Page 1373 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 75 Hodgkin Lymphoma 1219

both chemotherapy and RT while maintaining the excellent cure rate 1-year progression-free survival (PFS) of 94.5% (versus 100% in
and still reducing short- and long-term risk of complications. These CMT arm). As per the statistical analysis plan for this noninferiority
approaches are based on the distinction between the amounts of study, the primary endpoint will take place approximately 6.5 years
treatment required in early-favorable patients compared with that after recruitment, with additional long-term analyses of OS, to be
required for optimal outcome in early-unfavorable patients. The risk carried out after a median follow-up of 10 and 20 years.
factors that are used by different study groups to define early-stage Also, emerging data from the UK National Cancer Research
HL subgroups are listed in Table 75.4. All criteria include the pres- Institute (NCRI) RAPID trial shows that early-stage HL patients
ence of a large mediastinal mass and B symptoms and use the principal with a favorable PET-based response after three cycles of chemo-
5
that favorable disease should not have any of the risk factors listed therapy may have an excellent prognosis without consolidation RT.
(see Prognostic Factors, Risk Stratification, and Treatment Groups: This study randomized 420 PET-negative patients (after three cycles
Early-Stage Disease section, earlier). of ABVD) to receive IFRT versus no further treatment. After a
The most comprehensive and powerful studies attempting reduc- median follow-up of 45 months, this noninferiority trial revealed no
tion of treatment for early stage HL were published by the GHSG. difference in OS, but slightly, although not statistically significant,
In the HD10 randomized trial of 1370 patients with favorable higher 3-year PFS (intention to treat analysis) in patients receiving
disease, as few as two cycles of ABVD (adriamycin, bleomycin, vin- IFRT (93.8% versus 90.7%), where a margin of ≤7% PFS difference
5
blastine, and dacarbazine) followed by 20 Gy IFRT resulted in OS was deemed acceptable. Because 26 of 211 patients randomized to
of 96.6% and freedom from treatment failure (FFTF) of 91.2% at 5 receive consolidation RT died from unrelated causes, but were scored
years. The minimal combined modality approach has become the as events within the RT arm, this raised the observation arm under
standard of care for patients with early-stage favorable HL. HD10 the margin of noninferiority. When an “as-treated” analysis was
was one of the first large studies to show that reduction of treatment performed, the 3-year PFS was 97% for CMT versus 90.7% for
intensity of both chemotherapy and RT did not reduce efficacy, but chemotherapy alone (hazard ratio [HR] = 2.39, p = .03). 5
toxicity was decreased and side-effects of treatment were fewer. The More recently, in 2015, the Cochrane Hematological Malignan-
next step of the GHSG to reduce treatment was by testing the pos- cies Group conducted a systematic review of randomized controlled
sible elimination of either bleomycin or dacarbazine or both from trials that addressed the issue of whether PET-adapted therapy in
ABVD ×2 followed by IFRT (HD13 trial), but was not successful individuals with HL results in better PFS (OS was not available in
and data suggested that if using only two cycles of ABVD, both these very recent studies). In 1480 patients analyzed, PFS was shorter
bleomycin and dacarbazine should remain part of the regimen. in participants with PET-adapted therapy (without RT) than in those
In unfavorable early-stage patients the GHSG HD11 trial ran- receiving standard treatment with RT (HR 2.38; 95% confidence
domized 1397 patients between four cycles of ABVD and four cycles interval [CI] 1.62 to 3.50; p < .0001). This difference was also
of baseline BEACOPP (bleomycin, etoposide, doxorubicin, cyclo- apparent in comparisons of participants receiving no additional RT
phosphamide, vincristine, procarbazine, and prednisolone), and each (PET-adapted therapy) versus RT (standard therapy) (HR 1.86; 95%
chemotherapy arm was followed by either 30 Gy or 20 Gy IFRT. CI 1.07 to 3.23; p = .03) and in those receiving chemotherapy but
Four cycles of ABVD followed by IFRT of 30 Gy resulted in a 5-year no RT (PET-adapted therapy) versus standard RT (HR 3.00; 95%
FFTF of 85.3% and OS of 94.3% and was less toxic than baseline CI 1.75 to 5.14; p < .0001). Based on the data, the authors could
BEACOPP. Most groups recommend this approach of ABVD ×4 assume that of 1000 individuals receiving PET-adapted treatment
followed by IFRT of 30 Gy as the standard of care. It should be over 4 years, 222 individuals would experience disease progression or
noted, however, that patients with a combination of bulky disease death compared with 100 of 1000 individuals receiving standard
and B symptoms were not included in GHSG unfavorable early-stage treatment.
programs and were referred to advanced-stage disease studies.
Another approach studied by the GHSG for patients ≤60 years
who are eligible for a more intensive treatment involved using two TREATMENT OF ADVANCED-STAGE
cycles of escalated BEACOPP followed by two cycles of ABVD and HODGKIN LYMPHOMA
30 Gy IFRT (HD14 trial). After a median follow-up of 43 months,
FFTF with this protocol was superior in comparison with four cycles The improved outlook for patients with advanced-stage HL (stages
of ABVD followed by 30 Gy IFRT, but an advantage in OS could IIB−IV) over recent decades is largely attributed to the global drive
not be shown. to develop front-line chemotherapy regimens in which improved
Ultimately the standard practice for patients with unfavorable-risk efficacy is coupled with reduced treatment-associated toxicity. The
early-stage HL is four cycles of chemotherapy followed by IFRT identification of adverse prognostic factors at diagnosis has been
(30 Gy). Some current clinical trials are exploring new combinations instrumental to this cause, in allowing more appropriate stratification
of new chemotherapy combinations that include brentuximab of patients at baseline into groups in which therapy is risk-adapted.
vedotin (BV) and reduced radiation doses to explore even more In addition, the use of the IPS over the years to further subdivide
effective therapies. patients with advanced HL into more specific prognostic groups, each
with significantly different FFP rates, has paved the way for a more
preferable treatment approach that aims to achieve cure without
Response-Adapted Treatment Approach exposing the individual to the unnecessary risks associated with
overtreatment (see Prognostic Factors, Risk Stratification, and Treat-
In the era of FDG-PET imaging for assessment of metabolic response ment Groups section, earlier). In the 1960s the development of the
to induction chemotherapy, the need for consolidation RT has been drug combination MOPP (nitrogen mustard, vincristine [oncovin],
challenged in two important recent trials. procarbazine and prednisolone) was a pioneering step in the effective
The EORTC H10 trial, which used modern-involved node RT treatment of patients with advanced HL. With a complete remission
(INRT) techniques, randomized (both favorable and unfavorable (CR) rate of up to 80% and cure in more than 50% of patients, this
risk) patients to chemotherapy alone versus combined modality treat- regimen was heralded as revolutionary at the time not only within
ment (CMT) for those with a negative FDG-PET after two cycles of the field of lymphoma, in which patients with advanced HL had
ABVD. The outcomes appeared to be excellent (in terms of OS) in previously been considered incurable, but also for oncology as a
4
both arms of patients who received chemotherapy alone or CMT. whole; it was the first chemotherapy combination to be associated
This study enrolled 1137 patients and after 34 events, an interim with cancer cure. 6
analysis found an unacceptably high rate of treatment failures in the Today, the most widely used regimens are ABVD (adriamycin,
4
chemotherapy alone group, subsequently mandating its closure. The bleomycin, vinblastine, and dacarbazine) and BEACOPP (bleomycin,
most favorable subgroup of patients in this study, who had a negative etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine,
early PET scan after two cycles of ABVD only, experienced an inferior and prednisolone) (Table 75.6).