Seminars in Radiation Oncology
Volume 20, Issue 1 , Pages 30-44, January 2010

Hodgkin Lymphoma Across the Age Spectrum: Epidemiology, Therapy, and Late Effects

  • Angela Punnett, MD, FRCPC

      Affiliations

    • Division of Hematology and Oncology, Hospital for Sick Children, Toronto, ON
    • ,
  • Richard W. Tsang, MD, FRCPC

      Affiliations

    • Department of Radiation Oncology, Princess Margaret Hospital, The University of Toronto, Toronto, ON
    • ,
  • David C. Hodgson, MD, MPH, FRCPC

      Affiliations

    • Department of Radiation Oncology, Princess Margaret Hospital, The University of Toronto, Toronto, ON
    • Corresponding Author InformationAddress reprint requests to David C. Hodgson, MD, MPH, FRCPC, Department of Radiation Oncology, Princess Margaret Hospital, 610 University Avenue, Toronto, ON, Canada M5G 2M9

Article Outline

The treatment of Hodgkin lymphoma is one of the success stories of modern medicine. There is a unified pathologic classification schema, a noninvasive staging evaluation and an increasingly sophisticated approach to therapy with risk and response adapted therapies in pediatric and adult patient populations. Survival rates have continued to improve while treatment modifications to decrease late effects are studied across all populations. However, a strong age gradient exists with respect to patient outcomes with younger patients faring somewhat better than their adult counterparts and older adults faring significantly worse. There has been a growing appreciation for the differences in epidemiology across age groups and the potential differences in disease biology. Novel approaches to prognostic stratification and therapy on the basis of these differences may be necessary to maximize cure and minimize late effects across the ages.

 

Hodgkin lymphoma (HL) as a disease entity represents a spectrum of histopathologic and clinical presentations with notable similarities and differences across patient populations. With observations of trends in epidemiology data, age cohorts of HL patients are identifiable and provide potential insight into disease pathobiology and risk factors. Advances in the treatment of HL have produced significant improvements in long-term survival among both adult and pediatric patients.1 Since the early 1980s, reports of the late effects of radiation therapy (RT) doses ≥35 Gy on musculoskeletal and soft tissue growth in children led to RT dose reductions and the routine use of combined modality therapy (CMT) in pediatric treatment programs.2, 3 The approach to chemotherapy has differed somewhat between adult and pediatric regimens because of the specific concerns of the effects of alkylators and anthracyclines on the fertility and cardiac function of the developing child. However, with the growing awareness of the risks of infertility, second malignancy, cardiopulmonary, and endocrine function after treatment among all age groups, strategies to maximize cure rates while minimizing late effects are converging in adult and pediatric populations.4 Despite ongoing successes in therapy, there remain significant differences in outcome between age cohorts of HL patients with, most strikingly, a relatively poor outcome among the older adult population. This article will review HL across the age spectrum, underscoring the heterogeneity of the disease and exploring epidemiology, treatment development, and outcomes.

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Epidemiology 

HL is rare among children <5 years of age and relatively rare in the adult population, but is the most commonly diagnosed cancer among adolescents aged 15 to 19. In developed countries, there is a bimodal age distribution for HL with a peak in the adolescent/young adult (AYA) population and again after age >55 years.5 Epidemiologic studies suggest 2 distinct forms of pediatric HL: childhood, and AYA.6, 7, 8 Typical adult HL presents similarly to the disease observed in the AYA population, but HL in the older adult population may represent again a different epidemiologic entity (Table 1).

Table 1. Epidemiology of Hodgkin Lymphoma (HL) Across the Ages
Childhood HLAYA HLAdult HLOlder Adult HL
Age range≤14 yr15-35yr≥35 yr≥55 yr
Prevalence of HL cases10%-12%50%35%
Gender
Male:female2-3:11:1-1.3:11.2:1-1:1.1
Histology
Nodular sclerosis40%-45%65%-80%35%-40%
Mixed cellularity30%-45%10%-25%35%-50%
Lymphocyte depleted0%-3%1%-5%2%-6%
NLPHL8%-20%2%-8%7-10%
EBV associated27%-54%20%-25%34%-40%50%-56%
Risk factors: male, younger age, mixed cellularity histology, and economically disadvantaged countries
Other risk factors
Lower SES

Increasing family size


Higher SES

Smaller family size

Early birth order
Stage at presentation
30%-35% with stage III or IV disease

25% with B symptoms


40% with stage III or IV disease

30%-40% with B symptoms


55% with stage III or IV disease

50% with B symptoms

Trend to less bulky disease, less mediastinal mass but more advanced stage with higher IPS scores

Relative survival rates at 5 yr94% (<20 yr)90% (<50 yr) 65% (>50 yr)

NLPHL, nodular lymphocyte predominant HL; IPS, International prognostic score (see Table 2); SES, socioeconomic status.

Childhood HL is defined as affecting those ≤14 years of age.9 It demonstrates a male predominance and the histologic subtype is more likely to be mixed cellularity (30%-35%) or nodular lymphocyte predominant (10%-20%) than AYA or adult HL.10, 11, 12 Risk factors include increasing family size and lower socioeconomic status, and these may correlate with the increased proportion of Epstein-Barr virus (EBV)-associated HL observed in children and suggest that early viral exposure is a risk factor for developing HL in childhood.6, 7, 8, 13 EBV is more likely to be associated with mixed cellularity HL and both of these entities occur more commonly in less economically advantaged countries where the incidence of disease is higher in this younger population.14, 15

By comparison, AYA HL occurs in those aged 15 to 35 years and demonstrates no significant gender predilection. The most common histology is nodular sclerosis (70%-80%), similar to adult series.11, 12 Risk factors include higher socioeconomic status, early birth order, and smaller family size, suggesting that delayed exposure to EBV, or perhaps some other as yet undetermined common infectious agent, may be a risk factor for AYA HL.13, 16, 17

Older adults (ie, >45-55 years) often present with more advanced disease and have a worse prognosis. Data are emerging that these observations may be related to “Age-related EBV-associated B-cell lymphoproliferative disorder” that has morphologic features similar to classical HL, but a worse prognosis. This suggests that that an underlying difference in HL biology may exist among younger and older HL patients.18, 19 Indeed, the similarities in disease presentation at the 2 extremes of life, the basis of the “three disease hypothesis”,6, 20 may suggest an immune immaturity in the youngest patient population and an immune dysregulation in the oldest patient population. Certainly, an increased incidence of HL is associated with other altered immune states, including human immunodeficiency viral infection, other acquired immunodeficiency states (post solid organ or hematopoietic stem cell transplantation), and autoimmune disorders or family history of autoimmune disorders.21, 22, 23, 24, 25 EBV is identified with increased frequency in all of these clinical scenarios. Other evidence for the role of an altered immune state in the development of HL derives from the relatively rare but well described phenomenon of familial aggregation of HL and other lymphoproliferative diseases.26

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Diagnosis and Pre-Treatment Evaluation 

Clinical presentation with painless lymphadenopathy is common to all age groups. Excisional biopsy is recommended in both adult and pediatric populations to assess nodal architecture and increase the probability of detection of the relatively rare Reed–Sternberg cells in classical HL and L & H cells in nodular lymphocyte predominant HL. Clinical staging by the Ann Arbor staging system and its Cotswolds modification remains the standard for adult and pediatric HL.27 Necessary studies include computed tomography (CT) of the neck, chest, abdomen, and pelvis with intravenous contrast with document the extent of disease, including sites of bulk disease, extension into extranodal tissues, and metastases. The presence or absence of B symptoms on history is included in the clinical stage. Definitions of bulky disease depend on the anatomic site and clinical trial protocol.

Functional imaging with gallium-67 or 18-fluorodeoxyglucose positron emission tomography (FDG-PET) is used both to supplement clinical staging and in evaluating response during and after treatment.28, 29, 30 FDG-PET seems to be more sensitive for the detection of HL than gallium imaging and is the preferred modality when available.29, 30 FDG-PET will change the stage compared with CT-based imaging alone in approximately 25% of HL patients.29, 30

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Prognostic Categorization 

For the purposes of treatment selection, pediatric treatment programs typically divide patients into low, intermediate, and high-risk disease on the basis of clinical stage (ie, distribution of disease, bulk, and B symptoms). Although some studies of childhood HL have demonstrated adverse prognostic effect of male gender, elevated leukocyte count, and anemia, these have not been widely incorporated into pediatric risk-adapted therapy protocols.31 A prognostic score similar to that published for adult HL by the International Prognostic Factors Project on Advanced Hodgkin's disease, has not been created from multiinstitutional trials of pediatric patients.32 Adult treatment programs divide patients into 3 or 4 risk categories according to prognostic factors, such as clinical stage, anemia, age, and sedimentation rate (Table 2).

Table 2. Risk Groups Employed in Selected Trials of Pediatric and Adult HL
Study GroupRisk Features (RF)Low RiskIntermediate/Early Unfavorable RiskHigh Risk
Pediatric
Children's Oncology Group IA/IIA no bulk or extranodal extension
IA bulk or “E” extension

IB

IIA bulk or “E” extension

IIB

IIIA

IVA

IIIB, IVB
German Multicenter Studies (pediatric)
IA/B

IIA


IIB

IIIEA

IIIB


IIEB

IIIEA/B

IIIB

IVA/B

St. Jude/Stanford/Dana FarberCategorized as favorable or unfavorable risk by IPSIA/IIA no bulk
IA bulk

IB

IIA bulk

IIB

III

IV

Children's Cancer Group
Hilar lymphadenopathy

>4 sites nodal disease

Bulky disease


IA/B without RFs

IIA without RFs


IA/B with RFs

IIA with RFs

IIB

IIIA/B

IV
Adult
EORTC
Large mediastinal mass

Age ≥50 yr

Elevated ESR

≥4 involved regions

I/II supradiaphragmatic without RFsI/II supradiaphragmatic with RFsIII/IV
GHSG
Large mediastinal mass

Elevated ESR

Extranodal disease

≥3 involved regions

I/IIA without RFs
I/IIA with ≥1 risk factor

IIB with elevated ESR or ≥3 involved regions


IB/IIIA with large mediastinal mass or with extranodal lesions III/IV

ECOG-NCIC
Histology (LD or MC)

Age ≥40 yr

Elevated ESR or B symptoms

Four or more involved regions

I/II without risk factorsI/II with ≥1 risk factors
I/II with massive mediastinal disease

III/IV

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The Development of Contemporary Standard Therapy 

Initial treatment success in HL was observed with extended field RT alone at doses of 35 to 45 Gy in early stage disease.33, 34, 35 This was followed by the introduction of a noncross-resistant chemotherapy regimen MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) for advanced stage disease in adults36, 37 and then children.34, 38, 39, 40 The MOPP regimen was replaced with ABVD (adriamycin, bleomycin, vinblastine, dacarbazine), a regimen initially developed for use as a salvage therapy in adults relapsing after MOPP or RT.41 Not only is ABVD more effective at curing HL than MOPP, it is significantly less likely to induce second leukemias or permanent gonadal toxicity.42, 43, 44

Standard HL treatment protocols for both adult and pediatric HL patients have employed risk-adapted therapy, in which patients with more adverse prognostic factors receive more intensive therapy (Table 2). Within this paradigm, differences in treatment between adult and pediatric protocols have largely related to age-specific concerns regarding the late effects of alkylating agents, anthracycline, and radiation. For instance, due to concerns about cardiopulmonary toxicity among children using ABVD and the musculoskeletal and soft tissue effects of full dose RT, pediatric treatment programs moved early to CMT to limit cumulative doses of anthracyclines and to limit radiation dose to 15 to 25 Gy to lymph nodes regions initially involved with disease (involved-field RT, IFRT).2, 3

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Treatment of Favorable Risk Disease 

Adult Patients 

The standard treatment of stage IA/IIA nonbulky adult HL in North America is CMT with 2 to 4 cycles of ABVD followed by 30 Gy IFRT.44, 45, 46 This recommendation arises from the results of several studies demonstrating that chemotherapy combined with RT achieves superior disease control compared with RT alone (Table 3). For example, the South West Oncology Group (SWOG) reported a failure free survival of 94% in patients treated with 3 cycles of adriamycin and vinblastine in addition to subtotal nodal RT (STNI) and 81% in patients treated with STNI alone (P < 0.001).47 The EORTC/GELA H8F trial comparing STNI vs CMT with 3 cycles of MOPP-ABV followed by IFRT in favorable patients, showed significantly superior 5-year event free survival for CMT (98%, vs 74% for STNI), and superior overall survival (OS) (97%, vs 92% for STNI alone).4 Excellent disease-free and OS have been reported in the combined modality setting using IFRT fields limited to lymph node regions with radiologically enlarged nodes, and the dose can be decreased from the ≥40 Gy used historically to 30 Gy (and possibly lower) without compromising outcome.55, 56, 57

Table 3. Selected Trials of Therapy for Low-Risk/Favorable Hodgkin Lymphoma
TrialTreatment Regimens#PTSOutcomeFollow Up (y)
Adult
SWOG47 FFTFOS3
3 AV + STNI (36-40 Gy)16594%98%
STNI (36-40 Gy)16181%96%
P < 0.0001P = NS

EORTC/GELA

H8F4


 

3 MOPP/ABV + IFRT (36 Gy)

STNI


 

271

272


EFS (5 y)

98%

74%


OS (10 y)

97%

92%

7.5
P < 0.001P = 0.001

EORTC

H9F48


6 EBVP + IFRT (36 Gy)

6 EBVP + IFRT (20 Gy)

6 EBVP (no RT)


158

147

129


FFTF overall 79%

 

Accrual suspended-high relapse
GHSG2 ABVD + IFRT (30 Gy)204FFTF (all) = 97%2
HD10492 ABVD + IFRT (20 Gy)210
4 ABVD + IFRT (30 Gy)218OS (all) = 99%
4 ABVD + IFRT (20 Gy)215
Pediatric
SFOP MDH 9050 202EFSOS5
4 VBVP + IFRT (20 Gy) (good responders) 91%97.5%(all)
4 VBVP + 1-2 OPPA + IFRT (20-40 Gy) (poor responders) 78%
Stanford/StJude/Dana Farber51 EFSOS10
4 VAMP + IFRT (15-25.5 Gy)11089.4%96.1%
Children's Cancer Group52 EFSOS3
4 COPP/ABV4691%100%
4 COPP/ABV + IFRT (21 Gy)5497%100%
GPOH HD9053 EFSOS5
2 OPPA/OEPA + IFRT (20-35 Gy)26794%99.6%
GPOH HD9554 281DFSOS3
2 OPPA/OEPA (no RT if CR)28%97%97%(all)
2 OPPA/OEPA + IFRT (20-35 Gy) 94%

AV, adriamycin and vinblastine; STNI, subtotal nodal irradiation; MOPP/ABV, mechlorethamine, vincristine, prednisone, procarbazine/adriamycin, bleomycin, vinblastine; IFRT, involved field radiotherapy; EBVP, epirubicin, bleomycin, vinblastine, prednisone; ABVD, adriamycin, bleomycin, vinblastine, dacarbazine; VBVP, vinblastine, bleomycin, etoposide, prednisone; OPPA, vincristine, procarbazine, prednisone, adriamycin; VAMP, vinblastine, adriamycin, methotrexate, prednisone; COPP/ABV, cyclophosphamide, vincristine, procarbazine, prednisone/adriamycin, bleomycin, vinblastine; OEPA, vincristine, etoposide, prednisone, adriamycin; DFS, disease-free survival.

Pediatric Patients 

Several multiinstitutional trials demonstrate that children and adolescents with stage IA/IIA nonbulky HL can be effectively treated with 2 to 4 cycles of chemotherapy followed by 15 to 25 Gy IFRT.58 The Children's Cancer Group (CCG) 5942 trial randomized complete responders to 21 Gy IFRT or no further treatment following 4 to 6 cycles of COPP/ABV chemotherapy. Among favorable risk patients receiving CMI, 3 year event-free survival (EFS) and OS were 97% and 100%, respectively.52 The German-Austrian Multicenter Trial DAL-HD-95 treated favorable risk patients with 2 cycles of OPPA (vincristine, prednisone, procarbazine, and doxorubicin) for girls or 2 cycles of OEPA (procarbazine replaced by etoposide) for boys.54 RT was omitted among patients achieving a complete response (CR) to chemotherapy, using strict criteria (27% of treated patients), with the remaining patients receiving 20 to 35 Gy IFRT depending on the chemotherapy response. Reports demonstrate relapse rates less than 10%. These protocols differ from most adult protocols by modifying chemotherapy exposure according to sex to minimize the gonadotoxic effects of alkylating agents on males. Several regimens have successfully eliminated the use of alkylating agents altogether for favorable risk disease.53, 54, 55, 56, 57, 58, 59 Donaldson et al51 treated 110 children with stage I/IIA HL with 4 cycles of VAMP (vinblastine, doxorubicin, methotrexate, prednisone) chemotherapy followed by 15 Gy (for complete responders) or 25 Gy (for good partial responders) IFRT. Five years OS and EFS were 99%, and 93%, respectively.

Elimination of RT in Favorable Risk Disease 

Most favorable risk patients (children and adults) can be cured without RT, provided they receive a full course of adequate chemotherapy. However, efforts to eliminate RT from the treatment of all adults with favorable risk disease have not been met with uniform enthusiasm given the superior recurrence-free survival with CMT, and the undefined reduction in late toxicity that would be expected with the elimination of contemporary IFRT.60, 61 An National Cancer Institute, Canada—Eastern Cooperative Oncology Group (ECOG) phase III study randomized 399 patients with stages I/IIA disease between ABVD alone, or an RT containing treatment program (STNI alone in favorable disease, and ABVD × 2 followed by STNI in intermediate risk disease). Five-year freedom from progression was superior in patients treated with RT ± chemotherapy compared with 4 to 6 cycles of ABVD (93% vs 87%, P = 0.006), with no significant difference in OS (94% vs 96%, P = 0.4).62 In children, a study of 829 patients conducted by the Children's Cancer Study Group showed better outcome in patients randomized to receive risk-adapted chemotherapy (COPP/ABV) and 21 Gy IFRT (3-year event free survival 92%), compared with patients treated with the same chemotherapy alone (3-year event free survival 87%; P = 0.057, intent to treat analysis). Again, no difference was observed in 3-year OS (98% vs 99%).52 When analyzed according to treatment actually received, the combined modality approach produced a 3 year EFS of 93%, compared with 85% for chemotherapy alone (P = 0.0024).52

The Children's Oncology Group low-risk HL protocol (AHOD 0431) tested the hypothesis that favorable-risk (IA/IIA) patients could be successfully treated without IFRT when they experienced a complete radiologic response to 3 cycles of dose-dense chemotherapy [AV-PC; doxorubicin (A), vincristine (V), prednisone (P), cyclophosphamide (C) q3 weeks × 3 chemotherapy]. It was estimated that ≥65% of patients could be treated without RT, thereby reducing their risk of late effects. The relapse rate among patients whose CR was not confirmed by FDG-PET exceeded stopping rules, and in December 2008 accrual to the study was suspended. Some adult studies have had analogous results: for instance, the EORTC/GELA H9F trial was designed to evaluate IFRT dose reductions, including the omission of RT altogether, after 6 cycles of EBVP (epirubicin, bleomycin, vinblastine, prednisone). The chemotherapy-alone arm of the trial was suspended due to an unacceptably high relapse rate. The remaining treatment arms compare 20 vs 36 Gy IFRT.63 These results demonstrate the importance of adequate chemotherapy in any protocol that endeavors to omit IFRT and also that complete radiologic (ie, CT-evaluated) response to a full course of chemotherapy is not a sufficiently accurate indicator of long-term disease control to omit IFRT without increasing the risk of relapse. The most successful strategy is likely going to be a response adapted decision for the use of RT according to FDG-PET assessment, preferably early in the course of chemotherapy, ie, after 1 to 2 cycles, as discussed below.

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Intermediate/High Risk 

Adult Patients 

The standard of care for treatment of low stage unfavorable HL in adults is CMT. Multi-institutional studies have examined type of chemotherapy, number of cycles, and radiation dose and fields (Table 4). The EORTC H8U trial compared MOPP-ABV for 4 or 6 cycles plus IFRT to MOPP-ABV for 4 cycles with STNI. There was no statistical difference between the 3 arms with 10-year event free survival of 80%, 82%, and 80%, respectively (P = 0.80) and 10-year OS of 85%, 88%, and 84%, respectively (P = 0.93).75 The GHSG HD 11 study compared 4 cycles of ABVD to BEACOPP “baseline” (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone) chemotherapy given with IFRT either 20 or 30 Gy for low stage unfavorable risk patients.76 BEACOPP is a chemotherapy regiment developed for high risk disease by GHSG with the goal of increasing dose intensity and density. Data analysis with a median follow up of 40 months showed no statistical difference between the 4 arms with 3-year failure free survival of 87% and OS 96%.49

Table 4. Selected Trials of Therapy in Intermediate/High Risk Hodgkin Lymphoma
TrialTreatment Regimens#PTSOutcomeFollow Up (y)
Adult-intermediate
EORTC H7U EFSOS10
(Noordijk, 200664)6 EBVP + IFRT (36 Gy)16068%79%
6 MOPP/ABV + IFRT15688%87%
P < 0.0001P = 0.018
GHSG HD8 FFTFOS5
(Engert et al, 200355)4 COPP/ABVD + EFRT (30 Gy) + Bulk (10 Gy)53286%91%
4 COPP/ABVD + IFRT (30 Gy) + Bulk (10 Gy)53284%92%
NSNS
GHSG HDII 2
(Diehl and Fuchs, 200749)
4 ABVD + IFRT (30 Gy)

4 ABVD + IFRT (20 Gy)

4 BEACOPP + IFRT (30 Gy)

4 BEACOPP + IFRT (20 Gy)


264

257

262

268


ABVD:FFTF = 89%, OS = 98%

BEACOPP:FFTF = 91%, OS = 97%

After 30 Gy:FFTF = 93%, OS = 98%

After 20 Gy:FFTF = 91%, OS= 99%
EORTC/GELA RFSOS4
H8UA: 6 MOPP/ABV + IFRT (36 Gy)33594%90%
(Raemaekers, 200248)B: 4 MOPP/ABV + IFRT (36 Gy)33395%95%
C: 4 MOPP/ABV + STNI32796%93%
NSNS
Adult-high
Intergruppo Italiani Linfomi PFSOS5
(Gobbi et al, 200565)3 Stanford V1077382
6 ABVD1228590
6 MOPPEBVCAD1069489
P < 0.01
Consolidative RT to initial bulk or partial response
EORTC 20884 5
(Aleman et al, 200366, 67)6 to 8 MOPP/ABV EFSOS
CR randomized to IFRT (24 Gy)1727985
No further therapy1618491
P = 0.35P = 0.07
PR received IFRT (24 Gy)2507987
GELA H89 EFSOS10
(Ferme, 200668)8 MOPP/ABV927178
6 MOPP/ABV + STNI1147782
8 ABVPP1166790
6 ABVPP + STNI966977
P = 0.23P = 0.03
GHSG HD9 FFTFOS5
(Diehl et al, 200369, 70)8 COPP/ABVD26069%83%
8 BEACOPP base46976%88%
8 BEACOPP esc46687%91%
P < 0.001P = 0.002
IFRT to bulk at diagnosis or residual (30-40 Gy) required by 65% of patients
GHSG HD12 1571All Patients 5
(Diehl, 200871)8 BEACOPP esc FFTFOS
8 BEACOPP esc + IFRT (30 Gy) 85.5%91%
4 BEACOPP esc + 4 BEACOPP base
4 BEACOPP esc + 4 BEACOPP base + IFRT (30 Gy) Chemotherapy arms NS
IFRT to initial bulk or to residual disease in 35% of patients RT arms NS
Pediatric
GPOH HD-90 EFSOS5
(Schellong et al, 199953)2 OEPA/OPPA + 2 COPP + 20-35 Gy124 (IR)93%97%
2 OEPA/OPPA + 4 COPP + 20-35 Gy179 (HR)86%94%
GPOH HD-95 3
(Ruhl, 200472)2 OEPA/OPPA + 2 COPP + 20-35 Gy224 (IR)
91%

(all)

97%
2 OEPA/OPPA + 4 COPP + 20-35 Gy280 (HR) 84%
Pediatric Oncology Group EFSOS5
(Weiner et al, 199773)4 MOPP + 4 ABVD +/− TNI/STNI (21 Gy)17979%92%
Children's Cancer Group EFSOS3
(Nachman et al, 200252)6 COPP/ABV +/− IFRT (21 Gy) (intermediate risk)39488% (IFRT)95%
COPP/ABV + CHOP + AE +/− IFRT (21 Gy) (high risk)14191% (IFRT)100%
Stanford/StJude/DFCI 5
(Hudson et al, 200474)3 VAMP/3 COP + IFRT (15-25 Gy)15975.5%92.7%

EBVP, epirubicin, bleomycin, vinblastine, prednisone; IFRT, involved field radiotherapy; MOPP/ABV, mechlorethamine, vincristine, procarbazine, prednisone/adriamycin, bleomycin, vincristine; COPP/ABVD, cyclophosphamide, vincristine, procarbazine, prednisone/adriamycin, bleomycin, vinblastine, dacarbazine; EFRT, extended field radiotherapy; BEACOPP, bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; STNI, subtotal nodal irradiation; Stanford (V), mechlorethamine, adriamycin, vinblastine, vincristine, bleomycin, etoposide, prednisone; G-CSF, granulocyte-colony stimulating factor; MOPPEBVCAD, mechlorethamine, vincristine, procarbazine, prednisone, etoposide, bleomycin, vinblastine, cyclophosphamide, adriamycin, dacarbazine; ABVPP, adriamycin, bleomycin, vinblastine, procarbazine, prednisone; OEPA/OPPA, vincristine, etoposide, prednisone, adriamycin/vincristine, procarbazine, prednisone, adriamycin; CHOP, cyclophosphamide, adriamycin, vincristine, prednisone; AE, cytarabine, etoposide; VAMP, vinblastine, adriamcyin, methotrexate, prednisone.

Similarly the EORTC H9U study is comparing 4 or 6 cycles of ABVD to 4 cycles of BEACOPP with IFRT in both arms, and the GHSG HD14 trial is comparing 2 cycles of escalated BEACOPP followed by 2 cycles of ABVD vs 4 cycles of ABVD, both arms receiving 30 Gy IFRT. Mature results of these trials are pending.49 Single institution experience with the Stanford V regimen (doxorubicin, vinblastine, mechlorethamine, etoposide, vincristine, bleomycin, prednisone, and IFRT for tumor mass >5 cm) for unfavorable or advanced stage disease demonstrated 5-year failure free survival of 89% and OS 96%.77 The results for the Stanford V regimen did not compare favorably in an Italian trial comparing Stanford V with ABVD or MOPPEBVCAD for progression free survival (73%, 85%, 94%, respectively, P < 0.01), though there is concern that the RT after Stanford V chemotherapy was not delivered as intended in the original protocol.65 The current ECOG 2496 trial compares the Stanford V regimen with 6 to 8 cycles of ABVD. In summary, practice guidelines recommend therapy with ABVD for 4 to 6 cycles followed by IFRT, for low stage unfavorable/intermediate risk HL.

For advanced stage (IIIB/IV) adult patients, the preferred North American chemotherapy regimen for remains ABVD for 6 to 8 cycles after initial multiinstitutional studies demonstrating its superiority and improved toxicity profile over MOPP.42, 43, 44, 45 Alternate chemotherapy regimens developed to intensify therapy for high risk disease have met with variable success.65, 77, 78 The most successful of these has been BEACOPP, and this regimen forms the basis of a second internationally accepted therapy for advanced HL (NCCN guidelines).46, 69 The original therapeutic trial GHSG HD9 compared escalated BEACOPP with baseline BEACOPP and COPP/ABVD. Patients received RT for bulky disease at presentation (30 Gy) or for residual disease after 8 cycles (40 Gy) (approximately two-thirds of patients). With a median follow-up of 5 years, the results showed a statistically significant benefit for escalated BEACOPP with FFTF of 87%, 76% and 69%, and OS of 91%, 88%, and 83%, respectively.69 Hematologic toxicity and an increased rate of secondary leukemia was observed with the BEACOPP protocols, particularly the escalated regimen, but the overall incidence of second cancers (SCs) was highest in the COPP/ABVD arm.69 The subsequent GHSG HD12 study examined the use of 8 cycles of escalated BEACOPP to 4 cycles of escalated then 4 cycles of baseline BEACOPP. Patients were randomized to receive or not 30 Gy RT to sites of initial bulk disease or residual disease. Results were equivalent for the 2 chemotherapy arms with FFTF and OS rates of 90% vs 88% and 96% vs 94%, respectively.70 A multicenter pilot study of BEACOPP-14, a time-intensified baseline BEACOPP regimen designed with the goal of limiting toxicity, has been deemed feasible and promising.79

The role of radiotherapy in adults with advanced stage HL seems limited. Several randomized trials of adults in CR following chemotherapy for advanced stage HL found no benefit to the addition of RT in this context.66, 70, 80, 81 For instance, the aforementioned GHSG HD12 study randomized patients to receive or not 30 Gy RT following 8 cycles of BEACOPP based chemotherapy. There was no benefit to RT in an intention to treat analysis. In the EORTC 20884 trial, patients achieving CR were randomized to receive 24 Gy IFRT following 6 to 8 cycles of MOPP-ABV. Patients in PR after 6 cycles of chemotherapy received IFRT. The 5 year EFS and OS were 84% vs 79% (P = 0.35) and 91% and 85% (P = 0.07), respectively for the nonradiated group and radiated group.66 A meta-analysis of chemotherapy vs CMT trials suggested the latter is associated with inferior long-term survival.82

Consolidation RT contributes to improved disease control in the presence of bulk disease at presentation or in the presence of partial response in some analyses. For example, in a subgroup analysis, the Southwest Oncology Group did demonstrate improved relapse-free survival for patients with bulky, nodular sclerosing HL after IFRT.83 The EORTC 20884 demonstrated similar outcomes for patients in PR after MOPP-ABV chemotherapy who received IFRT as those in CR following chemotherapy (EFS 79% and OS 87%), although response assessment was not on the basis of FDG-PET.66 Even on the HD12 trial, 13% of patients on the chemotherapy alone arm received IFRT for residual disease or minor response at the recommendation of a review panel.84 Current guidelines recommend considering the use of IFRT after chemotherapy only to sites of initial bulky disease or remaining PET avid disease at the completion of chemotherapy (NCCN guidelines, BCCA guidelines).46

Pediatric Patients 

The outcome of pediatric patients with unfavorable risk factors is also substantially improved with intensification of chemotherapy, although the use of IFRT in advanced stage disease in children differs from that in adults in that several pediatric protocols use IFRT to all initially involved sites after chemotherapy.52 Pediatric trials have used a dose dense approach with stem cell factor support and early response to tailor therapy for early responders.85 The German HD-DAL 90 protocol treated intermediate- and high-risk patients with an additional 2 or 4 cycles of COPP (cyclophosphamide, vincristine, prednisone, procarbazine) following 2 cycles of OPPA (girls) or OEPA (boys). All patients received 20 to 35 Gy IFRT. Five years EFS in the intermediate- and high-risk groups was 93% and 86%, respectively, comparable to that observed in the low-risk group.53 In the subsequent HD-95 trial, which employed the same chemotherapy, but omitted IFRT in complete responders, the EFS for intermediate- and high-risk patients was 87%, and 83%, respectively.54 This study group has not recommended the omission of IFRT in all intermediate and advanced stage disease. The CCG 5942 protocol treated intermediate-risk disease with 6 cycles of COPP/ABV; those with high-risk disease received 2 courses of intensive multidrug chemotherapy with cytarabine/etoposide, COPP/ABV, and cyclophosphamide, vincristine, doxorubicin and methylprednisolone/prednisone followed by granulocyte colony-stimulating factor support. Complete responders were randomly assigned to 21 Gy IFRT or no further therapy. The 3-year EFS rate was improved in the group receiving IFRT (93% vs 85%) with no difference in OS noted (98% vs 99%).52

Intensive chemotherapy may be used to treat intermediate and high-risk disease without RT. The POG 8725 study randomized patients with intermediate or high-risk disease to 8 cycles of MOPP/AVBD with or without IFRT. EFS was 80% and 79% in the 2 treatment arms, with no significant difference in OS. However, long-term adverse effects of therapy were not evaluated.73

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Response Adapted Therapy 

Pediatric and adult HL protocols are converging on the goal of maintaining (or improving) high cure rates while limiting toxicity. Although protocols have tailored treatment intensity according to prognostic factors identified at the time of diagnosis (ie, risk-adapted therapy), current trials seek to further refine treatment on the basis of the early response to chemotherapy. Ongoing trials in North America and Europe intensify chemotherapy and/or RT for patients with suboptimal early response to chemotherapy, or limit treatment for those achieving a rapid early response, so-called “response-adapted therapy.”

Response-adapted approaches to chemotherapy for advanced HL are under study. For example, Dann et al86 in a multicenter trial assigned patients to 2 cycles of escalated or baseline BEACOPP according to the IPS score at presentation with subsequent therapy with escalated vs baseline BEACOPP therapy to 6 cycles determined by initial response. RT was provided to patients with bulk disease at presentation or areas of residual disease following chemotherapy. For all patients, EFS was 85% and OS 90% with no difference between the intermediate and high risk groups. FDG-PET avidity after 2 cycles was a significant predictor of treatment failure (27% vs 2.3% for PET positive vs negative patients, respectively). The HD15 trial compares 6 or 8 cycles of escalated BEACOPP to 8 cycles of BEACOPP-14 with 30 Gy RT given only to patients with PET positive residual disease, and the HD18 trial will study a response adapted approach after 2 cycles of escalated BEACOPP for all advanced HL patients. Those who remain PET positive will receive an additional 4 to 6 cycle of escalated BEACOPP and those who are PET negative will receive only 2 additional cycles. Similarly, the EORTC H10 treats stage I/II patients with 3 to 4 cycles of ABVD with 30 Gy INRT as the standard therapy, or randomizes to a PET-based modified treatment with ABVD alone, or BEACOPP with IFRT depending on the results of a FDG-PET scan after 2 cycles of chemotherapy. This is the approach of the recently completed COG study for intermediate risk HL using the ABVE-PC backbone. Patients considered rapid early responders (on the basis of CT-criteria) after 2 cycles were randomized to no IFRT when they have had a CR after 4 cycles. Patients considered slow early responders were randomized to 2 additional cycles of noncross resistant chemotherapy (total of 6 cycles) or standard 4 cycles. All slow responders received IFRT. A feasibility study of escalated BEACOPP for children with advanced stage HL was undertaken by the CCG (CCG-59704) with response assessed after 2 and 4 cycles.87 Rapid responders received consolidation therapy to 6 to 8 cycles with gender-adjusted regimens. Slow responders received 4 additional cycles of BEACOPP and IFRT. Final results of this study are awaited but the regimen was generally well tolerated.

Several issues remain to be clarified in response-adapted therapy. The optimal criteria identifying patients whose treatment can be reduced is uncertain. To date, CT measurements have been used to define disease response. However, FDG-PET will have an increasing role in response-based treatment regimens. It has a high negative predictive value in the evaluation of post-treatment residual disease.88, 89, 90, 91 Early interim FDG-PET response to chemotherapy has been found to be more predictive of outcome than pretreatment prognostic risk factors in adults.92, 93, 94 However, the optimal time to evaluate treatment response with FDG-PET is unclear, and the outcome of patients with discordant CT and FDG-PET results is unknown. The lower limit of treatment intensity for rapid early responders is uncertain, and perhaps for children with low-risk disease anthracycline exposure could potentially be reduced further. However, data are emerging that the negative predictive value of a normal FDG-PET scan may vary according to the chemotherapy regimen given, and that normalization of PET imaging after some chemotherapy regimens may not necessarily allow the safe omission of IFRT.95 Moreover, the optimal intensity of treatment for slow responders has yet to be determined.

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Involved Field RT and Involved Node RT 

IFRT treats the clinically involved region(s), with coverage of the whole nodal region as defined by Kaplan and Rosenberg, sometimes additionally covering uninvolved adjacent lymph node region(s).96 For example, for a patient with unilateral cervical and high paratracheal lymphadenopathy (stage II, two Kaplan nodal regions), common IFRT target volume would include bilateral cervical lymph nodes and the upper mediastinal lymph nodes (Fig. 1). This includes the contralateral cervical lymph nodes that did not contain gross disease, but may be deemed to harbor microscopic disease. Additionally, it is common in a CMT setting to not irradiate the whole nodal region, for example, excluding the highest lymph nodes in the neck when the gross disease was located in the supraclavicular fossa, and excluding the subcarinal area when the disease was located in the superior mediastinum. These practices aim to reduce salivary gland and oral cavity morbidity, and to optimally spare the heart from irradiation, respectively.

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  • Figure 1. 

    Involved-field radiation therapy RT. Fused computed tomography/18-fluorodeoxyglucose positron emission tomography imaging shows significant abnormality in the unilateral neck (small volume of abnormal upper paratracheal uptake not observed on cross section shown) (A). After ABVE-PC (doxorubicin, bleomycin, vincristine, and etoposide with prednisone and cyclophosphamide chemotherapy), both the computed tomography and FDG-PET imaging show significant response (B). Dose-distribution of involved-field RT treating involved nodes and adjacent nodal sites (C). Significantly less cardiac volume is treated than would be the case with historic mantle RT. Involved node radiation therapy would reduce the volume further to exclude any of the contralateral neck. (Color version of figure is available online.)

A further reduction of RT volume to cover just the nodal tissue involved by disease, without any attempt to include whole nodal region(s), is termed involved node RT (INRT).97 Its use is according to the observation that relapses in patients treated with chemotherapy alone occurred mostly in the initially involved lymph nodes.98 Using FDG PET and advances in radiation planning, it is possible to confine the radiation to the initially involved nodal tissues rather than the whole nodal chain. The hope is that a reduction in irradiation volume would translate into lower incidence of late complications. This goal may be particularly important in young females with anterior mediastinal disease, where exclusion of the hila and subcarinal nodes from the RT field would lead to significant reductions in breast dose. Moreover, children have been shown to be particularly susceptible to thyroid toxicity following RT, and the transition to INRT may potentially exclude the thyroid from the treated volume for many patients with supradiaphragmatic HL. Preliminary data of a policy of INRT (less strictly defined than above, and without FDG PET) in a CMT setting from British Columbia in Canada indicated no increase in relapses compared with IFRT or EFRT.99 The INRT concept has not been tested against IFRT in randomized setting, although the GHSG is planning such a study in their intermediate stage group (GHSG HD17). The EORTC/GELA intergroup trial (H10F), which tests the role of FDG-PET as a treatment selection strategy, uses INRT instead of IFRT.

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Hodgkin Lymphoma in the Elderly Patient 

The success over the years in treating children and young adults with HL is tempered by the ongoing challenge of reliably curing elderly patients. Many studies report short-term disease-free and OS rates approximately 65% and 70%, respectively for patients over age 60, in contrast to 85% and 95% among younger patients.19, 100, 101 In fact, data from the National Cancer Institute's Surveillance Epidemiology and End Results Registry indicate that males over 50 years of age diagnosed with HL have a relative survival rate comparable to those diagnosed with colorectal cancer (CRC). For older women, HL is a more fatal disease than breast cancer (Fig. 2). The cause of this seems to be multifactorial: elderly patients tend to present with more adverse risk factors, often tolerate initial treatment less well, and are generally not able to withstand aggressive salvage therapy that might be curative for younger patients.93, 103, 104, 105, 106, 107 Improvements in supportive care and recognition of past undertreatment have likely contributed to the improvement of older patients with respect to long-term survival.1

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  • Figure 2. 

    Age-related relative survival of Hodgkin lymphoma (HL). Graphs show relative survival rates by survival time, all races, 1988 to 2005. For females <50 years old, HL has a better relative survival than breast cancer (A), however for those aged >50, the relative survival is significantly worse for HL than breast cancer (B). For males <50 years old, HL has significantly better survival than colorectal cancer (C), but a comparable outcome for those aged 50 or older (D).102

In the GHSG HD8 trial for early-stage unfavorable patients, CMT produced a 5-year freedom from treatment failure (FFTF) of 64% in those aged ≥60 years and 87% among younger patients. Intensification of treatment with RT does not seem to be the solution to this problem; extended-field RT produced worse FFTF than IFRT among the elderly patients (58% vs 70%; P = 0.034).93 Similarly, the GHSG HD9 (elderly) protocol found no difference in disease control between BEACOPP and COPP-ABVD among elderly advanced-stage HL patients.103 In part, this was due to increased acute myelotoxicity of BEACOPP, and an ongoing study omits OEPA from this regimen with the goal of improving tolerability and complete treatment delivery. A small study of CHOP-21 schedule (cyclophosphamide, vincristine, prednisone and adriamycin) in elderly HL patients with HL reported good outcomes: 3-year OS and PFS of 91% and 82%, respectively.105 Three cycles of the nonadriamycin containing regimen VEPEMB (vinblastine, cyclophosphamide, procarbazine, etoposide, mitoxantrone, bleomycin, prednisolone) followed by IFRT produced 5 year failure-free survival and OS of 79% and 94%, respectively among a small study of early-stage elderly patients. Outcomes among advanced stage patients treated with this regimen were poor, however.108

On balance, it seems that anthracyclines are a key component to effective chemotherapy among elderly patients with advanced stage disease, despite the potential cardiotoxicity. Innovative approaches are required for elderly patients with advanced stage disease that permit the delivery of treatment that is both tolerable and effective.

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Late Effects 

Overall 5-year relative survival for HL is 85% with higher rates reported in younger populations.1, 109 Consequently, the emergence of late toxicity among survivors can limit long-term survival and affect quality of life. Mortality in the first 15 years after diagnosis relates to the primary disease and following that to SCs and cardiovascular disease.67 The relationship between age at HL treatment and the risk of late effects is a complex issue, requiring the consideration of the differences in normal tissue response to treatment exposures in young vs old, as well as the differences in the normal rate of cancer, heart disease, and infertility, all of which vary according to age.

A major clinical consideration is the effect of HL therapy on organ growth in the pediatric population, which is not an issue among adult patients. For example, full-dose RT produces bone and soft tissue hypoplasia in prepubertal children. For patients treated with mantle fields, this manifests as spinal and clavicular shortening and underdevelopment of the soft tissues in the neck. These issues have not been a significant problem with 21 Gy in 14 fractions, now the standard RT dose used in North American pediatric HL protocols. Doxorubicin has analogous age-related cardiotoxic effects.110, 111, 112 In adults, doxorubicin-related heart failure commonly occurs during or shortly after treatment with doses exceeding 550 mg/m2. In children, however, much lower doses may be associated with an eventual decline in cardiac performance, thought to be due to doxorubicin-related impairment of myocardial growth, which may not become symptomatic until many years after treatment.112, 113, 114 Contemporary chemotherapy regimens delivering <250 mg/m2 doxorubicin with low-dose IFRT seem to be associated with minimal early cardiac toxicity in children.74, 115

The risk of second solid cancer is age-related. The relative-risk is typically higher for young patients, and in particular the relative risk of breast cancer among adolescent females receiving >30 Gy mantle RT has been very high. This risk is substantially reduced among women treated at age >30 years. As the baseline risk of malignancies rise with attained age, the excess number of SCs rises over the course of a survivor's lifetime. This is particularly important for younger patients: in one study; female 5-year survivors treated at age 20 had a 30 year cumulative incidence of SC of 24%, which was 20% higher than in the age-matched general population. In contrast, women treated at age 40 had an estimated 30 year cumulative incidence of 27%, approximately 12% higher than expected.116

It has been postulated that the greater risk of breast cancer among adolescent females is due to the greater biological effect of radiation exposure to proliferating breast tissue in these young patients, though this hypothesis remains largely speculative.117 A study provides evidence for an alternative explanation: the risk of breast cancer among 770 female patients diagnosed before age 41 was associated with time interval between RT and menopause.118 This suggests that the increased risk of breast cancer among young women may be due in part to their more prolonged exposure to the breast-cancer promoting effects of endogenous estrogens following RT compared with women treated at older ages.

The elevated risk of SCs among young HL patients suggests that these survivors could benefit from cancer screening at an earlier age than older survivors, or members of the general population. For example, the UK Royal College of Radiology recommends the initiation of breast cancer screening 8 years after mediastinal RT, or age 25, whichever is later.119 In some circumstances, magnetic resonance imaging is recommended for breast cancer screening of young survivors due to recognized limitations of mammography among women with radiologically dense breast tissue. Likewise, although North American guidelines recommend that the average-risk general population undergo CRC screening starting at 50 years of age,120 the risk of CRC in HL survivors may be significantly elevated at younger ages.118 Some expert groups suggest that CRC screening be considered before age 50 for selected survivors.121

It is noteworthy that the risk of SC after contemporary treatment is not yet established, because reduction in alkylator exposure and the use of low-dose IFRT only became standard practice within the last 15 to 20 years. Second solid cancer risk seems to be radiation dose-dependent, with patients receiving <25 Gy mediastinal RT experiencing a lower risk of breast cancer than those receiving higher doses.122 Consequently, contemporary pediatric protocols that employ 21 Gy should be associated with a significantly lower risk of SC compared with that observed in the studies of the Late Effects Study Group.123 Further, the early equivalence of 20 vs 30 Gy IFRT in GHSG HD10, and the reductions in normal tissue volume associated with INRT described above may allow further substantial reductions in late effects among patients receiving RT.

Childhood HL survivors seem to be at greater risk of thyroid abnormalities than adult survivors, particularly if they have received RT.124 Thyroid late effects include hypothyroidism, hyperthyroidism, benign, and malignant thyroid nodules.124, 125 In the Childhood Cancer Survivor Study, 34% of 1791 5-year survivors of HL treated between 1970 and 1986 reported thyroid abnormalities, which can often appear late in follow-up.125 Stanford investigators observed thyroid abnormalities in 17% of children treated with RT dose <26 Gy; the prevalence increased to 78% for those who received ≥26 Gy.124 Of all thyroid nodules, <10% represent thyroid cancer, representing a RR of 18.3 (confidence interval 11.4-27.6) compared with SEER data.125

Preservation of fertility in HL survivors is a multifaceted issue influenced by patient age, sex, treatment, and social factors. Although fertility preservation has long been a consideration in the management of pediatric HL, as women in developed countries increasingly delay childbirth, fertility concerns among adult female HL patients become of greater clinical importance. Moreover, older females have less ovarian reserve and are more likely to be rendered infertile or menopausal than girls exposed to comparable intensity of gonadotoxic treatment.126

The major cause of infertility/gonadal dysfunction among HL survivors is exposure to alkylating agents, most commonly cyclophosphamide, procarbazine, and, more historically, mechlorethamine.127, 128, 129, 130, 131 Several studies have demonstrated that ABVD, the preferred chemotherapy regimen in North America for adult HL, chemotherapy is associated with significantly better preservation of fertility among males than alklyator-based regimens, such as MOPP or MOPP/ABV.132, 133, 134 A study of 36 adult females attempting pregnancy following ABVD chemotherapy found a median time-to-pregnancy was 2.0 months, and a 12 month pregnancy rate of 70%, which was not significantly different from that reported by 29 friend or sibling controls.135

The use of alkylating agents in pediatric HL varies substantially. The German GPOH studies use a gender-specific approach in which OEPA is used in place of procarbazine for males, because testicular germinal function is more sensitive to alkylators than ovarian function.54 The current COG protocols limit alkylators to doses compatible with preservation of fertility.

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Conclusions 

As treatment protocols among for HL patients developed among pediatric and adult clinical trial groups separately, differences emerged with respect to the dose of anthracyclines, alkylating agents, and RT dose. The motivation driving new treatment innovation—to maintain high cure rates when minimizing toxicity—has increasingly led to a common approach to the management of HL among adolescents and young adults. This is particularly well illustrated with the emergence of response-adapted therapy trials, which intensify or reduce therapy according to the early response to treatment.

However, important differences remain. Treatment of patient's age >50 to 60 years remains difficult. Also, it is not clear that the low-bulk mixed cellularity cases observed in young children require the same treatment approach as that used for adolescents with nodular sclerosing HL. A better understanding of the biology of HL will in time lead to further refinement of treatment that will likely differ across the age spectrum.

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PII: S1053-4296(09)00068-X

doi:10.1016/j.semradonc.2009.09.006

Seminars in Radiation Oncology
Volume 20, Issue 1 , Pages 30-44, January 2010

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