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Etoposide 100 mg/m2 IV Days 1, 2, 3 Dox 25 mg/m2 IV Day 1 Cyclo 650mg/m2 IV Day 1 Procarb 100 mg/m2 PO Days 1-7 Pred 40 mg/m2 PO Days 1-14 Bleo 10u/m2 IV Day 8 Vincristine 1.4 mg/m2 IV Day 8 Q 21 Days x 6 cycles

Etoposide 200 mg/m2 IV Days 1, 2, 3 Dox 35 mg/m2 IV Day 1 Cyclo 1,250 mg/m2 IV Day 1 Procarb 100 mg/m2 PO Days 1-7 Pred 40 mg/m2 PO Days 1-14 Bleo 10u/m2 IV Day 8 Vincristine 1.4 mg/m2 IV Day 8 G-CSF 5mcg/kg/day SQ Days 8-14 Q 21 Days x 6 cycles

Doxorubicin 25 mg/m2 IV Bleomycin 10u/m2 IV Vinblastine 6mg/m2 IV Dacarbazine 375 mg/m2 IV Days 1, 15 Q 28 Days x 2

bleomycin sulfate

filgrastim

ABVD regimen

BEACOPP regimen

cyclophosphamide

dacarbazine

doxorubicin hydrochloride

etoposide

prednisone

procarbazine hydrochloride

vinblastine sulfate

vincristine sulfate

Oliver W. Press, MD, PhD

RATIONALE: Drugs used in chemotherapy work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells. G-CSF may help lessen the side effects in patients receiving chemotherapy. Imaging procedures, such as fludeoxyglucose F 18-PET/CT imaging, may help doctors predict how patients will respond to treatment.

PURPOSE: This phase II trial is studying fludeoxyglucose F 18-PET/CT imaging to see how well it works in assessing response to combination chemotherapy and allow doctors to plan better additional further treatment in treating patients with stage III or stage IV Hodgkin lymphoma.

OBJECTIVES:

Primary

* To estimate the 2-year progression-free survival (PFS) of HIV-negative patients with stage III-IV Hodgkin lymphoma treated with response-adapted therapy based on fludeoxyglucose F 18 (FDG)-PET imaging after 2 courses of doxorubicin hydrochloride, bleomycin, vinblastine, and dacarbazine (ABVD).
* To estimate the 2-year PFS of patients who are PET-positive after treatment with 2 courses of ABVD and an escalated dose regimen comprising cyclophosphamide, doxorubicin hydrochloride, etoposide, vincristine sulfate, bleomycin, procarbazine hydrochloride, and prednisone (BEACOPP).

Secondary

* To estimate the 2-year overall survival (OS) of patients treated with these regimens.
* To estimate the response rate (i.e., complete and partial responses) in patients treated with these regimens.
* To evaluate the toxicity of these response-adapted regimens.
* To document the feasibility of centralized, real-time review of FDG-PET imaging for U.S. cooperative group studies.
* To prospectively evaluate the overall response rate, complete response rate, PFS, and OS of HIV-positive patients treated with these response-adapted regimens.

OUTLINE: This is a multicenter study.

All patients undergo baseline whole-body fludeoxyglucose F 18 (FDG)-PET/CT imaging before beginning chemotherapy. Patients then receive doxorubicin hydrochloride IV, bleomycin IV, vinblastine IV, and dacarbazine IV (ABVD) on days 1 and 15. Treatment repeats every 28 days for up to 2 courses in the absence of disease progression or unacceptable toxicity. Between days 22 and 25 of course 2, patients undergo a second FDG-PET/CT scan to assess response. Subsequent therapy is based on FDG-PET/CT scan results. Patients are stratified according to FDG-PET positivity (yes vs no). Patients who are FDG-PET-negative continue treatment with ABVD for up to 4 additional courses in the absence of disease progression or unacceptable toxicity. Patients who are FDG-PET-positive are then further stratified according to HIV positivity (yes or no) and receive 1 of the following treatment regimens:

* Escalated-dose BEACOPP chemotherapy: HIV-negative patients receive escalated-dose BEACOPP chemotherapy comprising doxorubicin hydrochloride IV and cyclophosphamide IV on day 1, etoposide IV on days 1-3, oral procarbazine hydrochloride on days 1-7, oral prednisone on days 1-14, and bleomycin IV and vincristine IV on day 8. Patients receive filgrastim (G-CSF) subcutaneously on days 8-14. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.
* Standard-dose BEACOPP chemotherapy: HIV-positive patients receive standard dose BEACOPP chemotherapy comprising doxorubicin hydrochloride IV and cyclophosphamide IV on day 1, etoposide IV on days 1-3, oral procarbazine hydrochloride on days 1-7, oral prednisone on days 1-14, and bleomycin IV and vincristine IV on day 8. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Six to eight weeks after completion of chemotherapy, patients undergo a post-treatment FDG-PET/CT scan.

Some patients may undergo bone marrow biopsy at 1 month after the last course of chemotherapy.

After completion of study treatment, patients are followed up periodically for 7 years.

S0816 Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma

A Phase II Trial of Response-Adapted Therapy of Stage III-IV Hodgkin Lymphoma Using Early Interim FDG-PET Imaging

Disease progression is defined using the 2007 revised Cheson et al. criteria that is at least 50% increase in sum of the product of the diameters (SPD) of target measurable nodal lesions over the smallest sum observed, or \>= 50% increase in greatest transverse diameter (GTD) of any nodal \> 1 cm in shortest axis, or \>= 50% increase in the SPD of other target measurable lesions over the smallest sum observed, any new bone marrow involvement, any new lesion, lymph node with long axis is \> 1.5 cm or if both long and short axes are \> 1 cm, PET positive if patients with no pretreatment PET scan or when PET scan was positive before therapy. Progression-free survival is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact.

Measured from date of registration to date of death due to any cause. Patients last known to be alive and are censored at date of last contact.

Complete Response (CR) is a complete disappearance of all disease with the exception of the following. If no PET scan or when the PET scan was positive before therapy, a post-treatment residual mass of any size is permitted if it is PET negative. If the PET scan was negative before therapy, all nodal masses at baseline must have regressed. No new lesions. Previously enlarged organs must have regressed and not be palpable. Bone marrow (BM) must be negative if positive at baseline. Normalization of markers. Partial Response (PR) is a 50% decrease in the sum of products of greatest diameters (SPD) for up to 6 identified dominant lesions, including spleenic and hepatic nodules from baseline. No new lesions and no increase in the size of liver, spleen or other nodes. If PET scan or when the PET scan was positive before therapy, PET should be positive in at least one previously involved site.

Adverse Events (AEs) are reported by the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. For each patient, worst grade of each event type is reported. Grade 3 = Severe, Grade 4 = Life-threatening, Grade 5 = Fatal.

Disease progression is defined using the 2007 revised Cheson et al. criteria that is at least 50% increase in sum of the product of the diameters (SPD) of target measurable nodal lesions over the smallest sum observed, or \>= 50% increase in greatest transverse diameter (GTD) of any nodal \> 1 cm in shortest axis, or \>= 50% increase in the SPD of other target measurable lesions over the smallest sum observed, any new bone marrow involvement, any new lesion, lymph node with long axis is \>1.5 cm or if both long and short axes are \> 1 cm, PET positive if patients with no pretreatment PET scan or when PET scan was positive before therapy. progression-free survival is measured from date of registration to date of first observation of progressive disease, or death due to any cause. Patients last known to be alive and progression-free are censored at date of last contact.

National Cancer Institute (NCI)

SWOG Cancer Research Network

Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 2 cycles

HIV-negative: Initial ABVD

Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 4 cycles

HIV-negative and PET-negative: Continued ABVD

Etoposide 200 mg/m\^2 IV Days 1, 2, 3, Doxorubicin 35 mg/m\^2 IV Day 1, Cyclophosphamide 1,250 mg/m\^2 IV Day 1, Procarbzine 100 mg/m\^2 PO Days 1-7, Prednisone 40 mg/m\^2 PO Days 1-14, Bleomycin 10u/m\^2 IV Day 8, Vincristine 1.4 mg/m\^2 IV Day 8, G-CSF 5mcg/kg/day SQ Days 8-14, Q 21 Days x 6 cycles

HIV-negative and PET-positive: BEACOPP Escalated

HIV-positive: Initial ABVD

HIV-positive and PET-negative: Continued ABVD

Etoposide 100 mg/m\^2 IV Days 1, 2, 3, Doxorubicin 25 mg/m\^2 IV Day 1, Cyclophosphamide 650 mg/m\^2 IV Day 1, Procarbzine 100 mg/m\^2 PO Days 1-7, Prednisone 40 mg/m\^2 PO Days 1-14, Bleomycin 10u/m\^2 IV Day 8, Vincristine 1.4 mg/m\^2 IV Day 8, Q 21 Days x 6 cycles

HIV-positive and PET-positive: BEACOPP Standard

Total

Age, Continuous

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

Only eligible and evaluable HIV-positive patients were included in the analysis.

Lymphoma Committee Statistician

HIV-negative patients treated with 2 cycles of ABVD followed by response-adapted therapy. Initial ABVD: Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 2 cycles. Interim PET-negative patients continue with 4 cycles of ABVD: Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 4 cycles. Interim PET-positive patients receive 6 cycles of escalated BEACOPP: Etoposide 200 mg/m\^2 IV Days 1, 2, 3, Doxorubicin 35 mg/m\^2 IV Day 1, Cyclophosphamide 1,250 mg/m\^2 IV Day 1, Procarbzine 100 mg/m\^2 PO Days 1-7, Prednisone 40 mg/m\^2 PO Days 1-14, Bleomycin 10u/m\^2 IV Day 8, Vincristine 1.4 mg/m\^2 IV Day 8, G-CSF 5mcg/kg/day SQ Days 8-14, Q 21 Days x 6 cycles.

HIV-negative: 2 Cycles of ABVD Followed by PET-directed Therap

Eligible and evaluable HIV-negative patients who started initial ABVD were included in the analysis regardless the response-adapted therapy after 2 initial cycles of ABVD was administered.

Percentage of HIV-negative Patients With 2-year Progression-free Survival (PFS) Treated With 2 Initial Cycles of Adriamycin, Bleomycin, Vnblastine, and Dacarbazine (ABVD) Followed by Response-adapted Therapy Based on Interim FDG-PET Imaging.

HIV-negative patients who are PET-positive are treated with 2 cycles of ABVD followed by escalated BEACOPP. Initial ABVD: Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 2 cycles. Interim PET-positive patients receive 6 cycles of escalated BEACOPP: Etoposide 200 mg/m\^2 IV Days 1, 2, 3, Doxorubicin 35 mg/m\^2 IV Day 1, Cyclophosphamide 1,250 mg/m\^2 IV Day 1, Procarbzine 100 mg/m\^2 PO Days 1-7, Prednisone 40 mg/m\^2 PO Days 1-14, Bleomycin 10u/m\^2 IV Day 8, Vincristine 1.4 mg/m\^2 IV Day 8, G-CSF 5mcg/kg/day SQ Days 8-14, Q 21 Days x 6 cycles.

HIV-negative: 2 Cycles of ABVD Followed by Escalated BEACOPP

Eligible and evaluable HIV-negative patients who were PET-positive after 2 cycles of ABVD were included in the analysis.

Percentage of HIV-negative Patients Who Are PET-positive After 2 Cycles of ABVD With 2-year PFS

HIV-negative:2 Cycles of ABVD Followed by PET-directed Therapy

Percentage of HIV-negative Patients With 2-year Overall Survival (OS) Treated With 2 Initial Cycles of ABVD Followed by Response-Adapted Therapy Based on Interim FDG-PET Imaging

Initial ABVD: Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 2 cycles Continued ABVD: Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 4 cycles

PET-negative: Continued ABVD After 2 Cycles of ABVD

Initial ABVD: Doxorubicin 25 mg/m\^2 IV, Bleomycin 10u/m\^2 IV, Vinblastine 6mg/m\^2 IV, Dacarbazine 375 mg/m\^2 IV Days 1,15 Q 28 Days x 2 cycles escalated BEACOPP: Etoposide 200 mg/m\^2 IV Days 1, 2, 3, Doxorubicin 35 mg/m\^2 IV Day 1, Cyclophosphamide 1,250 mg/m\^2 IV Day 1, Procarbzine 100 mg/m\^2 PO Days 1-7, Prednisone 40 mg/m\^2 PO Days 1-14, Bleomycin 10u/m\^2 IV Day 8, Vincristine 1.4 mg/m\^2 IV Day 8, G-CSF 5mcg/kg/day SQ Days 8-14, Q 21 Days x 6 cycles

PET-positive: BEACOPP Escalated After 2 Cycles of ABVD

Only eligible and evaluable HIV-negative patients who treated with response-adapted therapy based on FDG-PET imaging after 2 cycles of ABVD were included in the analysis

Complete and Partial Response Rates for HIV-negative Patients Treated With Response- Adapted Therapy Based on FDG-PET Imaging After 2 Cycles of ABVD

ALT, SGPT (serum glutamic pyruvic transaminase)

AST, SGOT

Adult respiratory distress syndrome (ARDS)

Albumin, serum-low (hypoalbuminemia)

Alkaline phosphatase

Allergic reaction/hypersensitivity

Anorexia

Arthritis (non-septic)

Carbon monoxide diffusion capacity (DL(co))

Colitis

Colitis, infectious (e.g., Clostridium difficile)

Constipation

Cough

Creatinine

Cytokine release syndrome/acute infusion reaction

Dehydration

Diarrhea

Dizziness

Dyspnea (shortness of breath)

FEV(1)

Fatigue (asthenia, lethargy, malaise)

Febrile neutropenia

Fever in absence of neutropenia, ANC lt1.0x10e9/L

Glucose, serum-high (hyperglycemia)

Heartburn/dyspepsia

Hemoglobin

Hemolysis

Hemorrhage, pulmonary/upper respiratory - Nose

Hypotension

Hypoxia

Inf (clin/microbio) w/Gr 3-4 neuts - Blood

Inf (clin/microbio) w/Gr 3-4 neuts - Colon

Inf (clin/microbio) w/Gr 3-4 neuts - Lung

Inf (clin/microbio) w/Gr 3-4 neuts - Meninges

Inf (clin/microbio) w/Gr 3-4 neuts - Mucosa

Inf (clin/microbio) w/Gr 3-4 neuts - Skin

Inf (clin/microbio) w/Gr 3-4 neuts - Soft tissue

Inf (clin/microbio) w/Gr 3-4 neuts - UTI

Inf (clin/microbio) w/Gr 3-4 neuts - Upper airway

Inf (clin/microbio) w/Gr 3-4 neuts - Vagina

Inf w/normal ANC or Gr 1-2 neutrophils - Catheter

Inf w/normal ANC or Gr 1-2 neutrophils - Lung

Inf w/normal ANC or Gr 1-2 neutrophils - Oral cav

Inf w/normal ANC or Gr 1-2 neutrophils - Skin

Infection with normal ANC or Grade 1 or 2 neutroph

Infection with unknown ANC - Lung (pneumonia)

Left ventricular systolic dysfunction

Leukocytes (total WBC)

Lymphopenia

Metabolic/Laboratory-Other (Specify)

Mood alteration - agitation

Mood alteration - anxiety

Mood alteration - depression

Mucositis/stomatitis (clinical exam) - Oral cavity

Mucositis/stomatitis (functional/symp) - Oral cav

Muscle weakness, not d/t neuropathy - body/general

Musculoskeletal/Soft Tissue-Other (Specify)

Nausea

Neuropathy: motor

Neuropathy: sensory

Neutrophils/granulocytes (ANC/AGC)

Osteonecrosis (avascular necrosis)

Pain - Abdomen NOS

Pain - Back

Pain - Bone

Pain - Cardiac/heart

Pain - Chest wall

Pain - Chest/thorax NOS

Pain - Extremity-limb

Pain - Head/headache

Pain - Joint

Pain - Muscle

Pain - Oral cavity

Pain - Skin

Pain - Stomach

Pain - Throat/pharynx/larynx

Pain - Tumor pain

Pain-Other (Specify)

Pancreatic endocrine: glucose intolerance

Phosphate, serum-low (hypophosphatemia)

Platelets

Pneumonitis/pulmonary infiltrates

Potassium, serum-high (hyperkalemia)

Potassium, serum-low (hypokalemia)

Rash/desquamation

Rigors/chills

Sodium, serum-low (hyponatremia)

Syncope (fainting)

Thrombosis/thrombus/embolism

Vomiting

Eligible HIV-negative patients who had received any treatment were included in the adverse event summaries. Six interim PET-positive patients who did not receive BEACOPP were excluded. patients Any CTCAE 4.0 event of Grade 3 (severe), Grade 4 (life threatening), or Grade 5 (fatal) which deemed to be related to protocol treatment are included.

Number of HIV-negative Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
S0816 Fludeoxyglucose F 18-PET/CT Imaging and Combination Chemotherapy With or Without Additional Chemotherapy and G-CSF in Treating Patients With Stage III or Stage IV Hodgkin Lymphoma	NCT00822120	Lymphoma Nonneoplastic C...	bleomycin sulfa... filgrastim ABVD regimen BEACOPP regimen cyclophosphamid... dacarbazine doxorubicin hyd... etoposide prednisone procarbazine hy... vinblastine sul... vincristine sul...	18 Years - 60 Years	SWOG Cancer Research Network
Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma	NCT00005584	Lymphoma	bleomycin sulfa... ABVD regimen BEACOPP regimen epirubicin hydr... prednisone vinblastine sul... radiation thera...	15 Years - 70 Years	European Organisation for Research and Treatment of Cancer - EORTC

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