical cancer.

Radiobiologically derived biphasic fractionation schemes to overcome the effects of tumour hypoxia.

OBJECTIVE: As a fractionated course of radiotherapy proceeds tumour shrinkage leads to resolution of hypoxia and the initiation of accelerated proliferation of radioresistant cancer cells with better repair capacity. We hypothesise that, in tumours with significant hypoxia, improved tumour control could be achieved with biphasic fractionation schedules that either use acceleration after 3-4 weeks of conventional radiotherapy or deliver a higher proportional dose towards the end of a course of treatment. We conducted a modelling study based on the concept of biological effective dose (BED) comparing such novel regimens with conventional fractionation. METHODS: The comparator conventional fractionation schedule 70 Gy in 35 fractions delivered over 7 weeks was tested against the following novel regimens, both of which were designed to be isoeffective in terms of late normal tissue toxicity.40 Gy in 20 fractions over 4 weeks followed by 22.32 Gy in 6 consecutive daily fractions (delayed acceleration)30.4 Gy in 27 fractions over 4 weeks followed by 40 Gy in 15 fractions over 3 weeks (temporal dose redistribution)The delayed acceleration regimen is exactly identical to that of the comparator schedule over the first 28 days and the BED gains with the novel schedule are achieved during the second phase of treatment when reoxygenation is complete. For the temporal redistribution regimen, it was assumed that the reoxygenation fraction progressively increases during the first 4 weeks of treatment and an iterative approach was used to calculate the final tumour BED for varying hypoxic fractions. RESULTS: Novel fractionation with delayed acceleration or temporal fractionation results in tumour BED gains equivalent to 3.5-8 Gy when delivered in 2 Gy fractions. CONCLUSION: In hypoxic tumours, novel fractionation strategies result in significantly higher tumour BED in comparison to conventional fractionation. ADVANCES IN KNOWLEDGE: We demonstrate that novel biphasic fractionation regimens could overcome the effects of tumour hypoxia resulting in biological dose escalation.

Breast Cancer Survival in Sri Lanka.

PURPOSE: In this study, we report survival data of the largest cohort of patients with breast cancer in Sri Lanka. PATIENTS AND METHODS: All female patients with histologically confirmed breast cancer treated at a single unit at the National Cancer Institute of Sri Lanka between 1994 and 2006 were included in the study. Clinical records were reviewed and data obtained on the following clinical and pathologic factors: age, histology, stage at presentation, grade, and immunohistochemistry profile. Treatment details such as type of surgery and use of systemic chemotherapy, hormonal therapy, trastuzumab, and radiation therapy were also collected. In localized cancer, disease-free survival (DFS) was the primary end point, while in patients who presented with de novo metastases, progression-free survival (PFS) was the primary end point. RESULTS: A significant proportion of patients presented with de novo metastases (14%) and locally advanced disease (18%). While 57% of patients had hormone-sensitive tumors, human epidermal growth factor receptor 2 overexpression was seen in 14%, and 29% had triple-negative tumors. Only 3% of patients with localized disease were treated with breast-conserving surgery, with the rest undergoing modified radical mastectomy. The 5- year DFS rate was 71.6% (95% CI, 69.2 to 74.0) in patients with localized disease. The median PFS in patients with metastatic disease was 20 months (95% CI, 18 to 22 months), while the median overall survival was 30 months (95% CI, 32 to 35 months). On multivariable analysis, immunohistochemical group and stage were prognostic factors in localized disease, while in patients with metastases, immunohistochemical group and tumor grade were associated with PFS. CONCLUSION: More effective screening and early detection programs along with increasing breast-conserving surgery will improve breast cancer outcomes in Sri Lanka.

Treatment of Primary in Metastatic Prostate Cancer: What Is the Standard of Care?

Until recently, men with metastatic prostate cancer were commenced on androgen deprivation therapy at diagnosis, followed by sequential lines of treatment with the development of castration resistance. However, the results of recent clinical trials, which revealed that the addition of radiotherapy to the prostate to a dose of 55 to 60 Gy in 20 fractions over 4 weeks in patients with low-volume metastatic hormone-sensitive prostate cancer, in addition to androgen deprivation therapy and another systemic treatment option, either docetaxel, abiraterone, enzalutamide, or apalutamide, has led to a paradigm change in the management of this disease.

Post-treatment lymphocytopaenia, integral body dose and overall survival in lung cancer patients treated with radical radiotherapy.

INTRODUCTION: Post-treatment lymphocytopaenia is a recognized complication of thoracic radiotherapy likely due to irradiation of a large volume of circulatory blood. We hypothesize that post-treatment absolute lymphocyte count (ALC) is associated with integral body dose and overall survival (OS) in lung cancer patients treated with radical radiotherapy. MATERIALS AND METHODS: Data on clinicopathological variables, dosimetric parameters, and pre and post-treatment blood counts were collected retrospectively in 217 lung cancer patients (131 with non-small cell lung cancer and 86 with small cell lung cancer) treated with radical radiotherapy. Induction chemotherapy followed by radiotherapy and concurrent chemoradiotherapy were delivered in 89 (42%) and 99 (47%) patients respectively. Multiple stepwise regression analysis was performed separately for ALC and absolute neutrophil count (ANC) to derive a model for prediction of post-treatment count and multivariate analysis was performed for OS using a Cox regression model. RESULTS: There was a significant decline in post-treatment counts for both ANC and ALC (p < 0.001). Multiple stepwise linear regression analysis confirmed pre-treatment ALC, body integral dose and use of concurrent chemotherapy as significant predictors of post-treatment ALC (R2 = 0.33, F(4,212) = 26.6 p < 0.001). Pre-treatment ANC, integral heart dose and number of fractions were significant predictors of post-treatment ANC (R2 = 0.18, F(3,213) = 16.38 p < 0.001). Low post-treatment ALC, high pre-treatment ANC, high planning target volume integral dose and lower number of fractions were predictive of inferior OS. CONCLUSIONS: There is a negative correlation between integral body dose and post-treatment ALC which is an adverse prognostic factor in lung cancer patients treated with radical radiotherapy.

Tolerability of Concurrent Chemoradiation Therapy With Gemcitabine (GemX), With and Without Prior Neoadjuvant Chemotherapy, in Muscle Invasive Bladder Cancer.

PURPOSE: The aim of this study is to assess the tolerability of concurrent chemoradiation therapy with gemcitabine (GemX) in muscle invasive bladder cancer following neoadjuvant chemotherapy (neoGemX) by use of patient- and provider-reported outcomes. METHODS AND MATERIALS: Seventy-eight patients were treated with GemX. Thirty-eight received prior neoadjuvant chemotherapy (NAC). Patients were prospectively assessed during treatment and at 6 weeks and 12 months after treatment completion. Radiation therapy was given to a total dose of 52.5 Gy in 20 fractions with weekly concurrent gemcitabine chemotherapy, 100 mg/m2. Toxicity was assessed by the care provider and by a patient-reported outcome questionnaire collecting scores on the late effects in normal tissues-subjective, objective, management, and analytic scales and was statistically compared at baseline and 12 months, as well as between the neoGemX and GemX groups. RESULTS: The median duration of follow-up was 15.9 months. The radiation therapy completion rate was 95%, and 96% of patients completed at least 3 cycles of gemcitabine. Bowel toxicity of grade 3 or greater was reported in 7 of 38 patients (18%) in the neoGemX group and 5 of 25 (20%) in the GemX group. Three GemX and two neoGemX patients had grade 3 or greater urinary toxicity. Forty-nine patients completed questionnaires and were included in the analysis. Scores on the late effects in normal tissues-subjective, objective, management, and analytic scales showed an expected peak by week 4 of treatment. There was no statistically significant difference between mean scores at baseline and 12 months after treatment completion or between the neoGemX and GemX groups. CONCLUSIONS: This study demonstrates that GemX, alone or following NAC, has manageable toxicity and acceptable treatment completion rates. Allowing for small patient numbers and the nonrandomized nature of this study, these results do not suggest any additional toxicity from the use of NAC prior to GemX.