Combination Chemotherapy Plus Low-Dose Radiation Therapy in Treating Patients With Stage I or Stage IIA Hodgkin's Lymphoma

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy use different ways to stop cancer cells from dividing so they stop growing or die. Radiation therapy uses high-energy x-rays to damage tumor cells. Combining chemotherapy with radiation therapy may kill more tumor cells. PURPOSE: This phase 2 trial is studying how well giving combination chemotherapy together with low-dose radiation therapy works in treating patients with stage I or stage IIA Hodgkin's lymphoma.

Detailed Description
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OBJECTIVES: Evaluate the freedom from progression in patients with stage I or IIA Hodgkin's lymphoma with a favorable prognosis treated with Stanford V-C chemotherapy comprising cyclophosphamide, doxorubicin, vinblastine, prednisone, vincristine, bleomycin, and etoposide with low-dose radiotherapy (RT). Minimize the early and late effects of treatment in these patients by avoiding staging laparotomy and its consequences, limiting cumulative doses of chemotherapy, and reducing the dose of RT to moderately bulky sites of disease. Assess early and late treatment-related toxicity, freedom from second disease progression, and overall survival at 5 and 10 years in patients treated with this regimen. Participants receive Stanford V-C chemotherapy comprising cyclophosphamide IV over 30 to 60 minutes weekly on weeks 1 and 5; doxorubicin IV and vinblastine IV over 5 minutes once weekly on weeks 1, 3, 5, and 7; oral prednisone every other day on weeks 1 to 8; vincristine IV, and bleomycin IV over 5 minutes once weekly on weeks 2, 4, 6, and 8; and etoposide IV over 60 minutes on days 1 and 2 of weeks 3 and 7. Prior to protocol amendment, participants were assigned to treatment on the basis of tumor size (< 5 cm vs 5 to 10 cm), with only the participants with larger tumors receiving RT. Beginning 2 to 3 weeks after completion of chemotherapy, participants in the +RT group will receive low-dose radiotherapy 5 days a week for approximately 3 weeks. Subsequent to amendment, all participants received RT. Participants are followed every 3 months for 2 years, every 6 months for 3 years, and then annually thereafter.

Official Title
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Risk-Adapted Stanford V-C With Radiotherapy for Clinical Stage I and IIA Favorable Hodgkin's Disease: The G5 Study

Conditions
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Lymphoma, Hodgkin Disease, Lymphoma, Hodgkin Disease, Lymphoma: Hodgkin

Intervention / Treatment
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* Drug: Vincristine
* Drug: Cyclophosphamide
* Drug: Doxorubicin
* Drug: Prednisone
* Drug: Bleomycin
* Drug: Etoposide
* Radiation: Low-dose radiotherapy (RT)


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Diagnosis of previously untreated stage I or IIA Hodgkin's lymphoma, eligible subtypes Nodular sclerosis Mixed cellularity Classical, not otherwise specified Age ≥ 18 years and ≤ 70 years Granulocytes ≥ 2 x 10e6/µL Platelets ≥ 150 x 10e6/µL Bilirubin ≤ 2.5 mg/dL Serum creatinine ≤ 2 mg/dL Patients > 50 years or those with a history of cardiac disease should have an ejection fraction ≥ 50% All scans, X-rays, laboratory tests must be performed within 6 weeks of enrollment Pathologic material reviewed at Stanford University Evaluation by Stanford Medical Oncology and Radiation Oncology with review at the Hodgkin's Disease Staging Conference Written informed consent EXCLUSION CRITERIA: Lymphocytic predominance Hodgkin's disease Prior treatment for Hodgkin's disease Mediastinal mass equal to or greater than one-third the maximum intrathoracic diameter on a standing posteroanterior chest x-ray Any lymph node mass > 10 cm in greatest trans-axial diameter Two or more extranodal sites of disease Constitutional (B) symptoms present at diagnosis Prior or concurrent malignancies within 5 years (EXCEPTION: basal cell carcinoma of the skin) Any medical contraindication to the planned treatment, including: Pregnant Positive antibody test for the human immunodeficiency virus (HIV)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 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: Patients with tumors 5 to 10 cm were to be assigned to concurrent radiotherapy, and participants with tumors less than 5 cm were initially planned to not receive radiotherapy.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stanford V-C + Low-dose Radiotherapy<br>Sanford V-C = Vinblastine, cyclophosphamide, doxorubicin, prednisone, bleomycin, + etoposide. Radiotherapy = 20 Gy modified involved field radiotherapy | Drug: Vincristine<br>* 1.4 mg/m² intravenously (IV) on week 2, 4, 6, 8<br>* Other names: 22-Oxovincaleukoblastine;Drug: Cyclophosphamide<br>* 650 mg/m², on week 1 and 5<br>* Other names: N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide;Drug: Doxorubicin<br>* 25 mg/m², on week 1, 3, 5, 7<br>* Other names: (8S-cis)-10-((3-amino-2,3,6-Trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione;Drug: Prednisone<br>* 40 mg/m², oral, every other day. Taper-reduction 10 mg/m² every other day during last 2 weeks of chemotherapy<br>* Other names: 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione;Drug: Bleomycin<br>* 5 u/m² intravenously (IV) on week 2, 4, 6, 8<br>* Other names: BLM;Drug: Etoposide<br>* 60 mg/m² x 2 intravenously (IV) on week 3, 7 (d 15, 16, 43, 44)<br>* Other names: 9-((4,6-O-Ethylidine-beta-D-glucopyranosyl)oxy)-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,4-dimethyloxyphenyl)furo(3',4'':6,7)naptho-(2,3-d)-1,3-dioxol-6(5aH)-one;Radiation: Low-dose radiotherapy (RT)<br>* 20 Grey (Gy) modified involved field radiotherapy administered as consolidative irradiation will beginning between 2 and 12 weeks after the completion of Stanford V-C chemotherapy regimen.<br>|
| Experimental: Stanford V-C only<br>Sanford V-C = Vinblastine, cyclophosphamide, doxorubicin, prednisone, bleomycin, + etoposide. | Drug: Vincristine<br>* 1.4 mg/m² intravenously (IV) on week 2, 4, 6, 8<br>* Other names: 22-Oxovincaleukoblastine;Drug: Cyclophosphamide<br>* 650 mg/m², on week 1 and 5<br>* Other names: N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide;Drug: Doxorubicin<br>* 25 mg/m², on week 1, 3, 5, 7<br>* Other names: (8S-cis)-10-((3-amino-2,3,6-Trideoxy-alpha-L-lyxo-hexopyranosyl)oxy)-7,8,9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-5,12-naphthacenedione;Drug: Prednisone<br>* 40 mg/m², oral, every other day. Taper-reduction 10 mg/m² every other day during last 2 weeks of chemotherapy<br>* Other names: 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione;Drug: Bleomycin<br>* 5 u/m² intravenously (IV) on week 2, 4, 6, 8<br>* Other names: BLM;Drug: Etoposide<br>* 60 mg/m² x 2 intravenously (IV) on week 3, 7 (d 15, 16, 43, 44)<br>* Other names: 9-((4,6-O-Ethylidine-beta-D-glucopyranosyl)oxy)-5,8,8a,9-tetrahydro-5-(4-hydroxy-3,4-dimethyloxyphenyl)furo(3',4'':6,7)naptho-(2,3-d)-1,3-dioxol-6(5aH)-one;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free Survival (PFS) | Progression-free survival was assessed for 3 years from the completion of treatment. Progression-free survival was considered to mean the proportion of patients (percentage) still alive without disease recurrence or progression. | up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Complete Response | The frequency of complete response (CR) is reported as the number (proportion) of subjects in complete response, as assessed during weeks 4 to 5 of chemotherapy. Per protocol, CR is defined as complete regression of all palpable and radiographic demonstrable disease by computed tomography (CT) scan or positron emission tomography-CT (PET-CT). | 5 weeks | 
| Early Treatment-related Toxicity | Early treatment-related toxicity was assessed as the number of treatment-related, non-serious adverse events that occurred during treatment or within 30 days of the completion of treatment. | Within 30 days of treatment | 
| Late Treatment-related Toxicity | Late treatment-related toxicity was assessed as the overall number of late-appearing toxicities (ie, related adverse events, after treatment completion) including but not limited to diagnosis of a 2nd cancer; hypothyroidism; infertility; pulmonary toxicity; or cardiac toxicity, at up to 16 years from date of diagnosis. | 16 years | 
| Second Hodgkin's Disease Progression | Second Hodgkin's disease progression is reported as the number of participants experiencing 2 instances of progression of the underlying Hodgkin's disease, assessed at up to 16 years from date of diagnosis. | 16 years | 
| Overall Survival (OS) | Overall survival was assessed at up to 16 years from date of diagnosis, and reported as the median years of survival with standard deviation. | 16 years | 
| Survival at 5 and 10 Years | Survival at 5 and 10 years is expressed at the percentage of subjects known to remain alive at those timepoints. | 5 and 10 years |