Radiation Dose Optimization in Diffuse Large B- Cell Lymphoma.

Patients who fit the eligibility criteria will be screened for the trial. Patients who consent to participate in the trial will be registered into the trial prior to the start of chemotherapy.

Patient registration / randomization procedure

After completion of staging, the patient is informed about this trial after checking the eligibility checklist.

The patient is informed about this trial, including the following main points: title and aim of the trial, nature of the treatment, side effects, reason for randomization, passing on of data and material samples and the patient's freedom to decide.

The patient receives an information brochure and an informed consent form. The written consent to participate in the trial and to randomization, if needed, in the presence of a witness takes place at least 24 hours after patient briefing. The signed original consent form and the record of the briefing remain in the patient's files. The patient receives a copy of each document. If after completion of staging the patient is qualified for a trial and gives written informed

Consent, then randomization will be performed by statistician at Clinical Research Secretariat, Institutional Review Board. For randomization, the following is required:

* All entry criteria satisfied; * No exclusion criterion satisfied; * Staging and stage allocation according to protocol; * Signed trial consent form in possession of the trial coordinator.

Randomization Patients will be randomized after the completion of 4-6 cycles of chemotherapy just prior to starting radiation.

The stratification variables used are

1. Response: Complete response and partial response. 2. Bulky disease. Bulky is defined as any nodal lesion measuring \> 7 cm and mediastinal mass greater than a third of the trans thoracic diameter at any level of thoracic vertebrae as determined by CT and Non bulky is lesion measuring \< 7 cm. 3. Revised International Prognostic Index: The negative prognostic factors used for this stratification are age \> 60 years, stage III/IV disease, elevated lactate dehydrogenase level, Eastern Cooperative Oncology Group (ECOG) performance status ≥ 2, more than one extranodal site of disease.

I: Very Good Risk: No risk factors. II: Good Risk: 1-2 Risk factors. III: Poor Risk: 3-5 Risk factors.

Radiation Therapy Protocol

Patient's positioning:

The patient positioning and immobilization would vary depending on the site being treated. In general patient will be positioned supine with an immobilization device. Orthogonal lasers will be used for patient alignment. Laser marks will be made on the thermoplastic mask will help in setting up the patient during treatment.

Simulation (patient data acquisition) guidelines. A planning CT scan will be acquired to delineate the target volumes namely gross tumor volume (GTV), clinical target volume (CTV), and planning target volume (PTV).

Patients will be positioned in actual treatment position depending on the site (as described above) on flat table couch with fiducials at a stable bony landmark. CT slices with 5mm thickness will be obtained.

PET CT at baseline will be used to guide the delineation of CTV. It will be fused electronically with the CT simulation scan so that original volumes of interest can be displayed on the simulation CT.

PTV will provide margin around the CTV to compensate for variability in daily treatment set-up. It includes the entire CTV plus a minimum 3D margin of 5 mm.

Dose-volume histograms (DVH) will be generated for each site and the plan will be evaluated in consideration of the expected normal tissue complication probability.

Dose computation. External Beam Planning System of Eclipse (Varian Medical Systems, Palo Alto, USA, V 8.6.14) will be used for generating the plans. Convolution algorithm will be used for dose calculation. The PTV will be treated with any combination of coplanar or non-coplanar 3-dimensional conformal fields shaped to deliver the prescribed dose while minimizing dose to the normal tissue OAR. Field arrangements will be determined by 3 D planning to produce the optimal conformal plan in accordance with volume definitions. The treatment plan used for each patient will be based on an analysis of the volumetric dose including DVH analyses of the PTV and critical organ at risk (OAR). Each field is to be treated daily.

The PTV will be outlined in all relevant planes. The dose distribution in form of isodose lines or dose color wash will be shown in all three planes through the beam axes.

Equipment and tools. Megavoltage beams will be used for treating patients. Beam's Eye View techniques will be used to select the beam isocenter and direction to fully encompass the target volume but minimizing the inclusion of the critical organs in order to select the plan that minimizes the dose to normal tissues. Visual displays in the axial planes to objectively candidate plans and Dose-Volume Histograms will also be part of the treatment planning procedures.

Dose prescription. Normalization of the treatment plan will cover 95% of the PTV with the prescription dose. The minimum PTV dose (to a volume of at least 0.03 cc) must not fall below 95% of the prescription dose. The maximum dose within the PTV must not exceed 107% of the prescribed dose. All RT doses will be calculated with inhomogeneity corrections that take into account the density differences within the irradiated volume (i.e., air, lung, soft tissues, and bones).

Dose recording. The following dose parameters will be recorded.

* Prescription point dose. * Minimum and maximum dose in the PTV and average dose in the PTV. * Hot spot outside the PTV. * Dose to organs at risk

Dose homogeneity.

* The dose will be prescribed to the PTV. Heterogeneity acceptable is 95% - 107%. * The minimal dose to the target volume, identified in the central plane fields dose distribution, will be 42.75 Gray (Gy) (95% of the protocol dose)in control arm and 34.2 Gy in experimental arm. * The maximal target dose (defined as the greatest dose in target volume which is delivered to an area greater than 2 cm ), identified in the central plane will be ≤ 107% of the prescribed dose.(48.15 Gy in control arm and 38.52 Gy in experimental arm). * If Intensity Modulated Radiotherapy (IMRT) is contemplated,International commission on Radiation Units (ICRU) 83 guidelines will be followed.

Treatment Verification. Electronic portal images, will be obtained during the course of treatment on the first day of treatment and once a week thereafter and will be compared with the digitally reconstructed images from CT scan.

Chemotherapy protocol All patients will receive 4-6 cycles of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) chemotherapy based on the stage of the disease.

Follow-up Protocol:

All patients will be followed up as follows:

* From completion of radiotherapy to 2 years: first visit at 3 months +/- 1 month and then 6 monthly. * Thereafter, the patient followed up yearly till death. The following investigations should be performed during every visit. * Clinical examination, weight, performance status, including the common toxicity criteria for adverse events (CTCAE) v4.0 scale for acute reactions and late effects * Lactate dehydrogenase ( S LDH), thyroid function test (TFT), Complete blood count (CBC), Renal function test( RFT) and liver function test (LFT) when clinically indicated. * A Fluoro De-oxy glucose positron emission Tomography with computed tomography (FDG-PET-CT) scan at 3 months after treatment is repeated if there was partial response after completion of chemotherapy (with PET positive disease) and in the event clinical suspicion of relapse. * 1 year post-radiotherapy:Pulmonary function test ( PFT) , 2D Echo and thereafter based on suspicion.

Treatment in case of progression In case of disease progression or relapse, the patient will be treated with salvage chemotherapy according to the hospital policy.

Treatment toxicity assessment Acute and late toxicity will be assessed using the National Cancer Institute-Common Toxicity Criteria (NCI-CTCAE version 4.0) Criteria of evaluation.

The definitions of endpoints used in this trial are :

Relapse: It is defined as the development of a new lesion either in previously treated area, outside the treated area and distant sites or B-symptoms following complete remission (CR) at least 3 months after end of treatment. If the interval is shorter the event is evaluated as a progression.

Toxic effects: These are measures using the CTCAE version 4 Quality of life (see special section on this) Survival: 1) Event Free Survival (EFS): From the time of randomization till relapse or progression or death due to any cause or death due to disease.

2\) Overall Survival (OS): From the time of randomization to death due to any cause /death due to disease.

Response rates will be measured using the Revised response criteria for Lymphoma by International Harmonization Project. The response will be measured as Complete response (CR), Partial response (PR), stable disease (SD) and Progressive disease (PD).

Statistical considerations. Statistical design Sample size calculation. The trial is a non-inferiority design. The expected EFS (Event Free Survival) in control arm is 70% at 2 years based on average EFS of patients treated with R-CHOP in trials from US and Group of adult lymphoma research (GELA) . The maximum acceptable non-inferiority margin is 7% with a hazard ratio of 1.3 corresponding to 63% EFS in experimental arm at 2 years.

• Local Control Rate [Срок оценки: 2 years]
• Overall Survival [Срок оценки: 2 years]
• Overall response rate [Срок оценки: 3 months]
• Late toxicity [Срок оценки: 2 years]
• Acute toxicity [Срок оценки: During radiation to 6 weeks from the end of radiation]
• Quality of Life scores [Срок оценки: 2 years]