58Radiotherapy dose fractionation Third edition
Hodgkin lymphoma
Background
Over the last 30 years, combination chemotherapy has become integral to the standard of
care for both early and late stage Hodgkin lymphoma. Previous techniques employing the
traditional mantle and inverted Y elds are no longer practiced. Involved eld radiotherapy
(IFRT), which has been the standard until recently, is being replaced by involved node
radiotherapy (INRT) or involved-site radiotherapy (ISRT), further reducing the treated
volume for consolidation or residual disease after chemotherapy.
1,2
There should be every
eort to reduce cardiac and lung doses when treating the mediastinum with good evidence
to support the use of intensity-modulated radiotheray (IMRT) and deep inspiration beath
hold (DIBH) in this setting.
3
Early Hodgkin lymphoma
Studies by the German Hodgkin Disease Study Group have shown no dierence in
outcome between two cycles of Adriamycin bleomycin vinblastine dacarbazine (ABVD)
and 20 Gray (Gy) in ten fraction IFRT in the favourable subgroup or four cycles of ABVD and
30 Gy IFRT in the unfavourable subgroup (Level 1b).
4–6
Radiotherapy after chemotherapy
in PET-negative patients reduces the later risk of relapse, but the absolute reduction in
progression-free survival (PFS) was only 4% at three years in the RAPID trial (Level 1b).
8,7
Recommendations
For patients with early Hodgkin lymphoma:
Favourable group: 2 cycles of ABVD chemotherapy followed by 20 Gy in 10 fractions
over 2 weeks (Grade A)
Unfavourable group: 4 cycles of ABVD followed by 30 Gy in 15 fractions over 3 weeks
(Grade A)
For selected patients who are PET negative after thee cycles of ABVD, the relative risks
of relapse from omitting radiotherapy and the late toxicity from giving radiotherapy
should be considered and discussed with the patient (Grade A)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
6
Advanced Hodgkin lymphoma
The role of radiotherapy in advanced Hodgkin disease after full-dose combination
chemotherapy is controversial. One overview showed that combined-modality therapy
conferred no survival benet but did increase the risk of long-term fatal complications
(cardiac and second cancer), while another, using UK National Cancer Research Institute
(NCRI) study data, has shown an improved survival in patients with Hodgkin lymphoma who
received radiotherapy compared to those who did not (Level 1a).
6,8,9
A European
Organisation for Research and Treatment of Cancer (EORTC) study demonstrated that
radiotherapy did not improve the outcome for patients who had a complete remission after
mustine, vincristine, procarbazine, prednisolone-adriamycin bleomycin vinblastine (MOPP-
ABV) chemotherapy, but that irradiation may benet patients with a partial response after
8.
Lymphoma
59Radiotherapy dose fractionation Third edition
chemotherapy (Level 1b).
5,9
Recommendation
In advanced Hodgkin lymphoma, radiotherapy for residual disease is indicated after
partial response to chemotherapy.
30–34 Gy in 15–20 fractions over 3 to 4 weeks (Grade B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
6
Relapsed Hodgkin lymphoma
High-dose chemotherapy and stem cell transplantation remain the international standard of
care for many younger patients with relapsed Hodgkin lymphoma.
In some patients with a single site of relapse, particularly occurring late, after previous
treatment, re-induction as for early disease combined with IFRT may be appropriate, using
a dose of 30–34 Gy in 15–20 fractions over 3–4 weeks.
If the site has not previously been irradiated, radiotherapy alone has been used for selected
patients (Grade D).
6,11
Recommendations
For palliative treatments no denitive recommendations can be made and dose will
depend on the clinical situation. The following may be used:
30 Gy in 10 fractions over 2 weeks (Grade D)
20 Gy in 5 fractions over 1 week (Grade D)
Single doses of 7–8 Gy (Grade D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
6
Nodular lymphocyte Hodgkin lymphoma
IFRT alone, without chemotherapy, results in high PFS and overall survival (OS) rates and is
considered an adequate treatment for early stage disease.
12
A dose of 30 Gy in 15 fractions
over three weeks is recommended (Grade D).
6
Aggressive non-Hodgkin lymphoma (NHL)
In aggressive lymphomas, radiotherapy alone is not recommended except in palliative
situations or where the patient is too frail for chemotherapy.
Consolidation IFRT in aggressive non-Hodgkin lymphoma
Following the landmark study comparing eight cycles of cyclophosphamide, doxorubicin,
vincristine and prednisone (CHOP) chemotherapy to three cycles of CHOP followed by
IFRT with 40–45 Gy in 1.8–2 Gy fractions, combined modality therapy was established
as the standard of care.
13
Longer term follow-up has shown convergence of the survival
60Radiotherapy dose fractionation Third edition
curves, as a result of an excess of relapses and deaths from lymphoma in the group given
CHOP plus radiotherapy (Level 1b).
14,6
In a further study, patients who received eight
cycles of CHOP chemotherapy and achieved complete remission, 30 Gy in daily 2 Gy
fractions improved local control (Level 1b).
15,16
A further trial in patients aged <61 years
with no adverse prognostic factors has shown improved event-free and overall survival
rates with doxorubicin, cyclophosphamide, vindesine, bleomycin and prednisone (ACVBP)
chemotherapy over those achieved by CHOP plus IFRT (Level 1b).
6,16
There are therefore two treatment approaches to the patient with early aggressive NHL:
short-course immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine
and prednisone (R-CHOP) followed by IFRT or full-course R-CHOP with six to eight cycles
alone. The relative merits should be discussed with the patient. There is no evidence to
suggest that early PET response can be used to individualise treatment the schedule
atpresent.
Recent evidence from the rituximab with CHOP over age 60 years (RICOVER) trial suggests
that there may be a role for radiotherapy in advanced stage diuse large B-cell lymphoma
(DLBCL) given to bulky sites of disease at presentation after chemotherapy (Level 2b).
6,17
Radiotherapy is also considered for mediastinal B-cell lymphoma and extranodal sites after
full-course chemotherapy.
18
A randomised trial of radiotherapy dose comparing 30 Gy to 40–45 Gy (all in daily two Gy
fractions) has demonstrated that in aggressive NHL 30 Gy is equivalent to a higher dose for
local PFS and OS. All patients with aggressive NHL receiving radiotherapy should therefore
be given 30 Gy in 15 fractions over three weeks (Level 1b).
6,19
Recommendation
For patients with aggressive non-Hodgkin lymphoma:
30 Gy in 15 fractions over 3 weeks is recommended as part of planned combined
modality therapy (Grade B).
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
6
Mantle cell lymphoma
This disease has a poor prognosis. The vast majority of patients require systemic treatment,
although the standard of care is not yet established. In combined modality treatment, there
is no evidence that mantle cell lymphomas respond dierently to radiation compared to
other aggressive lymphomas. A recent retrospective multi-institutional study of stage 1–2
patients reported favourable outcomes with combined modality or radiotherapy alone with
two-thirds and half of the patients being free of disease at ve and ten years respectively.
Median dose was 35 Gy (range 12–45 Gy) (Grade C).
6,20
61Radiotherapy dose fractionation Third edition
Natural killer (NK)/T-cell lymphoma
This is a rare entity in Western countries but is common in East Asia and Latin America.
20
Chemoradiation using cisplatin-based schedules and l-asparaginase are now standard,
followed by consolidation chemotherapy. This type of lymphoma requires a higher dose
than other T-cell lymphomas and a dose of at least 50 Gy in 25 fractions over ve weeks
should be given (Grade C).
6,22
Central nervous system lymphoma (CNS) lymphoma
The role of radiotherapy in CNS lymphoma is controversial in view of the signicant late
eects on cognitive function. It may be indicated after chemotherapy, particularly where
there is an incomplete response and also in relapsed disease. Standard lymphoma doses
are considered inadequate in the CNS and recommended doses would be 40–45 Gy in
20–25 fractions over four to ve weeks (Grade C).
6,23
Mycosis fungoides
This will typically be a widespread skin inltration with radiotherapy used for palliation of
thicker plaques. Doses of 8 Gy in two fractions or 12 Gy in three fractions are recommended
(Grade C).
6,24
Indolent lymphoma
Indolent lymphoma includes follicular lymphoma, small lymphocytic lymphoma and
marginal zone lymphoma. Stage I indolent lymphoma has, for many years, been treated with
radical IFRT. In advanced stage indolent lymphoma, IFRT may be indicated for control of
local symptomatic disease.
A randomised trial comparing 24 Gy to 40 Gy (all in 2 Gy fractions) included patients with
early stage indolent lymphoma. There was no dierence in local PFS or OS between these
two dose arms. A subsequent study randomised patients with follicular and marginal zone
lymphoma to receive either 24 Gy in 12 fractions or 4 Gy in two fractions. At 12 weeks,
the complete response rate was 68% after 24 Gy and 49% after 4 Gy. Local PFS was also
strongly in favour of the 24 Gy arm with a hazard ratio for local progression of 3.42 (95%
condence interval [CI]: 2.10–5.57).Toxicity was low in both arms (Level 1b).
6,25
Recommendation
For the radical treatment of stage I, indolent lymphoma, or durable palliation in
more advanced stages:
24 Gy in 12 fractions over 2.5 weeks (Grade B)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
6
62Radiotherapy dose fractionation Third edition
Palliative treatment of non-Hodgkin lymphoma
In patients with follicular lymphoma, high response rates have been achieved after low-
dose IFRT (4 Gy in 1 or 2 fractions), however, the randomised trial comparing 4 Gy to
24 Gy showed that, while eective in many patients, 4 Gy was inferior for local control
(Level1b).
6,25,26
Where short-term palliation is the aim of treatment, 4 Gy in 2 fractions may
be considered.
For aggressive lymphoma, a single dose of 8 Gy or short-course palliation such as 20 Gy
in ve fractions or 30 Gy in ten fractions are eective and appropriate for the palliative
treatment of many patients with a limited prognosis (Grade D).
6
Recommendations
In the palliative management of lymphoma, there is evidence to support the
following regimens:
Indolent lymphoma:
24 Gy in daily 2 Gy fractions over 2.5 weeks (Grade A)
For short-term palliation in follicular or marginal zone lymphoma:
4 Gy in 2 fractions (Grade A)
Intermediate/high-grade lymphoma:
Single dose 8–10 Gy (Grade D)
20 Gy in 5 fractions over 1 week (Grade D)
30 Gy in 10 fractions over 2 weeks (Grade D)
The types of evidence and the grading of recommendations used within this review are based on
those proposed by the Oxford Centre for Evidence-based Medicine.
6
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