Chemotherapy only for localized Hodgkin lymphoma

Authors


David J. Straus MD, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
(fax: 646 422 2291; e-mail: strausd@mskcc.org).

Abstract

Abstract.  Straus DJ (Memorial Sloan-Kettering Cancer Center, New York, NY, USA). Chemotherapy only for localized Hodgkin lymphoma (Review). J Intern Med 2011; 270: 197–205.

Radiation therapy (RT) alone and more recently in combination with chemotherapy (combined modality therapy; CMT) has been the cornerstone of curative treatment for early-stage Hodgkin lymphoma (HL) for over 40 years. Because of increasing awareness of the late morbidity and mortality associated with RT, recent treatment regimens have attempted to limit its use. Chemotherapy only has been demonstrated to be a treatment option for most patients with localized HL. Current clinical trials have targeted subgroups of such patients who may be at an increased risk of recurrence for the addition of limited RT to chemotherapy.

Introduction

Radiation therapy (RT) alone and the combined modalities therapies of chemotherapy and RT for localized Hodgkin lymphoma (HL) have achieved excellent results for over 30 years. ‘Localized Hodgkin lymphoma’ in this review refers to patients with ‘early’ clinical stages I and II HL. Combined modality therapy (CMT) with chemotherapy and radiation therapy has largely supplanted extended field radiation therapy (EF RT), and recent approaches have attempted to reduce early and late toxicity by reducing RT fields and doses along with reduction in the number of cycles of chemotherapy. Chemotherapy alone, with RT limited to subpopulations who might benefit from its use, is another approach with the potential to reduce late toxicity.

Long-term toxicity of treatment

The risks of sterility and secondary leukaemias and myelodysplastic syndromes have been reduced with the current standard ABVD (doxorubicin, bleomycin vinblastine, dacarbazine) chemotherapy regimen as compared with older alkylating-based chemotherapy regimens of the MOPP (nitrogen mustard, vincristine, procarbazine, prednisone) type [1, 2].

Most of the late complications of treatment seen in HL survivors are related to RT (Table 1). The rate of second malignancies is approximately 1% per year [3, 4]. Amongst solid tumours, only alkylating agent-based regimens are associated with an increased risk of lung cancer [5]. Second malignancies are the leading cause of late morbidity and mortality [6, 7].

Table 1. Hodgkin lymphoma: long-term complications of treatment associated with radiation therapy
Second malignancy: 26–28% at 25–30 years [ 3, 4 ]
Thyroid insufficiency and nodules [ 59 ]
Fibrosis
Neuromuscular: Neck muscle wasting (‘neck drop’) [12]
Cardiovascular damage
 Cardiac
  2- to 7-fold increase in MI, angina pectoris, CHF [11]
  Heart valve fibrosis [10]
  Conduction abnormalities [10]
  Restrictive cardiomyopathy [10]
 Carotid intima thickening, stenosis and increased risk of stroke [60]
Lymphedema
Pulmonary and pericardial fibrosis (decreased with modern techniques)
Brachial plexopathy [13]

Cardiovascular damage is the second most frequent cause of late mortality and morbidity [6, 7]. Carotid stenosis risk is increased after cervical RT, and the relative risk of stroke is increased 5–6 times after mantle RT [8]. Patients who receive mantle field RT have a 2–7 times increased risk of fatal myocardial infarction [9]. Heart valve fibrosis requiring surgical replacement [8] and more subtle abnormalities such as restrictive cardiomyopathy and conduction abnormalities have also been reported following mediastinal RT [10]. Overall, there appears to be a 3–5 times increased risk of cardiovascular disease with long follow-up of HL survivors treated mostly with RT alone or combined with chemotherapy. Anthracyclines appear to increase the risk of congestive heart failure and valvular disease beyond that seen with mediastinal RT [11].

Neck muscle wasting causing difficulty with neck extension is common following RT to the neck and may cause discomfort [12]. Pulmonary and pericardial fibrosis and brachial plexopathies because of fibrosis are less common late complications of RT [13]. Secondary hypothyroidism is usually manageable with thyroid replacement therapy.

There are limited data on the overall health status of long-term HL survivors. The Childhood Cancer Survivor Study [7] looked at frequencies of chronic conditions in 10, 397 survivors of childhood cancer and 30 034 siblings. A severity score was designed based on the Common Terminology Criteria for Adverse Events (version 3), which graded conditions as mild (grade 1), moderate (grade 2), severe (grade 3) life-threatening or disabling (grade 4) or fatal (grade 5). Amongst 1876 adult survivors of childhood HL, the relative risk of a grade 3 or 4 chronic ailment was 10.2 (8.3–10.5). The cumulative incidence of a grade 3–5 chronic condition was approximately 40% between 20 and 25 years.

We conducted a survey-based cohort study of patients treated as adults on first-line therapy protocols for HL at Memorial Sloan-Kettering Cancer Center (MSKCC) from 1975 to 2000 [14]. The protocols included five CMT trials and one that included a CT-only arm. The RT was limited in field size by contemporary standards, and in the two protocols for advanced stages, the RT dose was limited to 20–30 Gy. Self-reported late health conditions were assigned severity scores as was carried out with the Childhood Cancer Survivor Study. Cause-specific mortality was determined by chart review and National Death Index search. Survival was estimated using the method of Kaplan–Meier and cause-specific mortality using competing risk methodology.

Of the 746 patients for whom follow-up was available, 519 were alive and survey data were available for 233 patients. Median age at survey was 49 years (range, 25–88), median age at diagnosis was 29 years (range, 14–66) and median time from last treatment was 21 years. Seventy per cent of treated patients were alive at the time of survey, with a median overall survival (OS) of 32 years. One hundred and seven had died because of HL and 100 because of other causes. Ninety-four per cent of patients reported at least one late morbidity, 48% at least one grade 3/4 morbidity and 21% at least two grade 3/4 morbidities.

Mortality rates for the cohort follow a curve with two linear phases, an earlier steep phase representing death because of HL and a second phase beginning at 6 years postdiagnosis primarily because of causes other than HL. At 22 years, deaths because of other causes exceeded those because of HL led by second malignancies and cardiovascular events. Similar results were reported for cause-specific survival from two cancer centres in the Netherlands for 1261 patients with HL treated before age 41 years between 1965 and 1987 [6]. In that study, deaths from other causes exceeded those because of HL after 20 years from the start of treatment. Second malignancies followed by cardiovascular events were also the most common causes of deaths not because of HL.

The causes of late morbidity and mortality were the same in our study, and most have been associated with RT in the literature. This was despite limitations of RT field size and dose by contemporary although not necessarily by current standards with respect to field size. However, with larger numbers in a cohort study of HL patients treated in five centres in the Netherlands treated between 1965 and 1995, whilst the relative risk of breast cancer was increased 2- to 8-fold in patients receiving any RT to the mediastinum, there was an additional 2.7-fold higher risk in women who had received full mantle RT as compared with women who received only mediastinal RT [15]. Follow-up time was shorter for patients who receive mediastinal RT only than those who received mantle RT, and further follow-up will be necessary to see whether this difference holds up.

Combined modality treatment

Several prospective randomized clinical trials have established a decreased relapse rate in stages I and II HL with CMT as compared to EF RT, although no difference in survival has been observed [16–20].

Excellent results have been recently achieved with a reduced number of cycles of chemotherapy and standard or low-dose involved field radiation therapy (IF RT). In the HD10 trial of the German Hodgkin Study Group (GHSG), freedom from treatment failure (FFTF) rate at 5 years was 90–93% for two or four cycles of ABVD with either 20 or 30 Gy IF RT for favourable stage I and II HL patients (one or two sites without bulk, extra-nodal extension or elevated ESR) [21]. Excellent results in early-stage unfavourable HL (stages IA, IB and IIA with one or more of these risk factors: ≥3 lymph node sites, bulky mediastinal mass, extra-nodal extension and/or elevated ESR or stage IIB with ≥3 nodal sites and/or elevated ESR) with CMT were also reported in the GHSG HD11 study that compared four cycles of ABVD with four cycles of standard-dose BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) and subsequently 30 Gy vs. 20 Gy IF RT. The best 5-year FFTF were similar in three of the four arms (4 ABVD + 30 Gy IF RT, four standard BEACOPP + 30 Gy IF RT and four standard BEACOPP + 20 Gy IF RT). For the entire trial at 5 years, FFTF was 85.0%, OS 94.5% and progression-free survival (PFS) 86% [22]. These studies provide benchmarks for current CMT trials in stages I and II HL.

A major concern has been the late toxicities of treatment most of which are attributable to the RT even with CMT. Little long-term data are available with this approach, but follow-up beyond 15 years (median of 10 years) was reported by an Italian group for the treatment of IA and IIA nonbulky HL with four cycles of ABVD and limited RT in most patients (extended field 23%, involved field 77%) [1]. The reported projected 15-year event-free survival and OS were 78% and 86%, respectively. However, even with limited treatment, the 5- and 12-year risks of second malignancies were 4% and 8% and of cardiovascular events were 5.5% and 14%. This a cause for concern regarding involved field RT in combined modality programmes for early-stage HL, although current involved fields may be even more limited than those employed in the past.

We found that reduced doses of RT to 2000–3000 cGy did not seem to reduce long-term toxicity of RT. A similar finding was recently reported from Stanford on the high incidence of second cancers in survivors of paediatric HL treated with CMT including low-dose RT (15–25 Gy with optional 10 Gy boosts to bulky sites). The cumulative incidence of second malignancies was 17% at 20 years after HL diagnosis [23].

In the HD10 study with 1370 patients accrued, it is noteworthy that the rate of secondary neoplasia at a median follow-up of 7.5 years is 4.6%, similar in all four arms of the trial, and it may increase with further follow-up. Also, of 57 deaths (4.8%) in the HD10 trial, 10 were owing to HL whilst 11 were owing to secondary neoplasias, nine owing to cardiovascular events, seven to acute toxicity of treatment and five to salvage therapy [21]. In the HD11 trial of 1395 patients at a median follow-up time of 6.8 years, there have been 52 second cancers (3.7%) at a median follow-up time of 6.8 years. At a median follow-up time for survival of 7.6 years, 105 patients have died (7.5%). Causes of deaths were HL in 36% and other causes in 64% (18% second malignancies, 13% cardiovascular events) [22]. Further follow up of more contemporary combined modality programmes will be necessary to see whether late toxicities will be reduced as compared with regimens with more extensive chemotherapy and RT.

Chemotherapy alone in the treatment of nonbulky early stages of HL

Recently several studies have suggested that chemotherapy alone is a reasonable treatment option for patients with early-stage nonbulky HL. Combined modality treatment remains the standard treatment for early-stage HL with bulky disease (mediastinal mass >1/3rd the thoracic diameter or peripheral nodal mass >10 cm), because RT to regions of tumour bulk in combination with chemotherapy has been demonstrated to reduce the risk of recurrence [24, 25]. Positron emission tomography (PET) may eventually define a subgroup of patients with early-stage bulky disease who can be followed without additional RT after chemotherapy [26].

Three randomized trials comparing chemotherapy alone to CMT have been reported (Table 2). One trial was conducted in unselected patients with nonbulky stages I, II and IIIA and the other two in subsets of stage I and II patients. To determine whether CMT is superior to chemotherapy alone, 152 untreated unselected HL patients with CS IA, IB, IIA, IIB and IIIA without bulk disease treated at MSKCC between 1990 and 2000 were prospectively randomized to six cycles of doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) alone or six cycles of ABVD followed by RT (3600 cGy: involved field for 11 patients, modified extended field for the rest). Sixty-five of 76 patients randomized to receive RT actually received it and 11 did not (four progressed, one bleomycin toxicity, six refused). For ABVD+RT, the complete remission (CR) percentage was 94% and no major response 6%. For ABVD alone, 94% achieved a CR, 1.5% a partial response (PR) and no major response 4.5%. At 60-month CR duration, freedom from progression (FFP) and OS for ABVD + RT versus ABVD alone are 91% vs. 87% (P = 0.61), 86% vs. 81% (P = 0.61) and 97% vs. 90% (P = 0.08), respectively (logrank). The 95% confidence intervals for CR duration, FFP and OS differences at 5 years were (−8%, 15%), (−8%, 18%) and (−4%, 12%), respectively. Although significant differences were not seen, it is possible that a benefit in outcome of <20% for CMT might be seen in a larger trial [27].

Table 2. Localized Hodgkin lymphoma: trials with chemotherapy only
StudyTreatmentNo. of patientsMedian follow-upFFP or PFS (%)OS (%)
  1. FFP, freedom from progression; OS, overall survival; PFS, progression-free survival.

Randomized trials
 Straus et al. [27]ABVD versus ABVD + RT15267 months5 years
ABVD: 81
ABVD + RT: 86
5 years
ABVD: 90
ABVD + RT: 97
 Meyer et al. [28]ABVD versus RT ± ABVD3994.2 years5 years
ABVD: 87
RT ± ABVD: 93
5 years
ABVD: 96
RT ± ABVD: 94
 Eghblai et al. [29]EBVD versus EBVD + 36 Gy RT versus EBVD + 20 Gy RT78351 months4 years EFS
EBVP: 68
EBVP + 36 Gy RT: 88
EBVP + 20 Gy RT: 85%
4 years EFS
EBVP: 93
EBVP + 36 Gy RT: 98
EBVP + 20 Gy RT: 100%
Single arm studies
 Rueda Domínguez et al. [31]ABVD9578 months7 years
96
7 years
84
 Canellos et al. [33]ABVD71 (ABVD 69)60 months5 years
92
5 years
100
 Olcese et al. [32]ABVD63 (ABVD 60)60 months50 months dFS (CR 86%)
83
50 months
97

The results of a randomized phase II trial conducted by the National Cancer Institute of Canada (NCIC) and the Eastern Cooperative Oncology Group were also reported [28]. In this trial, patients with CS IA and IIA HL without tumour bulk or intra-abdominal disease were enrolled between 1994 and 2002 and were randomized to ‘standard’ treatment [subtotal lymphoid irradiation (STLI)] for more favourable; two cycles of ABVD + STLI for less favourable (age ≥ 40 years, ESR ≥ 50 mm h−1, mixed cellularity or lymphocyte depletion histology and/or age ≥40 years) or ‘experimental’ treatment (4–6 cycles of ABVD alone). ‘Low-risk patients’ (single node stage IA with all of lymphocyte predominant or nodular sclerosis histology, bulk < 3 cm, ESR < 50 mm and disease in high neck or epitrochlear regions) were excluded. On the ‘experimental’ arm, 29% of patients received only four cycles of ABVD, although it is not clear that excessive relapses were seen in this subgroup. At a median duration of follow-up of 4.2 years, the estimated 5-year PFS was 93% for patients in the ‘standard’ arm and 87% for those in the ‘experimental’ arm, a difference that was statistically significant. There was no difference in event-free survival or OS. In view of the salvageability of the small excess for patients who might relapse after chemotherapy alone and the late morbidity of treatment that is mostly attributable to RT, the clinical meaning of a 6% difference in PFS is unclear. Also, it is quite possible that events will continue to occur in the combined modality arm with time attributed to late effects of RT. The primary endpoint of this study is the OS in the two arms at 12 years, and this has not been reported as yet. Six cycles of ABVD alone have been more commonly used for Hodgkin’s disease patients than four cycles for which this is the first reported experience. It is possible that four cycles of ABVD without RT are less adequate chemotherapy than the more standard six cycles. Also, neither STLI nor two cycles of ABVD + STLI are currently the most commonly used ‘standard’ treatments for early-stage HL. Thus, the results of this trial are not conclusive.

Preliminary results of the EORTC-GELA H9-F trial were reported in abstract form [29]. This trial randomized early-stage patients with HL and favourable features to chemotherapy alone with epirubicin, bleomycin vinblastine and prednisone (EBVP), EBVP and 20 Gy involved field radiation therapy (IF RT) or EBVP and 36 Gy IF RT. The ‘favourable’ group of stage I and II patients in the EORTC is defined as age <50 years, A + ESR < 50 or B + ESR < 30 mm h−1 and ratio of mediastinal to thoracic diameter of <0.35. The 4-year event-free survival was 69% for EBVP alone versus 85% for EBVP and 20 Gy IF RT and 88% for EBVP and 36 Gy IF RT (P < 0.001). The EBVP only arm was discontinued because of this difference. There was no difference in OS in the three arms of the trial. A potential flaw of this trial is that EBVP may be inferior to standard chemotherapy. In their H7-U trial for early-stage patients with unfavourable features, EBVP and IF RT were inferior to the more standard MOPP/ABV hybrid and IF RT [30].

Several nonrandomized trials have demonstrated similar results with chemotherapy only in early-stage HL (Table 2). A nonrandomized study from Spain demonstrated PFS of 87% and an OS of 97% at 78 months in 80 unselected patients with nonbulky stages I and II Hodgkin’s disease treated between 1990 and 2002 with six cycles of ABVD alone, results similar to the MSKCC experience [31]. A retrospective comparison of treatment with ABVD alone versus CMT (ABVD + RT or Stanford V) reported from the Liguria region of Italy demonstrated a similar disease-free survival (80% chemotherapy + RT, 83% chemotherapy alone) and OS at 60 months median follow-up time. There were no secondary malignancies amongst 63 patients treated with ABVD alone as compared with four second malignancies, two of which (breast and lung) may have been related to RT, amongst 76 patients treated with CMT [32]. In a recent retrospective review of 75 patients with nonbulky stages IA, IIA and IIB HL from the Dana-Farber Cancer Institute treated with chemotherapy only between 1992 and 2007 (six ABVD: 71 patients; four ABVD: two patients; two ABVD two etoposide, vinblastine, doxorubicin: two patients; other chemotherapy: two patients), there were no deaths and the progression-free survival at a median follow-up time of 52 months was 92% [33].

Pulmonary toxicity with ABVD

Pulmonary toxicity from bleomycin treatment is a problem with the ABVD regimen. The major nonhaematologic toxicity is pulmonary and related to bleomycin. In the trial conducted at MSKCC, 33 patients (22%) discontinued bleomycin because of a decrease in DLCO. Ten of the symptomatic patients received brief courses of corticosteroids, and there was one death because of bleomycin during treatment in a 65-year-old woman [27, 34]. Similar findings were recently reported by Bonadonna and colleagues [34]. A publication from the Mayo Clinic reviewed bleomycin toxicity amongst 141 patients treated with bleomycin-containing chemotherapy between 1986 and 2003 [35]. Bleomycin pulmonary toxicity was observed in 18% of these patients with a mortality rate of 4.2%. The median 5-year survival of patients with bleomycin pulmonary toxicity was 63% as compared with 90% amongst those who had no toxicity. Patients over 40 years of age were at the highest risk of bleomycin pulmonary toxicity overall and associated mortality. In univariate analysis, use of ABVD as compared to other bleomycin-containing regimens and use of filgrastim were risk factors for the development of bleomycin pulmonary toxicity. Although the association with filgrastim has not been noted by others, most clinicians try to limit the amounts of filgrastim used in these patients based on this finding. The use of filgrastim or pegfilgrastim at all with ABVD is controversial [36–39], although filgrastim support is standard with more intensive regimens like escalated and dose-intense BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) [40].

Triplet chemotherapy without bleomycin

Gemcitabine is one of the most active single agents for relapsed HL with response rates of 39–43% and less pulmonary toxicity than bleomycin [41, 42]. Promising results were reported in relapsed and refractory HL patients with the combination of gemcitabine, vinorelbine and liposomal doxorubicin in CALGB 59804 [43]. For these reasons, CALGB conducted a phase II trial of gemcitabine, vinblastine and doxorubicin (AVG) as initial treatment for patients with nonbulky stages I and II HL (CALGB 50203) [44]. Although the populations of patients treated had several adverse prognostic features including advanced age and multiple sites of involvement, the results were lower than anticipated. The CR + CRu rate [45] was 72.7% (81% by PET criteria [46] with 3-year PFS of 77%. The results in patients with favourable prognostic features were comparable to those with ABVD alone. Although this was not a randomized trial formally comparing AVG to a more standard regimen such as ABVD, this regimen is not being pursued in future trials.

Dacarbazine, an alkylating agent, but not of the nitrogen mustard class, was initially selected for the ABVD regimen based on a single small phase II report. However, it may be an important component of combination chemotherapy for HL. Several reports have demonstrated that patients on ABVD who must have bleomycin discontinued because of toxicity can be continued on AVD with the omission of bleomycin and have a similar outcome to patients who receive a full course of ABVD [27, 35, 47]. Promising results are being seen with two cycles of AVD and involved field RT in favourable early-stage HL in the HD13 trial [48] of the German Hodgkin Study Group.

Prognostic significance of PET scans performed during treatment and after treatment

[18F]FDG PET scanning has been found to be useful in predicting recurrences in residual masses following treatment for Hodgkin’s disease. False-negative studies are less common (negative predictive value 95%) than false positives (positive predictive value 60%) [49].

In British Columbia, patients with advanced stages or early stages with tumour bulk had CT scans performed after six cycles of ABVD. Those with residual masses ≥2.5 cm had PET CT scans performed. Patients who were PET+ received additional consolidative RT and those who were PET− were followed. Although there was a significantly lower 2-year disease-free survival for patients who were PET+ as compared to those who were PET−, there was no difference in 2-year disease-free survival between patients with or without initial bulky disease who were PET−. Although consolidative RT remains standard for patients with initial bulky disease, if confirmed, these results suggest that PET/CT scans may identify a subpopulation of these patients who will not require RT [26].

The studies of Kostakoglu et al. [50], Hutchings et al. [51, 52] and Gallamini et al. [53] have demonstrated that PFSs are inferior for patients who are PET+ during chemotherapy after 1–3 cycles of treatment. The data for stages I and II disease are limited. There was 1 relapse amongst 57 stage I and II patients who were PET− after two or three cycles of chemotherapy, usually ABVD, and RT and two of seven patients who were PET+ relapsed after 2–3 cycles of chemotherapy in a retrospective series reported by Hutchings. In the AVG trial, the estimated 2-year PFS was 88% for patients PET− after two cycles of AVG as compared with 54% for those who were PET+ [44].

Perspectives: current clinical trials

Although results of a number of clinical trials with chemotherapy only for patients with early-stage HL are encouraging, there may be subgroups of patients who would benefit from CMT. The results of studies with interim PET have provided a biomarker that is being used to direct therapy in a number of clinical trials.

There are several trials that have recently opened or are in development investigating treatment tailored to risk of recurrence after PET scan results early during treatment (Table 3).

Table 3. Localized Hodgkin lymphoma: interim PET risk-adapted trials (Clinical Trials.gov Identifier)
TrialSponsorActiveEligibilityStudy design
  1. FFP, freedom from progression; GHSG, German Hodgkin Study Group.

RAPID
NCT00943423
UK2003Nonbulky I–IIABVD × 3:
If PET−ve → obs versus 30 Gy RT
If PET+ve → ABVD × 1 + 30 Gy RT
H10
NCT00433433
EORTC/
GELA (Amended August 2010)
2006Favourable I–IIABVD × 3 + INRT versus PET-directed therapy
ABVD × 2:
If PET−ve ABVD × 1 + INRT
If PET+ve, escBEACOPP × 2 + INRT
Unfavour. I–IIABVD × 4 + INRT versus PET-directed therapy
ABVD × 2:
If PET−ve ABVD × 2 + INRT
If PET+ve, escBEACOPP × 2 + INRT
HD16
NCT00736320
GHSG2009Favourable I–IIABVD × 2 + 30 Gy IFRT versus PET-directed therapy ABVD × 2:
If PET−ve ABVD × 2
If PET+ve 30 Gy IFRT
HD17
Planned
GHSGPendingUnfavour. I–IIescBEACOPP × 2 + ABVD × 2 + 20 Gy IFRT versus PET-directed therapy EscBeaCOPP × 2:
If PET−ve ABVD × 2
If PET+ve ABVD × 2 + 20 Gy INRT
CALGB 50203
NCT01132807
US Intergroup2010Nonbulky I–IIABVD × 2
If PET−ve: ABVD × 2
If PET+ve: escBEACOPP × 2 + IFRT
CALGB 50801
NTC01118026
CALGB2010Bulky I–IIABVD × 2
If PET−ve: ABVD × 2
If PET+ve: escBEACOPP × 2 + IFRT

Preliminary results of a trial from Argentina were recently reported. One hundred and seventy-three HL patients (79% stages I and II and 17% bulky disease) had PET after three cycles of ABVD. Treatment was stopped for 79% of patients who were PET−. PET+ patients in PR received three more cycles of ABVD + IF RT, whilst PET + patients in less than PR received ESHAP and autologous stem cell transplantation. The 36-month PFS was 87% and OS 100% for cycle 3 PET – patients as compared with PFS 62% and OS 86% for cycle 3 PET + patients [54].

The RAPID trial conducted in the United Kingdom performed a PET scan after three cycles of ABVD in stage IA and IIA patients with supradiaphragmatic HL. If the PET scan is negative, patients are randomized between no further treatment and involved field RT. If the PET scan is positive, patients receive a 4th cycle of ABVD and IF RT. Accrual of 600 patients has been completed following the third planned interim analysis, and the number of events amongst PET-negative patients was low. The Independent Data Monitoring Committee found no reason to prematurely close the trial [55, 56]. The HD16 trial of the GHSG is comparing standard CMT for favourable early-stage HL: ABVD × 2 + IF RT versus PET-directed therapy (ABVD × 2 then PET−: ABVD × 2, PET+: IF RT).

The Intergroup in the United States has three coordinated trials for patients with early-stage nonbulky, early-stage bulky and advanced stages of HL all exploring the use of a more intensive regimen than ABVD, escalated BEACOPP [57], in patients who are PET+ following two cycles of ABVD, a strategy suggested in a small study reported by Dann and colleagues [58]. In the protocols for early-stage HL, involved field RT is also added to escalated BEACOPP for patients whose PET/CT scans are positive during treatment. These risk-adapted trials may improve the treatment result in subgroups of early-stage HL patients who may be a higher risk of relapse with ABVD alone.

Conclusion

A number of recent clinical trials for the treatment of early-stage HL have demonstrated that results with chemotherapy only are similar to those with chemotherapy and RT for patients with localized HL, although relapse rates may be slightly higher with chemotherapy only. In view of the late morbidity and mortality related to RT, chemotherapy only is a good treatment option for the majority of early-stage patients. A number of new clinical trials are addressing the role of functional imaging with PET scans in identifying patients at high risk of relapse with chemotherapy for whom IF RT with or without more intensive chemotherapy might be appropriate.

Conflict of interest statement

No conflicts of interest to declare.

Acknowledgements

Dr. Straus receives research support from Mr. Daniel Moon and Family, The Lymphoma Foundation, The Adam Spector Fund for Hodgkin’s Research and The Ernest & Jeanette Dicker Charitable Foundation.

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