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

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

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.

Study Overview

• Status: Completed
• Conditions: Lymphoma; Hodgkin Disease; Lymphoma, Hodgkin Disease; Lymphoma: Hodgkin
• Intervention / Treatment: Drug: Vincristine; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Prednisone; Drug: Bleomycin; Drug: Etoposide; Radiation: Low-dose radiotherapy (RT)

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 76
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine
    • Vallejo, California, United States, 94589
      • Kaiser Permanente Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stanford V-C + Low-dose Radiotherapy; "Sanford V-C" = Vinblastine, cyclophosphamide, doxorubicin, prednisone, bleomycin, + etoposide. Radiotherapy = 20 Gy modified involved field radiotherapy	Drug: Vincristine; 1.4 mg/m² intravenously (IV) on week 2, 4, 6, 8; Other Names: VCR; Oncovin; Vincasar; 22-Oxovincaleukoblastine; Vincristin; Vinblastine; Leurocristine sulfate; LCR; Vincristina; Vincristinum; 22-Oxovincaleukoblastin; Drug: Cyclophosphamide; 650 mg/m², on week 1 and 5; Other Names: Cytoxan; Ciclofosfamida; Cyclophosphamidum; Cytophosphane; Ledoxina; Neosar; Cyclophosphamid; Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester; 2-[Bis(2-chloroethylamino)]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide; N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide; Drug: Doxorubicin; 25 mg/m², on week 1, 3, 5, 7; Other Names: Adriamycin; Rubex; Doxorubicinum; Doxorubicine; Hydroxydaunomycin HCl; Hydroxydoxorubicin HCl; Hydroxydaunorubicin; 14-hydroxydaunomycin; 14-hydroxydaunorubicine; (1S,3S)-3-Glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside; (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; 40 mg/m², oral, every other day. Taper-reduction 10 mg/m² every other day during last 2 weeks of chemotherapy; Other Names: Deltasone; Orasone; Meticorten; Prednisonum; Rayos; Dehydrocortisone; Liquid Pred; Prednicot; predniSONE Intensol; Sterapred; Prednisona; 1,2-Dehydrocortisone; 1,4-Pregnadiene-17alpha,21-diol-3,11,20-trione; 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione; Drug: Bleomycin; 5 u/m² intravenously (IV) on week 2, 4, 6, 8; Other Names: Bleomycin A2; Bleomycine; Bleocin; Bleomicin; Bleomicina; Bleomycinum; BLM; Drug: Etoposide; 60 mg/m² x 2 intravenously (IV) on week 3, 7 (d 15, 16, 43, 44); Other Names: Toposar; Vepesid; VP-16; Etopophos; Etoposido; Etoposidum; trans-Etoposide; 4-demethylepipodophyllotoxin β-D-ethylideneglucoside; 4'-Demethylepipodophyllotoxin 9-(4,6-O-(R)-ethylidene-beta-D-glucopyranoside); 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); 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.
Experimental: Stanford V-C only; "Sanford V-C" = Vinblastine, cyclophosphamide, doxorubicin, prednisone, bleomycin, + etoposide.	Drug: Vincristine; 1.4 mg/m² intravenously (IV) on week 2, 4, 6, 8; Other Names: VCR; Oncovin; Vincasar; 22-Oxovincaleukoblastine; Vincristin; Vinblastine; Leurocristine sulfate; LCR; Vincristina; Vincristinum; 22-Oxovincaleukoblastin; Drug: Cyclophosphamide; 650 mg/m², on week 1 and 5; Other Names: Cytoxan; Ciclofosfamida; Cyclophosphamidum; Cytophosphane; Ledoxina; Neosar; Cyclophosphamid; Bis(2-chloroethyl)phosphoramide cyclic propanolamide ester; 2-[Bis(2-chloroethylamino)]-tetrahydro-2H-1,3,2-oxazaphosphorine-2-oxide; N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine 2-oxide; Drug: Doxorubicin; 25 mg/m², on week 1, 3, 5, 7; Other Names: Adriamycin; Rubex; Doxorubicinum; Doxorubicine; Hydroxydaunomycin HCl; Hydroxydoxorubicin HCl; Hydroxydaunorubicin; 14-hydroxydaunomycin; 14-hydroxydaunorubicine; (1S,3S)-3-Glycoloyl-3,5,12-trihydroxy-10-methoxy-6,11-dioxo-1,2,3,4,6,11-hexahydrotetracen-1-yl 3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranoside; (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; 40 mg/m², oral, every other day. Taper-reduction 10 mg/m² every other day during last 2 weeks of chemotherapy; Other Names: Deltasone; Orasone; Meticorten; Prednisonum; Rayos; Dehydrocortisone; Liquid Pred; Prednicot; predniSONE Intensol; Sterapred; Prednisona; 1,2-Dehydrocortisone; 1,4-Pregnadiene-17alpha,21-diol-3,11,20-trione; 17,21-Dihydroxypregna-1,4-diene-3,11,20-trione; Drug: Bleomycin; 5 u/m² intravenously (IV) on week 2, 4, 6, 8; Other Names: Bleomycin A2; Bleomycine; Bleocin; Bleomicin; Bleomicina; Bleomycinum; BLM; Drug: Etoposide; 60 mg/m² x 2 intravenously (IV) on week 3, 7 (d 15, 16, 43, 44); Other Names: Toposar; Vepesid; VP-16; Etopophos; Etoposido; Etoposidum; trans-Etoposide; 4-demethylepipodophyllotoxin β-D-ethylideneglucoside; 4'-Demethylepipodophyllotoxin 9-(4,6-O-(R)-ethylidene-beta-D-glucopyranoside); 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?

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

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: Ranjana H Advani, MD, Stanford University

Study record dates

Study Major Dates

• Study Start: June 1, 2001
• Primary Completion (Actual): April 26, 2013
• Study Completion (Actual): February 13, 2017

Study Registration Dates

• First Submitted: November 9, 2001
• First Submitted That Met QC Criteria: January 26, 2003
• First Posted (Estimate): January 27, 2003

Study Record Updates

• Last Update Posted (Actual): July 24, 2018
• Last Update Submitted That Met QC Criteria: June 25, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma; Hodgkin Disease; 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; Etoposide; Etoposide phosphate; Prednisone; Doxorubicin; Liposomal doxorubicin; Vincristine; Bleomycin; Vinblastine
• Other Study ID Numbers: IRB-13081; LYMHD0002 (Other Identifier: OnCore)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No