Response Criteria

Clinical management of patients with CHL involves initial treatment with chemotherapy or combined modality therapy, followed by restaging at the completion of chemotherapy to assess treatment response. Assessment of response to initial treatment is essential because the need for additional treatment is based on the treatment response.

The International Working Group (IWG) published the guidelines for response criteria in 1999.⁸ In 2007, the IWG guidelines were revised by the International Harmonization Project (IHP) to incorporate immunohistochemistry, flow cytometry, and PET scans into the definition of response.^9,10 The IHP response criteria were initially developed for the interpretation of PET scans at treatment completion. In recent years, these criteria have also been used for interim response assessment.¹¹

In 2009, the Deauville criteria were defined for the interpretation of interim and end-of-treatment PET scans based on the visual assessment of ¹⁸F-fluorodeoxyglucose (FDG) uptake in the involved sites. These criteria use a 5-point scale (5-PS) to determine the FDG uptake in the involved sites relative to that of the mediastinum and liver.^12–14 In the 5-PS (Deauville criteria), scores of 1 to 4 refer to initially involved sites and a score of 5 refers to an initially involved site and/or new lesions related to lymphoma.^12,13 PET scans with a score of 1 or 2 are considered “negative” and those with a score of 4 and 5 are considered “positive.”¹⁵ In some situations, a score of 3 may be considered negative; however, for deescalation of therapy based on interim PET scans, a threshold for positivity that includes a score of 3 using the mediastinal blood pool uptake as the reference is appropriate (PET scans with a score of 1–2 are considered negative and those with a score of 3–5 are considered positive).¹⁶ The 5-PS (Deauville criteria) has been validated in international multicenter trials for PET-guided interim response assessment and risk-adapted therapy in patients with HL.^17–21

Role of PET Scans

PET imaging including integrated PET and CT (PET/CT) has become an important tool for initial staging and response assessment at the completion of treatment in patients with HL.^11,14 In a meta-analysis, PET scans showed high positivity and specificity when used to stage and restage patients with lymphoma.²² PET positivity at the end of treatment has been shown to be a significant adverse risk factor in patients with early-stage and advanced-stage disease.^23–25 PET scans are increasingly being used to assess treatment response during therapy. Interim PET scans may be useful to identify a subgroup of patients with early-stage disease that can be treated with chemotherapy alone.²¹

The NCCN Guidelines emphasize that the value of interim PET scans remains unclear for many clinical scenarios and that all measures of response should be considered in the context of management decisions. It is important that the Deauville score be incorporated into the nuclear medicine PET scan report, because subsequent management often depends on that score.

The guidelines recommend biopsy for all patients with a score of Deauville 5. In general, patients with a positive biopsy result should be managed as described for refractory disease. For those with a negative biopsy, complete response (CR) should be documented, including reversion of PET to “negative” within 3 months after therapy completion.

Diagnosis and Workup

Core needle biopsy may be adequate for diagnosis, but the panel recommends excisional lymph node biopsy generally be performed (see HODG-1; page 610). The role of fine-needle aspiration (FNA) biopsy in the diagnosis of lymphoma is still controversial.^35–37 A diagnostic assessment based solely on FNA biopsy is insufficient except in unusual circumstances when, in combination with immunohistochemistry, it is judged to be diagnostic of HL by an expert hematopathologist or cytopathologist. Immunostaining for CD3, CD15, CD20, CD30, CD45, CD79a, and PAX5 is recommended for CHL.

Workup should include a thorough history and physical examination; standard laboratory tests; PET/CT (skull base to mid-thigh); and diagnostic contrast-enhanced CT. A chest radiograph is encouraged for patients with a large mediastinal mass. In patients with newly diagnosed HL undergoing pretreatment staging with PET/CT, routine bone marrow biopsy is not required if the PET scan is negative or displays a homogenous pattern of bone marrow uptake.³⁸ The bone marrow may be assumed to be involved if the PET scan displays multifocal (≥3) skeletal lesions.^38,39 However, a bone marrow biopsy may be performed if cytopenias are present. In select cases, MRI and PET/MRI with contrast (skull base to mid-thigh) may also be considered for anatomic imaging.

Evaluation of ejection fraction is recommended for most patients undergoing doxorubicin-based chemotherapy. HIV and hepatitis B or C testing should be encouraged for patients with risk factors for HIV or unusual disease presentations. Pulmonary function tests, including the test of the diffusing capacity of the lungs for carbon monoxide, are recommended for patients receiving bleomycin-based chemotherapy. Haemophilus influenzae (H-flu), pneumococcal, and meningococcal vaccines are recommended if splenic RT is contemplated. A diagnostic neck CT scan with contrast is useful in select cases of patients if the neck is positive on PET/CT or in whom RT to the neck is planned.

A pregnancy test should be performed before women of childbearing age undergo treatment. Alkylating agent–based chemotherapy is associated with a higher risk of premature ovarian failure compared with chemotherapy with non–alkylating agent–based chemotherapy.⁴⁰ The guidelines recommend fertility preservation (semen cryopreservation in male patients, ovarian tissue or oocyte cryo-preservation in female patients) before the initiation of chemotherapy with alkylating agents or pelvic RT.^41,42 Oophoropexy should be considered to preserve ovarian function in premenopausal women if pelvic RT is contemplated.⁴³

Stage I–II Favorable Disease: RT alone was a standard treatment option for patients with early-stage HL for many decades.⁴⁴ However, the potential long-term toxicity of high-dose, large-field irradiation includes an increased risk for heart disease, pulmonary dysfunction, and secondary cancers.⁴⁵ With the incorporation of chemotherapy regimens routinely used in advanced disease (ABVD [doxorubicin, bleomycin, vinblastine, and dacarbazine] and Stanford V) into the management of patients with early-stage disease, combined modality therapy (chemotherapy and RT) has replaced RT alone as the preferred treatment for patients with early-stage, favorable disease.

The ABVD regimen was developed as an alternative to MOPP (mechlorethamine, vincristine, prednisone, and procarbazine) and is associated with lower rates of sterility and leukemia.⁴⁶ The Stanford V regimen is a brief but dose-intensive regimen with significantly fewer cumulative doses of doxorubicin and bleomycin than those used in ABVD, alternating MOPP/ABVD, BEACOPP, or other hybrid regimens, thereby reducing the risks for chemotherapy-related infertility, secondary neoplasms, and cardiac and pulmonary toxicity.^47,48 RT is an integral part of the Stanford V regimen.⁴⁹

Bonadonna et al⁴⁶ initially established the safety and efficacy of ABVD (4 cycles) followed by 36 Gy of involved-field RT (IFRT) as the standard treatment for patients with early-stage disease. The HD10 trial from the GHSG investigated the reduction of the number of cycles of ABVD and the IFRT dose in patients with stage I–II disease with no risk factors.⁵⁰ The definitions of unfavorable risk factors and lymph node sites used to determine clinical disease staging are outlined on HODG-A (page 619). It is worth noting that the GHSG and EORTC do not define the lymph node regions strictly according to the Ann Arbor criteria. Patients were not eligible if they had ≥3 sites of disease, any E-lesions, bulky mediastinal adenopathy, ESR >50, or ESR >30 in conjunction with B symptoms. In this trial, 1,370 patients were randomized to 1 of 4 treatment groups: 4 cycles of ABVD followed by 30 or 20 Gy of IFRT, or 2 cycles of ABVD followed by 30 or 20 Gy of IFRT.⁵⁰ The final analysis of this trial showed that (with a median follow-up of 79–91 months) there were no significant differences between 4 and 2 cycles of ABVD in terms of 5-year overall survival (OS; 97.1% and 96.6%), freedom from treatment failure (FFTF; 93.0% vs 91.1%), and progression-free survival (PFS; 93.5% vs 91.2%). With respect to the dose of IFRT, the OS (97.7% vs 97.5%), FFTF (93.4% vs 92.9%), and PFS (93.7% vs 93.2%) were also not significantly different between 30 and 20 Gy IFRT.⁵⁰ More importantly, no significant differences were seen in OS, PFS, and FFTF among the 4 treatment arms. The results of the HD10 study confirm that 2 cycles of ABVD with 20 Gy of IFRT is an effective primary treatment for patients with a very favorable presentation of early-stage disease with no risk factors, thereby minimizing the risk of late effects.

The G4 study conducted by the Stanford and Kaiser hospitals evaluated the efficacy of the abbreviated Stanford V chemotherapy (8 weeks or 2 cycles) followed by IFRT (30 Gy) in patients with nonbulky stage IA or IIA disease.⁵¹ Among the 87 patients included in the study, unfavorable risk factors according to GHSG criteria (>2 nodal sites, ESR ≥50, or extranodal involvement) were present in 42 patients (48%), and 33 patients (38%) had unfavorable characters defined by EORTC criteria (>3 nodal sites, ESR ≥50, mixed cellularity, and ≥50 years of age). At a median follow-up of 10.6 years, the estimated 10-year freedom from progression (FFP), disease-specific survival, and OS rates were 94%, 99%, and 94%, respectively. Among patients with GHSG criteria, FFP was 100% for patients with favorable disease and 88% for those with unfavorable nonbulky disease. The FFP was 98% and 88%, respectively, for patients with favorable and unfavorable disease according to EORTC criteria. No late cardiac or pulmonary toxicities were observed. No patient developed secondary acute myeloid leukemia or a myelodysplastic syndromes (MDS).

Two studies from Europe have evaluated the value of interim PET scans in defining the need for IFRT in patients with stage I–II favorable disease (the UK RAPID trial and the EORTC H10 trial).^21,52,53 The interim analysis of the EORTC H10 trial (n=1,137; 444 patients with stage I–II favorable disease; 693 patients with stage I–II unfavorable disease) showed that combined modality therapy (ABVD + involved-node RT [INRT]) resulted in fewer early progressions compared with treatment with ABVD alone, even in patients with early-stage favorable disease and a negative PET scan after 2 cycles of ABVD.⁵³

Chemotherapy with ABVD alone has also been investigated as a treatment option for patients with early-stage nonbulky disease (stage I–II). The RAPID trial showed that patients with stages IA–IIA disease with a negative PET scan after 3 cycles of ABVD have an excellent outcome with or without IFRT.²¹ In this study (n=602; 426 patients had a negative PET scan after 3 cycles of ABVD), patients with stage IA–IIA favorable disease (no B symptoms or mediastinal bulky disease) and a Deauville score of 1 to 2 on interim PET scan after 3 cycles ABVD were randomized to either IFRT (n=209) or observation (n=211). After a median follow-up of 60 months, the estimated 3-year PFS rate was 94.6% for those treated with IFRT compared with 90.8% for those who received no further treatment. The corresponding 3-year OS rates were 97.1% and 99.0%, respectively,²¹ suggesting a benefit for combined modality therapy but not necessarily superiority over chemotherapy alone with this regimen.

Combined modality therapy (ABVD or Stanford V chemotherapy plus IFRT) is the preferred treatment for patients with stage I–II favorable disease.⁵⁴ However, ABVD alone could be a reasonable choice of treatment, especially for younger patients who are in CR after 2 cycles (as documented by CT scan) or for those with a Deauville score of 1 to 3 on PET scan after 2 to 4 cycles of ABVD, in order to avoid the long-term risks of RT.

NCCN Recommendations: Combined modality therapy (ABVD plus involved site RT [ISRT]⁵⁰ [category 1] or Stanford V chemotherapy⁵¹) or chemotherapy (ABVD alone²¹) are included as treatment options for patients with stage IA to IIA favorable disease (absence of all NCCN unfavorable risk factors: bulky mediastinal or >10 cm disease, B symptoms, ESR ≥50, and >3 nodal sites of disease) (see HODG-3 and HODG-4; page 612).

For patients who fulfill the GHSG criteria for favorable stage IA to IIA disease, 2 cycles of ABVD followed by interim restaging with PET is recommended. For patients with a Deauville score of 1 to 4, a planned course of ISRT (20 Gy) is recommended,⁵⁰ whereas biopsy is recommended for those with a score of Deauville 5 after completion of chemotherapy. ISRT followed by observation is recommended for patients with a negative biopsy, and those with a positive biopsy should be managed as described for refractory disease.

Three treatment regimens are also recommended as suitable options for all patients with nonbulky, favorable stage IA to IIA disease. The first option is used when there is a preference to treat patients with chemotherapy alone and involves an initial administration of 3 cycles of ABVD followed by interim restaging with PET. After interim restaging, and consistent with the results of the RAPID trial, no further treatment is recommended for patients with a Deauville score of 1 or 2.²¹ However, these patients may receive an optional additional cycle of ABVD (total of 4). For patients with a Deauville score of 3 to 4, an additional cycle of ABVD (total of 4) and ISRT (30 Gy) is recommended. Biopsy is recommended for patients with a Deauville score of 5, and patients with a negative biopsy should be managed with an additional cycle of ABVD (total of 4) and ISRT (30 Gy). If biopsy is positive, patients should be managed as described for refractory disease.

If there is a preference to treat patients with combined modality therapy, patients are administered 2 cycles of ABVD and restaged with PET. An additional cycle of ABVD (total of 3) and ISRT (30 Gy) is recommended for patients with a Deauville score of 1 to 2. Patients with a Deauville score of 3 to 4 can either be treated with 2 additional cycles of ABVD (total of 4) and ISRT (30 Gy) or 2 cycles of escalated BEACOPP and ISRT (30 Gy). A Deauville score of 5 warrants a biopsy. If the results are negative, patients can be managed as described for those with a Deauville score of 3 to 4, and if results are positive, they should be managed as described for refractory disease.

The third option is treatment with the Stanford V regimen for 8 weeks followed by interim PET restaging. Patients with a Deauville score of 1 to 4 are treated with 30 Gy ISRT, which is optimally instituted within 3 weeks of completion of chemotherapy.⁵¹ A Deauville score of 5 warrants a biopsy. If the results are negative, patients are treated with 30 Gy ISRT, and if positive, they should be managed as described for refractory disease. The combined modality treatment regimen with Stanford V offers an alternative when it is desirable to limit the patient's exposure to bleomycin.⁵¹

Stage I–II Unfavorable Disease: The HD8 trial from the GHSG investigated the efficacy of IFRT versus extended-field RT in the context of combined modality therapy for patients with early-stage unfavorable HL with ≥1 risk factors (large mediastinal mass, extranodal disease, splenic involvement, elevated ESR with or without B symptoms, and >2 lymph node areas of involvement).⁵² No significant differences in FFTF or OS were seen when larger radiation fields were used. IFRT was also associated with less acute toxicity and fewer secondary malignancies. This established combined modality therapy with IFRT as the standard of care for these patients.^52,55

To investigate the number of cycles of chemotherapy required for maximal efficacy in combined modality therapy, the EORTC-H9U trial randomized 808 patients with stage I–II unfavorable disease to 3 treatment arms and compared 6 cycles of ABVD, 4 cycles of ABVD, and 4 cycles of BEACOPP, followed by IFRT (30 Gy) in all arms.⁵⁶ At 4 years of follow-up, when the number of ABVD cycles was reduced from 6 to 4, the trial showed similar event-free survival (EFS; 94% vs 89%) and OS (96% vs 95%) rates, but increased toxicity was observed in the BEACOPP arm.⁵⁶

The HD11 trial from the GHSG demonstrated that 4 cycles of ABVD followed by 30 Gy IFRT is an effective treatment option for patients with early-stage unfavorable disease.⁵⁷ In this study, 1,395 patients with stage I–II unfavorable disease (stage IA, IB, or IIA with ≥1 of the following risk factors: bulky mediastinal mass; extranodal involvement; ESR ≥50 or ESR ≥30 with B symptoms; or ≥3 involved lymph nodes and stage IIB disease with no bulky mediastinal mass or extranodal involvement) were randomized to either ABVD (4 cycles followed by 30 or 20 Gy IFRT) or standard-dose BEACOPP (4 cycles followed by 30 or 20 Gy IFRT). BEACOPP was more effective than ABVD when followed by 20 Gy IFRT (5-year FFTF and PFS rates were 86.8% and 87%, respectively, for BEACOPP; the corresponding rates were 81% and 82%, respectively, for ABVD). However, no difference was seen between the 2 regimens when followed by 30 Gy of IFRT. BEACOPP was also associated with more toxicity than ABVD.

The EORTC H10 trial (n=1,137; 444 patients with stage I–II favorable disease; 693 patients with stage I–II unfavorable disease) aimed to demonstrate prognostic significance of early interim PET after 2 cycles of chemotherapy.⁵³ The H10U trial within this study randomized patients into 2 treatment arms. In the standard arm, patients were treated with 2 cycles of ABVD, underwent interim PET, and were treated with 2 additional cycles of ABVD with INRT (30–36 Gy). In the experimental arm, patients were treated with 2 cycles of ABVD, underwent interim PET scans, and, if found to be PET-negative, were treated with an additional 4 cycles of ABVD. If patients were found to be PET-positive after the initial 2 cycles of ABVD, chemotherapy was intensified with 2 cycles of escalated BEACOPP with INRT (30–36 Gy). Although interim analysis demonstrated that chemotherapy alone is a viable treatment option, PET scans showed that combined modality therapy (ABVD + INRT) resulted in fewer early progressions compared with treatment with ABVD alone.⁵³

The results of the prospective study conducted by the Stanford group demonstrated the efficacy of the Stanford V regimen followed by RT to initially bulky sites for patients with locally extensive and advanced-stage disease.⁵⁸ In this study, 142 patients with locally extensive mediastinal stage I or II disease or stage III or IV disease were treated with Stanford V chemotherapy (12 weeks) followed by RT (36 Gy) to initial bulky sites (≥5 cm) or macroscopic splenic disease. With a median follow-up of 5.4 years, the 5-year FFP and OS rates were 89% and 96%, respectively. No patients progressed during treatment and there were no treatment-related deaths or secondary leukemia. Among 16 patients who experienced relapse, the freedom from second relapse was 69% at 5 years.

A randomized Italian study reported that ABVD and MOPPEBVCAD (mechlorethamine, vincristine, procarbazine, prednisone, epidoxorubicin, bleomycin, vinblastine, lomustine, doxorubicin, and vindesine) were superior to the Stanford V regimen in response rate, failure-free survival (FFS), and PFS in patients with intermediate-stage and advanced-stage HL.⁵⁹ However, interpretation of these results was difficult because the timing of response evaluation was different among the arms (8 and 12 weeks for Stanford V, 16 weeks for ABVD, and 24 weeks for MOPPEBVCAD). In addition, modifications of the RT protocol in the Stanford V arm were substantial, including limitation of the number of sites irradiated (no more than 2) and a different definition of bulky disease.

Other investigators have confirmed that the Stanford V regimen is highly effective for locally extensive and advanced HL with a low toxicity profile when RT is administered according to Stanford V protocol guidelines.^60–62 In the Memorial Sloan Kettering Cancer Center study, 126 patients with either locally extensive or advanced disease were treated with the 12-week Stanford V chemotherapy regimen followed by 36 Gy of IFRT to bulky sites (≥5 cm) and/or to macroscopic splenic disease,⁶¹ with 5- and 7-year OS rates of 90% and 88%, respectively. Of the patients for whom the Stanford V regimen failed, 58% underwent successful second-line therapy with high-dose therapy and autologous stem cell rescue (HDT/ASCR). Aversa et al⁶⁰ from an Italian study group also reported similar findings in patients with bulky or advanced disease. The randomized trial conducted by the United Kingdom National Cancer Research Institute Lymphoma Group (study ISRCTN 64141244) also showed that the efficacies of Stanford V and ABVD were comparable in terms of overall response rate (ORR) and 5-year PFS and OS rates in patients with stage IIB, III, or IV disease or stage I–IIA HL with bulky disease or other adverse features. RT was administered in both arms to sites of previous bulky sites (>5 cm) and to splenic deposits.⁶² At the median follow-up of 4.3 years, the ORR, 5-year PFS, and 5-year OS rates were 91%, 76%, and 90%, respectively, for ABVD and 92%, 74%, and 92%, respectively, for Stanford V.

The phase III intergroup trial (E2496) also confirmed no significant differences between ABVD and Stanford V in terms of response rates, FFS, OS, and toxicity in patients with locally extensive (stage I–IIA/B and bulky mediastinal disease) and stage III–IV disease.^63,64 In this trial, 854 patients were randomized to ABVD (n=428; 6–8 cycles plus 36 Gy RT only for patients with bulky mediastinal disease) or Stanford V (n=426; 12 weeks of chemotherapy plus 36 Gy RT for sites ≥5 cm or for macroscopic splenic disease). The primary end point was FFS, defined as the time from randomization to progression, relapse, or death, whichever occurred first. With a median follow-up of 6.4 years, no difference between the arms was seen for ORR (clinical CR rates were 72.7% for ABVD and 68.7% for Stanford V), OS (88% at 5 years for both ABVD and Stanford V; P=.86), or FFS (74% for ABVD and 71% for Stanford V at 5 years; P=.32). Toxicity was also similar in both groups. The planned subgroup analysis showed that the outcome of patients with locally extensive disease was significantly better than that of patients with stage III–IV disease.⁶⁴ The 3- and 5-year FFS rates were 82% for patients with locally extensive disease and 71% and 67%, respectively, for patients with stage III–IV disease (P=.001). The 5-year OS rates were 94% and 85%, respectively (P<.001).

The GHSG HD14 trial showed that BEACOPP followed by ABVD and IFRT significantly improved tumor control and PFS in patients with early-stage unfavorable disease (stage IA, IB, or IIA HL with at least one of the following risk factors: bulky mediastinal mass; extranodal involvement; ESR ≥50 [without B symptoms] or ESR ≥30 [with B symptoms]; or ≥3 involved lymph nodes) and stage IIB disease with either of the latter 2 risk factors.⁶⁵ In this trial, 1,528 patients were randomized to 4 cycles of ABVD (n=765) or 2 cycles of escalated-dose BEACOPP followed by 2 cycles of ABVD (n=763). Chemotherapy was followed by 30 Gy of IFRT in both arms. At a median follow-up of 43 months, the 5-year FFTF rate was 94.8% compared with 87.7% for ABVD (P<.001). The 5-year PFS rate was 95.4% and 89.1%, respectively (P<.001). The 5-year OS rate was not significantly different between the 2 arms (97.2% and 96.8%, respectively; P=.731). The rate of progression or relapse was also lower in patients treated with BEACOPP followed by ABVD (2.5% vs 8.4%; P<.001).

The Response-Adapted Therapy in Advanced Hodgkin Lymphoma (RATHL) trial has also examined the use of interim PET to guide treatment for patients with advanced disease, which included 500 patients (41.6%) who had stage II HL with various risk factors (B symptoms, bulky disease, or at least 3 involved sites).^17,66 In the randomized trial, 1,119 patients with stage II–IV disease received 2 cycles of ABVD and underwent interim PET scans. Patients with a Deauville score of 1 to 3 were assigned in a 1:1 ratio to continue treatment with 4 cycles of either ABVD or AVD. At a median of 41 months, the 3-year PFS and OS rates between the ABVD and AVD groups did not differ significantly (85.7% vs 84.4% and 97.2% vs 97.6% respectively). However, the omission of bleomycin from the ABVD regimen after negative PET results (ie, Deauville score of 1–3) led to a decrease in the incidence of pulmonary toxic effects compared with continued ABVD.⁶⁶

Overall, these results suggest that ABVD plus 30 Gy of IFRT remains the standard of care for patients with early-stage unfavorable disease. Stanford V (when given as described with RT) or BEACOPP followed by ABVD are acceptable alternatives for some patients.

NCCN Recommendations: ABVD followed by ISRT⁵⁷ or AVD,⁶⁶ ABVD followed by escalated BEACOPP and ISRT,⁵³ Stanford V plus ISRT,^58,64 or escalated BEACOPP (2 cycles) followed by ABVD (2 cycles) and ISRT for selected patients aged <60 years⁶⁵ are included as options for patients with stage I–II unfavorable disease (see HODG-6 and HODG-7; pages 613 and 614). In the HD14 trial that evaluated escalated BEACOPP followed by ABVD and ISRT, patients with bulky disease in combination with either B symptoms or extranodal disease were excluded.⁶⁵ These patients are managed as described for stage III–IV disease.

Stage I–II (Unfavorable Nonbulky Disease): ABVD is initially administered for 2 cycles followed by interim restaging with PET. Patients with a Deauville score of 1 to 2 can be treated with 2 additional cycles of ABVD (total of 4) and ISRT, or 4 cycles of AVD (total of 6) with or without ISRT. Patients with a Deauville score of 3 to 4 are treated with either 2 additional cycles of ABVD alone (total of 4) or 2 cycles of escalated BEACOPP. PET restaging may be considered at this point and patients are followed up with ISRT. Biopsy is recommended for patients with a Deauville score of 5 after initial treatment with 2 cycles of ABVD. If the biopsy is negative, patients are treated with 4 cycles of AVD (total of 6) with ISRT. All patients with a positive biopsy should be managed as described for refractory disease.

Stage I–II (Unfavorable Bulky Mediastinal Disease or Adenopathy >10 cm With or Without B Symptoms): ABVD is initially administered for 2 cycles followed by interim restaging with PET. This is a category 1 recommendation. Patients with a Deauville score of 1 to 3 are treated with a combination of 2 additional cycles of ABVD (total of 4) and ISRT or with 4 cycles of AVD (total of 6) with or without ISRT. Patients with a Deauville score of 4 are treated with 2 additional cycles of ABVD (total of 4) and ISRT or 2 cycles of escalated BEACOPP and ISRT (30 Gy). Biopsy is recommended for all patients with a Deauville score of 5 after initial treatment with 2 cycles of ABVD. If the biopsy is negative, patients should either receive 2 additional cycles of ABVD (total of 4) and ISRT or 2 cycles of escalated BEACOPP and ISRT. Patients with a positive biopsy should be managed as described for refractory disease.

Stage I–II (Unfavorable Nonbulky Disease and Unfavorable Bulky Mediastinal Disease or Adenopathy >10 cm With or Without B Symptoms): Stanford V is administered for 12 weeks (3 cycles) followed by ISRT (30–36 Gy) to patients with stage I–II nonbulky and bulky disease and/or B symptoms (see HODG-8; page 615).^58,64 Patients are restaged with PET at the completion of chemotherapy. ISRT to initial sites >5 cm is recommended for all patients with a Deauville score of 1 to 4. ISRT should be instituted within 2 to 3 weeks of completion of chemotherapy. Biopsy is recommended for all patients with a Deauville score of 5 after completion of therapy. ISRT should be given if the biopsy is negative. Patients with a positive biopsy should be managed as described for refractory disease. If the patients present with unfavorable nonbulky disease and other unfavorable factors (elevated ESR or >3 sites of disease), they are treated with 8 weeks of Stanford V followed by restaging and treated with ISRT (30 Gy) as described for stage IA–IIA favorable disease.⁵¹

Patients receiving escalated BEACOPP (2 cycles) and ABVD (2 cycles) are restaged after completion of chemotherapy (see HODG-9; page 615). ISRT is recommended for those with a Deauville score of 1 to 4 and biopsy is recommended for patients with a Deauville score of 5. ISRT should be given if the biopsy is negative. Patients with a positive biopsy should be managed as described for refractory disease.

Stage III–IV: Although chemotherapy is always used for patients with advanced-stage disease, combined modality therapy is the management approach for some treatment regimens, especially for patients with bulky disease, and is used for poor responders to chemotherapy in other treatment regimens.^58,64,67

The landmark randomized trial by the CALBG showed that ABVD alone or alternating with MOPP was superior to MOPP alone in patients with newly diagnosed advanced HL (stage III–IV).⁶⁸ ABVD also was less myelotoxic than MOPP or ABVD alternating with MOPP, and has since been the standard treatment for patients with stage III–IV disease. Stanford V and BEACOPP are the other 2 regimens developed to improve the outcome of patients with advanced disease.

The results from prospective studies conducted by the Stanford group and other investigators have demonstrated the efficacy of Stanford V and IFRT in patients with advanced-stage disease.^58,60–62 The recently completed phase III intergroup trial (E2496) also showed no significant difference in ORR, FFS, OS, and toxicity between ABVD and Stanford V (with RT, when indicated, according to Stanford V protocol guidelines) in patients with stage III–IV disease.⁶⁴ However, among patients with high-risk disease (IPS ≥3), the 5-year FFS rate was significantly better for ABVD than Stanford V (67% vs 57%; P=.02), but no significant difference was seen in 5-year OS rate (84% vs 77%; P=.15).

The efficacy of BEACOPP in patients with advanced disease was demonstrated in 2 phase III randomized trials conducted by the GHSG.^69,70 In the HD9 study, 1,196 patients with stage IIB and IIIA disease with risk factors or stage IIIB and IV disease were randomized to undergo 8 cycles of COPP-ABVD, 8 cycles of standard-dose BEACOPP, or 8 cycles of escalated-dose BEACOPP.⁶⁹ Each regimen was followed by RT to initial sites of disease >5 cm. Most patients in each treatment arm had stage III–IV disease. At 5-year analysis, escalated-dose BEACOPP showed better tumor control and OS than COPP-ABVD and significantly lower rates of early progression than COPP-ABVD or standard-dose BEACOPP. The 10-year analysis confirmed that escalated-dose BEACOPP was significantly better than standard-dose BEACOPP or COPP-ABVD in terms of FFTF (82%, 70%, and 64%, respectively) and OS rates (86%, 80%, and 75%, respectively). Escalated-dose BEACOPP was significantly better than standard-dose BEACOPP in terms of FFTF (P<.0001) and OS (P=.0053).⁷⁰

The final results of the HD12 study (n=1,670) that compared 8 cycles of escalated-dose BEACOPP with 4 cycles of escalated-dose BEACOPP followed by 4 cycles of standard-dose BEACOPP, with or without RT, also confirmed the efficiency of escalated-dose BEACOPP for patients with advanced-stage HL who have risk factors, as reported in the HD9 trial.⁷¹ In this study, at 5 years, the FFTF (86.4% and 84.8%, respectively) and PFS (87.5% and 85%, respectively) were better (although the difference was not significant) for 8 cycles of escalated-dose BEACOPP compared with 4 cycles of escalated-dose BEACOPP followed by 4 cycles of standard-dose BEACOPP. The 5-year OS rate, however, was not different (92% and 90.3%, respectively).⁷¹

The final analysis of the HD15 trial reported by Engert et al⁶⁷ showed that 6 cycles of escalated-dose BEACOPP followed by PET-guided RT resulted in significantly superior OS and tumor control than 8 cycles of escalated-dose BEACOPP in patients with advanced-stage disease (stage IIB with large mediastinal mass or stage III–IV). In this study, 2,182 patients were randomly assigned to 1 of the 3 treatment groups: 8 cycles of escalated-dose BEACOPP (n=728), 6 cycles of escalated-dose BEACOPP (n=726), or 8 cycles of a time-intensified standard-dose BEACOPP (n=728). RT (30 Gy) was restricted to patients with PET-positive residual sites (≥2.5 cm) after chemotherapy. The 5-year FFTF rates were 84.4%, 89.3%, and 85.4%, respectively, for the 3 groups. The corresponding OS rates were 91.9%, 95.3%, and 94.5%, respectively, and were significantly better with 6 cycles of escalated-dose BEACOPP than with 8 cycles of escalated-dose BEACOPP (P=.019). Escalated-dose BEACOPP was also associated with less treatment-related mortality (TRM; 4.6% vs 7.5% for 8 cycles of escalated-dose BEACOPP and 5.2% for 8 cycles of time-intensified standard-dose BEACOPP) and fewer secondary cancers (2.4% vs 4.7% and 3.1%, respectively, for 8 cycles of escalated-dose BEACOPP and 8 cycles of time-intensified standard-dose BEACOPP). These results confirm that 6 cycles of escalated-dose BEACOPP followed by PET-guided RT is an acceptable treatment for patients with advanced-stage disease.

Results from studies that have compared escalated-dose BEACOPP with standard-dose BEACOPP or ABVD failed to show an OS advantage for escalated-dose BEACOPP, although it resulted in better tumor control in patients with advanced disease.^72–75 However, some of these studies were not sufficiently powered to determine differences in OS due to small patient numbers. The EORTC 20012 trial evaluated BEACOPP (4 cycles of escalated-dose and 4 cycles of standard-dose) and ABVD (8 cycles) in high-risk patients with stage III–IV disease and IPS ≥3 (274 patients in the BEACOPP arm and 275 patients in the ABVD arm).⁷² The results showed that there was no improvement in OS (86.7% and 90.3, respectively, at 4 years; P=.208) or EFS (63.7% and 69.3%, respectively, at 4 years; P=.312), although the PFS was significantly better with BEACOPP (83.4% vs 72.8% for ABVD; P=.005). Early discontinuations were also more frequent with BEACOPP. The median follow-up was 3.6 years.⁷² The long-term follow-up analysis of the HD2000 trial also showed that the risk of secondary malignancy at 10 years was significantly higher with BEACOPP than with ABVD (6.6 vs 0.9; P=.027).⁷⁶

Several trials have addressed the role of consolidative RT after completion of chemotherapy in patients with stage III–IV disease.

The SWOG multicenter study showed no improvement in OS rates for patients who underwent low-dose IFRT after MOP-BAP (mechlorethamine, vincristine, procarbazine plus bleomycin, doxorubicin, and prednisone), but the remission duration was prolonged in several subgroups, especially in patients with bulky nodular sclerosis CHL.⁷⁷ In the randomized trial (EORTC 20884 trial) that assessed the role of consolidation RT following MOPP-ABV chemotherapy in patients with advanced disease, 739 patients with untreated stage III to IV disease received 6 to 8 cycles of MOPP-ABV. Patients with CR on CT imaging after chemotherapy were randomized to no further treatment or IFRT, and those with a partial response (PR) received IFRT to involved nodal areas and extranodal sites.⁷⁸ The 8-year OS and EFS rates in the PR group were 76% and 84%, respectively. These outcomes were not significantly different in patients with CR (with or without IFRT), suggesting that consolidative IFRT is beneficial for patients experiencing PR after chemotherapy.

In the randomized controlled trial from the United Kingdom Lymphoma Group (LY09 trial) that compared ABVD with 2 other multidrug regimens, IFRT was recommended for incomplete response to chemotherapy or bulk disease at presentation.⁷⁹ PFS was superior for patients who received RT (5-year PFS was 71% without RT and 86% with RT) and a similar advantage was seen for OS. The final results of the HD12 trial also showed that consolidation RT was beneficial for patients with residual disease after escalated-dose BEACOPP (FFTF was 90.4% and 87%, respectively), whereas this effect was not seen in patients with initial bulk disease who were in CR after chemotherapy.⁷¹ In contrast, Laskar et al⁸⁰ reported a survival advantage for consolidative RT in patients experiencing CR after initial chemotherapy, particularly in patients aged <15 years and those with B symptoms and bulky and advanced disease. However, this study included patients with a different distribution of histologic subtypes of HL compared with those included in Western studies, and most patients had early-stage HL. Of note, none of these studies incorporated PET scan for the evaluation of response.

In the HD15 trial, RT (30 Gy) after BEACOPP chemotherapy was restricted to those patients in PR with PET-positive residual disease (≥2.5 cm). PET-negative patients received no additional RT.⁶⁷ Of the 739 qualified patients with residual disease (≥2.5 cm) after 6 to 8 cycles of BEACOPP, 548 (74%) were PET-negative; 191 patients (26%) were PET-positive and received consolidative RT. The final analysis showed that the prognosis of patients in PR with PET-negative persistent residual disease after chemotherapy was similar to that of those who were in CR as measured by conventional CT (4-year PFS was 92.1%), suggesting that consolidative RT could be omitted in patients with a PET-negative PR.⁶⁷ However, the use of consolidative RT was effective for patients with PET-positive PR, because the 4-year PFS in this group was 86.2%. In relapse analysis of the HD15 trial, of 225 patients with PET-positive disease after BEACOPP chemotherapy and RT, 197 (89%) were relapse-free for the duration of their follow-up (median 42 months).⁸¹

Two European trials evaluated the role of HDT/ASCR as a consolidative therapy for patients with advanced-stage and unfavorable HL that responded to initial chemotherapy.^82,83 Neither trial showed an advantage for HDT/ASCR over conventional chemotherapy for patients with unfavorable and advanced HL experiencing CR or PR after an initial course of doxorubicin-based chemotherapy. Instead, additional courses of the same conventional chemotherapy used as initial treatment produced equivalent or better outcomes than HDT/ASCR.

NCCN Recommendations: ABVD, Stanford V (selected patients with IPS <3), or escalated-dose BEACOPP (in selected patients aged <60 years with an IPS of ≥4) are included as options for primary treatment for patients with stage III–IV disease (see HODG-10; page 616).^{61,64,66,67,84} In this setting, the ABVD regimen is preferred.

ABVD is initially administered for 2 cycles followed by restaging with PET. Patients with a Deauville score of 1 to 3 are treated with 4 cycles of AVD based on results from the RATHL trial.⁶⁶ Consistent with the results of the E2496 study, observation or ISRT to initially bulky or selected PET-positive sites are included as options for patients with a Deauville score of 1 to 3 after 2 cycles of ABVD and 4 cycles of AVD.⁶⁴ In patients with a positive PET scan (Deauville score of 4 to 5), treatment with 2 additional cycles of ABVD (total of 4) is recommended. Patients are then restaged with PET, and 2 additional cycles of ABVD (total of 6) administered with or without ISRT is an option for those with a negative interim PET scan (Deauville score of 1 to 3). A biopsy is recommended for patients with a Deauville score of 4 or 5. If the biopsy is negative, treatment with 2 additional cycles of ABVD (total of 6) administered with or without ISRT is an option. Patients with a positive biopsy should be managed as described for refractory disease.

Several studies have reported that early intensification to escalated BEACOPP in patients with a positive interim PET scan (based on the 5-PS) after 2 cycles of ABVD is associated with favorable outcomes.^66,85,86 Based on these findings, the guidelines recommend escalated BEACOPP (4 cycles) as an option for patients with a Deauville score of 4 or 5 after 2 cycles of ABVD. Patients are then restaged with PET, with observation or ISRT to initially bulky or selected PET-positive sites included as options for patients with a Deauville score of 1 to 3, and biopsy recommended for patients with a Deauville score of 4 or 5. If the biopsy is negative, treatment with ISRT directed to PET-positive sites is an option. Patients with a positive biopsy should be managed as described for refractory disease.

Stanford V is administered for 12 weeks (3 cycles) followed by restaging after chemotherapy (see HODG-11; page 617). ISRT (30–36 Gy; within 2–3 weeks after completion of chemotherapy) to initial sites >5 cm and involved spleen is recommended for patients with a Deauville score of 1 to 4 and for those with a Deauville score of 5 with a negative biopsy.^61,62 Patients with a positive biopsy should be managed as described for refractory disease.

Escalated-dose BEACOPP is administered for 6 cycles followed by restaging with PET (see HODG-12; page 617). No further treatment is necessary for patients with a Deauville score of 1 or 2. Based on the final results of the HD12 and HD15 trials, ISRT to residual PET-positive sites >2.5 cm is recommended for patients with a Deauville score of 3 or 4 after 6 cycles of BEACOPP.^67,71 Biopsy is recommended for all patients with a Deauville score of 5 after 6 cycles of BEACOPP. Observation or ISRT to the initially bulky or PET-positive sites are included as options for patients with a negative biopsy. Patients with a positive biopsy should be managed as described for refractory disease.

The feasibility of de-escalation of therapy to ABVD in patients with advanced-stage disease (IPS ≥3) who experienced CR after 2 cycles of escalated BEACOPP has been demonstrated in studies conducted by the Israeli Study Group.⁸⁷ Interim restaging with PET after 2 cycles of escalated BEACOPP with a possible de-escalation of therapy (4 cycles of ABVD) may be considered in patients with a negative interim PET.

Follow-up After Completion of Treatment

Recommendations included in the guidelines are largely based on the clinical practices at NCCN Member Institutions and are not supported by high-level evidence, because there are very few data available on the follow-up and monitoring of late effects in patients with HL after completion of treatment.⁸⁸

The panel agrees that given the long-term risks of the therapies for HL, patients should be followed up with an oncologist who is aware of these risks and complications, especially during the first 5 years after treatment to detect recurrence and then annually because of the risk for late complications, including secondary cancers and cardiovascular disease (see HODG-14; page 618). The follow-up schedule should be individualized, depending on clinical circumstances such as patient's age, stage of disease, and initial treatment modality. Patients should be encouraged to undergo counseling on issues regarding survivorship, long-term treatment effects, health habits, and psychosocial issues. It is recommended that the patient be provided with a treatment summary at the completion of therapy, including details of RT, OARs, and cumulative anthracycline dosage given.

Monitoring for Late Effects

Secondary cancers, cardiovascular disease, hypothyroidism, and fertility issues are the most serious late effects among long-term survivors of HL. The incidence of these late effects increases with longer follow-up time. The risk may be less with current treatment programs compared with those used >10 years ago.

Secondary Cancers: Solid tumors are the most common secondary cancers and most develop >10 years after treatment completion. The risk of developing secondary cancers is highest when RT is used as a component of first-line treatment. A meta-analysis by Franklin et al⁸⁹ showed that the risk of developing secondary cancers was lower with combined modality treatment than with RT alone as the initial treatment. The risk was marginally higher with combined modality treatment compared with chemotherapy alone as initial treatment. Lung and breast cancers are the most common secondary cancers in patients with HL. Annual breast screening [mammography and MRI] beginning no later than 8 to 10 years after completion of therapy or at age 40 years (whichever occurs earlier) is recommended for women who have received chest or axillary irradiation.⁹⁰ The NCCN Guidelines recommend breast MRI in addition to mammography for women who received irradiation to the chest between 10 and 30 years of age, which is consistent with the recommendation of the American Cancer Society guidelines.⁹¹ The NCCN Guidelines recommend that routine surveillance tests for cervical, colorectal, endometrial, lung, and prostate cancers be performed as per the American Cancer Society guidelines.

Cardiovascular Disease: Mediastinal irradiation and anthracycline-based chemotherapy are the highest risk factors for developing cardiac disease, which may be asymptomatic.^92–94 RT-induced cardiotoxicity is usually observed more than 5 to 10 years after completion of treatment. However, cardiovascular symptoms may emerge at any age. Coronary CT angiography abnormalities have been detected in nearly 15% of patients within the first 5 years after treatment, and the incidence significantly increases 10 years after treatment.⁹⁵ In a multivariate analysis, patient's age at treatment, hypercholesterolemia, hypertension, and RT dose to the coronary artery origins were identified as independent prognostic factors.

Based on data regarding increased long-term risk of cardiac disease, annual blood pressure monitoring (even in asymptomatic individuals) and aggressive management of cardiovascular risk factors is recommended.⁹⁰ A baseline stress test or echocardiogram and carotid ultrasound (for patients treated with neck RT) should be considered at 10-year intervals after treatment completion.

Hypothyroidism: Abnormal thyroid function, mostly hypothyroidism, is reported in approximately 50% of long-term survivors who received neck or upper mediastinal irradiation.⁸⁸ A careful thyroid examination should be a part of the physical examination. Thyroid function tests should be performed at least annually to rule out hypothyroidism, especially in patients treated with RT to the neck.

Myelosuppression: Myelosuppression is the most common side effect of chemotherapy and is associated with increased risk of infections. It is uncommon for myelosuppression to continue for very long beyond completion of the primary treatment program. However, patients who undergo HDT/ASCR or allogeneic hematopoietic stem cell transplant may be at continued risk for infection. Pneumococcal, meningococcal, and H-flu revaccinations are recommended every 5 years for patients treated with splenic RT or splenectomy.

Infertility: Certain chemotherapy combinations (eg, BEACOPP) may cause immediate and permanent infertility in both men and women.^96,97 Other combinations (eg, ABVD) are only rarely associated with infertility.^42,98 Because women who have received chemotherapy with alkylating agents and who maintain short-term fertility may experience premature menopause,⁴⁰ this should be taken into consideration with respect to family planning.

Pulmonary Toxicity: Bleomycin-induced pulmonary toxicity (BPT) is well documented in patients with HL treated with bleomycin-containing chemotherapy regimens. Risk factors include older age, cumulative bleomycin dose, pulmonary irradiation, and prior history of lung disease. Some reports have suggested that the use of growth factors increases the incidence of pulmonary toxicity, and their concurrent use with chemotherapy significantly decreases OS rate.⁹⁹ Recently, 2 separate studies confirmed that ABVD chemotherapy can be safely administered at the full-dose intensity without any growth factor support.^100,101 The NCCN Guidelines do not recommend the routine use of growth factors with ABVD regimens.