The Palliative Benefit of Involved-site Radiotherapy for Patients With Advanced-stage Diffuse Large B-cell Lymphoma

The Palliative Benefit of Involved-site Radiotherapy Following Effective Chemotherapy for Patients With Advanced-stage Diffuse Large B-cell Lymphoma: Wuhan University Cancer Center - NHL04 Trial

The standard treatment approach for patients with stage III-IV DLBCL is combination chemotherapy. Receipt of consolidation radiotherapy (RT) after effective chemotherapy was associated with improved in-field control and event-free survival. However, it is uncertain for the radiotherapy field size to treat for these patients after chemotherapy. Involved-field radiotherapy (IFRT) after effective chemotherapy is a common strategy for patients with stage III-IV DLBCL. There is not a clinical trial to research whether the sequential narrowed radiotherapy field size (involved-site radiotherapy, ISRT) can obtain the same efficacy as IFRT and decrease toxicities related to radiotherapy.

Study Overview

• Status: Recruiting
• Conditions: Diffuse Large B-cell Lymphoma
• Intervention / Treatment: Radiation: Consolidation involved-site radiotherapy (ISRT); Drug: cyclophosphamide; Drug: doxorubicin; Drug: vincristine; Drug: prednisone; Radiation: Consolidation involved-field radiotherapy (IFRT)

Detailed Description

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Approximately 50% of patients present with stage III-IV disease at diagnosis. The standard treatment approach for these patients is combination chemotherapy. the role of radiation therapy (RT) after effective system therapy in stage III-IV DLBCL (advanced-stage DLBCL) is controversial. The recommended approaches for patients with stage III-IV disease by The National Comprehensive Cancer Network (NCCN) are that consolidation RT is managed for patients who achieved a complete response (CR) to chemotherapy and palliative RT for patients with partial response (PR) after chemotherapy. However, it is uncertain for the radiotherapy field size to treat for these patients after chemotherapy.

Some benefits of consolidation RT after chemotherapy exist for patients with advanced-stage DLBCL. One of the important aims of treatment for these patients is the improvement of event-free survival (EFS). After patients receive chemotherapy alone, the most common site of disease recurrence is at sites of initial disease involvement. The complications related to chemotherapy, including second malignancies and other non-neoplastic late events, were needed to emphasize for those patients managed with more cycles' regimens alone to increase the efficacy of patients with advanced-stage DLBCL. Receipt of consolidation RT was associated with improved in-field control and EFS though no difference in overall survival (OS) when compared to patients without consolidation RT. Several randomized and retrospective studies demonstrated that the EFS (even the OS) can be improved by consolidation RT for patients with advanced-stage DLBCL after CHOP or CHOP-like chemotherapy. The patients randomized among those diagnosed initially with bulky disease (>10 cm), those achieving CR or PR after chemotherapy, and even those in stage IV with bone marrow involved.

The complications related to consolidation RT also need to be additionally explored for those patients since the efficacy of advanced-stage DLBCL has improved by combined-modality therapy (CMT). Especially, considerable difficulties in the continuous salvage options are unavoidable because of the risk of blood cell production disorders associated to extensive-field radiotherapy. Consolidation involved-field radiotherapy (IFRT) after effective chemotherapy is common palliative strategy for patients with advanced-stage DLBCL. The morbidity of treatment may be decreased further by RT with the radiation field size reduction. Involved-site radiotherapy (ISRT), based on a modified involved field, aims to reduce the radiation volume treated and the probability of late effects. Its radiation targets include a gross tumor volume (GTV), a clinical target volume (CTV), and a planning target volume (PTV), which were defined in International Commission on Radiation Units and Measurements Report (ICRU) 50. This is based on defining the site of gross disease before chemotherapy, the GTV and using a CT-based volume with an expansion to form a CTV in the cranio-caudal direction. There is not a clinical trial to research whether the sequential narrowed radiotherapy field size (involved-site radiotherapy, ISRT) can obtain the same efficacy as IFRT and decrease toxicities related to radiotherapy.

To evaluate the differences between IFRT and ISRT in the efficacy and complications related to consolidation RT for patients with advanced-stage DLBCL who achieved effective chemotherapy. The CTV of ISRT is defined as the region including the prechemotherapy volume of disease with 1.5 cm margin expanded cranio-caudally in the direction of potential lymphatic spread. The CTV should not extend into air in the transverse plane and should be limited in the involved lymph node region defined by the Cancer and Leukemia Group B (CALGB). The PTV is then extended from CTV by adding the necessary margin for setup error and organ motion.

• Study Type: Interventional
• Enrollment (Anticipated): 120
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Wei Du, MD; Phone Number: 0086-18972161688; Email: cuicandu@126.com

Study Locations

• China
  • Hubei
    • Wuhan, Hubei, China, 430071
      • Recruiting
      • DiDeng

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Both male and female aged range from 18 years to 65 years.
• Eastern Cooperative Oncology Group(ECOG) performance status of 0 or 1.
• All patients had histologically confirmed Diffuse large B-cell lymphoma.
• Advanced-stage DLBCL patients at newly diagnosed or recurrent without RT in initial management.
• Adequate organ function.
• Negative pregnancy test.
• Signed informed consent document on file.

Exclusion Criteria:

• Woman who were pregnant or lactating.
• With severe local infection or general infective disease.
• Primary lymphoma in special organ including cuticula, center never system, gastrointestinal tract, testicle, and lung.
• With other second primary malignancy except cutaneum carcinoma.
• Being or planning to participate in other study.
• Any patient who in the opinion of the investigator should not participate in the study.

Withdrawal Criteria:

• Patient are free to withdrawal completely from the study at any time upon request.
• Patient in the study may be stopped with the patient agreement at any time at the discretion of investigator.
• In-field progression on irradiation ongoing.
• Poor tolerability adverse events in the period of chemotherapy or irradiation after enrolled in the study.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: ISRT group; Six cycles Chemotherapy (cyclophosphamide 750mg/square meter on day 1 + doxorubicin 50mg/square meter on day 1 + vincristine 1.4mg/square meter on day 1 (up to a maximal dose of 2 mg) + prednisone 60mg/square meter on day 1 through 5, repeated at 21-day intervals) . Consolidation involved-site radiotherapy (ISRT) following in patient with complete or partial response beginning 1 month after last cycle of chemotherapy.	Radiation: Consolidation involved-site radiotherapy (ISRT); 6 cycles modern CHOP chemotherapy followed consolidation involved-site radiotherapy (ISRT). Involved-site radiotherapy (ISRT) is based on defining the site of gross disease before chemotherapy, the GTV and using a CT-based volume with an expansion to form a CTV in the cranio-caudal direction. The general dose had been guided that 30-36Gy in 15~18 fractions of 2 Gy 5 days per week was managed for patients with complete response (CR) after chemotherapy and 40-50Gy in 20~25 fractions of 2 Gy 5 days per week for partial response (PR).; Drug: cyclophosphamide; Patients in both arms will be given cyclophosphamide chemotherapy; Drug: doxorubicin; Patients in both arms will be given doxorubicin chemotherapy; Drug: vincristine; Patients in both arms will be given vincristine chemotherapy; Drug: prednisone; Patients in both arms will be given prednisone chemotherapy
Active Comparator: IFRT group; Six cycles Chemotherapy (cyclophosphamide 750mg/square meter on day 1 + doxorubicin 50mg/square meter on day 1 + vincristine 1.4mg/square meter on day 1 (up to a maximal dose of 2 mg) + prednisone 60mg/square meter on day 1 through 5, repeated at 21-day intervals). Consolidation involved-field radiotherapy (IFRT) following in patient with complete or partial response beginning 1 month after last cycle of chemotherapy.	Drug: cyclophosphamide; Patients in both arms will be given cyclophosphamide chemotherapy; Drug: doxorubicin; Patients in both arms will be given doxorubicin chemotherapy; Drug: vincristine; Patients in both arms will be given vincristine chemotherapy; Drug: prednisone; Patients in both arms will be given prednisone chemotherapy; Radiation: Consolidation involved-field radiotherapy (IFRT); 6 cycles modern CHOP chemotherapy followed consolidation involved-field radiotherapy (IFRT). Radiotherapy field of IFRT defined by CALGB is encompassed the prechemotherapy gross tumor. The general dose had been guided that 30-36Gy in 15~18 fractions of 2 Gy 5 days per week was managed for patients with complete response (CR) after chemotherapy and 40-50Gy in 20~25 fractions of 2 Gy 5 days per week for partial response (PR).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression-free survival - PFS	Treatment failure was defined as any recurrence of non-Hodgkin lymphoma.	from the date of diagnosis to the date of treatment failure or death from any cause, whichever occurs first, Assessed up to 100 months.
Adverse events with grade 3 or 4 - AEs	Toxicity was scored according to the toxicity scale of the National Cancer Institute Common Terminology Criteria for Adverse Events 3.0.	The time from the day of treatment to the day of the first documented disease progression or death from any cause, Assessed up to 24 months.

Secondary Outcome Measures

Outcome Measure	Time Frame
Overall survival - OS	From the initial diagnosis of follicular lymphoma to death from any cause, Assessed up to 120 months.
Rate of in-field progression	From the start of RT to the first documented disease progression within the radiotherapy field, Assessed up to 60 months.
Rate of out-field progression	From the start of RT to the first documented disease progression outside the radiotherapy field, Assessed up to 60 months.
Rate of regional failure	From the start of RT to the first documented disease progression outside of ISRT field but within the involved region defined as CALGB, Assessed up to 60 months.

Collaborators and Investigators

• Sponsor: Wuhan University

Study record dates

Study Major Dates

• Study Start: October 1, 2015
• Primary Completion (Anticipated): October 1, 2019
• Study Completion (Anticipated): October 1, 2025

Study Registration Dates

• First Submitted: May 7, 2015
• First Submitted That Met QC Criteria: May 15, 2015
• First Posted (Estimate): May 20, 2015

Study Record Updates

• Last Update Posted (Estimate): December 14, 2015
• Last Update Submitted That Met QC Criteria: December 11, 2015
• Last Verified: December 1, 2015

More Information

Terms related to this study

• Keywords: chemotherapy; advanced-stage DLBCL; ISRT
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Cyclophosphamide; Prednisone; Doxorubicin; Vincristine
• Other Study ID Numbers: WUCC-NHL04 Trial