Non-Hodgkin's lymphoma: diagnosis and management

This guideline covers diagnosing and managing non-Hodgkin's lymphoma in people aged 16 years and over. It aims to improve care for people with non-Hodgkin's lymphoma by promoting the best tests for diagnosis and staging and the most effective treatments for 6 of the subtypes. Tests and treatments covered include excision biopsy, radiotherapy, immunochemotherapy and stem cell transplantation.

# Recommendations
People have the right to be involved in discussions and make informed decisions about their care, as described in NICE's information on making decisions about your care.
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# Diagnosis
Malignant lymphoma is an HIV indicator condition as described in HIV in Europe's HIV indicator conditions. Also see recommendations 1.1.5 and 1.1.8 in the NICE guideline on HIV testing.

## Type of biopsy
Consider an excision biopsy as the first diagnostic procedure for people with suspected nonHodgkin's lymphoma at first presentation.
In people with suspected nonHodgkin's lymphoma for whom the risk of a surgical procedure outweighs the potential benefits of an excision biopsy, consider a needle core biopsy procedure. Take the maximum number of cores of the largest possible calibre.
For people with suspected nonHodgkin's lymphoma in whom a diagnosis is not possible after a needle core biopsy procedure, offer an excision biopsy (if surgically feasible) in preference to a second needle core biopsy procedure.
Pathology departments should ensure that tissue is conserved when handling needle core biopsies, so that further analysis can be carried out if needed.

## Diagnosing Bcell lymphomas: gene testing strategies
Consider using FISH (fluorescence in situ hybridisation) to identify a MYC rearrangement in all people newly presenting with histologically highgrade Bcell lymphoma.
If a MYC rearrangement is found, use FISH to identify the immunoglobulin partner and the presence of BCL2 and BCL6 rearrangements.

## Stratifying highgrade Bcell lymphomas using laboratory techniques
Do not use immunohistochemistry to assess the prognostic value associated with cell of origin in people with diffuse large Bcell lymphoma.
Interpret FISH results (MYC, BCL2 and BCL6 rearrangements) in the context of other prognostic factors (particularly the person's age and International Prognostic Index ).
Explain FISH results and their potential prognostic value to people with Bcell lymphoma.

# Staging using FDGPETCT (fluorodeoxyglucosepositron emission tomographyCT)

## Confirming staging
Offer FDGPETCT imaging to confirm staging for people diagnosed with:
stage I diffuse large Bcell lymphoma by clinical and CT criteria
stage I or localised stage II follicular lymphoma if disease is thought to be encompassable within a radiotherapy field
stage I or II Burkitt lymphoma with other lowrisk features.
For people diagnosed with other subtypes or stages of nonHodgkin's lymphoma not listed in recommendation 1.2.1, consider FDGPETCT imaging to confirm staging if the results will alter management.

## Assessing response to treatment for diffuse large Bcell lymphoma
Do not routinely offer FDGPETCT imaging for interim assessment during treatment for diffuse large Bcell lymphoma.

## Endoftreatment assessment
Offer FDGPETCT imaging to assess response at completion of planned treatment for people with:
diffuse large Bcell lymphoma
Burkitt lymphoma.
For people with other subtypes of nonHodgkin's lymphoma not listed in recommendation 1.2.4, do not routinely offer FDGPETCT imaging to assess response at completion of planned treatment unless the results will alter management.
Consider FDGPETCT imaging to assess response to treatment before autologous stem cell transplantation for people with highgrade nonHodgkin's lymphoma.

# Management of follicular lymphoma

## Firstline treatment for stage IIA follicular lymphoma
Offer local radiotherapy as firstline treatment to people with localised stage IIA follicular lymphoma.
Consider 'watch and wait' (observation without therapy) as firstline treatment for people with stage IIA follicular lymphoma who are asymptomatic and for whom treatment with a single radiotherapy volume is not suitable.
Offer the same treatments that might be offered to people with advancedstage (stages III and IV) symptomatic follicular lymphoma to people with stage IIA follicular lymphoma who are symptomatic and for whom radiotherapy is not suitable.

## Treating advancedstage asymptomatic follicular lymphoma
Offer rituximab induction therapy to people with advancedstage (stages III and IV) follicular lymphoma who are asymptomatic.

## Treating advancedstage symptomatic follicular lymphoma
Rituximab, in combination with:
cyclophosphamide, vincristine and prednisolone (CVP)
cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP)
mitoxantrone, chlorambucil and prednisolone (MCP)
cyclophosphamide, doxorubicin, etoposide, prednisolone and interferon (CHVPi) or
chlorambucilis recommended as an option for the treatment of symptomatic stage III and IV follicular lymphoma in previously untreated people. 
Rituximab maintenance therapy is recommended as an option for the treatment of people with follicular nonHodgkin's lymphoma that has responded to firstline induction therapy with rituximab in combination with chemotherapy. 
The guideline committee did not assess evidence or develop recommendations on bendamustine for treating people with follicular lymphoma, because a NICE technology appraisal on 'the clinical and cost effectiveness of bendamustine in combination with rituximab within its licensed indication for the firstline treatment of advanced indolent nonHodgkin's lymphoma' was in development. This technology appraisal is currently suspended.

## Treating advancedstage relapsed or refractory follicular lymphoma
The recommendations in this section are from NICE's technology appraisal guidance on rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma.
Rituximab, within its marketing authorisation, in combination with chemotherapy, is recommended as an option for the induction of remission in people with relapsed stage III or IV follicular nonHodgkin's lymphoma.
Rituximab monotherapy as maintenance therapy, within its marketing authorisation, is recommended as an option for the treatment of people with relapsed stage III or IV follicular nonHodgkin's lymphoma in remission induced with chemotherapy with or without rituximab.
Rituximab monotherapy, within its marketing authorisation, is recommended as an option for the treatment of people with relapsed or refractory stage III or IV follicular nonHodgkin's lymphoma, when all alternative treatment options have been exhausted (that is, if there is resistance to or intolerance of chemotherapy).

## Consolidation with stem cell transplantation
Offer consolidation with autologous stem cell transplantation for people with follicular lymphoma in second or subsequent remission (complete or partial) who have not already had a transplant and who are fit enough for transplantation.
Consider consolidation with allogeneic stem cell transplantation for people with follicular lymphoma in second or subsequent remission (complete or partial):
who are fit enough for transplantation and
for whom a suitable donor can be found and
when autologous stem cell transplantation has not resulted in remission or is inappropriate (for example, because stem cell harvesting is not possible).

## Treating transformed follicular lymphoma
Consider consolidation with autologous stem cell transplantation for people with transformation of previously diagnosed follicular lymphoma that has responded to treatment and who are fit enough for transplantation.
Consider consolidation with autologous or allogeneic stem cell transplantation for people with transformation of follicular lymphoma who need more than 1 line of treatment for a response and who are fit enough for transplantation.
Do not offer consolidation with highdose therapy and autologous or allogeneic stem cell transplantation to people presenting with concurrent diagnoses of follicular lymphoma and diffuse large Bcell lymphoma that have responded to firstline treatment.

# Management of MALT lymphoma

## Firstline treatment
Offer 1 or more lines of Helicobacter pylori eradication therapy, without any concurrent therapy, to people with H. pyloripositive gastric MALT lymphoma (see the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults).
Consider H. pylori eradication therapy for people with H. pylorinegative gastric MALT lymphoma (see the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults).
Consider 'watch and wait' (observation without therapy) for people with gastric MALT lymphoma that responds clinically and endoscopically to H. pylori eradication therapy but who have residual disease shown by surveillance biopsies of the stomach, unless highrisk features are present.
For people with residual MALT lymphoma after H. pylori eradication therapy who are at high risk of progression , consider a choice of the following, in discussion with the person:
chemotherapy (for example, chlorambucil or CVP) in combination with rituximabor
gastric radiotherapy.
For people with progressive gastric MALT lymphoma, offer a choice of:
chemotherapy (for example, chlorambucil or CVP) in combination with rituximabor
gastric radiotherapy.
Offer H. pylori eradication therapy to people with disseminated H. pyloripositive gastric MALT lymphoma (see the NICE guideline on gastro-oesophageal reflux disease and dyspepsia in adults).
Offer chemotherapy (for example, chlorambucil or CVP) in combination with rituximab to people with disseminated gastric MALT lymphoma who need treatment; for example, people who are symptomatic or with threatened vital organ function.
Consider 'watch and wait' (observation without therapy) for people with disseminated gastric MALT lymphoma who are asymptomatic and do not have threatened vital organ function.
For people with nongastric MALT lymphoma, take into account the following before recommending any treatment:
site of involvement and potential for organ dysfunction
whether it is localised or disseminated
the morbidity associated with any treatment proposed
the person's overall fitness.
Offer chemotherapy (for example, chlorambucil or CVP) in combination with rituximab to people with nongastric MALT lymphoma for whom radiotherapy is not suitable or who have disseminated disease and need treatment.
Consider radiotherapy for people with localised disease sites of nongastric MALT lymphoma, irrespective of stage.
Consider 'watch and wait' (observation without therapy) for people with clinically nonprogressive localised nongastric MALT lymphoma that is unlikely to result in vital organ dysfunction, who are asymptomatic and for whom radiotherapy is not suitable.

# Management of mantle cell lymphoma

## Firstline treatment
Offer chemotherapy in combination with rituximab as firstline treatment for people with advancedstage mantle cell lymphoma who are symptomatic. Take the person's fitness into account when deciding on the intensity of chemotherapy.
Consider cytarabinecontaining immunochemotherapy for people with advancedstage mantle cell lymphoma who are fit enough to tolerate an intensive approach.
Consider radiotherapy for people with localised stage I or II mantle cell lymphoma.
Consider 'watch and wait' (observation without therapy) until disease progression for people with clinically nonprogressive mantle cell lymphoma who are asymptomatic and for whom radiotherapy is not suitable.
Bortezomib is recommended, within its marketing authorisation, as an option for previously untreated mantle cell lymphoma in adults for whom haematopoietic stem cell transplantation is unsuitable. 
The guideline committee did not assess evidence or develop recommendations on bendamustine for treating people with mantle cell lymphoma, because a NICE technology appraisal on 'the clinical and cost effectiveness of bendamustine in combination with rituximab within its licensed indication for the firstline treatment of mantle cell lymphoma' was in development. This technology appraisal is currently suspended.

## Consolidation with stem cell transplantation
Consider consolidation with autologous stem cell transplantation for people with chemosensitive mantle cell lymphoma (that is, there has been at least a partial response to induction chemotherapy) who are fit enough for transplantation.

## Maintenance strategies
Consider maintenance rituximab, every 2 months until disease progression, for people with newly diagnosed mantle cell lymphoma who are not fit enough for highdose chemotherapy and where there has been a response to RCHOPbased immunochemotherapy.
Consider maintenance rituximab, every 2 months for 3 years, for people with newly diagnosed mantle cell lymphoma who are in remission after cytarabinebased induction and highdose chemotherapy.

# Management of diffuse large Bcell lymphoma

## Radiotherapy in firstline treatment
Consider consolidation radiotherapy delivering 30 Gy to sites involved with bulk disease at diagnosis for people with advancedstage diffuse large Bcell lymphoma that has responded to firstline immunochemotherapy. For each person, balance the possible late effects of radiotherapy with the possible increased need for salvage therapy if it is omitted, and discuss the options with them.

## Central nervous system prophylaxis
Explain to people with diffuse large Bcell lymphoma that they have an increased risk of central nervous system lymphoma if the testis, breast, adrenal gland or kidney is affected.
Explain to people with diffuse large Bcell lymphoma that they may have an increased risk of central nervous system lymphoma if they have 2 or more of the following factors:
elevated lactate dehydrogenase (LDH)
age over 60 years
poor performance status (ECOG score of 2 or more)
more than one extranodal site involved
stage III or IV disease.Explain that the level of risk increases with the number of factors involved.
Offer central nervous systemdirected prophylactic therapy to people with diffuse large Bcell lymphoma:
that involves the testis, breast, adrenal gland or kidney or
who have 4 or 5 of the factors associated with increased risk of central nervous system relapse listed in recommendation 1.6.3.
Consider central nervous systemdirected prophylactic therapy for people with diffuse large Bcell lymphoma who have 2 or 3 of the factors associated with increased risk of central nervous system relapse listed in recommendation 1.6.3.

## Salvage therapy and consolidation with stem cell transplantation
Offer salvage therapy with multiagent immunochemotherapy to people with relapsed or refractory diffuse large Bcell lymphoma who are fit enough to tolerate intensive therapy:
explain that this is primarily to obtain sufficient response to allow consolidation with autologous or allogeneic stem cell transplantation, but is also beneficial even if not followed by transplantation
consider RGDP immunochemotherapy, which is as effective as other commonly used salvage regimens and less toxic.
Offer consolidation with autologous stem cell transplantation to people with chemosensitive diffuse large Bcell lymphoma (that is, there has been at least a partial response to chemotherapy) who are fit enough for transplantation.
Consider consolidation with allogeneic stem cell transplantation for people with chemosensitive diffuse large Bcell lymphoma (that is, there has been at least a partial response to chemotherapy):
that relapses after autologous stem cell transplantation or
in whom stem cell harvesting is not possible.

# Management of Burkitt lymphoma

## Firstline treatment
Offer intensive immunochemotherapy to people with Burkitt lymphoma who are fit enough to tolerate it. Consider using one of the following:
RBFM
RCODOXM/RIVAC
RHyperCVAD (HDMTX)
RLMB.
For people with lowrisk Burkitt lymphoma, consider using the less intensive DAEPOCHR regimen supplemented with intravenous and/or intrathecal methotrexate.
Offer less intensive immunochemotherapy to people with Burkitt lymphoma who are not fit enough to tolerate intensive chemotherapy. Consider using one of the following, alone or supplemented with intravenous and/or intrathecal methotrexate:
RCHOP
RCHEOP
DAEPOCHR.

# Management of peripheral Tcell lymphoma

## Firstline treatment
Consider CHOP chemotherapy as firstline treatment for people with peripheral Tcell lymphoma.

## Consolidation therapy
Consider consolidation with autologous stem cell transplantation for people with chemosensitive peripheral Tcell lymphoma (that is, there has been at least a partial response to firstline chemotherapy) who are fit enough for transplantation.

# Information and support
To help people with nonHodgkin's lymphoma (and their family members or carers as appropriate) to make decisions about care, follow the recommendations in the NICE guidelines on patient experience in adult NHS services, improving outcomes in haematological cancers  the manual (patientcentred care), improving supportive and palliative care for adults with cancer and care of dying adults in the last days of life. Pay particular attention to the following areas:
establishing the best way of communicating with the person
timing and format of information
information about treatment, including benefits, shortterm risks and late effects
financial support and benefit advice
fertility issues
sexual function
support groups
access to wellbeing services and psychological support.
Give people with nonHodgkin's lymphoma (and their family members or carers as appropriate) detailed information about the nature and purpose of diagnostic and staging tests, including:
bone marrow biopsies
central line insertion
core and excision biopsies
CT and PETCT scans
lumbar punctures.
If 'watch and wait' (observation without therapy) is suggested for a person with nonHodgkin's lymphoma:
explain to them (and their family members or carers as appropriate) about what this involves and why it is being advised
address any increased anxiety that results from this approach.
Explain to people with lowgrade nonHodgkin's lymphoma about the possibility of transformation to highgrade lymphoma, taking into account the person's needs and preferences. Involve family members or carers as appropriate.
Ensure that people with nonHodgkin's lymphoma have:
a named key worker at diagnosis and during treatment and
contact details for the specialist team after treatment.
Discuss exercise and lifestyle with people with nonHodgkin's lymphoma from diagnosis onwards.

# Followup for people with diffuse large Bcell lymphoma
For people in complete remission after firstline treatment with curative intent for diffuse large Bcell lymphoma:
-ffer regular clinical assessment
consider stopping regular clinical assessment aimed at detecting relapse 3 years after completing treatment for people in ongoing complete remission
-ffer urgent appointments to people who experience a recurrence of lymphoma symptoms or new symptoms that suggest disease relapse
do not offer LDH surveillance for detecting relapse
do not offer routine surveillance imaging (including chest Xray, CT and PETCT) for detecting relapse in people who are asymptomatic.

# Survivorship
Provide endoftreatment summaries for people with nonHodgkin's lymphoma (and their GPs). Discuss these with the person, highlighting personal and general risk factors, including late effects related to their lymphoma subtype and/or its treatment.
Provide information to people with nonHodgkin's lymphoma when they complete treatment about how to recognise possible relapse and late effects of treatment.
At 3 years after a person with nonHodgkin's lymphoma completes a course of treatment, consider switching surveillance of late effects of treatment to nurseled or GPled services.
  At the time of publication (July 2016) rituximab did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information. The evidence reviewed for the guideline supports the standard monotherapy dosage of 4 doses of 375 mg/m2 at weekly intervals.
  At the time of publication (July 2016) rituximab did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information.
  At the time of publication (July 2016) cytarabine did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information.
  At the time of publication (July 2016) rituximab did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information. The evidence reviewed for the guideline supports a dosage of 375 mg/m2 every 2 months until disease progression.
  At the time of publication (July 2016) rituximab did not have a UK marketing authorisation for this indication. The prescriber should follow relevant professional guidance, taking full responsibility for the decision. Informed consent should be obtained and documented. See the General Medical Council's Prescribing guidance: prescribing unlicensed medicines for further information. The evidence reviewed for the guideline supports a dosage of 375 mg/m2 every 2 months for 3 years.# Putting this guideline into practice
NICE has produced tools and resources to help you put this guideline into practice.
Putting recommendations into practice can take time. How long may vary from guideline to guideline, and depends on how much change in practice or services is needed. Implementing change is most effective when aligned with local priorities.
Changes recommended for clinical practice that can be done quickly  like changes in prescribing practice  should be shared quickly. This is because healthcare professionals should use guidelines to guide their work  as is required by professional regulating bodies such as the General Medical and Nursing and Midwifery Councils.
Changes should be implemented as soon as possible, unless there is a good reason for not doing so (for example, if it would be better value for money if a package of recommendations were all implemented at once).
Different organisations may need different approaches to implementation, depending on their size and function. Sometimes individual practitioners may be able to respond to recommendations to improve their practice more quickly than large organisations.
Here are some pointers to help organisations put NICE guidelines into practice:
. Raise awareness through routine communication channels, such as email or newsletters, regular meetings, internal staff briefings and other communications with all relevant partner organisations. Identify things staff can include in their own practice straight away.
. Identify a lead with an interest in the topic to champion the guideline and motivate others to support its use and make service changes, and to find out any significant issues locally.
. Carry out a baseline assessment against the recommendations to find out whether there are gaps in current service provision.
. Think about what data you need to measure improvement and plan how you will collect it. You may want to work with other health and social care organisations and specialist groups to compare current practice with the recommendations. This may also help identify local issues that will slow or prevent implementation.
. Develop an action plan, with the steps needed to put the guideline into practice, and make sure it is ready as soon as possible. Big, complex changes may take longer to implement, but some may be quick and easy to do. An action plan will help in both cases.
. For very big changes include milestones and a business case, which will set out additional costs, savings and possible areas for disinvestment. A small project group could develop the action plan. The group might include the guideline champion, a senior organisational sponsor, staff involved in the associated services, finance and information professionals.
. Implement the action plan with oversight from the lead and the project group. Big projects may also need project management support.
. Review and monitor how well the guideline is being implemented through the project group. Share progress with those involved in making improvements, as well as relevant boards and local partners.
NICE provides a comprehensive programme of support and resources to maximise uptake and use of evidence and guidance. See our into practice pages for more information.
Also see Leng G, Moore V, Abraham S, editors (2014) Achieving high quality care  practical experience from NICE. Chichester: Wiley.# Context
NonHodgkin's lymphoma is the sixth most common cancer in the UK. There are many different subtypes of the disease, with markedly different clinical courses and requirements for therapy. Diagnosing nonHodgkin's lymphoma and identifying the precise subtype is challenging, and optimising the diagnostic process is central to improved management. Significant improvements in our understanding of the biology of nonHodgkin's lymphoma have contributed to improved diagnosis and also allowed for more targeted therapies.
The treatment of nonHodgkin's lymphoma has been a beacon for the development of specific treatment strategies (now applied to many other forms of cancer), but paradoxically there is a paucity of large randomised clinical trials to define best practice in treating the various subtypes. As a consequence there are considerable differences between centres and countries in the ways in which some subtypes of the disease are diagnosed and managed.
There have been some improvements in outcome for people with nonHodgkin's lymphoma in the last decade, but these have been relatively modest and there is still a need for improvement. This is a rapidly developing field, with a number of new therapies proving to be exciting in initial studies. It is too soon, however, to judge their longterm impact, and ongoing assessment of these new agents compared with standard therapy will be needed.
This guideline covers adults and young people (16 years and older) who are referred to secondary care with suspected nonHodgkin's lymphoma, or who have newly diagnosed or relapsed nonHodgkin's lymphoma. It addresses a number of areas where there is uncertainty or variation in clinical practice, in relation to diagnosing nonHodgkin's lymphoma and management of the subtypes at different times in the course of the disease. It is not intended as a comprehensive guide to diagnosing and treating lymphomas. Topics include the best type of biopsy for diagnosis, genetic testing, the role of FDGPETCT imaging in staging, patient information needs and survivorship. Management of the more common subtypes is covered: that is, follicular lymphoma, MALT lymphoma, mantle cell lymphoma, diffuse large Bcell lymphoma, Burkitt lymphoma and peripheral Tcell lymphoma.
This guideline aims to facilitate standardisation of practice in treating nonHodgkin's lymphoma. But because of the rapid development of new therapies as a result of improved understanding of the biology of the disease, continual reevaluation will be essential.# Recommendations for research
The guideline committee has made the following recommendations for research.

# Baseline FDGPETCT imaging for people with diffuse large Bcell lymphoma stage II or above
In people with diffuse large Bcell lymphoma stage II or above, does a baseline FDGPETCT scan have any advantages over a baseline CT scan in the correct interpretation of the endoftreatment FDGPETCT scan?

## Why this is important
A number of consensusbased guidelines and a body of clinical opinion advocate baseline FDGPETCT imaging as being important for interpreting endoftreatment response using FDGPETCT, although there is little published evidence for this. Baseline FDGPETCT is also considered to have an important contribution 'over and above' that of contrastenhanced diagnostic CT in assigning the International Prognostic Index (IPI), in terms of identifying disease stage and number of extranodal sites involved (influencing the decision to offer central nervous system prophylaxis). A prospective trial is needed to determine whether baseline FDGPETCT is needed to interpret endoftreatment FDGPETCT and its role in assigning IPI. People with newly histologically diagnosed diffuse large Bcell lymphoma would have baseline contrastenhanced CT, baseline FDGPETCT and endoftreatment FDGPETCT imaging. Readers would need to be trained in both imaging techniques and be experienced members of lymphoma multidisciplinary teams. The reference standard would be histological confirmation of any positive or equivocal endoftreatment FDGPETCT findings, or followup if there is a negative endoftreatment scan.

# Factors predicting outcomes for people with highgrade transformation of follicular lymphoma
In people with highgrade transformation of follicular lymphoma, which biological and clinical factors predict good outcomes with immunochemotherapy alone?

## Why this is important
Before rituximab, it was accepted that highgrade transformation of follicular lymphoma to diffuse large Bcell lymphoma portended a poor prognosis. Recent data suggest that although transformation remains an important clinical event, outcomes have improved. It is unclear which people are likely to do well with conventional treatment (such as RCHOP) and which people may benefit from intensive treatment with, for example, highdose therapy and autologous stem cell transplantation. Many factors are likely to influence outcome, including clinical factors (such as age, stage at transformation and extranodal involvement at transformation), radiological findings (such as early improvement of disease identified using an interim FDGPETCT scan) and molecular factors (such as certain driver mutations present at transformation, the presence of MYC translocation and response of circulating tumour DNA to treatment). A better understanding of which factors are associated with highrisk or lowrisk disease would enable therapy to be tailored to the person's needs, reducing unnecessary toxicity for people at low risk and reserving intensive therapy for people at high risk. Outcomes of interest include progressionfree survival and overall survival in subgroups defined by clinical factors, radiological findings and molecular analyses.

# Radiotherapy in firstline treatment of diffuse large Bcell lymphoma
In people presenting with diffuse large Bcell lymphoma and sites of bulky disease, are outcomes improved by radiotherapy to those sites following a full course of chemotherapy?

## Why this is important
The role of radiotherapy to sites of original bulky disease in treating diffuse large Bcell lymphoma is uncertain. Some clinical teams will consider radiotherapy in this setting while others will not because of concerns about morbidity and late effects of treatment. In a recent randomised trial of chemotherapy in people over 60 years old with diffuse large Bcell lymphoma, people having radiotherapy were identified and compared with a cohort having no radiotherapy. Significant improvements in eventfree, progressionfree and overall survival were seen in the group having radiotherapy. These results have encouraged some teams to reconsider radiotherapy for bulky diffuse large Bcell lymphoma. A definitive randomised trial is needed to address this question. Outcomes of interest include overall survival, diseasefree survival, progressionfree survival, treatmentrelated mortality, treatmentrelated morbidity, healthrelated quality of life, patient satisfaction, patient preference and overall response rate (complete or partial remission).