Initial treatment of advanced (stage III-IV) classic Hodgkin lymphoma

INTRODUCTION — Classic Hodgkin lymphoma (cHL) refers to lymphomas that are characterized by malignant Reed-Sternberg cells in a reactive cellular background, which generally arises within a lymph node area and spreads in an orderly fashion to contiguous areas of lymph nodes [1]. Once the diagnosis of cHL has been established, subsequent therapy is based upon the stage of the disease, as currently defined by the Cotswolds classification (table 1). (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

In this discussion, advanced stage cHL refers to clinical stage (CS) III and IV disease. CS III describes involvement of lymph nodes or lymphoid structures on both sides of the diaphragm. CS IV refers to diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without lymph node disease. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

The initial treatment of advanced stage cHL will be reviewed here. The following are discussed separately:

●The evaluation of the patient before, during, and after therapy. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

●The treatment of favorable early stage cHL. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

●The treatment of unfavorable early stage cHL. (See "Treatment of unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults".)

●The treatment of relapsed or refractory cHL. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

●The treatment of nodular lymphocyte predominant Hodgkin lymphoma. (See "Treatment of nodular lymphocyte-predominant Hodgkin lymphoma".)

●Management of the adult survivor of cHL. (See "Approach to the adult survivor of classic Hodgkin lymphoma".)

PRETREATMENT EVALUATION

Studies — The initial evaluation of a patient with cHL must establish the precise histologic subtype, the extent and sites of disease, and the performance status of the patient. This evaluation is described in detail separately. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)

International prognostic score — Patients with advanced stage cHL can be further divided into prognostic groups using the international prognostic score (IPS), which incorporates seven factors (ie, serum albumin, hemoglobin, gender, age, stage, white blood cell count, and absolute lymphocyte count) to delineate six prognostic groups with very different rates of freedom from progression at five years, demonstrating that even among those with advanced stage disease the prognosis is quite variable (table 2) (calculator 1). (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma", section on 'International Prognostic Score (IPS)'.)

INITIAL TREATMENT

General approach

Choice of initial therapy — Combination chemotherapy with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) (table 3) is the preferred therapy for most patients with advanced cHL [2-5].

For select patients, acceptable alternative regimens include BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (table 4):

●ABVD is administered every 14 days, and two treatments are considered one 28-day cycle. Response to therapy is assessed by positron emission tomography (PET) after two cycles of chemotherapy (PET2). A full course of ABVD treatment is six cycles and, as such, the total duration of chemotherapy is 24 weeks. Adverse events include cytopenias, nausea/vomiting, neuropathy, bleomycin-associated pulmonary toxicity, and long-term cardiopulmonary complications. (See 'ABVD chemotherapy' below and 'Response adapted therapy' below.)

●BV+AVD adds brentuximab vedotin, but eliminates bleomycin from the ABVD backbone. BV+AVD is repeated every 14 days in 28-day cycles, two treatments are considered one cycle, and six cycles of chemotherapy require 24 weeks. Cytokine support is needed to lessen infectious complications. Acute adverse events include cytopenias, and peripheral neuropathy; long-term toxicities are less well defined. (See 'BV+AVD' below.)

●BEACOPP may have particular utility in younger patients with a high-risk disease (eg, international prognostic score [IPS] ≥4). BEACOPP is administered with growth factor support on days 1 and 8 of a 21-day cycle for four to eight treatment cycles (a total 12 to 24 weeks of chemotherapy). Four or six cycles of escalated BEACOPP (eBEACOPP) is at least as effective and less toxic than eight cycles of eBEACOPP, which was shown to be superior to standard (baseline) BEACOPP or COPP/ABVD. When compared with ABVD, eBEACOPP has more toxicity, including bone marrow suppression, secondary malignancies, and sterility. Escalated BEACOPP should only be used for younger patients (<60 years), because toxicities are particularly severe in older patients. It is unknown how eBEACOPP affects the ability to provide effective salvage therapy (eg, autologous hematopoietic cell transplantation) to patients who relapse. (See 'BEACOPP chemotherapy' below and 'Response adapted therapy' below.)

For most patients with advanced stage cHL, we suggest treatment with ABVD, although eBEACOPP is a reasonable alternative, as discussed below. Compared with ABVD, eBEACOPP achieves superior progression-survival (PFS) at five years and may result in superior overall survival (OS), but this advantage may be lost over time due to second malignancies and cardiac toxicity, which account for the majority of late deaths [6]. The greatest potential benefit of eBEACOPP is seen with IPS ≥4. Details on the efficacy and toxicities associated with these regimens are presented in detail in the sections that follow.

The antibody-drug conjugate brentuximab vedotin (BV; anti-CD30 antibody complexed with monomethyl auristatin E) was effective and well-tolerated when combined with AVD (doxorubicin, vinblastine, and dacarbazine) in a phase 1 study of initial treatment of advanced stage cHL [7]. After more than five years of follow-up, treatment of 26 patients with BV+AVD achieved 92 percent failure-free survival and 100 percent overall survival [8]. No unexpected toxicities were detected and the two patients who relapsed achieved a second remission. Importantly, addition of BV to ABVD caused excessive pulmonary toxicity that was not seen when BV was combined with AVD (ie, no bleomycin). A phase III study is underway to test BV plus AVD versus ABVD. Additional details regarding BV are presented separately. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma".)

Despite guidelines for the treatment of cHL, there must remain room for individualization of care to accommodate concerns about the risks of relapse versus toxicity. As an example, availability of effective salvage therapy for relapsed disease (eg, immunotherapy) may influence concerns regarding treatments associated with a higher risk of recurrence but less toxicity.

Response adapted therapy — Mid-treatment positron emission tomography (PET) has prognostic value. Although modification of therapy based on PET after two cycles of chemotherapy (PET2) is often done in clinical practice, its use remains controversial. Initial studies suggest that treatment de-escalation may be safe in PET2 early responders; data regarding treatment escalation in patients without an early response are currently inconclusive.

PET-response adapted therapy will be discussed here. The prognostic value of mid-treatment PET is presented separately. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment", section on 'Radiologic studies'.)

Use of mid-treatment PET-response adapted therapy must closely follow the methods used in trials that demonstrated its efficacy. It should take into account the method for PET interpretation, pre-treatment PET/computed tomography (CT) results, initial therapy, timing of the scan, and cutoff values. It is also important to consider the individual patient’s preferences, values, and risk factors. As an example, a decision to de-escalate ABVD to AVD (ie, bleomycin withdrawal) based on a negative PET2 scan may be especially attractive to a patient with additional risk factors for bleomycin toxicity (eg, older age, underlying pulmonary disease, active smokers), but less important for others.

There is a paucity of data regarding the preferred approach for patients with a positive PET2 scan (ie, Deauville score of 4 or 5). Outside of a clinical trial, many clinicians will continue ABVD therapy for a PET2 negative scan (ie, Deauville 1-3) or switch to eBEACOPP for patients with a positive PET2 scan.

Randomized studies that support treatment de-escalation based on PET2 early response include:

●A multicenter trial reported equivalent outcomes in 935 patients who were randomly assigned to de-escalation with four additional cycles of AVD versus four additional cycles of ABVD after achieving a negative PET2 scan following two cycles of ABVD for advanced stage cHL [9]. This study, RATHL (Response-Adapted Therapy in Advanced Hodgkin Lymphoma), included patients with stages IIB to IV disease or stage IIA with adverse features (ie, bulky disease or at least three involved sites, who constituted 42 percent of participants). AVD and ABVD achieved equivalent three-year progression-free survival (PFS; 84 versus 86 percent, respectively) and overall survival (OS; 98 versus 97 percent). Omission of bleomycin lowered the incidence of fatigue and respiratory events and led to better preservation of pulmonary function.

●German Hodgkin Study Group HD18 reported equivalent five-year PFS with four cycles of escalated BEACOPP (eBEACOPP) versus either six or eight cycles of eBEACOPP in >1000 patients with advanced stage cHL who achieved PET2 negativity after two cycles of eBEACOPP [10]. Four cycles of eBEACOPP was associated with fewer severe infections, less organ toxicity, and no deaths (versus six deaths in patients treated with six or eight cycles).

●AHL2011 randomly assigned 823 patients with advanced stage cHL to standard care using eBEACOPP versus de-escalation to ABVD for a negative PET2 scan following two cycles of eBEACOPP [11]. In the PET-driven arm, treatment de-escalation to ABVD was achieved for 84 percent of patients, while 12 percent continued to receive eBEACOPP because of a positive PET2 scan. Compared with the standard eBEACOPP arm, patients on the PET-driven arm achieved equivalent five-year PFS (86 percent) with less toxicity.

Treatment escalation for positive PET scan can achieve results that are superior to historical controls treated with six to eight cycles of ABVD, but randomized trials are necessary to confirm a benefit to escalation of therapy. The following studies are informative:

●In HD18, addition of rituximab (R) to eBEACOPP did not improve outcomes in patients whose PET scan was positive after two cycles of eBEACOPP [10]. Five-year PFS was 90 versus 88 percent in the 434 PET-2 positive patients who were randomly assigned to six additional cycles of eBEACOPP versus six additional cycles of R-eBEACOPP.

●In the RATHL study (above), the 172 patients with a PET score of 4 or 5 after two cycles of ABVD were nonrandomly assigned to BEACOPP with estimated three-year PFS and OS rates of 68 and 88 percent, respectively [9].

●In GITIL/FIL HD 0607, 150 patients with positive PET scan after two cycles of ABVD were randomly assigned to four cycles of eBEACOPP followed by standard BEACOPP with or without rituximab; three-year PFS was 63 versus 57 percent, respectively [12].

●SWOG S0816 reported two year PFS of 64 percent among 64 patients who received escalated BEACOPP after PET-2 positive scan [13].

ABVD chemotherapy — ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is the standard initial chemotherapy for patients with cHL (table 4) [14]. ABVD is administered every 14 days in 28-day cycles (table 3). Patients are monitored with imaging studies for response during treatment and receive two cycles of chemotherapy beyond best response, up to six cycles (24 weeks). (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

ABVD efficacy — Approximately 80 percent of patients with advanced stage cHL will attain a complete response after treatment with ABVD [14-21]. Up to one-quarter of patients will have disease progression requiring further therapy; half of those will have long-term survival with autologous hematopoietic cell transplantation. OS rates at 4, 7, and 10 years are approximately 90, 75, and 55 percent, respectively.

The efficacy of ABVD has been demonstrated in many prospective trials. These trials have shown ABVD to be superior to MOPP and to have equal efficacy and less toxicity than alternating MOPP-ABVD and MOPP/ABV hybrids [2,15]. Initial studies comparing ABVD with BEACOPP demonstrated similar OS rates. Trials comparing ABVD with BEACOPP are presented below. (See 'BEACOPP efficacy' below.)

ABVD toxicity — ABVD is associated with both acute and long-term toxicity.

Acute — The most common severe (grade 3/4) acute toxicities seen with ABVD include neutropenia (34 percent), nausea/vomiting (13 percent), and alopecia (31 percent) [21]. Severe myelosuppression is rare when ABVD is administered alone [17], and treatment should not be held for neutropenia. Because of the modest incidence of neutropenia, prophylactic treatment with granulocyte colony-stimulating factor (G-CSF) is not required [22,23]. Severe infections, anemia, and thrombocytopenia are not common, occurring in 2, 5, and 3 percent of patients, respectively [21]. The rate of anticipatory nausea and vomiting has decreased substantially with the development and routine use of potent antiemetic agents. (See "Prevention of chemotherapy-induced nausea and vomiting in adults".)

Bleomycin-induced pulmonary toxicity may occur quite often (approximately 20 to 30 percent of patients) and usually develops subacutely while on therapy or up to six months after treatment. Bleomycin-induced pulmonary toxicity adversely affects survival in patients who are treated for cHL. In one study, it was associated with a mortality rate of 4.2 percent and with a significantly decreased five-year OS (63 percent in patients who developed bleomycin-induced pulmonary toxicity as compared with 90 percent in those who are unaffected) [24]. The omission of bleomycin in patients who developed bleomycin-induced pulmonary toxicity (either symptomatic or asymptomatic) had no impact on response rates or survival. (See "Bleomycin-induced lung injury".)

Acute reactions to bleomycin, including fever, the hyperpyrexia syndrome, and anaphylactoid reactions have also been described. (See "Infusion reactions to systemic chemotherapy", section on 'Bleomycin'.)

Long term — Long-term complications of ABVD include bleomycin-related pulmonary toxicity and doxorubicin-associated cardiotoxicity. There does not appear to be an increased rate of myelodysplasia or secondary leukemia, and fertility is preserved in the majority of patients.

ABVD may result in late bleomycin-related pulmonary toxicity, particularly when used in combination with mediastinal irradiation. Fatal pulmonary complications have occurred [15,24,25]. Following ABVD, there may be a significant decline in median forced vital capacity and diffusing capacity (DLCO) [25-27]. The diagnosis and management of bleomycin-induced lung injury is presented separately. (See "Bleomycin-induced lung injury".)

●In one study of 60 early-stage patients with cHL receiving ABVD with or without mediastinal irradiation, 53 percent reported dyspnea on exertion or cough during ABVD, 37 percent had a significant decline in pulmonary function, and 23 percent required discontinuation of bleomycin [27]. At longer follow-up, only one patient reported persistent dyspnea with minimal exertion.

●In another study of 141 patients treated with bleomycin-containing chemotherapy for newly diagnosed cHL, pulmonary toxicity was diagnosed in 25, with a subsequent mortality of 24 percent, all in patients >40 years of age [24]. Other reported risk factors for the development of this complication include mediastinal irradiation, treatment with G-CSF, and use in children [24,26,28-30].

Cardiomyopathy is a recognized complication of doxorubicin therapy but is not commonly seen in patients receiving ABVD. Patients who are treated with six cycles of ABVD receive a total doxorubicin dose of 300 mg/m²; cardiomyopathy is rarely seen in patients who receive a total dose less than 400 mg/m². However, ABVD may be associated with a risk of long-term cardiac toxicity. A large British study documented that the risk for myocardial infarction after treatment with ABVD alone (without radiotherapy) was 7.8 times higher than that the age-adjusted normal population [31]. Children appear to be more susceptible to doxorubicin cardiotoxicity [28,29]. (See "Clinical manifestations, diagnosis, and treatment of anthracycline-induced cardiotoxicity" and "Risk and prevention of anthracycline cardiotoxicity".)

ABVD does not result in a high incidence of permanent azoospermia or amenorrhea [17,32,33]. In one study, for example, azoospermia and oligospermia after ABVD occurred in 36 and 20 percent of patients, respectively, with recovery to normal values in all cases [32,33].

The 15-year cumulative risk of acute myeloid leukemia after ABVD has been estimated to be less than 1 percent. (See "Second malignancies after treatment of classic Hodgkin lymphoma", section on 'Acute leukemia'.)

BV+AVD — BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) is built on the backbone of ABVD but adds brentuximab vedotin (an anti-CD30 antibody complexed with monomethyl auristatin) and eliminates bleomycin. BV+AVD is an acceptable alternative to ABVD and may be preferable for patients at higher risk for pulmonary toxicity (eg, older age, underlying pulmonary disease, active smokers). Advanced stage cHL is treated with six cycles of BV+AVD.

Short-term outcomes with BV+AVD are at least as favorable as ABVD [7,8]. BV+AVD causes less pulmonary toxicity and more peripheral neuropathy and neutropenia. In one study, patients who were treated with BV+AVD had 100 percent five-year survival and only 2 of 26 patients relapsed [7].

ECHELON-1 is a phase III trial that randomly assigned >1300 patients with stage III or IV cHL to BV+AVD versus ABVD [8]. The study reported that BV+AVD achieved marginally superior results at two years for the primary outcome, modified progression-free survival (mPFS; 82 versus 77 percent, respectively; HR 0.72, 95% CI 0.60 to 0.98); mPFS is a composite measure that included time to progression, death, and non-complete response with use of subsequent anticancer therapy. OS did not differ significantly between the trial arms. While a statistically significant benefit for the primary outcome was seen, some experts challenge the clinical relevance of an improvement in mPFS.

Some toxicities were higher with BV+AVD, and growth factor support is needed with this treatment. Neutropenia was more common with BV+AVD than ABVD (58 versus 45 percent, respectively), but G-CSF reduced the frequency of febrile neutropenia to 11 percent of patients treated with BV+AVD [8]. Peripheral neuropathy occurred in 67 percent of patients on BV+AVD and 43 percent of patients on ABVD, but most neuropathy was temporary or at least partially reversible. Pulmonary toxicity (grade 3/4) was greater with ABVD (3 versus 1 percent, respectively). Cost may also influence selection of this treatment because BV+AVD, especially considering the need for G-CSF, is considerably more expensive than ABVD.

Brentuximab vedotin is approved by the US Food and Drug Administration for previously untreated advanced stage cHL [34].

BEACOPP chemotherapy — The German Hodgkin's Lymphoma Study Group (GHSG) developed the BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen (table 4) that can be given in standard or escalated doses [35-37]. When compared with standard ABVD, escalated BEACOPP produces superior progression-free survival (PFS) rates, but has increased toxicity (ie, neutropenia and infections) and no clear advantage in overall survival (OS) [21,38]. While indirect comparisons suggest that escalated BEACOPP may result in superior five-year survival, longer follow-up is needed to see whether this translates into superior long-term survival [6]. Complete response rates with BEACOPP are approximately 80 to 95 percent with five-year PFS and OS rates of 81 and 92 percent, respectively.

Regimens — Multiple versions of BEACOPP have been developed. Eight cycles of escalated BEACOPP was initially shown to be superior to standard (baseline) BEACOPP or COPP/ABVD [39]. In a subsequent randomized trial, compared with eight cycles, six cycles of escalated BEACOPP resulted in superior freedom from treatment failure and OS [40]. In other studies, four cycles of escalated BEACOPP were administered followed by four cycles of either escalated or standard-dose BEACOPP, depending upon the response to the first four cycles.

●Standard-dose BEACOPP (also known as baseline BEACOPP) – When compared with ABVD and MOPP, dose intensity was increased in the BEACOPP regimen by adding etoposide and increasing the frequency of treatment cycles (from every 28 days to every 21 days), thereby providing more chemotherapy in a shorter time period [41].

●Escalated BEACOPP – Further dose intensification was accomplished with the escalated BEACOPP regimen, which is also repeated at 21-day intervals. This regimen has increased doses of doxorubicin (from 25 to 35 mg/m²), cyclophosphamide (from 650 to 1250 mg/m²), and etoposide (from 100 to 200 mg/m²) [39]. Hematologic growth factor support was added on day 8. [42]

BEACOPP efficacy — Eighty to 95 percent of patients with advanced cHL will attain a complete response with BEACOPP. Up to 20 percent (higher rates with baseline BEACOPP than escalated BEACOPP) will have disease progression by five-years and will require further therapy. The OS rate at five years is approximately 92 percent. When compared with ABVD, BEACOPP provides better initial tumor control, but no difference in event-free survival or OS when relapsed or refractory disease is managed with high dose chemotherapy followed by autologous stem cell support.

Several randomized trials have compared BEACOPP with ABVD-based therapy [21,38,39,41-47]. Taken together, these studies demonstrate that BEACOPP is associated with higher response rates and better rates of PFS than those seen with ABVD, but no improvement in OS. This was best illustrated in a 2011 meta-analysis that included data from four randomized trials with a total of 2868 adult patients with newly diagnosed advanced stage or unfavorable early stage cHL [48]. BEACOPP resulted in significantly longer PFS (hazard ratio 0.53; 95% CI 0.44-0.64), but no different in OS (hazard ratio 0.80; 95% CI 0.59-1.09). BEACOPP was associated with significantly more severe hematologic toxicity, infections, and occurrence of myelodysplastic syndrome and acute myeloid leukemia.

It appears that the degree of the PFS benefit may be greatest among the highest risk patients. However, this comes at the cost of increased toxicity with no clear improvement in OS when compared with ABVD alone. Initial treatment with BEACOPP exposes approximately 73 percent of patients with advanced stage cHL (those cured by ABVD) to excess toxicity that may include such effects as sterility and secondary malignancies. In comparison, initial treatment with ABVD avoids these toxicities in the majority of patients, but requires that approximately one in eight patients proceed to high dose chemotherapy and autologous stem cell rescue at progression, a treatment with potential complications of acute toxic effects, sterility, and secondary malignancies. (See 'BEACOPP toxicities' below.)

Reducing the number of escalated BEACOPP treatment cycles from eight to six results in superior efficacy and less toxicity [40]. In another study, outcomes were equivalent, but toxicity was less, for patients who were randomly assigned to a total of four cycles versus six or eight cycles of escalated BEACOPP after they achieved a negative PET scan following two cycles of escalated BEACOPP, as described above [10]. (See 'Response adapted therapy' above.)

There have been no direct comparisons of four or six cycles of escalated BEACOPP versus ABVD. A network meta-analysis of 14 trials with a total of 9993 patients with advanced stage cHL followed for a median of 5.9 years suggested that, when compared with ABVD, six cycles of escalated BEACOPP resulted in superior OS at five years (95 versus 88 percent; hazard ratio 0.38, 95% CI 0.20-0.75) [6]. There were no direct comparisons between these two treatment options, and 711 and 1670 patients had received six cycles of escalated BEACOPP and ABVD, respectively. There were limited data regarding toxicity, and follow-up is too short to determine how an expected increase in long-term toxicity following BEACOPP may impact long-term survival.

BEACOPP toxicities — Common complications of BEACOPP therapy include bone marrow suppression, infection, nausea, hair loss, second malignancies, and sterility. The treatment-related mortality (TRM) rate among patients enrolled on clinical trials of BEACOPP is approximately 2 percent [49]. Higher TRM is seen in older patients (≥40 to 50 years) and those with a poor performance status (ECOG PS ≥2).

Short term — BEACOPP, especially increased dose BEACOPP, is associated with more acute toxicities than ABVD [39,50]. Patients who received increased dose BEACOPP in clinical trials had a higher incidence of grade 3/4 hematologic toxicities, including leukopenia (98 versus 22 percent with ABVD), thrombocytopenia (70 versus 3 percent), and anemia (66 versus 5 percent). Other acute grade 3/4 toxicities that occurred in more than 10 percent of patients included infection (22 versus 2 percent with ABVD), nausea (20 versus 13 percent), and hair loss (79 versus 31 percent). The administration of erythropoietin in conjunction with BEACOPP decreases the number of red cell transfusions required during therapy, but has no impact on treatment associated fatigue [51].

We suggest not treating patients ≥60 years old with BEACOPP, because of its toxicity in older patients. Of 42 patients age 66 to 75 who received standard dose BEACOPP, 21 percent died of acute toxicity [52].

Acceptable rates of TRM can be achieved with escalated BEACOPP when given by experienced centers to young patients with a good performance status. Retrospective analysis of 3402 patients enrolled on prospective trials of escalated BEACOPP (HD9, HD12, HD15) reported a TRM rate of 1.9 percent [49]. Neutropenic infections accounted for the majority of deaths (56 of 64; 88 percent). TRM was highest among older patients and those with a poor performance status. Age and performance status (PS) could be used to divide patients into risk groups with different TRM rates:

●Age <40 years with ECOG PS <2 (2164 patients) – TRM 0.7 percent

●Age <40 years with ECOG PS ≥2 (108 patients) – TRM 0.9 percent

●Age 40 to 49 years with ECOG PS <2 (592 patients) – TRM 1.7 percent

●Age 40 to 49 years with ECOG PS ≥2 (40 patients) – TRM 15 percent

●Age ≥50 years with ECOG PS <2 (453 patients) – TRM 5.7 percent

●Age ≥50 years with ECOG PS ≥2 (45 patients) – TRM 13.3 percent

Another analysis examined the impact of bleomycin and vincristine dose reductions in 3309 patients with cHL enrolled on prospective trials of escalated BEACOPP (HD12, HD15) [53]. A minority of patients received fewer than five cycles of bleomycin (4.7 percent) or fewer than four cycles of vincristine (6.6 percent). When compared with those who received more cycles of these agents, these patients had similar rates of PFS or OS at five years. These results suggest that discontinuation of bleomycin or vincristine due to drug toxicity does not impact the efficacy of BEACOPP in this population.

Long term — The main long-term complications of BEACOPP are second malignancies and sterility [54]. The following findings have been noted in prospective trials:

●At five years, the rate of secondary acute leukemia was significantly higher with escalated BEACOPP compared with BEACOPP or COPP/ABVD (2.5 versus 0.6 and 0.4 percent, respectively) [39]. The rate at 10 years was higher than that at five years only with BEACOPP (1.5 versus 0.6 percent) [44].

●At five years, non-Hodgkin lymphoma developed in 1.0, 0.9, and 2.7 percent of patients receiving escalated BEACOPP, standard BEACOPP, or COPP/ABVD, respectively [39]. The frequency of non-Hodgkin lymphoma was similar at 10 years [44].

●At 10 years, the overall rates of secondary malignancy were 6.8, 8.9, and 6.7 percent of patients treated with escalated BEACOPP, baseline BEACOPP, and COPP-ABVD, respectively [44].

The overall issue of secondary malignancies following the treatment of cHL is discussed in detail separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)

Gonadal toxicity also appears to be a significant risk with BEACOPP regimens. Women have high rates of amenorrhea and infertility, while men commonly develop azoospermia [55,56]. Neither oral contraceptives not GnRH-analogues have been effective in preserving fertility in this population [57].

Data on gonadal toxicity were reported for 417 male and 232 female survivors of advanced stage cHL treated with BEACOPP on the German HD15 trial and followed for a median of four years [58]. Women tested for anti-müllerian hormone, a marker of ovarian reserve, consistently demonstrated depletion of the ovarian follicle pool suggesting that they would have a poor response to in vitro fertilization. When compared with older women, a higher percentage of women <30 years were able to recover menstrual activity (82 versus 45 percent). While approximately half of female survivors expressed a desire to have children, only 15 percent reported successful pregnancies. The majority (89 percent) of men had evidence of oligospermia, and approximately 20 percent had low testosterone levels (<2.8 ng/L). Twelve men were able to successfully father children, 2 after natural fertilization and 10 after assisted reproduction.

IS THERE A ROLE FOR RADIATION?

Overview — The role of consolidation radiotherapy (RT) after chemotherapy induction for advanced stage cHL is controversial. The addition of RT to initial chemotherapy appears to improve freedom from progression, but not survival [59,60]. Proponents advocate its use because the majority of relapses following systemic chemotherapy for cHL are in previously involved or unirradiated sites [61,62]. Opponents of its use question its necessity and raise concerns about the long-term side effects. (See 'Radiation toxicity' below.)

Most clinicians agree that RT is probably not beneficial and potentially detrimental in patients without initially bulky disease who achieve a complete remission (CR) with ABVD and will receive an additional two cycles of ABVD.

Whether or not consolidative RT should be administered to patients with initial bulky mediastinal disease (>10 cm or >1/3 the chest diameter) remains an unresolved issue. Factors to be taken into account when making this decision include the patient's age, sex, history of prior radiation, and the size and location of the proposed radiation field. We suggest the use of consolidation RT after ABVD for most patients with initial bulky mediastinal disease.

Field and dose — The International Lymphoma Radiation Oncology Group (ILROG) of experts has published field and dose guidelines for modern RT in cHL [63]. Involved site radiation therapy (ISRT) is preferred over larger radiation fields. ISRT is based on the initial involved volume in the treated site and reduced in consideration of the node regression after chemotherapy such that most uninvolved normal organs are spared of radiation. For most cases, ISRT results in significantly smaller radiation fields than the involved field radiation used previously. These guidelines detail the design and technique considerations [63]. For patients who achieve a CR with chemotherapy, the recommended radiation dose for consolidation ISRT is 30 Gy. For those with residual abnormalities of borderline significance on PET, the dose to the residual abnormal site can be increased to 36 Gy. Further details regarding ISRT are presented separately. (See "Treatment of favorable prognosis early (stage I-II) classic Hodgkin lymphoma".)

Radiation efficacy

General — Numerous prospective and retrospective studies have evaluated the use of consolidation RT in patients with advanced stage cHL with mixed results [2,61,62,64-72]. The interpretation of these studies has been controversial. Many randomized trials did not contain adequate numbers of patients to detect a survival benefit [59]. Thus, they suffer from possible false-negative outcomes (type 2 error) due to insufficient power. This problem is magnified in some studies by the attrition of patients who fail to achieve CR, or who refuse randomization following chemotherapy.

After ABVD — Indications for RT after ABVD include initial bulky mediastinal disease (>10 cm or >1/3 the chest diameter) and/or the presence of residual abnormalities on imaging studies after completion of chemotherapy (ie, partial response [PR]). RT is probably not beneficial in patients without initially bulky disease who achieve a CR with ABVD and will receive an additional two cycles of ABVD. A possible exception to this is in patients with nodular sclerosis cHL who may have improved tumor control with RT [60]. (See 'General' above.)

While the optimal use of adjuvant radiation remains ill-defined as part of initial therapy in patients with advanced stage cHL, its use is further discussed below. The decision to incorporate adjuvant radiation into the treatment plan after ABVD must be individualized. Factors to be taken into account when making this decision include the patient's age, sex, history of prior radiation, and the size and location of the proposed radiation field. Given this information, we use the following approach to determining whether a patient should receive consolidation RT:

●For patients with advanced stage cHL and initial bulky mediastinal disease (>10 cm or >1/3 the chest diameter), we suggest the use of consolidation RT after ABVD rather than observation. The radiation dose is usually 30 to 36 Gy, and depends upon field size, initial disease volume, and response to chemotherapy. Observation may be appropriate for select patients, such as young women in whom substantial breast tissue would be included in the radiation fields.

●For patients with nonbulky advanced stage cHL who achieve a CR with ABVD, we suggest observation rather than the use of consolidation RT.

●Patients treated with ABVD who achieve a PR, with residual PET abnormalities, should undergo biopsy of the suspected residual disease. If the biopsy demonstrates residual disease, additional therapy is administered as appropriate for relapsed/refractory disease. Alternatively, consolidation with RT or close observation with short interval follow-up may be chosen in select circumstances in which a biopsy may prove difficult or dangerous, or when PET residual abnormality is of borderline significance.

Complete remission — The omission of RT for patients who achieve a CR with ABVD is supported by a phase III European Organisation for Research and Treatment of Cancer (EORTC) trial that randomly assigned 333 patients to consolidation RT or observation after the achievement of a CR with a MOPP/ABV hybrid regimen [73]. When compared with patients who received RT, patients who did not receive RT had similar rates of event-free survival (77 versus 73 percent) and overall survival (85 versus 78 percent) at eight years. Patients who received RT had a nonsignificant trend towards a higher rate of secondary cancer at eight years (13 versus 6 percent). However, there are several limitations to this trial: the chemotherapy regimen (MOPP/ABV hybrid) is no longer in use due to its excessive toxicity; most patients received eight cycles of chemotherapy and still the fraction of patients randomized in CR was only 65 percent, and, most patients with bulky disease were not randomized. It is also unexplained why the excess in leukemia cases that was reported only in CR patients who received low-dose radiation consolidation has not been observed in the larger group of partial responders who have all received radiation as well.

Partial response — The use of RT in patients with a PR after ABVD is supported by the EORTC trial described above. In this same trial, 247 patients achieved a PR after MOPP/ABV, 227 of whom were given consolidation RT [73]. When compared with those who had achieved a CR after MOPP/ABV, those patients who received RT after achieving a PR had similar rates of event-free survival (76 percent) and overall survival (84 percent) at eight years. In this trial, response was determined using computed tomography (CT) criteria. It is likely that a percentage of patients who achieve a PR by CT criteria had fibrosis rather than residual cHL suggesting that some of these patients were potentially overtreated. Response criteria now incorporate findings from PET scans. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment", section on 'Response categories'.)

Bulky disease — Bulky mediastinal disease (>10 cm or >1/3 the chest diameter) is an adverse prognostic marker in patients with advanced stage cHL [74]. The use of consolidation RT in this group of patients is largely based upon retrospective analyses.

●A nonrandomized study of RT embedded within a randomized trial of chemotherapy (ABVD versus two other multidrug regimens) in newly diagnosed advanced stage cHL included 222 patients who received RT mostly due to bulky disease or incomplete response [72]. Although the radiation group included mostly patients with these unfavorable features, the addition of consolidation RT resulted in superior progression-free survival (hazard ratio [HR] 0.40, 95% CI 0.23-0.69). Overall survival was also significantly better for those who received RT (HR, 0.47; 95% CI 0.29-0.77). Median follow-up was seven years.

●A single-center retrospective analysis of 104 patients with stage III cHL who achieved a CR after ABVD and followed for a median of 5.8 years compared outcomes between the 40 patients who received consolidative RT and those who did not [75]. Patients who did not receive RT had inferior rates of disease-free survival at five (78 versus 94 percent) and 10 (45 versus 81 percent) years, and lower rates of overall survival at five (91 versus 98 percent) and 10 (72 versus 80 percent) years post-treatment. The potential benefit from RT appeared to be greatest for patients with initial disease above the diaphragm.

Although not definitive, these observations provide support for combined modality treatment in patients with initially bulky disease even if a CR has been documented by PET/CT scan, especially if initial PET response remains above Deauville level 2 (ie, uptake greater than mediastinum) [76]. Additional support for this approach comes from the extrapolation of data from patients with early stage disease with bulky mediastinal disease, which suggests that the addition of RT to chemotherapy results in significantly higher disease-free survival rates and a trend towards improved overall survival. (See "Treatment of unfavorable prognosis early (stage I-II) classic Hodgkin lymphoma in adults", section on 'Combined modality therapy (CMT)'.)

After BEACOPP — The addition of RT improves freedom from treatment failure rates in patients with advanced stage cHL who have residual disease after the completion of BEACOPP [77]. However, patients with advanced stage cHL who still have residual disease on CT scan after escalated BEACOPP but are PET-negative maintain a progression-free survival rate of 94 to 96 percent without receiving additional RT [40,78].

Therefore, our current approach to the use of consolidation therapy for patients treated with BEACOPP is dependent on their response to the initial chemotherapy:

●For patients who achieve a CR after BEACOPP, we suggest observation rather than RT.

●For patients who have residual disease on PET scan after BEACOPP, we suggest the use of consolidation RT rather than observation.

Radiation toxicity — The side effects of RT depend largely on the area irradiated, the dose of radiation, and the technique employed. RT techniques have changed dramatically over the past few decades resulting in uncertainty regarding the long-term side effects of RT.

In addition, there may be differences in both short-term and long-term toxicities when different combination chemotherapeutic regimens are combined with RT. Although many of the short-term toxicities can be avoided by administering sequential rather than concurrent chemotherapy and radiation, combinations of both treatments have the potential to increase late complications, most notably, secondary malignancies and cardiopulmonary toxicity. Approximately half of patients who received upper mediastinal or neck irradiation will develop hypothyroidism. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Late complications'.)

Acute side effects — Acute side effects of RT include fatigue and a mild sun-exposure-like dermatitis in the involved field (table 5). Irradiation of the head and neck can result in dry mouth, change in taste, and pharyngitis. Subdiaphragmatic irradiation is associated with a loss of appetite, nausea, and increased bowel movements. Myelosuppression can occur if more than one field is irradiated. (See "Overview of gastrointestinal toxicity of radiation therapy".)

Complications occurring in fewer than 5 percent of patients include:

●Mediastinal irradiation can be associated with radiation pneumonitis and/or acute pericarditis. (See "Radiation-induced lung injury".)

●Radiation of the cervical and/or thoracic spinal cord can be associated with Lhermitte sign (electric shock-like sensation down the backs of the legs with neck flexion), that typically presents within six weeks to three months of treatment, and generally resolves spontaneously.

Cardiac and pulmonary toxicity — Mediastinal RT for cHL may be a cause of late cardiac disease including constrictive or effusive pericarditis, conduction abnormalities, valvular defects, accelerated coronary artery atherosclerosis, or direct myocardial injury. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

The dose of RT and field size are important risk factors for cardiac morbidity. Current practice, which restricts the dose to the whole heart, blocks the subcarinal region part way into treatment, limits concurrent exposure to cardiac toxins such as anthracyclines, and permits lower radiation dose and volume by the use of pre-irradiation chemotherapy, may be associated with a lower risk of cardiac toxicity.

Pulmonary fibrosis can develop as a result of RT or chemotherapy for advanced cHL. Decreased diffusing capacity (DLCO) and restrictive changes may be detected by pulmonary function testing prior to the onset of symptoms. Children may be more likely to show enhanced toxicity after combined modality treatment because of the increased sensitivity of the lung to damage from bleomycin [79]. (See "Bleomycin-induced lung injury" and "Radiation-induced lung injury".)

Adding gemcitabine or thoracic irradiation increases the risk of bleomycin lung toxicity, whether it is administered prior to or simultaneously with bleomycin. However, the rates of symptomatic pulmonary complications in patients treated with ABVD and radiation do not seem to be greater than after radiation alone [17,27]. In one study of 60 patients with early stage cHL receiving ABVD with or without mediastinal irradiation, 53 percent reported dyspnea on exertion or cough during ABVD and 37 percent had a significant decline in forced vital capacity (FVC) and DLCO [27]. Following RT, there was a further decrease in FVC, but functional status was not significantly altered.

Other chemotherapy regimens have also been associated with increased RT-associated pulmonary toxicity. In two studies in advanced stage cHL that used gemcitabine together with other agents, including bleomycin, severe pulmonary toxicity, including treatment-related fatalities, were recorded, leading to the termination of these treatment programs [80,81]. Unacceptable rates of pulmonary toxicity have been observed in two of three studies of patients with early stage cHL treated with vinblastine, bleomycin, and methotrexate plus radiation [82-84].

Second malignancy — RT for cHL has been associated with an increased risk of developing second malignancies. It is difficult to quantify the magnitude of this risk with modern RT because of the long latency for solid tumors, the potential contribution of chemotherapy, and the major recent changes in RT technique. The use of lower doses of RT and limited field size may reduce the risk of second cancers [85,86]. This is discussed in more detail separately. (See "Second malignancies after treatment of classic Hodgkin lymphoma".)

IS THERE A ROLE FOR TRANSPLANT? — Hematopoietic cell transplantation (HCT) is not recommended for patients with cHL in first remission. Instead, HCT is reserved for the treatment of relapsed disease. (See "Treatment of relapsed or refractory classic Hodgkin lymphoma", section on 'Hematopoietic cell transplantation (HCT)'.)

Attempts to identify a high-risk population that might benefit from early HCT have been unsuccessful. Such a strategy would require the ability to clearly identify poor-risk patients because of the 5 to 10 percent early mortality and the appreciable risk of late myelodysplastic syndrome or acute myeloid leukemia associated with HCT. Although a variety of prognostic factors can help to risk stratify patients with cHL, it has proven difficult to identify a group of patients at very high risk for recurrence.

An international trial randomly assigned 163 patients with poor-risk disease who achieved CR or PR with four initial cycles of an ABVD-containing regimen to high dose chemotherapy plus autologous HCT versus an additional four cycles of conventional chemotherapy [87]. Poor-risk disease was defined as the presence of at least two of the following features: high lactate dehydrogenase level, large mediastinal mass, involvement of more than one extranodal site, anemia, and inguinal involvement. After a median of 48 months, the five-year failure-free survival rate was 75 percent in the high dose arm and 82 percent in the conventional arm, and the five-year overall survival rate was 88 percent for both arms.

MODIFICATION FOR SPECIAL POPULATIONS

Pregnancy — Approximately 3 percent of patients will be pregnant at the time cHL is diagnosed. The management of such patients must take into account the effect of treatment on the fetus and the mother. This is discussed in more detail separately. (See "Management of classic Hodgkin lymphoma during pregnancy".)

Older adults — There is a bimodal age distribution curve for cHL. The pattern of age-specific incidence differs by geographic location and appears to parallel the level of industrial development. In the United States and other economically advantaged countries, there is one peak in young adults (approximately age 20 years) and one in older age (approximately age 65 years). (See "Hodgkin lymphoma: Epidemiology and risk factors", section on 'Age and race'.)

The assessment of an older adult with cHL includes those studies used for the pretreatment evaluation of younger adults with cHL in addition to more specific investigations of physical functioning, nutrition, and comorbid conditions. Comprehensive geriatric assessment of cancer patients is presented separately. (See "Comprehensive geriatric assessment for patients with cancer".)

Treatment of older adults (ie, ≥60 years old) with cHL has not been well studied, and older adults should be encouraged to participate in clinical trials. Older adults have accounted for a minority of patients included in randomized trials and they are more likely to have comorbidities that can limit treatment options and increase the risk of toxicity [88-92]. However, older adults should be offered curative therapy such as that used for younger adults whenever possible. The amount of chemotherapy administered in the initial treatment of cHL affects overall survival.

For most older adults with cHL treated outside of a clinical trial, we suggest treatment with ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine). This is primarily based on the larger general experience with ABVD across all populations and increased toxicity with more intensive therapy. BEACOPP should not be used in patients ≥60 years old. (See 'Choice of initial therapy' above.)

We believe that bleomycin should not be routinely omitted or dose-reduced, except as described below. We perform pulmonary function tests after two treatment cycles and omit bleomycin from subsequent cycles in patients who develop symptomatic or asymptomatic bleomycin-induced pulmonary toxicity during treatment. In addition, we often omit bleomycin from subsequent cycles in those attaining a PET score of 1, 2, or 3 after two cycles of ABVD as described above. (See 'Response adapted therapy' above.)

Examples of patients for whom bleomycin may reasonably be omitted include:

●Age >80 years, very frail, or unlikely to be cured

●Creatinine clearance ≤5 mL/minute

●Active smokers and/or significant underlying pulmonary disease

Because older patients are vulnerable to potentially severe bleomycin toxicity, some experts have advocated omitting bleomycin in older patients to minimize pulmonary toxicity [92]. However, studies in early stage disease reported higher rates of treatment failure when bleomycin is omitted from ABVD, and it is unknown whether the routine omission of bleomycin in ABVD compromises cure rates [93]. Randomized trials have also shown that the omission of bleomycin reduces the rate of pulmonary toxicity among older adults receiving four cycles of chemotherapy, but not among those receiving two cycles [94]. Prospective studies are evaluating novel approaches that omit bleomycin (eg, substituting brentuximab vedotin for bleomycin [95]). Use of such regimens should be restricted to the clinical trial setting. Importantly, adding brentuximab vedotin without omitting bleomycin results in unacceptably high rates of potentially fatal pulmonary toxicity [96].

In a retrospective analysis of 147 older adults (≥60 years) treated with ABVD for newly diagnosed cHL of all stages, 117 (80 percent) achieved a complete remission and the estimated overall survival rate at five years was 67 percent [92]. Toxicity necessitated changes to the treatment schedule/dose in 48 patients. Severe (grade 3/4) toxicity occurred in 63 patients (43 percent) and included pulmonary toxicity (26 percent), hematologic toxicity (10 percent), and infection (3 percent). There were 15 treatment-related deaths, including seven deaths due to pulmonary toxicity. Pulmonary toxicity developed at a median of five months from the first cycle and was not clearly predicted by clinical features (eg, underlying lung disease, tobacco history, age, radiotherapy, or G-CSF use). This study emphasizes the potential curability of cHL in older adults and the need for close monitoring during therapy.

In contrast, BEACOPP has been associated with unacceptable toxicities in patients over the age of 60. In one study, of 42 patients age 66 to 75 who received standard dose BEACOPP, 21 percent died of acute toxicity [52].

The relatively poor results for elderly patients are accompanied by difficulties in maintaining dose intensity with standard cHL regimens. In an attempt to improve outcomes, prospective trials have evaluated the use of other regimens in this population. However, none of these has demonstrated superior outcomes in a randomized trial. As examples:

●In one small study employing CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) for elderly cHL patients, dose intensity was maintained with this every three week regimen and good results were achieved [97].

●In another study of 59 older adults treated with the novel combination of prednisone, vinblastine, doxorubicin, gemcitabine (PVAG), toxicity was acceptable and rates of complete response, progression-free survival at three years, and overall survival at three years were 78, 66, and 58 percent, respectively [98].

●One trial evaluated single agent brentuximab vedotin in 27 frail older adults (median age 78 years) with previously untreated cHL (63 percent advanced stage) [99]. The overall response rate was 92 percent (73 percent complete). After a median follow-up of 17 months, the median progression-free survival was 10.5 months. Median overall survival had not been reached, and survival times ranged from 5 to 25 months. Peripheral neuropathy was seen in the majority of patients (78 percent) and reports of severe neuropathy occurred in the presence of coexisting diabetes mellitus and hypothyroidism. Good response rates were also reported in an abstract presentation of a phase 2 multicenter study that evaluated sequential brentuximab vedotin plus AVD (doxorubicin, vinblastine, and dacarbazine) as first-line treatment in elderly patients with cHL [100]. Evaluation in larger populations is needed. However, these and similar studies suggest a future role for brentuximab vedotin in patients otherwise too frail to tolerate standard curative regimens.

Adolescents — It appears that adult treatment protocols may be safe and provide comparable efficacy to pediatric protocols in the treatment of adolescents with cHL [101]. (See "Overview of Hodgkin lymphoma in children and adolescents".)

HIV-infected patients — Treatment of patients with HIV who develop cHL is complicated by their immunocompromised state and also requires specific treatment for their HIV. As such, treatment of these patients is discussed in more detail separately. (See "HIV-related lymphomas: Treatment of systemic lymphoma" and "HIV infection and malignancy: Management considerations", section on 'Hodgkin lymphoma'.)

MONITORING DURING THERAPY — Patients with cHL are re-evaluated at regular intervals during treatment to assess the response. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment".)

FOLLOW-UP — After the completion of therapy, patients are assessed for disease response using the International Working Group response criteria that incorporates findings on computed tomography (CT) and positron emission tomography (PET) scans. (See "Monitoring of the patient with classic Hodgkin lymphoma during and after treatment", section on 'Response categories'.)

Patients treated for cHL must also be followed at regular intervals to assess for recurrent disease and long-term complications of therapy. (See "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Post-treatment management' and "Approach to the adult survivor of classic Hodgkin lymphoma", section on 'Late complications'.)

CLINICAL TRIALS — Often there is no better therapy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of Hodgkin lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient education" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Hodgkin lymphoma in adults (Beyond the Basics)" and "Patient education: Hematopoietic cell transplantation (bone marrow transplantation) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS — Once the diagnosis of classic Hodgkin lymphoma (cHL) has been established, subsequent therapy is based upon the stage of the disease, as currently defined by the Cotswolds classification (table 1). In this discussion, advanced stage cHL refers to clinical stage (CS) III and IV disease. CS III describes involvement of lymph nodes or lymphoid structures on both sides of the diaphragm. CS IV refers to diffuse or disseminated involvement of one or more extranodal organs or tissues, with or without lymph node disease. (See "Pretreatment evaluation, staging, and treatment stratification of classic Hodgkin lymphoma".)

●For most patients with advanced stage cHL, we suggest response adapted ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) chemotherapy (table 3) rather than alternative chemotherapy regimens (table 4) (Grade 2B). The preference for ABVD in this setting is informed by the favorable balance of outcomes versus toxicity, and long experience with this regimen. (See 'General approach' above.)

Other acceptable regimens for advanced stage cHL include:

•BV+AVD (brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine) (see 'BV+AVD' above)

•BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) (see 'BEACOPP chemotherapy' above)

Selection of an alternative to ABVD is informed by comorbid medical conditions, physician/institutional experience, and patient preference. Such considerations must weigh short- and long-term outcomes and toxicities. (See 'General approach' above.)

●The number of cycles of ABVD chemotherapy is informed by the response on positron emission tomography (PET) scan after two treatment cycles (PET2; ie, response adapted therapy). Patients who attain a PET2 score of 1, 2, or 3 ("PET2-negative") may reasonably complete therapy with four additional cycles of AVD (without bleomycin). The decision for an individual patient must take into account the risk of pulmonary toxicity with further bleomycin versus the potentially small increase in relapse with bleomycin omission. This approach is most attractive for those at high risk for bleomycin toxicity (eg, older age, underlying pulmonary disease, active smokers). Younger patients who wish to minimize their chance of relapse may choose to complete therapy with four more cycles of ABVD. (See 'Response adapted therapy' above.)

●The role of consolidation radiotherapy (RT) after chemotherapy induction for advanced stage cHL is controversial. RT appears to improve freedom from progression but not overall survival. Its use depends primarily upon the initial chemotherapy administered and the patient's response to that chemotherapy. (See 'General' above.)

●The decision to proceed with adjuvant radiation after ABVD must be individualized. Factors to be taken into account when making this decision include the patient's age, sex, history of prior radiation, and the size and location of the proposed radiation field. In general, we use the following approach:

•For patients with advanced stage cHL and initial bulky mediastinal disease (>10 cm or >1/3 the chest diameter), we suggest the use of consolidation involved site RT after ABVD rather than observation (Grade 2C). The radiation dose is usually 30 to 36 Gy, and depends upon field size, initial disease volume, and response to chemotherapy. (See 'After ABVD' above.)

•For patients with nonbulky advanced stage cHL who achieve a complete remission with ABVD, we suggest observation rather than the use of consolidation RT (Grade 2B).

•Patients treated with ABVD who achieve a partial response, with residual PET abnormalities, should undergo biopsy of the suspected residual disease. If the biopsy demonstrates residual disease, additional therapy is administered as appropriate for relapsed/refractory disease. Alternatively, consolidation with RT or close observation with short interval follow-up may be chosen in select circumstances in which a biopsy may prove difficult or dangerous or when PET residual abnormality is of borderline significance.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Steven Horwitz, MD, who contributed to earlier versions of this topic review.