Pediatric Hodgkin Lymphoma Treatment Trial With Low Cumulative Doses of Chemotherapy Agents and Reduced Radiation.

Study Overview
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Brief Summary
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This trial proposes a therapy for pediatric Hodgkin lymphoma with the objective of achieving high levels of long lasting complete remission with less risk of late effects. Patients of both genders, between 2 and 18 years, with newly diagnosed classical Hodgkin lymphoma are admitted. Initial staging provides stratification in three groups: low, intermediate and high risk. An initial set of two chemotherapy courses is administered to all cases after which a new disease assessment is performed. According to disease response a final therapy group is assigned. Rapid early responders benefit from less chemotherapy. At the end of chemotherapy, radiotherapy is delivered only to patients who do not achieve a complete response. Thus therapy is tailored to initial extension and disease responsiveness. Complete responders at the end of chemotherapy do not receive radiotherapy. Those who are in partial remission receive low dose (30Gy) involved node radiotherapy. Stable or progressive disease at any moment is assumed as a trial failure and new therapeutic strategies are offered to patients off protocol. Chemotherapy is based upon regimes with well known effectiveness in Hodgkin lymphoma. (i.e. ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine and ESHAP: Etoposide, methyl prednisolone, citarabine and cisplatin). The schedules are delivered with low cumulative drug doses and avoiding the use of toxic alkylating agents. Risks of secondary leukemia and infertility are thus minimized. Doxorubicin and bleomycin do not achieve cumulative doses that may expose to significant risk of heart or lung damage. Radiotherapy reduction avoids late radiation sequels. This clinical study proposes a therapeutic approach based on chemotherapy that do not sum up high cumulative toxic doses. Therapy is tailored according to initial risk assessment and disease responsiveness. Those who achieve a complete response to chemotherapy do not receive additional radiotherapy, thus avoiding further late effects.

Detailed Description
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This trial proposes a therapy for pediatric Hodgkin lymphoma with the objective of achieving high levels of long lasting complete remission with less risk of late effects. Patients of both genders, between 2 and 18 years, with newly diagnosed classical Hodgkin lymphoma are admitted. An open surgical biopsy with histopatological diagnosis is preferred. Initial staging provides stratification in three groups: low, intermediate and high risk. An initial set of two chemotherapy courses is administered to all cases after which an early disease response assessment is performed. According to disease response a final therapy group is assigned (7 arms). Imaging with PET-CT and Deauville Score is preferred for initial and further disease assessment. Complete response is defined by volume reduction and metabolic remission. In case PET-CT is not available, CT and ultrasound with volume reduction standards to assess response may be used. Rapid early responders who achieve complete remission (CR) benefit from less chemotherapy. Those who are in partial remission at the end of chemotherapy (late disease assessment) receive low dose (30Gy) involved node radiotherapy. At the end of chemotherapy, radiotherapy is delivered only to patients who do not achieve a CR. Thus, therapy is tailored according to initial extension and disease responsiveness. Complete responders at the end of chemotherapy do not receive radiotherapy. To avoid radiotherapy in the majority of cases constitutes a principal goal of this trial. Stable or progressive disease at any moment is assumed as a trial failure and new therapeutic strategies are offered to these patients off protocol. Chemotherapy is based upon regimes with well known effectiveness in Hodgkin lymphoma. (i.e. ABVD: doxorubicin, bleomycin, vinblastine and dacarbazine and ESHAP: Etoposide, methyl prednisolone, citarabine and cisplatin). Low risk arms (Arms A, B and B2) receive no more than 4 cycles of ABVD. Intermediate risk Arm C, 5 cycles of ABVD and Arm D 4 cycles of ABVD and 2 courses of ESHAP. High risk Arm E receives 3 cycles of ABVD and 3 Cycles of ESHAP, Arm F receives 4 courses of ABVD and 4 courses of ESHAP. The schedules are delivered projecting low cumulative drug doses and avoiding the use of toxic alkylating agents. Risks of secondary leukemia and infertility are thus minimized. Doxorubicin and bleomycin do not achieve cumulative doses that may expose to significant risk of heart or lung damage. Radiotherapy reduction avoids late radiation sequels. Cardiac, lung , thyroid and any other toxic effects are prospectively assessed at onset and regularly during and after therapy. The main event-free and overall survival proportions end points will be analyzed annually during the following 10 years after the last patient registration. This clinical study proposes a therapeutic approach based on chemotherapy that do not sum up high cumulative toxic doses. Therapy is tailored according to initial risk assessment and disease responsiveness. Those who achieve a complete response after chemotherapy do not receive additional radiotherapy, thus avoiding further late effects.

Official Title
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Non Randomized, Multicenter, Prospective Pediatric Hodgkin Lymphoma Treatment Trial Stratified According to Initial Risk Factors and Response to Chemotherapy, Reduced Cumulative Doses of Antineoplastic Agents and Radiotherapy.

Conditions
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Pediatric Hodgkin's Disease

Intervention / Treatment
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* Radiation: No radiotherapy if CR at the end of chemotherapy.
* Drug: Low risk with complete early response after two cycles of ABVD chemotherapy schedule. Only one more ABVD course is delivered.
* Drug: Low risk with partial remisssion after 4 cycles of ABVD chemotherapy schedule. Two ESHAP courses are delivered.
* Radiation: IN 30Gy RT in case of PR at the end of chemotherapy
* Drug: Intermediate risk with complete early response after two cycles of ABVD chemotherapy schedule. Three more ABVD courses are delivered.
* Drug: Intermediate risk with partial remission after two cycles of ABVD chemotherapy schedule. Four more chemotherapy courses are delivered alternating ESHAP and ABVD.
* Drug: High risk with complete early response after 1 ABVD and 1 ESHAP courses. Four more chemotherapy courses are delivered alternating ESHAP and ABVD.
* Drug: High risk with partial remission after 1 ABVD and 1 ESHAP courses. Six more chemotherapy courses are delivered alternating ESHAP and ABVD.
* Drug: Low risk with partial remission at early response assessment after two cycles of ABVD chemotherpay schedule. Two ABVD courses are delivered.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathological diagnosis of classical Hodgkin lymphoma. Normal renal, hepatic, pulmonary and metabolic function standards. Informed consent signed by patient and/or legal caretakers. Exclusion Criteria: Lymphocyte predominant nodular Hodgkin lymphoma Any form of immunodeficiency before diagnosis. (primary immunodeficiencies, trasplant recipients or immunosuppressive therapies of any kind including corticoid therapies during 28 days before diagnosis). Pregnancy and breastfeeding period. Sexually active female patients who do not accept an effective contraceptive method during therapy. Positive HIV serology. Penfigus or hepatic ductopenia. Hodgkin lymphoma as a secondary malignant disease.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Initial disease risk assignment defines three arms: low, intermediate and high risk. After early disease response assessment 7 Arms are defined, treated with more intense chemotherapy according to initial risk and therapy response. Finally radiotherapy is delivered only to patients who do not achieve complete remission after chemotherapy at late disease response assessment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Low risk with complete early response after two cycles of ABVD chemotherapy schedule. Only one more ABVD course is delivered. No radiotherapy if CR at the end of chemotherapy. | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Drug: Low risk with complete early response after two cycles of ABVD chemotherapy schedule. Only one more ABVD course is delivered.<br>* Low risk with complete early response after two cycles of ABVD chemotherapy schedule. Only one more ABVD course is delivered.<br>|
| Experimental: Group B<br>Low risk with partial remission at early response assessment after two cycles of ABVD chemotherpay schedule. Two ABVD courses are delivered. No radiotherapy if CR at the end of chemotherapy | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Drug: Low risk with partial remission at early response assessment after two cycles of ABVD chemotherpay schedule. Two ABVD courses are delivered.<br>* Low risk with partial remission at early response assessment after two cycles of ABVD chemotherpay schedule. Two ABVD courses are delivered.<br>|
| Experimental: Group B2<br>Low risk with partial remisssion after 4 cycles of ABVD chemotherapy schedule. Two ESHAP courses are delivered. No radiotherapy if CR at the end of chemotherapy. IN 30Gy RT in case of PR at the end of chemotherapy | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Drug: Low risk with partial remisssion after 4 cycles of ABVD chemotherapy schedule. Two ESHAP courses are delivered.<br>* Low risk with partial remission at early response assessment after two cycles of ABVD chemotherpay schedule. Two ABVD courses are delivered.<br>Radiation: IN 30Gy RT in case of PR at the end of chemotherapy<br>* Low risk with partial remisssion after 4 cycles of ABVD and 2 ESHAP courses: IN 30Gy RT<br>|
| Experimental: Group C<br>Intermediate risk with complete early response after two cycles of ABVD chemotherapy schedule. Three more ABVD courses are delivered. No radiotherapy if CR at the end of chemotherapy. | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Drug: Intermediate risk with complete early response after two cycles of ABVD chemotherapy schedule. Three more ABVD courses are delivered.<br>* Intermediate risk with complete early response after two cycles of ABVD chemotherapy schedule. Three more ABVD courses are delivered.<br>|
| Experimental: Group D<br>Intermediate risk with partial remission after two cycles of ABVD chemotherapy schedule. Four more chemotherapy courses are delivered alternating ESHAP and ABVD. No radiotherapy if CR at the end of chemotherapy. IN 30Gy RT in case of PR at the end of chemotherapy | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Radiation: IN 30Gy RT in case of PR at the end of chemotherapy<br>* Low risk with partial remisssion after 4 cycles of ABVD and 2 ESHAP courses: IN 30Gy RT<br>Drug: Intermediate risk with partial remission after two cycles of ABVD chemotherapy schedule. Four more chemotherapy courses are delivered alternating ESHAP and ABVD.<br>* Intermediate risk with partial remission after two cycles of ABVD chemotherapy schedule. Four more chemotherapy courses are delivered alternating ESHAP and ABVD.<br>|
| Experimental: Group E<br>High risk with complete early response after 1 ABVD and 1 ESHAP courses. Four more chemotherapy courses are delivered alternating ESHAP and ABVD. No radiotherapy if CR at the end of chemotherapy | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Drug: High risk with complete early response after 1 ABVD and 1 ESHAP courses. Four more chemotherapy courses are delivered alternating ESHAP and ABVD.<br>* High risk with complete early response after 1 ABVD and 1 ESHAP courses. Four more chemotherapy courses are delivered alternating ESHAP and ABVD.<br>|
| Experimental: Group F<br>High risk with partial remission after 1 ABVD and 1 ESHAP courses. Six more chemotherapy courses are delivered alternating ESHAP and ABVD. No radiotherapy if CR at the end of chemotherapy. IN 30Gy RT in case of PR at the end of chemotherapy | Radiation: No radiotherapy if CR at the end of chemotherapy.<br>* Adapted chemotherapy without radiotherapy<br>Radiation: IN 30Gy RT in case of PR at the end of chemotherapy<br>* Low risk with partial remisssion after 4 cycles of ABVD and 2 ESHAP courses: IN 30Gy RT<br>Drug: High risk with partial remission after 1 ABVD and 1 ESHAP courses. Six more chemotherapy courses are delivered alternating ESHAP and ABVD.<br>* High risk with partial remission after 1 ABVD and 1 ESHAP courses. Six more chemotherapy courses are delivered alternating ESHAP and ABVD.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event-free Survival | Event free survival probability (event= relapse or death) | 3-10 years | 
| Overall Survival | Overall survival probability (event= death) | 3-10 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute, chronic or late toxic events | Number of patientsexperiencing treatment-related adverse effects and mortality according to CTCAE v4.0 | 0-10 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric Hodgkin Lymphoma, therapy, reduced radiotherapy