STEP 4: Treatment

Step 4 describes the optimal treatments for low-grade lymphomas, the training and experience required of the treating clinicians and the health service characteristics required for optimal cancer care.

All health services must have clinical governance systems that meet the following integral requirements:

  • identifying safety and quality measures
  • monitoring and reporting on performance and outcomes
  • identifying areas for improvement in safety and quality (ACSQHC 2020).

Step 4 outlines the treatment options for low-grade lymphomas. For detailed clinical information on treatment options refer to these resources:

  • ESMO 2020: Follicular lymphoma: a guide for patients
  • BSH 2020: Guideline on the investigation and management of follicular lymphoma
  • Trotman et 2019: Front-line management of indolent NHL in Australia. Part 1: Follicular lymphoma
  • Cheah et al. 2019: Front line management of indolent non Hodgkin lymphoma in Australia. Part 2: mantle cell lymphoma and marginal zone lymphoma.

The intent of treatment can be defined as one or more of the following, which are not exclusive:

  • curative
  • improvement in quality of life and/or longevity with close observation, initiation of local or systemic therapy or a combination
  • symptom

The treatment intent should be established in a multidisciplinary setting, documented in the patient’s medical record and conveyed to the patient and carer as appropriate.

The potential benefits need to be balanced against the morbidity and mortality risks of treatment.

The lead clinician should discuss the proposed treatment program, including advantages and disadvantages of each treatment and associated potential side effects with the patient and their carer or family before treatment consent is obtained and begins so the patient can make an informed decision. Supportive care services should also be considered during this decision-making process.

Patients should be asked about their use of (current or intended) complementary therapies (see Appendix D).

Timeframes for starting treatment should be informed by evidence-based guidelines where they exist. The treatment team should recognise that shorter timeframes for appropriate consultations and starting therapy can promote a better experience for patients.

Initiate advance care planning discussions with patients before treatment begins (this could include appointing a substitute decision-maker and completing an advance care directive). Formally involving a palliative care team/service may benefit any patient, so it is important to know and respect each person’s preference (Australian Government Department of Health 2021a).

The current recommended therapeutic approach is based on the type of low-grade lymphoma, clinical risk factors, presence of symptoms and patient perspective (ESMO 2020).

See the following Australian, British and European guidelines for detailed information regarding therapies.

For stage II FL (non-contiguous lymph nodes, or not amenable to radiation therapy) and advanced stage FL (stages III and IV), the decision to start treatment is guided by symptoms and disease bulk. Approximately one-third of initial presentations occur in patients with low-volume disseminated disease. The importance of ‘watch and wait’ is true even in the modern immunochemotherapy era. The frequency of clinical review during this observation is based on the tempo of the disease, the comfort the patient has with a ‘watch and wait’ approach and the likelihood that they will recognise and re-present in the event of signs of relapse.

Watchful waiting can cause significant anxiety in patients. Appropriate support should be made available (see 3.6.3 Supportive care). Alternate approaches such as treatment with rituximab monotherapy may delay the need for subsequent treatment.

Asymptomatic advance-stage nodal MZL can also be managed with a watchful waiting approach.

An indolent form of MCL, commonly a leukaemic presentation, indicated by lack of symptoms and low tumour burden, can be followed with watchful waiting.

Radiation therapy has an important role in specific scenarios within indolent lymphoma subtypes:

  • Early-stage FL (stage I and stage II in which lymph nodes are contiguous) is potentially curable with radiation Further adjuvant immunochemotherapy may confer additional progression-free survival
  • In centres with radiation expertise, there may be a role for curative radiation therapy (total nodal irradiation) in a highly select group of patients with low-volume, advanced-stage disease
  • Radiation therapy is appropriate in early-stage MZL (including gastric, cutaneous, unilateral and bilateral orbital MALT, and other localised MZLs) with potential curative intent. Note eradication of Helicobacter pylori infection should be performed first – it may induce remission without the need for radiation therapy in some cases
  • In localised relapse of low-grade lymphomas, it may defer the need for systemic immunochemotherapy
  • It may be used for symptom control in advanced-stage low-grade lymphomas, where lymphoma is impairing quality of life.

Timeframe for starting treatment

Begin within four weeks, as prioritised by a multidisciplinary team decision (see 3.4 Treatment planning). Start earlier for life- or organ-threatening indications. Delaying radiation therapy (e.g. for further monitoring) may cause distress and should be discussed with the patient.

Training and experience required of the appropriate specialists

Fellow of the Royal Australian and New Zealand College of Radiologists or equivalent, with adequate training and experience, institutional credentialing and agreed scope of practice in lymphoma management.

The training and experience of the radiation oncologist should be documented.

Health service unit characteristics

To provide safe and quality care for patients having radiation therapy, health services should have these features:

  • linear accelerator (LINAC) capable of image-guided radiation therapy (IGRT)
  • dedicated CT planning
  • access to MRI and PET imaging
  • automatic record-verify of all radiation treatments delivered
  • a treatment planning system
  • trained medical physicists, radiation therapists and nurses with radiation therapy experience
  • coordination for combined therapy with systemic therapy, especially where facilities are not co-located
  • participation in Australian Clinical Dosimetry Service audits
  • an incident management system linked with a quality management

Systemic therapy is appropriate in most patients with non-contiguous stage II or stage III–IV disease who are symptomatic by GELF/BCNI criteria, and considered fit enough to experience a positive risk-benefit balance of undergoing treatment (Ardeshna et al. 2003; Brice et al. 1997). The choice of initial systemic therapy needs to consider the potential for sequencing of subsequent therapies, including potential future stem cell mobilisation.

Follicular lymphoma

Initial treatment with chemotherapy and anti-CD20 monoclonal antibody is often followed by continued therapy with anti-CD20 antibody maintenance for another two years. Given that ongoing maintenance antibody therapy increases progression-free survival but does not prolong overall survival, it is important the patient understands both the benefits in prolonging remission as well as the additional infectious toxicities of using maintenance antibody therapy.

Nodal marginal zone lymphoma

Initial treatment with chemotherapy and anti-CD20 monoclonal antibody is recommended.

Extranodal marginal zone lymphoma

Helicobacter pylori eradication therapy should be given to all patients with gastric MALT, irrespective of stage and Helicobacter pylori status. In those who remain Helicobacter pylori positive, second- line eradication therapy is recommended. Regression of lymphoma following successful eradication of Helicobacter pylori may be delayed, and so it is appropriate to wait 12 months before starting another treatment.

In other instances of localised MALT (e.g. conjunctival MALT), a trial of systemic therapy with antibiotics may be appropriate before radiation therapy.

MALT can also be treated with chemotherapy and anti-CD20 monoclonal antibody.

Splenic marginal zone lymphoma

Recognised first-line therapeutic options are rituximab monotherapy, splenectomy (after appropriate vaccinations) or chemotherapy and anti-CD20 monoclonal antibody combinations. While half of splenectomised patients do not need further treatment for SMZL, splenectomy may bring about complications and is increasingly being replaced with rituximab +/- chemotherapy as initial therapy, especially in patients with a heavy bone marrow disease burden.

Mantle cell lymphoma

MCL causing symptoms should be treated with systemic chemotherapy and anti-CD20 monoclonal antibody combination, incorporating high-dose cytarabine in younger, fitter patients, followed by consolidation with autologous stem cell transplantation (ASCT). Rituximab maintenance after ASCT has been shown to improve overall survival.

In older, more frail patients, chemotherapy and anti-CD20 monoclonal antibody combinations is appropriate. Where bendamustine-containing regimens are used, meticulous monitoring for infections is necessary.

Timeframes for starting treatment

The decision to start treatment may occur after a long period of watch and wait. In FL and MZL, the decision of when to start systemic therapy is guided by the presence of symptoms and organ dysfunction according to the GELF/BCNI criteria. Once the patient meets the criteria to start, treatment should begin within four weeks. Most symptomatic MCL patients should begin treatment with systemic therapy within two weeks of completing staging.

Training and experience required of the appropriate specialists

The following training and experience is required of the appropriate specialist(s): Haematologists and medical oncologists must have training and experience of this standard:

  • Fellow of the Royal Australian College of Physicians (or equivalent)
  • adequate training and experience that enables institutional credentialing and agreed scope of practice within this area (ACSQHC 2015).

Cancer nurses should have accredited training in these areas:

  • anti-cancer treatment administration
  • specialised nursing care for patients undergoing cancer treatments, including side effects and symptom management
  • the handling and disposal of cytotoxic waste (ACSQHC 2020).

Systemic therapy should be prepared by a pharmacist whose background includes this experience:

  • adequate training in systemic therapy medication, including dosing calculations according to protocols, formulations and/or

If no haematologists or medical oncologist is locally available (e.g. regional or remote areas), some components of less complex therapies may be delivered by a general practitioner or nurse with training and experience that enables credentialing and agreed scope of practice within this area. This should be in line with a detailed treatment plan or agreed protocol, and with communication as agreed with the haematologists or medical oncologist or as clinically required.

Health service characteristics

To provide safe and quality care for patients having systemic therapy, health services should have these features:

  • a clearly defined path to emergency care and advice after hours
  • access to basic haematology and biochemistry testing
  • cytotoxic drugs prepared in a pharmacy with appropriate facilities
  • occupational health and safety guidelines for handling cytotoxic drugs, including safe prescribing, preparation, dispensing, supplying, administering, storing, manufacturing, compounding and monitoring the effects of medicines (ACSQHC 2011)
  • guidelines and protocols for delivering treatment safely (including dealing with extravasation of drugs)
  • coordination for combined therapy with radiation therapy, especially where facilities are not co-located
  • timely access to pathology and blood

Antimicrobial prophylaxis and immunoglobulin supplementation (in hypogammaglobulinaemic patients who meet national prescribing criteria) is recommended. Specific antimicrobial prophylaxis should be prescribed based on established guidelines (national guidelines and eviQ) and the results of tests for occult or latent infection (see 3.1 Specialist diagnostic work-up). This includes, but

is not limited to, the particular risk of reactivation of latent hepatitis B associated with anti-CD20 monoclonal antibodies. Patients with hepatitis B core antibody require a documented plan for antiviral therapy and ongoing monitoring.

Yearly seasonal flu vaccination and five-yearly pneumococcal vaccination should be encouraged in accordance with the Australian National Immunisation Schedule, as should COVID vaccination boosters as/if the evolving evidence supports this approach.

The primary role of surgery in low-grade lymphomas is to obtain a biopsy specimen. Surgery is

a beneficial component of indolent lymphoma treatment in a minority of cases such as in relieving mechanical obstruction caused by lymphoma (e.g. an acute bowel obstruction in duodenal follicular lymphoma).

Splenectomy is an important therapeutic option for SMZL (see 4.2.3 Systemic therapy).

Documented evidence of the surgeon’s training and experience, including their relevant organ- specific sub-specialty experience with low-grade lymphomas and procedures to be undertaken, should be available.

Health service characteristics

To provide safe and quality care for patients having surgery, health services should have these features:

  • critical care support
  • 24-hour medical staff availability
  • 24-hour operating room access and intensive care unit
  • diagnostic imaging
  • pathology
  • PET

While chemoimmunotherapy has been the cornerstone of frontline treatment for advanced disease in cases of relapse, several other therapeutic strategies are under development.

Promising therapeutic agents include:

  • small molecules targeting signal transduction (PI3K inhibitors, BTK inhibitors)
  • monoclonal antibodies targeting other cell surface proteins (CD19, CD47)
  • epigenetic modifiers (EZH2 and HDAC inhibitors)
  • immune checkpoint inhibitors (PD1, PD-L1, TIGIT)
  • engineered CARs (CAR T- and CAR NK-cells)
  • bispecific T-cell engagers
  • antibody drug conjugates
  • radioimmunoconjugates
  • cancer vaccines
  • immunomodulatory

Many of these agents are in advanced stages of development and have proven efficacy and manageable toxicity. Clinical trial participation is a good therapeutic consideration, particularly for patients who have progressed after two lines of therapy. ASCT and sometimes allogeneic stem cell transplantation is still a good option for certain patients with relapsed disease.

Palliative care is a multidisciplinary approach to symptom management, psychosocial support and assistance in identifying care goals for patients with serious illness and their families.

Early referral to palliative care can improve the quality of life for people with cancer, improve caregiver outcomes and, in some cases, may have survival benefits (Haines 2011; Temel et al. 2010; Zimmermann et al. 2014).

The lead clinician should ensure patients receive timely and appropriate referral to palliative care services. Referral should be based on need rather than prognosis. Emphasise the value of palliative care in improving symptom management and quality of life to patients and their carers at any stage of disease. This is specifically important to explain to patients with a low-grade lymphoma and their families, due to the often lengthy course of the disease.

The ‘Dying to Talk’ resource may help health professionals when initiating discussions with patients about future care needs (see ‘More information’). Ensure that carers and families receive information, support and guidance about their role in palliative care (Palliative Care Australia 2018).

Patients, with support from their family or carer and treating team, should be encouraged to consider appointing a substitute decision-maker and to complete an advance care directive. Refer to step 6 for a more detailed description of managing patients with refractory, relapsed, residual or progressive disease.

More information

These online resources are useful:

The team should support the patient to participate in research or clinical trials where available and appropriate. Many emerging treatments are only available on clinical trials that may require referral to certain trial centres.

For more information visit:

See validated screening tools mentioned in Principle 4 ‘Supportive care’.

Patients with low-grade lymphomas may undergo another period of watchful waiting before their initial therapy and this can lead to anxieties related to the stress and uncertainty of observation. Ongoing patient education from their lymphoma specialist and, if further support is needed, a referral to a psychologist with experience in lymphoma is recommended (see 3.6.3 Supportive care).

A number of specific challenges and needs may arise for patients at this time:

  • assistance for dealing with emotional and psychological issues, including body image concerns, fatigue, quitting smoking, traumatic experiences, existential anxiety, treatment phobias, anxiety/ depression, interpersonal problems and sexuality concerns
  • potential isolation from normal support networks, particularly for rural patients who are staying away from home for treatment
  • cognitive changes as a result of treatment (e.g. altered memory, attention and concentration)
  • diet needs – these are likely to change over time during the different phases of treatment
  • nutritional assessment and support for malnutrition due to ongoing treatment side effects (including weight loss, reduced oral intake and cachexia), which may require monitoring and nutrition intervention from a dietitian
  • management of gastrointestinal symptoms (including vomiting, mucositis, reflux and early satiety), difficulty swallowing and decrease in appetite require optimal symptom control
  • management of physical symptoms such as nausea and loss of appetite
  • decline in mobility or functional status as a result of treatment
  • assistance with beginning or resuming regular exercise with referral to an exercise physiologist or physiotherapist (COSA 2018; Hayes et al. 2019).

Early involvement of general practitioners may lead to improved cancer survivorship care following acute treatment. General practitioners can address many supportive care needs through good communication and clear guidance from the specialist team (Emery 2014).

Patients, carers and families may have these additional issues and needs:

  • financial issues related to loss of income (through reduced capacity to work or loss of work) and additional expenses as a result of illness or treatment
  • advance care planning, which may involve appointing a substitute decision-maker and completing an advance care directive
  • legal issues (completing a will, care of dependent children) or making an insurance, superannuation or social security claim on the basis of terminal illness or permanent disability.

Cancer Council 13 11 20, Leukaemia Foundation 1800 620 420 and Lymphoma Australia 1800 953 081 information and support lines can assist with information and referral to local support services.

For more information on supportive care and needs that may arise for different population groups, see Appendices A, B and C.

Rehabilitation may be required at any point of the care pathway. If it is required before treatment, it is referred to as prehabilitation (see section 3.6.1).

All members of the multidisciplinary team have an important role in promoting rehabilitation. Team members may include occupational therapists, speech pathologists, dietitians, social workers, psychologists, physiotherapists, exercise physiologists and rehabilitation specialists.

To maximise the safety and therapeutic effect of exercise for people with cancer, all team members should recommend that people with cancer work towards achieving, and then maintaining, recommended levels of exercise and physical activity as per relevant guidelines. Exercise should be prescribed and delivered under the direction of an accredited exercise physiologist or physiotherapist with experience in cancer care (Vardy et al. 2019). The focus of intervention from these health professionals is tailoring evidence-based exercise recommendations to the individual patient’s needs and abilities, with a focus on the patient transitioning to ongoing self-managed exercise.

Other issues that may need to be dealt with include managing cancer-related fatigue, improving physical endurance, achieving independence in daily tasks, optimising nutritional intake, returning to work and ongoing adjustment to cancer and its consequences. Referrals to dietitians, psychosocial support, return-to-work programs and community support organisations can help in managing these issues.

The lead or nominated clinician should take responsibility for these tasks:

  • discussing treatment options with patients and carers, including the treatment intent and expected outcomes, and providing a written version of the plan and any referrals
  • providing patient and carers with information about the possible side effects of treatment, managing symptoms between active treatments, how to access care, self-management strategies and emergency contacts
  • encouraging patients to use question prompt lists and audio recordings, and to have a support person present to aid informed decision making
  • initiating a discussion about advance care planning and involving carers or family if the patient

The general practitioner plays an important role in coordinating care for patients, including helping to manage side effects and other comorbidities, and offering support when patients have questions or worries. For most patients, simultaneous care provided by their general practitioner is very important.

The lead clinician, in discussion with the patient’s general practitioner, should consider these points:

  • the general practitioner’s role in symptom management, supportive care and referral to local services
  • using a chronic disease management plan and mental health care management plan
  • how to ensure regular and timely two-way communication about:
  • the treatment plan, including intent and potential side effects
  • supportive and palliative care requirements
  • the patient’s prognosis and their understanding of this
  • enrolment in research or clinical trials
  • changes in treatment or medications
  • the presence of an advance care directive or appointment of a substitute decision-maker
  • recommendations from the multidisciplinary

More information

Refer to Principle 6 ‘Communication’ for communication skills training programs and resources.