LymphoTEC - Validation study to spare lymphocytes during radiation in genito-urinary cancers
- Conditions
- Malignant neoplasm of bladder, unspecified, (2) ICD-10 Condition: C61||Malignant neoplasm of prostate,
- Registration Number
- CTRI/2022/11/047550
- Lead Sponsor
- Tata memorial centre
- Brief Summary
Therapeutic ratio forms the guiding principle of radiation planning and treatment delivery (1). One of theearly attempts to provide a guidance tool for limiting normal organ injury was Emami et al study publishedin 1991 that provided a consensus framework of normal tissue radiation dose limits and tissue complicationprobability as TD 5/5 (the probability of 5% complication within five years from treatment) and TD 50 / 5(the probability of 50% complication within five years) (2). The advent of modern radiation techniques suchas inverse planning and image guidance as well as increased use of concurrent systemic therapy posed newchallenges to optimally define the normal organ tissue constraints. This led to the Quantitative Analyses ofNormal Tissue Effects in the Clinic (QUANTEC) framework published in 2010 based on thedose/volume/outcome data (3,4). Further understanding of the differential radiation sensitivity of thenormal tissues in growing children compared to adults led to the Pediatric Normal Tissue Effects in theClinic (PENTEC) initiative (5). The evolution of stereotactic body radiation therapy and hypo fractionationhas led to the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative(6).In recent times, modulating the immune system with immunotherapy, CAR T cell therapy etc is being tried to improve cancer control. Lymphocytes form the central dogma of cancer immunotherapy paradigm.Broadly lymphocytes can be classified into T cells and B cells. B cells identify circulating antigens leading tosecretion of antibodies helping in combating bacterial infections. In contrast, T cells recognize proteins thatare presented by MHC molecules through a process of antigen presentation. CD8+ T cells recognize MHCclass 1 presented molecules and are cytotoxic to cancer cells as well as infected cells. Some of these T cellsthat recognize cancer cells or infected cells evolve into memory cells and are conditioned to respondstrongly to re-challenge by the same antigen (7). Radiation is an integral component of cancer treatment insolid malignancies. Interestingly, lymphocytes are the most radiosensitive cells in the body mainly due tothe lack of adequate DNA repair machinery. Radiation related lymphopenia was identified as early as the1930s but its impact on tumor control and overall survival outcomes has been correlated recently (8).Multiple reports have shown that radiation delivery for tumors in close proximity to lymphoid organs suchas bone marrow, spleen, or unintended radiation to circulating pools of lymphocytes traversing organs suchas heart and lung is known to deplete the circulating lymphocyte populations(9–12). Multiple retrospectiveand small prospective studies have shown radiation related lymphopenia to be associated with detrimentalsurvival endpoints [13 - 16]. In a recent systematic review and meta-analysis by Thiraviyam et al on genitourinarycancers, the incidence of radiation related grade 4 (CTCAE v4) lymphopenia was 30% [16]. In astudy by Sini et al on 121 prostate cancers receiving radiotherapy, pelvic bone marrow V40 (Volumereceiving 40 Gy) was associated with severe lymphopenia [17]. Currently, there are no standardized doseconstraints that are available to limit the radiation dose to the resident and circulating lymphocytepopulations. This is much more pertinent in the current immunotherapy era wherein ongoing clinical trialsare trying to optimally time and sequence radiation and immunotherapy combinations for potentiallysynergistic and or additive effects [18]. We performed a systematic review of studies in published literatureto create guideline of dose constraint for reduction of radiation related lymphopenia (attached in appendix).Data for creation of this guideline was derived from mainly retrospective data. Therefore, we propose aLymphocyte sparing Normal Tissue Effects in the Clinic (LymphoTEC) prospective validation study whereindose constraints sparing the immune system should be integrated into the QUANTEC guidelines so as toreduce the incidence of lymphopenia.Therapeutic ratio forms the guiding principle of radiation planning and treatment delivery (1). One of theearly attempts to provide a guidance tool for limiting normal organ injury was Emami et al study publishedin 1991 that provided a consensus framework of normal tissue radiation dose limits and tissue complicationprobability as TD 5/5 (the probability of 5% complication within five years from treatment) and TD 50 / 5(the probability of 50% complication within five years) (2). The advent of modern radiation techniques suchas inverse planning and image guidance as well as increased use of concurrent systemic therapy posed newchallenges to optimally define the normal organ tissue constraints. This led to the Quantitative Analyses ofNormal Tissue Effects in the Clinic (QUANTEC) framework published in 2010 based on thedose/volume/outcome data (3,4). Further understanding of the differential radiation sensitivity of thenormal tissues in growing children compared to adults led to the Pediatric Normal Tissue Effects in theClinic (PENTEC) initiative (5). The evolution of stereotactic body radiation therapy and hypo fractionationhas led to the High Dose per Fraction, Hypofractionated Treatment Effects in the Clinic (HyTEC) initiative(6).In recent times, modulating the immune system with immunotherapy, CAR T cell therapy etc is being triedto improve cancer control. Lymphocytes form the central dogma of cancer immunotherapy paradigm.Broadly lymphocytes can be classified into T cells and B cells. B cells identify circulating antigens leading tosecretion of antibodies helping in combating bacterial infections. In contrast, T cells recognize proteins thatare presented by MHC molecules through a process of antigen presentation. CD8+ T cells recognize MHCclass 1 presented molecules and are cytotoxic to cancer cells as well as infected cells. Some of these T cellsthat recognize cancer cells or infected cells evolve into memory cells and are conditioned to respondstrongly to re-challenge by the same antigen (7). Radiation is an integral component of cancer treatment in solid malignancies. Interestingly, lymphocytes are the most radiosensitive cells in the body mainly due tothe lack of adequate DNA repair machinery. Radiation related lymphopenia was identified as early as the1930s but its impact on tumor control and overall survival outcomes has been correlated recently (8).Multiple reports have shown that radiation delivery for tumors in close proximity to lymphoid organs suchas bone marrow, spleen, or unintended radiation to circulating pools of lymphocytes traversing organs suchas heart and lung is known to deplete the circulating lymphocyte population(9–12). Multiple retrospective and small prospective studies have shown radiation related lymphopenia tobe associated with detrimental survival endpoints [13 - 16]. In a recent systematic review and meta-analysisby Thiraviyam et al on genito-urinary cancers, the incidence of radiation related grade 4 (CTCAE v4)lymphopenia was 30% [16]. In a study by Sini et al on 121 prostate cancers receiving radiotherapy, pelvicbone marrow V40 (Volume receiving 40 Gy) was associated with severe lymphopenia [17]. Currently, thereare no standardized dose constraints that are available to limit the radiation dose to the resident andcirculating lymphocyte populations. This is much more pertinent in the current immunotherapy era whereinongoing clinical trials are trying to optimally time and sequence radiation and immunotherapy combinationsfor potentially synergistic and or additive effects [18]. We performed a systematic review of studies inpublished literature to create guideline of dose constraint for reduction of radiation related lymphopenia(attached in appendix). Data for creation of this guideline was derived from mainly retrospective data.Therefore, we propose a Lymphocyte sparing Normal Tissue Effects in the Clinic (LymphoTEC) prospectivevalidation study wherein dose constraints sparing the immune system should be integrated into theQUANTEC guidelines so as to reduce the incidence of lymphopenia.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Not Yet Recruiting
- Sex
- All
- Target Recruitment
- 42
- Patients of high risk localized prostate cancer receiving radiotherapy Patients of locally advanced prostate cancer receiving radiotherapy Patients of muscle invasive bladder cancer receiving pelvic radiotherapy Baseline blood lymphocyte count > 800/mm3 Patients must be ≥ 18 years of age, have the ability to understand, and the willingness to sign a written informed consent document.
- Patients must have an Eastern Cooperative Oncology Group performance status ≤ 2.
- Patients receiving prostate only radiotherapy Patients receiving urinary bladder only radiotherapy Patients receiving hypofractionated radiotherapy Baseline lymphocyte count less than 500/mm3 Eastern Cooperative Oncology Group performance status 3 or higher Patients receiving concurrent mitomycin C, cisplatin or other chemotherapeutic agents in bladder cancer HIV positive patients and patients with immunodeficiency states Current smokers Receipt of any other investigational agents or participation in another trial protocol Excessive artifact not allowing proper contouring of target or bone marrow e.g. Hip replacement Inability to lie flat during or tolerate PET/CT, PET/MRI or SABR.
- Refusal to sign informed consent.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Incidence of acute lymphopenia (CTCAE v5: Grade 2 or higher) 4 months after radiotherapy
- Secondary Outcome Measures
Name Time Method na na
Trial Locations
- Locations (1)
MPMMCC/ HBCH
🇮🇳Varanasi, UTTAR PRADESH, India
MPMMCC/ HBCH🇮🇳Varanasi, UTTAR PRADESH, IndiaPrashanth GiridharPrincipal investigatorprashanth.jipmer@gmail.com