| CTRI Number |
CTRI/2022/11/047550 [Registered on: 23/11/2022] Trial Registered Prospectively |
| Last Modified On: |
22/11/2022 |
| Post Graduate Thesis |
No |
| Type of Trial |
Interventional |
|
Type of Study
|
Radiation Therapy |
| Study Design |
Single Arm Study |
|
Public Title of Study
|
LymphoTEC - Validation study to spare lymphocytes during radiation in genito-urinary cancers |
|
Scientific Title of Study
|
LymphoTEC GU - A prospective validation study of dosimetric parameters for irradiation induced lymphopenia in genito-urinary cancer |
| Trial Acronym |
|
|
Secondary IDs if Any
|
| Secondary ID |
Identifier |
| NIL |
NIL |
|
|
Details of Principal Investigator or overall Trial Coordinator (multi-center study)
|
| Name |
Prashanth Giridhar |
| Designation |
Assistant Professor |
| Affiliation |
Department of Radiation Oncology, Tata memorial centre, Varanasi |
| Address |
Department of Radiation Oncology
MPMMCC/ HBCH
Tata memorial centre
Sunderbagiya, Varanasi
Varanasi
UTTAR PRADESH
221005
India |
| Phone |
|
| Fax |
|
| Email |
prashanth.jipmer@gmail.com |
|
Details of Contact Person
Scientific Query
|
| Name |
Prashanth Giridhar |
| Designation |
Assistant Professor |
| Affiliation |
Department of Radiation Oncology, Tata memorial centre, Varanasi |
| Address |
Department of Radiation Oncology
MPMMCC/ HBCH
Tata memorial centre
Sunderbagiya, Varanasi
Varanasi
UTTAR PRADESH
221005
India |
| Phone |
|
| Fax |
|
| Email |
prashanth.jipmer@gmail.com |
|
Details of Contact Person
Public Query
|
| Name |
Prashanth Giridhar |
| Designation |
Assistant Professor |
| Affiliation |
Department of Radiation Oncology, Tata memorial centre, Varanasi |
| Address |
Department of Radiation Oncology
MPMMCC/ HBCH
Tata memorial centre
Sunderbagiya, Varanasi
Varanasi
UTTAR PRADESH
221005
India |
| Phone |
|
| Fax |
|
| Email |
prashanth.jipmer@gmail.com |
|
|
Source of Monetary or Material Support
|
| Tata memorial centre
Parel East, Parel, Mumbai, Maharashtra 400012 |
|
|
Primary Sponsor
|
| Name |
Tata memorial centre |
| Address |
MPMMCC/ HBCH
Sunderbagiya, Varanasi
221005 |
| Type of Sponsor |
Research institution and hospital |
|
|
Details of Secondary Sponsor
|
|
|
Countries of Recruitment
|
India |
|
Sites of Study
|
| No of Sites = 1 |
| Name of Principal
Investigator |
Name of Site |
Site Address |
Phone/Fax/Email |
| Prashanth Giridhar |
MPMMCC/ HBCH |
Department of Radiation Oncology
Tata memorial centre
Sunderbagiya, Varanasi 221005
Varanasi
UTTAR PRADESH |
809881729
prashanth.jipmer@gmail.com |
|
|
Details of Ethics Committee
|
| No of Ethics Committees= 1 |
| Name of Committee |
Approval Status |
| Institutional ethics committee |
Approved |
|
|
Regulatory Clearance Status from DCGI
|
|
|
Health Condition / Problems Studied
|
| Health Type |
Condition |
| Patients |
(1) ICD-10 Condition: C679||Malignant neoplasm of bladder, unspecified, (2) ICD-10 Condition: C61||Malignant neoplasm of prostate, |
|
|
Intervention / Comparator Agent
|
| Type |
Name |
Details |
| Intervention |
Computer based optimisation |
LymphoTEC guideline to spare lymphocytes
Duration: 5 - 6 weeks during radiotherapy |
| Comparator Agent |
NA |
NA |
|
|
Inclusion Criteria
|
| Age From |
18.00 Year(s) |
| Age To |
99.00 Year(s) |
| Gender |
Both |
| Details |
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.
|
|
| ExclusionCriteria |
| Details |
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 |
|
|
Method of Generating Random Sequence
|
Not Applicable |
|
Method of Concealment
|
Not Applicable |
|
Blinding/Masking
|
Not Applicable |
|
Primary Outcome
|
| Outcome |
TimePoints |
| Incidence of acute lymphopenia (CTCAE v5: Grade 2 or higher) |
4 months after radiotherapy |
|
|
Secondary Outcome
|
|
|
Target Sample Size
|
Total Sample Size="42"
Sample Size from India="42"
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" |
|
Phase of Trial
|
Phase 2 |
|
Date of First Enrollment (India)
|
25/11/2022 |
| Date of Study Completion (India) |
Applicable only for Completed/Terminated trials |
| Date of First Enrollment (Global) |
Date Missing |
| Date of Study Completion (Global) |
Applicable only for Completed/Terminated trials |
|
Estimated Duration of Trial
|
Years="2"
Months="0"
Days="0" |
|
Recruitment Status of Trial (Global)
|
Not Yet Recruiting |
| Recruitment Status of Trial (India) |
Not Yet Recruiting |
|
Publication Details
|
NA |
|
Individual Participant Data (IPD) Sharing Statement
|
Will individual participant data (IPD) be shared publicly (including data dictionaries)?
Response - NO
|
|
Brief Summary
|
Therapeutic ratio forms the guiding principle of radiation planning and treatment delivery (1). One of the
early attempts to provide a guidance tool for limiting normal organ injury was Emami et al study published
in 1991 that provided a consensus framework of normal tissue radiation dose limits and tissue complication
probability 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 such
as inverse planning and image guidance as well as increased use of concurrent systemic therapy posed new
challenges to optimally define the normal organ tissue constraints. This led to the Quantitative Analyses of
Normal Tissue Effects in the Clinic (QUANTEC) framework published in 2010 based on the
dose/volume/outcome data (3,4). Further understanding of the differential radiation sensitivity of the
normal tissues in growing children compared to adults led to the Pediatric Normal Tissue Effects in the
Clinic (PENTEC) initiative (5). The evolution of stereotactic body radiation therapy and hypo fractionation
has 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 to
secretion of antibodies helping in combating bacterial infections. In contrast, T cells recognize proteins that
are presented by MHC molecules through a process of antigen presentation. CD8+ T cells recognize MHC
class 1 presented molecules and are cytotoxic to cancer cells as well as infected cells. Some of these T cells
that recognize cancer cells or infected cells evolve into memory cells and are conditioned to respond
strongly 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 to
the lack of adequate DNA repair machinery. Radiation related lymphopenia was identified as early as the
1930s 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 such
as bone marrow, spleen, or unintended radiation to circulating pools of lymphocytes traversing organs such
as heart and lung is known to deplete the circulating lymphocyte populations(9–12). Multiple retrospective
and small prospective studies have shown radiation related lymphopenia to be associated with detrimental
survival endpoints [13 - 16]. In a recent systematic review and meta-analysis by Thiraviyam et al on genitourinary
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, pelvic bone marrow V40 (Volume
receiving 40 Gy) was associated with severe lymphopenia [17]. Currently, there are no standardized dose
constraints that are available to limit the radiation dose to the resident and circulating lymphocyte
populations. This is much more pertinent in the current immunotherapy era wherein ongoing clinical trials
are trying to optimally time and sequence radiation and immunotherapy combinations for potentially
synergistic and or additive effects [18]. We performed a systematic review of studies in published 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) prospective validation study wherein
dose constraints sparing the immune system should be integrated into the QUANTEC guidelines so as to
reduce the incidence of lymphopenia.
Therapeutic ratio forms the guiding principle of radiation planning and treatment delivery (1). One of the
early attempts to provide a guidance tool for limiting normal organ injury was Emami et al study published
in 1991 that provided a consensus framework of normal tissue radiation dose limits and tissue complication
probability 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 such
as inverse planning and image guidance as well as increased use of concurrent systemic therapy posed new
challenges to optimally define the normal organ tissue constraints. This led to the Quantitative Analyses of
Normal Tissue Effects in the Clinic (QUANTEC) framework published in 2010 based on the
dose/volume/outcome data (3,4). Further understanding of the differential radiation sensitivity of the
normal tissues in growing children compared to adults led to the Pediatric Normal Tissue Effects in the
Clinic (PENTEC) initiative (5). The evolution of stereotactic body radiation therapy and hypo fractionation
has 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 to
secretion of antibodies helping in combating bacterial infections. In contrast, T cells recognize proteins that
are presented by MHC molecules through a process of antigen presentation. CD8+ T cells recognize MHC
class 1 presented molecules and are cytotoxic to cancer cells as well as infected cells. Some of these T cells
that recognize cancer cells or infected cells evolve into memory cells and are conditioned to respond
strongly 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 to
the lack of adequate DNA repair machinery. Radiation related lymphopenia was identified as early as the
1930s 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 such
as bone marrow, spleen, or unintended radiation to circulating pools of lymphocytes traversing organs such
as heart and lung is known to deplete the circulating lymphocyte population
(9–12). Multiple retrospective and small prospective studies have shown radiation related lymphopenia to
be associated with detrimental survival endpoints [13 - 16]. In a recent systematic review and meta-analysis
by 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, pelvic
bone marrow V40 (Volume receiving 40 Gy) was associated with severe lymphopenia [17]. Currently, there
are no standardized dose constraints that are available to limit the radiation dose to the resident and
circulating lymphocyte populations. This is much more pertinent in the current immunotherapy era wherein
ongoing clinical trials are trying to optimally time and sequence radiation and immunotherapy combinations
for potentially synergistic and or additive effects [18]. We performed a systematic review of studies in
published 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) prospective
validation study wherein dose constraints sparing the immune system should be integrated into the
QUANTEC guidelines so as to reduce the incidence of lymphopenia. |