Current standard for most of the locally advanced rectal cancers is preoperative chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy. Short-course preoperative radiation with delayed surgery has been shown to induce tumour down-staging in both randomized and observational studies. The concept of neo-adjuvant chemotherapy has been proven successful in gastric cancer, hepatic metastases from colorectal cancer and is currently tested in primary colon cancer.
Radiation Oncology in 21st Century - Changing the ParadigmsApollo Hospitals
Since its inception radiation therapy has been used as one of
the essential treatment options in the management of malignant and some benign tumors. With better understanding of tumor biology many new molecules have been added to the armamentarium of an oncologist. There is continuous improvement in surgical techniques with more emphasis on minimally invasive, organ- and function-preserving techniques. Neoadjuvant chemotherapy with or without addition of radiation therapy has helped surgeon downsizing the tumor and obtaining clearer margins.
Radiation Oncology in 21st Century - Changing the ParadigmsApollo Hospitals
Since its inception radiation therapy has been used as one of
the essential treatment options in the management of malignant and some benign tumors. With better understanding of tumor biology many new molecules have been added to the armamentarium of an oncologist. There is continuous improvement in surgical techniques with more emphasis on minimally invasive, organ- and function-preserving techniques. Neoadjuvant chemotherapy with or without addition of radiation therapy has helped surgeon downsizing the tumor and obtaining clearer margins.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...daranisaha
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Hypofractionation in early breast cancer is no more a research scholars topic. Multiple studies with robust data have proven its utility. It may hold an important role in many countries with constrained resources. This is a short presentation incorporating important completed and ongoing trials. Feel free to use this.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...daranisaha
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...JohnJulie1
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...eshaasini
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...semualkaira
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...NainaAnon
Upper rectal cancer management is controversial. The present series reports the outcomes of treatment comparing neoadjuvant chemoradiation (NCRT) versus upfront surgery.
Clinics of Oncology | Oncology Journals | Open Access JournalEditorSara
Clinics of OncologyTM (ISSN 2640-1037) - Impact Factor 1.920* is a medical specialty that focuses on the use of operative techniques to investigate and resolve certain medical conditions caused by disease or traumatic injury.
Upper Rectal Cancer: Benefit After Preoperative Chemoradiation Versus Upfront...semualkaira
In this retrospective study we enrolled patients with upper rectal or sigmoid junction locally advanced tumors (stages II-III). At the first Institution patients received NCRT followed by surgery (study group); at the second Institution patients were referred to upfront surgery (control group). Overall survival was the main endpoint of the analysis. Local relapse and other clinical variables were also analyzed.
Co-Chairs, Nasser Altorki, MD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to NSCLC for this CME/MOC activity titled “How to Integrate Perioperative Immunotherapy Into Multimodal Treatment Plans to Improve Outcomes in Resectable NSCLC.” For the full presentation, downloadable Practice Aids, and complete CME/MOC information, and to apply for credit, please visit us at https://bit.ly/3xb6WS1. CME/MOC credit will be available until June 14, 2023.
Chair & Moderator, Prof. Solange Peters, MD, PhD, Mark M. Awad, MD, PhD, and Jonathan D. Spicer, MD, PhD, FRCSC, prepared useful Practice Aids pertaining to Cancer Immunotherapy for this CME/MOC/CC activity titled “Parsing the Practicalities of Pathologic Response Assessment After Neoadjuvant Immunotherapy to Facilitate Progress in Early-Stage Cancers.” For the full presentation, downloadable Practice Aids, and complete CME/MOC/CC information, and to apply for credit, please visit us at https://bit.ly/3uRHyjk. CME/MOC/CC credit will be available until May 9, 2023.
A dramatic increase in the incidence of the diffuse form of gastric adenocarcinomas and particularly signet ring cell carcinomas has been observed in Western countries. Evidence is accruing that signet ring cell carcinomas may have inherent chemo resistance leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach.
Definition: Small cell lung carcinoma (SCLC) is a type of lung cancer that typically starts in the bronchi (large airways) and tends to grow and spread quickly. It accounts for approximately 10-15% of all lung cancers.
Characteristics: SCLC is characterized by small, oat-shaped cancer cells that rapidly divide and form large tumors. It is often associated with a history of smoking and has a strong correlation with tobacco exposure.
Aggressive nature: SCLC is considered highly aggressive, with a tendency to metastasize (spread) early to the lymph nodes and other distant parts of the body, such as the liver, bones, and brain. This rapid spread makes early detection and treatment crucial.
Limited and extensive stage: SCLC is classified into two stages: limited stage and extensive stage. Limited stage means the cancer is confined to one side of the chest and potentially adjacent lymph nodes, whereas extensive stage indicates that the cancer has spread beyond the chest to distant organs.
Treatment approach: The treatment of SCLC typically involves a combination of chemotherapy and radiation therapy. Surgery is generally not recommended for SCLC due to its aggressive nature and tendency to spread early. Chemotherapy, often in combination with immunotherapy, is the mainstay of treatment and can help shrink tumors and control the disease.
Prognosis: The prognosis for SCLC is generally poorer compared to non-small cell lung carcinoma (NSCLC) due to its more aggressive behavior and earlier metastasis. However, treatment advances and research efforts continue to improve outcomes for SCLC patients.
Supportive care: As with any cancer diagnosis, supportive care plays a critical role in managing SCLC. This includes addressing symptoms, managing pain, providing emotional support, and ensuring optimal quality of life for patients.
It's important to consult with healthcare professionals for an accurate diagnosis, personalized treatment plan, and ongoing monitoring for individuals suspected or diagnosed with small cell lung carcinoma.
Long Term Effects of Using Medicinal Mushroom Preparations in Human Colorecta...Neven Jakopovic
52 patients with bowel cancer and 89 with breast cancer used medicinal mushroom extracts from Myko San company with standard oncological treatments. In this cohort study, lasting from 2005-2010, we analysed the long term effects of using medicinal mushroom products in cancer patients.
While medicinal mushrooms are not 'magic bullets', this study provides unquestionable evidence of the benefits of their use as supportive therapy in cancer patients, leading to significantly improved outcomes.
This work was presented by Neven Jakopovic at the 6th International Medicinal Mushroom Conference in Zagreb, Croatia, in 2011.
Similar to Short-course radiotherapy followed by neo-adjuvant chemotherapy in locally advanced rectal cancer – the RAPIDO trial (20)
Incidence of pneumonia and risk factors among patients with head and neck can...Enrique Moreno Gonzalez
This study investigated the incidence and patient- and treatment-related risk factors related to pneumonia acquired during radiotherapy (PNRT) in head and neck cancer (HNC) patients.
Gene expression analysis of a Helicobacter pyloriinfected and high-salt diet-...Enrique Moreno Gonzalez
Helicobacter pylori (H. pylori) infection and excessive salt intake are known as important risk factors for stomach cancer in humans. However, interactions of these two factors with gene expression profiles during gastric carcinogenesis remain unclear. In the present study, we investigated the global gene expression associated with stomach carcinogenesis and prognosis of human gastric cancer using a mouse model.
Acute myeloid leukemia (AML) is a hematopoietic malignancy with a dismal outcome in the majority of cases. A detailed understanding of the genetic alterations and gene expression changes that contribute to its pathogenesis is important to improve prognostication, disease monitoring, and therapy. In this context, leukemia-associated misexpression of microRNAs (miRNAs) has been studied, but no coherent picture has emerged yet, thus warranting further investigations.
Recently, a phase II clinical trial in hepatocellular carcinoma (HCC) has suggested that the combination of sorafenib and 5-fluorouracil (5-FU) is feasible and side effects are manageable. However, preclinical experimental data explaining the interaction mechanism(s) are lacking. Our objective is to investigate the anticancer efficacy and mechanism of combined sorafenib and 5-FU therapy in vitro in HCC cell lines MHCC97H and SMMC-7721.
Differences in microRNA expression during tumor development in the transition...Enrique Moreno Gonzalez
The prostate is divided into three glandular zones, the peripheral zone (PZ), the transition zone (TZ), and the central zone. Most prostate tumors arise in the peripheral zone (70-75%) and in the transition zone (20-25%) while only 10% arise in the central zone. The aim of this study was to investigate if differences in miRNA expression could be a possible explanation for the difference in propensity of tumors in the zones of the prostate.
Multicentric and multifocal versus unifocal breast cancer: differences in the...Enrique Moreno Gonzalez
The aim of this study was to evaluate the expression of the cell adhesion-related glycoproteins MUC-1, β-catenin and E-cadherin in multicentric/multifocal breast cancer in comparison to unifocal disease in order to identify potential differences in the biology of these tumor types.
The life in sight application study (LISA): design of a randomized controlled...Enrique Moreno Gonzalez
It is widely recognized that spiritual care plays an important role in physical and psychosocial well-being of cancer patients, but there is little evidence based research on the effects of spiritual care. We will conduct a randomized controlled trial on spiritual care using a brief structured interview scheme supported by an e-application. The aim is to examine whether an assisted reflection on life events and ultimate life goals can improve quality of life of cancer patients.
Clinical and experimental studies regarding the expression and diagnostic val...Enrique Moreno Gonzalez
Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is a multifunctional Ig-like cell adhesion molecule that has a wide range of biological functions. According to previous reports, serum CEACAM1 is dysregulated in different malignant tumours and associated with tumour progression. However, the serum CEACAM1 expression in nonsmall-cell lung carcinomas (NSCLC) is unclear. The different expression ratio of CEACAM1-S and CEACAM1-L isoform has seldom been investigated in NSCLC. This research is intended to study the serum CEACAM1 and the ratio of CEACAM1-S/L isoforms in NSCLC.
Assessment of preoperative exercise capacity in hepatocellular carcinoma pati...Enrique Moreno Gonzalez
Cardiopulmonary exercise testing measures oxygen uptake at increasing levels of work and predicts cardiopulmonary performance under conditions of stress, such as after abdominal surgery. Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. This study examined the relationship between preoperative exercise capacity and event-free survival in hepatocellular carcinoma (HCC) patients with chronic liver injury who underwent hepatectomy.
Overexpression of YAP 1 contributes to progressive features and poor prognosi...Enrique Moreno Gonzalez
Yes-associated protein 1 (YAP 1), the nuclear effector of the Hippo pathway, is a key regulator of organ size and a candidate human oncogene in multiple tumors. However, the expression dynamics of YAP 1 in urothelial carcinoma of the bladder (UCB) and its clinical/prognostic significance are unclear.
CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1a...Enrique Moreno Gonzalez
Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion.
Abnormal expression of Pygopus 2 correlates with a malignant phenotype in hum...Enrique Moreno Gonzalez
Pygopus 2 (Pygo2) is a Pygo family member and an important component of the Wnt signaling transcriptional complex. Despite this data, no clinical studies investigating Pygo2 expression in lung cancer have yet been reported.
Differentiation of irradiation and cetuximab induced skin reactions in patien...Enrique Moreno Gonzalez
In order to improve the clinical outcome of patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) not being capable to receive platinum-based chemoradiation, radiotherapy can be intensified by addition of cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor (EGFR). The radioimmunotherapy with cetuximab is a feasible treatment option showing a favourable toxicity profile. The most frequent side effect of radiotherapy is radiation dermatitis, the most common side effect of treatment with cetuximab is acneiform rash. Incidence and severity of these frequent, often overlapping and sometimes limiting skin reactions, however, are not well explored. A clinical and molecular differentiation between radiogenic skin reactions and skin reactions caused by cetuximab which may correlate with outcome, have never been described before.
Cholestasis induces reversible accumulation of periplakin in mouse liverEnrique Moreno Gonzalez
Periplakin (PPL) is a rod-shaped cytolinker protein thought to connect cellular adhesion junctional complexes to cytoskeletal filaments. PPL serves as a structural component of the cornified envelope in the skin and interacts with various types of proteins in cultured cells; its level decreases dramatically during tumorigenic progression in human epithelial tissues. Despite these intriguing observations, the physiological roles of PPL, especially in noncutaneous tissues, are still largely unknown. Because we observed a marked fluctuation of PPL expression in mouse liver in association with the bile acid receptor farnesoid X receptor (FXR) and cholestasis, we sought to characterize the role of PPL in the liver and determine its contributions to the etiology and pathogenesis of cholestasis.
Functional p53 is required for rapid restoration of daunorubicin-induced lesi...Enrique Moreno Gonzalez
The tumour suppressor and transcription factor p53 is a major determinant of the therapeutic response to anthracyclines. In healthy tissue, p53 is also considered pivotal for side effects of anthracycline treatment such as lesions in haematopoietic tissues like the spleen. We used a Trp53null mouse to explore the significance of p53 in anthracycline (daunorubicin) induced lesions in the spleen.
Post-diagnosis hemoglobin change associates with overall survival of multiple...Enrique Moreno Gonzalez
Anemia refers to low hemoglobin (Hb) level and is a risk factor of cancer patient survival. The National Comprehensive Cancer Network recently suggested that post-diagnosis Hb change, regardless of baseline Hb level, indicates the potential presence of anemia. However, there is no epidemiological study evaluating whether Hb change has direct prognostic values for cancer patients at the population level.
Cost-effectiveness of MRI for breast cancer screening in BRCA1/2 mutation car...Enrique Moreno Gonzalez
Women with mutations in BRCA1 or BRCA2 are at high risk of developing breast cancer and, in British Columbia, Canada, are offered screening with both magnetic resonance imaging (MRI) and mammography to facilitate early detection. MRI is more sensitive than mammography but is more costly and produces more false positive results. The purpose of this study was to calculate the cost-effectiveness of MRI screening for breast cancer in BRCA1/2 mutation carriers in a Canadian setting.
Impaired mitochondrial beta-oxidation in patients with chronic hepatitis C: r...Enrique Moreno Gonzalez
Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.
Intraepithelial lymphocyte distribution differs between the bulb and the seco...Enrique Moreno Gonzalez
Evaluation of intraepithelial duodenal lymphocytosis (IDL) is important in celiac disease (CD). There is no established cut-off value for increased number of IELs in the bulb. We therefore investigated the relation between IEL counts in the bulb and duodenal specimens in non-celiac subjects.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
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MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
2. Short-course radiotherapy followed by neo-adjuvant
chemotherapy in locally advanced rectal cancer –
the RAPIDO trial
Per J Nilsson1*
*
Corresponding author
Email: per.nilsson@karolinska.se
Boudewijin van Etten2
Email: b.van.etten@umcg.nl
Geke AP Hospers3
Email: g.a.p.hospers@umcg.nl
Lars Påhlman4
Email: Lars.Pahlman@surgsci.uu.se
Cornelis JH van de Velde5
Email: C.J.H.van_de_Velde@lumc.nl
Regina GH Beets-Tan6
Email: r.beets.tan@mumc.nl
Lennart Blomqvist7
Email: lennart.k.blomqvist@ki.se
Jannet C Beukema8
Email: j.c.beukema@rt.umcg.nl
Ellen Kapiteijn9
Email: H.W.Kapiteijn@lumc.nl
Corrie AM Marijnen10
Email: C.A.M.Marijnen@lumc.nl
Iris D Nagtegaal11
Email: I.Nagtegaal@pathol.umcn.nl
Theo Wiggers2
Email: t.wiggers@umcg.nl
Bengt Glimelius12,13
Email: bengt.glimelius@onkologi.uu.se
1
Department of Molecular Medicine and Surgery, Karolinska Institutet and
Center for Surgical Gastroenterology, Karolinska University Hospital, Solna
P9:03, SE 171 76 Stockholm, Sweden
3. 2
Department of Surgery, University Medical Center Groningen, Groningen, The
Netherlands
3
Department of Medical Oncology, University Medical Center Groningen,
Groningen, The Netherlands
4
Department of Surgical Science, Uppsala University, Uppsala, Sweden
5
Department of Surgery, Leiden University Medical Center, Leiden, The
Netherlands
6
Department of Radiology, Maastricht University Medical Center, Maastricht,
The Netherlands
7
Department of Diagnostic Radiology, Karolinska University Hospital Solna,
Stockholm, Sweden
8
Department of Radiation Oncology, University Medical Center Groningen,
Groningen, The Netherlands
9
Department of Medical Oncology, Leiden University Medical Center, Leiden,
The Netherlands
10
Department of Clinical Oncology, Leiden University Medical Center, Leiden,
The Netherlands
11
Department of Pathology, Radboud University, Nijmegen Medical Center,
Nijmegen, The Netherlands
12
Department of Radiology, Oncology and Radiation Science, Uppsala
University, Uppsala, Sweden
13
Department of Oncology and Pathology, Karolinska Institutet, Solna, Sweden
Abstract
Background
Current standard for most of the locally advanced rectal cancers is preoperative
chemoradiotherapy, and, variably per institution, postoperative adjuvant chemotherapy.
Short-course preoperative radiation with delayed surgery has been shown to induce tumour
down-staging in both randomized and observational studies. The concept of neo-adjuvant
chemotherapy has been proven successful in gastric cancer, hepatic metastases from
colorectal cancer and is currently tested in primary colon cancer.
Methods and design
Patients with rectal cancer with high risk features for local or systemic failure on magnetic
resonance imaging are randomized to either a standard arm or an experimental arm. The
4. standard arm consists of chemoradiation (1.8 Gy x 25 or 2 Gy x 25 with capecitabine)
preoperatively, followed by selective postoperative adjuvant chemotherapy. Postoperative
chemotherapy is optional and may be omitted by participating institutions. The experimental
arm includes short-course radiotherapy (5 Gy x 5) followed by full-dose chemotherapy
(capecitabine and oxaliplatin) in 6 cycles before surgery. In the experimental arm, no
postoperative chemotherapy is prescribed. Surgery is performed according to TME principles
in both study arms. The hypothesis is that short-course radiotherapy with neo-adjuvant
chemotherapy increases disease-free and overall survival without compromising local
control. Primary end-point is disease-free survival at 3 years. Secondary endpoints include
overall survival, local control, toxicity profile, and treatment completion rate, rate of
pathological complete response and microscopically radical resection, and quality of life.
Discussion
Following the advances in rectal cancer management, increased focus on survival rather than
only on local control is now justified. In an experimental arm, short-course radiotherapy is
combined with full-dose chemotherapy preoperatively, an alternative that offers advantages
compared to concomitant chemoradiotherapy with or without postoperative chemotherapy. In
a multi-centre setting this regimen is compared to current standard with the aim of improving
survival for patients with locally advanced rectal cancer.
Trial registration
ClinicalTrials.gov NCT01558921
Keywords
Rectal cancer, Radiotherapy, Chemotherapy, Neo-adjuvant, Magnetic resonance imaging
Background
Over the past decades, management of rectal cancer has evolved immensely leading to
improved patient outcomes. Although increased awareness, introduction of screening
programmes [1] and enhanced perioperative care [2] have played roles in reducing mortality
and morbidity rates, two distinct therapeutic developments have been of key importance.
Firstly, surgical techniques have been refined [3,4] and disseminated to the colorectal surgical
community [5]. Randomized controlled studies to prove the effects of new surgical
techniques are difficult to design and run, but observational data clearly indicate benefits [6-
8]. Secondly, (neo)adjuvant therapies including radiotherapy and chemotherapy have become
integrated parts of rectal cancer management.
The Uppsala trial on pre- or postoperative radiotherapy for rectal cancer was the starting
point for a line of development towards full acceptance for preoperative short-course
radiotherapy [9]. The Stockholm I trial run in parallel [10], and the subsequent Swedish
Rectal Cancer Trial with randomization between surgery alone and preoperative radiotherapy
with 5 Gy x 5 in resectable rectal cancer showed not only improved local control but also a
survival benefit [11]. Criticism against these trials regarding the quality of surgery performed
was met in the Dutch TME trial where only surgeons trained in total mesorectal excision
5. (TME) were operating. This study confirmed improved local control with the use of
preoperative short-course radiotherapy although no significant effects on survival could be
seen, apart from certain subgroups [12,13]. Randomized data indicating decreased short-term
toxicity and no differences in long-term oncologic outcomes and late toxicity compared to
preoperative chemoradiation in resectable rectal cancer suggest that short-course radiation
should be preferred in these patients [14].
There is an overwhelming body of evidence supporting adjuvant chemotherapy in colon
cancer with indisputable effects on survival [15]. However, in rectal cancer the corresponding
evidence is weaker although a recent metaanalysis [16] showed favourable outcomes with the
use of fluoropyrimidine-based chemotherapy. Another systematic overview questioned its
use, particularly after preoperative chemoradiotherapy [17]. The risk of developing
metachronous metastases in intermediate and locally advanced rectal cancer is 25–65 % [18-
20] and systemic chemotherapy aim to treat occult or micrometastatic disease that may later
appear as distant metastases. At least two arguments against postoperative delivery of
chemotherapy can be brought up. Firstly, rectal cancer surgery is connected with a substantial
risk of postoperative complications that may lead to patient inability to tolerate postoperative
chemotherapy [21,22]. Secondly, in an early disease phase when microscopic dissemination
is limited the efficacy of systemic chemotherapy would theoretically be expected to be the
greatest. Surgery, particularly if extensive, may also accelerate tumor growth [23,24].
Neoadjuvant chemotherapy has been proven favourable in the management of colorectal liver
metastases [25], in gastric cancer [26,27] and is currently being studied in colon cancer in the
ongoing FOxTROT trial [28].
Magnetic resonance imaging (MRI) is currently the most accepted modality for preoperative
local staging of rectal cancer. Following the MERCURY-trial and further studies there are
criteria, although not yet universally accepted or used, for identification of patients with a
high risk of local and/or systemic relapse [29]. For patients with early, clearly resectable
tumours (also designated “good”) surgery alone may provide excellent results with respect to
both local control and survival. In slightly more advanced tumours, or “intermediate”
following the terminology of the European Rectal Cancer Consensus Conference (EURECA-
CC2) [30] or the European Society of Medical Oncology (ESMO) Consensus Guidelines
[31], the increased risk of local recurrence justifies preoperative radiotherapy. Short-course
radiotherapy with immediate surgery is a valid option in this situation as it reduces the risk of
recurrence by 60-70% [32,33]. However, in this “intermediate” group (also designated
“bad”), frequently termed “locally advanced”, chemoradiation is the preferred option by
many [22,30,34]. In patients showing high-risk features on MRI, tumours best termed
“locally advanced”, or “ugly”, there is a substantial risk of treatment failure either locally or
systemically and chemoradiation is the reference regimen, since the addition of chemotherapy
to conventionally fractionated radiotherapy improves local control and cancer-specific
survival [35]. However, some patients may be considered too frail for chemoradiation and
three recent reports have shown promising results with a strategy of delivering 5 Gy x 5 with
delayed surgery [36-38]. These studies, although non-randomized, support the notion that
also short-course preoperative radiation results in down-staging if surgery is postponed. In
addition, a Dutch phase II trial [39], in which patients with resectable metastatic rectal cancer
were given short-course radiation followed by preoperative chemotherapy including
bevacizumab reported high response rates and radical (R0) resection was achieved in 80 % of
the patients.
6. Following evidence of tumour down-staging or down-sizing with short-course radiation and
arguments for neo-adjuvant rather than adjuvant chemotherapy there is a rationale for
applying this concept on patients with rectal cancer at high risk of local or systemic failure.
The present RAPIDO (Radiotherapy And Preoperative Induction therapy followed by
Dedicated Operation) trial has been designed to assess whether short-course radiation
followed by up-front chemotherapy before surgery improves 3-year disease-free survival
(DFS) in patients with locally advanced rectal cancer compared to conventional
chemoradiation with optional (according to institution policy) postoperative adjuvant
chemotherapy.
Methods/design
Study design
The study is a two-arm prospective randomized multicentre trial. The treatment algorithm is
presented in Figure 1.
Figure 1 Treatment algorithm.
Study objectives
The study compares two different preoperative regimens for locally advanced rectal cancer.
The primary outcome measure is DFS after 3 years. Secondary objectives are to describe the
toxicity profile, the rate of completion of preoperative treatment, the fraction of patients with
a radical resection (R0) and to determine the rate of pathological complete response (pCR).
Furthermore, local recurrence rate after 3 years follow-up, quality of life (QoL), functional
outcome and overall survival (OS) are secondary endpoints.
Trial organisation
The RAPIDO-trial has been jointly designed by Uppsala Akademiska Hospital, Sweden,
Leiden University Medical Center, The Netherlands, University Medical Center Groningen,
The Netherlands and Karolinska University Hospital, Stockholm, Sweden. The trial is
investigator initiated and sponsors are the Dutch Colorectal Cancer Group (DCCG) and the
Nordic Gastrointestinal Tumour Adjuvant Therapy Group (NGTATG). The RAPIDO-trial
data management is financed by the Dutch and Swedish cancer societies.
Coordination and monitoring
The trial is coordinated by the datacenter at Leiden University Medical Center, The
Netherlands. The trial office is responsible for overall trial management, trial registration
(ClinicalTrials.gov NCT01558921, EudraCT number 2010-023957-12, CKS number 2011–
4997, NL36315.042.11, NTR 3230), database management and quality assurance. A
monitoring committee appointed by the trial sponsors performs on-site monitoring of
recruited patients according to the ICH Harmonized Tripartite Guideline for Good Clinical
Practice (GCP).
7. Ethics, informed consent and safety
The final protocol was first approved by the ethics committees of Uppsala University,
Sweden and University Medical Center Groningen, The Netherlands. As centres have and
will join this trial, appropriate approval from respective local ethics committee is obtained.
This study is conducted in accordance with the most recent version of the Declaration of
Helsinki and with the laws and regulations of each participating country. The protocol has
been written, and the study will be conducted according to GCP. Written informed consent,
signed and personally dated, is obtained from each patient before inclusion in the trial.
Information that participation is voluntary and the nature, scope and possible consequences of
the trial are explained to all patients by a physician. Prior to when valid consent has been
obtained, the investigator will not undertake any measures specifically required only for the
trial. Serious adverse events (SAE) or suspected unexpected serious adverse reactions
(SUSAR), as defined by the protocol, will be reported to the datacenter at Leiden University
Medical Center, The Netherlands and to the respective national trial coordinators who will
report to competent authorities and ethical committees according to regulations applicable in
each participating country.
Statistics
DFS at 3 years is the primary end-point but the immediate anti-tumour secondary endpoints
R0 and pCR rates are also of relevance. All efficacy analyses will be on an intention-to-treat
basis. Per-protocol analyses will be performed as secondary analyses. Survival curves for
DFS and OS will be plotted using the method of Kaplan and Meier. Cumulative incidence of
local recurrence will be computed accounting for death as competing risk. Differences in
survival will be tested with the log-rank test. Hazard ratios and 95% confidence intervals (CI)
will be computed using Cox regression. All tests will be two-sided. A table will present the
completion rate of the neo-adjuvant treatment, pCR frequency and percentages, fraction of
patients with a R0 resection with 90 and 95% CI. Safety analyses will be based on treatment
received and will include only eligible patients. Frequency and percentages for toxicity will
be presented according to the Common Terminology Criteria for Adverse Events (CTCAE)
version 4. All proportions will be presented with 95% CI. Fifty percent DFS is described in
several studies with locally advanced rectal cancer patients [18-20,35]. The hypothesis is that
the new treatment (Arm B) increases DFS after 3 years of follow-up from 50 to 60%. This
difference corresponds to a hazard ratio of 0.737. A two-sided log rank test with a total of
452 DFS events achieves 90% power at α= 0.05 significance level to detect a hazard ratio of
0.737 when the proportion surviving in the control group is 50%. Based on four years of
uniform accrual and two years of additional follow-up after the last patient has been included
(six years total), a total of 842 evaluable patients will be required . With a drop-out of 5% the
total number of patients to be included is 885. Interim analyses are planned with 50% and
75% of the DFS information for efficacy. Both interim analyses will be conducted by a team
external to the sponsor team and each analysis will include the primary efficacy endpoint and
key safety parameters.
Randomization and stratification
Randomization is done centrally at the datacenter at Leiden University Medical Center, The
Netherlands. Patients will be stratified according to institution, performance score (0 or 1),
clinical T-stage (cT3 or cT4) and clinical node status (cN- or cN+).
8. Patient selection
Inclusion in the RAPIDO trial requires that certain tumour and patient criteria are met. A
staging MRI of specified quality is mandatory [40]. The inclusion and exclusion criteria are
presented in Table 1. It is recognised that all MRI criteria indicate that the risk of systemic
failure is high whereas all do not indicate an increased risk of local failure [29,41].
9. Table 1 Inclusion and exclusion criteria
Inclusion criteria
General Age ≥ 18 years
ECOG performance score ≤ 1
Written informed consent
Staging done within 5 weeks prior to randomization
Adequate potential for follow-up
Mentally and physically fit for chemotherapy
Adequate blood counts:
White blood cell count ≥4.0 x 109
/L
Platelet count ≥100 x 109
/L
Clinically acceptable haemoglobin levels
Creatinine levels indicating renal clearance ≥ 50 ml/min
Bilirubin < 35 µmol/L
Primary tumour
characteristics
Biopsy proven rectal adenocarcinoma*
Locally advanced tumour fulfilling at least one of the following
criteria on pelvic MRI:
cT4a
cT4b
cN2
Extramural vascular invasion (EMVI+)
Involved mesorectal fascia (MRF+)
Metastatic lateral lymphnodes (LN+)
Exclusion criteria Extensive tumour growth into sacrum above S3
Tumour involving lumbosacral nerve roots
Distant metastasis (M1)
Recurrent rectal cancer
FAP or HNPCC
Active Crohn’s disease or ulcerative colitis
Concomitant malignancies (except basocellular carcinoma or in-situ
cervical carcinoma)
Known DPD deficiency
Contraindications to MRI (e.g. pacemaker)
Inability to give informed consent
Concurrent uncontrolled medical condition
Any investigational treatment for rectal cancer within past month
Pregnancy or breast feeding
Known malabsorption syndromes or lack of physical integrity of upper
gastrointestinal tract
Myocardial infarction within past 12 months or
clinically significant cardiac disease
Symptoms or history of peripheral neuropathy
ECOG Eastern Cooperative Oncology Group, * lower border of tumour < 16 cm with a rigid
rectoscope, MRI Magnetic resonance imaging, cT4a, cT4b and cN2: Clinical stage according
to TNM version 5, S3: sacral vertebra 3, FAP Familial adenomatous polyposis, HNPCC
Hereditary non-polyposis colorectal cancer, DPD Dihydropyrimidine dehydrogenase.
10. Preoperative therapy
Patients are randomized to one of two arms of preoperative treatments. Arm A is considered
the standard arm and Arm B the experimental arm. In both arms, radiotherapy is delivered
with CT-based 3D-conformal treatment planning with a defined pelvic clinical target volume
(CTV). Arm A consists of chemoradiation with a dose to the planning target volume (PTV)
of 45 Gy with 1.8 Gy in 25 fractions given 5 times a week. The dose to the boost PTV,
encompassing the primary tumour and pathological lymph nodes is 5.4 Gy in 3 fractions
leading to a total dose of 50.4 Gy. It is possible to deliver the treatment as 25 fractions of 2
Gy at centres who use this as their standard. An extra boost is possible to deliver towards the
primary tumour area at risk of non-radical surgery [42] with 1.8 - 2 Gy x 2–4. The extra boost
can be given intraoperatively (IORT). The radiotherapy is given in combination with
capecitabin in a dose of 825 mg/m2
twice daily on all days of radiotherapy, including
weekends. In Arm B, patients will receive a total dose of 25 Gy to the pelvic PTV delivered
in fractions of 5 Gy during 5 days with a maximum overall treatment time of 8 days. An extra
boost of 2 Gy x 2–3 is possible to deliver. With an optimal starting time at 11–18 days after
the last day of radiotherapy, patients will receive neo-adjuvant chemotherapy. However, if
radiation-related toxicity occurs, commencement of chemotherapy may be delayed up until 4
weeks after termination of radiotherapy. Chemotherapy is given in 3 week cycles and consists
of capecitabine 1000 mg/m2
twice daily, day 1–14 combined with oxaliplatin 130 mg/m2
once every 3 weeks. In total, 6 cycles of chemotherapy are prescribed preoperatively.
Treatment-related toxicity is monitored through the preoperative phase and dose modification
can be made according to specified protocol schedules.
Response and resectabilty evaluation
Patients randomized to Arm A will undergo response evaluation with MRI of the pelvis and
computerized tomography (CT) of chest and abdomen after the full course of chemoradiation
prior to surgery. Patients in Arm B who have received short-course radiotherapy and
neoadjuvant chemotherapy will have MRI and CT after the last cycle of chemotherapy but
prior to surgery. An additional response evaluation with MRI and CT is possible to perform
after the third neo-adjuvant cycle. Response evaluation will be at a multidisciplinary team
conference and patients with progressive or irresectable disease will receive palliative
treatment. Radiological assessment will be according to the Response Evaluation Criteria in
Solid Tumours (RECIST 1.1) [43].
Surgery and histopathology
In Arm A surgery should be performed 6–8 weeks after termination of chemoradiation. In
Arm B patients should undergo surgery 2–4 weeks after the last cycle of neoadjuvant
chemotherapy. Surgical treatment should not differ between the two trial groups and can be
done open or laparoscopically. Surgery should be performed according to the TME
principles, however, in tumours located in the proximal part of rectum partial mesorectal
excision (PME) is permitted provided that a 5 cm distal margin in mesorectum can be safely
obtained. Surgery may include anterior resection, abdominoperineal resection or a low
Hartmann’s procedure. Potentially invaded structures are resected en bloc with rectum.
Pathological evaluation of resected specimens will be according to guidelines included in the
study protocol. The 5th
edition of TNM will be used. In addition, circumferential resection
margin (CRM) will be assessed and a margin of 1 mm or less is considered positive. CRM
will be measured both for the primary tumour and for lymph nodes or tumour deposits, when
11. present. Tumour regression grade (TRG) will be assessed according a three-tier grade (no
regression, regression, and complete regression). Also, the quality of the resected specimen
will be evaluated with separate scoring for the mesorectum and the anal canal. After inclusion
of the last patient, a committee of experienced rectal pathologists will be appointed for
central review of histopathology.
Adjuvant chemotherapy and follow-up
Patients who receive chemoradiotherapy in Arm A can be treated with postoperative
chemotherapy according to the local protocol of each participating centre. If patients are
eligible for postoperative chemotherapy this should consist of 8 cycles of capecitabine 1000
mg/m2
twice daily, day 1–14 combined with oxaliplatin 130 mg/m2
once every 3 weeks.
Patients treated in Arm B with short-course radiotherapy and neoadjuvant chemotherapy do
not receive any postoperative chemotherapy. A minimum standardized follow-up schedule
for all included patients is prescribed. This includes visits with history including
morbidity/toxicity assessment, physical examination and measurement of carcinoembryonic
antigen (CEA) at 6, 12, 36 and 60 months. Toxicity will be assessed and recorded according
to CTCAEv4.0. QoL assessment using EORTC questionnaires QLQ-C30 and QLQ-CR29
will be performed at 36 and 60 months. All patients will also have CT of thorax and abdomen
(or chest x-ray and liver ultrasonography) at 12 and 36 months. All suspicious findings
should prompt further evaluation and examinations.
Translational research
It is highly desirable to attach translational research to provide insights to prognosis and
prediction of response to radiation and chemotherapy to the RAPIDO-trial. Analyses of both
tumour tissue and serum/plasma with tissue microarray, proteomics and genomics would all
generate increased knowledge. Hence, a schedule for collection of serum/plasma and of fresh
tissue for freezing, at different stages of treatment in each arm, is defined in the study
protocol. Pending on local resources and regulations, participation in the translational part of
RAPIDO is optional.
Discussion
Improved staging, introduction of multidisciplinary decision-making, refined surgery and
appropriate use of preoperative radiotherapy, together with quality assessment by pathology
and registries have all contributed to substantially lowering rates of local recurrence in rectal
cancer from historical figures of above 30% to below 10% in many cohorts. Although there
are certain subgroups who still suffer a high risk of not having R0 surgery or a local failure,
the problem of local control can be seen as solved for a majority of rectal cancer patients.
However, the improvements regarding local control achieved over the past decades are not
matched by same-size improvements with respect to survival. Without compromising local
therapy, it may therefore be justified to shift focus from local control to systemic control and
survival when designing trials aiming at further development of rectal cancer treatment.
The primary aim of adjuvant systemic chemotherapy is to treat occult disease dissemination
that may later occur as distant metastases. Current standard for locally advanced rectal cancer
includes preoperative chemoradiation but, because of the risk of toxicity, dosage of
chemotherapeutic agents must be reduced which may negatively affect the systemic efficacy.
12. In many centres additional chemotherapy is administered postoperatively. However, since
rectal cancer surgery is afflicted with high rates of postoperative complications, a substantial
number of eligible patients are not fit to receive chemotherapy postoperatively [21,22,44]. In
addition, when preoperative chemoradiation is administered (5 weeks) followed by surgery
after 6–8 weeks and patients having to recover after surgery for 5–6 weeks, postoperative
chemotherapy for suspected occult metastases cannot be delivered until after 4–5 months. On
the other hand, neo-adjuvant chemotherapy yields favourable outcomes in oesophageal and
gastric cancer [26,27], in colorectal hepatic metastases [25] and is currently investigated in
primary colon cancer [28]. In contrast to these trials, in which chemotherapy is delivered pre-
and postoperatively, all chemotherapy is given preoperatively in the experimental arm of the
RAPIDO-trial. This was also the regimen in the Dutch “M1”-trial [39]. In this trial 50
patients with metastatic rectal cancer received short-course radiation followed by 6 cycles of
full-dose capecitabine/oxaliplatin and bevacizumab preoperatively. The completion rate for
all 6 cycles of chemotherapy was 85% and more than 90% received 4 cycles or more, and
toxicity reported was mostly mild. Thus, the assumption that preoperatively administered
chemotherapy is more likely to be accepted in full-dose than concomitant or postoperative
appears to be valid.
Two randomized trials have compared short-course preoperative radiotherapy to preoperative
chemoradiation in patients with resectable rectal cancer [45,46]. No evidence that
chemoradiation was superior concerning local control or survival was provided in these
studies. Furthermore, there were no indications of differences in late toxicity between the two
regimens and short-course radiation resulted in less acute toxicity [14]. In these studies, in
which patients underwent surgery the immediate week following short-course radiotherapy
down-staging occurred to a much greater extent in patients who had received chemoradiation
with delayed surgery. However, in an interim analysis of the on-going Stockholm III trial,
also in resectable (intermediate stage) rectal cancer, the rate of pCR after short-course
radiotherapy with delayed surgery was 12.5% [47]. Additionally, there are also other
randomized data [39] and observational data [36-38] indicating a down-staging effect of
short-course radiotherapy, given that surgery is after a delay. Among patients who underwent
resection of the primary tumour in the “M1”-trial (approximately 75% with T3/T4N+
tumours), 91% had a R0 resection and pCR was found in 27% [39]. None of the included
patients was considered inoperable because of primary tumour progression and only one
patient suffered local symptoms which occurred due to massive tumour response with tumour
necrosis and an abscess. The observational data from Stockholm also indicate that the risk of
tumour progression during the “waiting time” is low even if chemotherapy is not
administered in this period [38,47]. With this background, a rationale to test short-course
radiation also for the locally advanced tumours appears to exist.
The RAPIDO-trial is designed with the aim of improving survival without compromising
local control in patients with locally advanced rectal cancer. The aforementioned support in
the literature for down-staging following short-course radiation with delayed surgery and the
rationale for neo-adjuvant chemotherapy opens a window to test the combination of these two
concepts, and to compare results with current standard being preoperative chemoradiotherapy
with or without adjuvant chemotherapy. Although it is reasonable to assume that neo-
adjuvant chemotherapy not only has systemic effects but also acts on the primary tumour it
would be difficult to gain acceptance for a trial in which surgery is postponed after a
prolonged chemotherapy period. Even if chemotherapy with the addition of biologics has
improved substantially during the past decade [48], the medical therapy has limited cell kill
effect and is the weakest component in the treatment armamentarium. The initial 5 Gy x 5
13. will prevent local progression during the prolonged chemotherapy aimed at killing all
potential subclincal cancer cells, without postponing the start of the systemic therapy more
than marginally. Most adjuvant schedules in colorectal cancer consist of 8 cycles (24 weeks)
of chemotherapy but in the “M1”-trial only 6 cycles were given preoperatively [39], an
approach that reduces the “waiting time” between short-course radiation and surgery.
Bevacizumab was included in that trial but there is no evidence supporting an effect of either
bevacizumab or cetuximab against sub-clinical disease [49,50] which renders it superfluous
in the RAPIDO setting.
In the RAPIDO-trial, the logistically simple approach with initial local therapy with short-
course radiotherapy followed by systemic adjuvant full-dose up-front chemotherapy in 6
cycles, before local treatment is finalized with surgery according to TME-principles, is being
explored. If this concept in the RAPIDO trial yields improved survival with maintained
results regarding local control, the established management of locally advanced rectal cancer
with preoperative chemoradiation is challenged.
Competing interests
The authors have no competing interests to declare.
Authors’ contributions
The study protocol was originally conceived by BG, GAPH, LP and CJHvdV. The study
protocol was drafted by BvE and PJN with the exception of parts relating to radiology which
were drafted by LB and RGHB-T and parts relating to pathology which were drafted by IDN.
JCB, EK, CAMM and TW have all participated in critical review relating study design and
protocol. This article was conceived and drafted by PJN and BG. Critical review and
contributions for finalising the article were provided by all other authors. All authors have
read and approved both the study protocol and this article.
Acknowledgements
The RAPIDO study receives funding from the Swedish Cancer Society, the Dutch Cancer
Society and through the regional agreement on medical training and clinical research (ALF)
between Stockholm County Council and the Karolinska Institutet.
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19. Locally
advanced
rectal cancer
Randomization
Obstruction:
Diverting stoma
Standard Arm A
Chemo -
radiotherapy
Week 1-6
Response
evaluation by
MRI and CT
Week 12
Experimental
Arm B
5 Gy x 5
Week 1
Six cycles of
CAPOX
Week 3 -18
Unresectable
Palliation
Response
evaluation by
MRI and CT
Week 21
Unresectable
Palliation
Resectable
Surgery
Week 22 -24
Resectable
Surgery
Week 14 -16
Optional:
Adjuvant eight
cycles of CAPOX
Week 20 -40
Figure 1