Special Report – Haematological Malignancy by The Magazine Production Company

SPECIAL REPORT

Haematological Malignancy Watch and Wait vs. Palliative Therapy and Supportive Care Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy Indolent Haematological Malignancies Leukaemia Non-Hodgkin Lymphoma Myeloma Myelodysplastic Syndromes and Myeloproliferative Neoplasms Prodromal Conditions Practice Points

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

SPECIAL REPORT

Haematological Malignancy Watch and Wait vs. Palliative Therapy and Supportive Care

Contents

Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy Indolent Haematological Malignancies Leukaemia Non-Hodgkin Lymphoma

FOREWORD

Martin Richards, Editor

Myeloma Myelodysplastic Syndromes and Myeloproliferative Neoplasms Prodromal Conditions Practice Points

WATCH AND WAIT FOR HAEMATOLOGICAL MALIGNANCY

Ken Campbell, Clinical Information Officer, Leukaemia Research Trust, London Sponsored by

Published by Global Business Media

Published by Global Business Media Global Business Media Limited 62 The Street Ashtead Surrey KT21 1AT United Kingdom Switchboard: +44 (0)1737 850 939 Fax: +44 (0)1737 851 952 Email: info@globalbusinessmedia.org Website: www.globalbusinessmedia.org Publisher Kevin Bell Business Development Director Marie-Anne Brooks Editor Martin Richards

Watch and Wait vs. Palliative Therapy and Supportive Care

Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy

Indolent Haematological Malignancies

Leukaemia

Non-Hodgkin Lymphoma

Indolent Aggressive

Myeloma

Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Production Manager Paul Davies

Prodromal Conditions

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Practice Points

Senior Project Manager Steve Banks Advertising Executives Michael McCarthy Abigail Coombes

Psychological Considerations The opinions and views expressed in the editorial content in this publication are those of the authors alone and do not necessarily represent the views of any organisation with which they may be associated.

Infection Prophylaxis and Management

Material in advertisements and promotional features may be considered to represent the views of the advertisers and promoters. The views and opinions expressed in this publication do not necessarily express the views of the Publishers or the Editor. While every care has been taken in the preparation of this publication, neither the Publishers nor the Editor are responsible for such opinions and views or for any inaccuracies in the articles.

REFERENCES

Indications for Referral

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Foreword

ach year in the UK, several thousand patients are diagnosed with blood cancers but are told that they will not receive any treatment,

possibly for many years or even decades. Some patients will never require treatment; in other cases the disease will eventually show signs of progressing indicating a need to start treatment. Most patients in this situation will have chronic lymphocytic leukaemia or indolent lymphoma â&#x20AC;&#x201C; a smaller proportion will have very early stage myeloma. The common feature is that, unlike most solid tumours, these conditions are widely disseminated at the time of diagnosis and there is no point at which early treatment has a high chance of eradicating the disease and achieving cure. Even in the case of lymphoma where there are discrete anatomical lesions, there are malignant cells within the circulation even at the earliest stages. The practice of deferring treatment, known as watch and wait, should be distinguished from palliative care. Patients who are on watch and wait have treatable conditions and the decision not to treat is based on good quality studies indicating no benefit from early treatment. Palliative care is intended purely to suppress symptoms and signs of the condition, although this may prolong survival, it has no direct impact on the disease process. In patients who transition from watch and wait to active treatment, their treatment is in almost all cases, definitive therapy. Patients being managed on a watch and wait may experience stress, as may family members. They will need careful monitoring for signs of progression and may have disease-related problems such as fatigue or relative immunosuppression. Primary care practitioners can offer valuable support, both in psychosocial care and in medical monitoring of these patients.

Martin Richards Editor

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Watch and Wait for Haematological Malignancy Ken Campbell, Clinical Information Officer, Leukaemia Research Trust, London

Although there are exceptions, for most solid cancers there is a consensus that early treatment is indicated; this is particularly the case in cancers with a high risk of metastasis. If the cancer is removed while disease is localised there is a much higher cure rate than when secondary tumours are present.

Watch and wait refers to deferred treatment

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for a condition, usually based on published data showing that there is no clear benefit from early treatment

or a number of haematological malignancies a policy of “watch and wait” is preferred. Even though this approach is based on high quality clinical studies which show no survival benefit from early treatment, patients still may be anxious about by being told that they have a cancer diagnosis but that they are to receive no treatment. Many patients refer to this as “watch and worry”. Alternative terms are sometimes used to reduce anxiety; examples are “watchful monitoring” or “active monitoring” or “expectant management”. This article will discuss the basis for watch and wait and the difference between this and palliative care; briefly describe those haematological malignancies for which a watch and wait policy is commonly applied; describe the criteria for when to start treatment and indicate what special considerations may apply to primary care of such patients.

Watch and Wait vs. Palliative Therapy and Supportive Care The distinction between watch and wait and palliative and supportive therapy is critically

important. Watch and wait refers to deferred treatment for a condition, usually based on published data showing that there is no clear benefit from early treatment; it does not relate to the fitness of the patient to undergo treatment. Palliative therapy is offered to a patient for whom the potential benefits of more disease-directed treatment are insufficient to offset the sideeffects of definitive treatment. Palliation (from Latin palliare – to cloak) is aimed at alleviating symptoms of the disease. Supportive care refers to treatments such as transfusion (RBC or platelet) or infection prophylaxis or treatment. Supportive care often forms a major part of palliative therapy, but is also a key element of definitive treatment. Much of the improvement in survival for haematological malignancy is thought to derive from improvements in supportive care lowering the treatment-related mortality (TRM). Palliative therapy may be offered to a patient with an aggressive malignancy if the patient is too unfit, through advanced age and/or comorbidity, to receive definitive therapy. It may also be offered if a patient is deemed unlikely to survive for long, even with definitive treatment. The central consideration in palliative therapy is

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On the basis of their natural history, haematological malignancies can be broadly divided into aggressive and indolent conditions.

to maintain quality of life; palliative therapy will, in many cases, prolong survival, but this is not the principal objective. It is important to emphasize to patients that palliative therapy and end of life care are not synonymous – a patient may sometimes spend a prolonged period receiving palliative therapy before entering the terminal phase of their condition.

Treatment Options for Patients with Newly-Diagnosed Haematological Malignancy • Definitive Therapy – Directed at the underlying disease process, whether or not aimed at cure – Typically a higher toxicity than palliative care; may not be feasible for some patients • Palliative Therapy – Aimed at controlling symptoms – May prolong survival but this is not the primary aim – Quality of life is typically the deciding factor in choice of treatment • Supportive Care – Aimed at limiting adverse effects of disease and/or treatment – Prevention and effective therapy for anaemia, infections, etc. – Component of both definitive and palliative therapy – Effective supportive care is crucial in reducing mortality and morbidity • Watch and wait – Evidence-based elective decision to defer initial therapy – Not therapeutic nihilism, based on risk/benefit analysis not on cost or availability of therapy – A patient receiving palliative or supportive care is not, by definition, on watch and wait Confusion may be caused by the use of the term “watch and wait” to cover monitoring of patients who have received definitive therapy. Here the choice is between consolidation treatment, also called maintenance, and observation. In this article the term always refers to management of the newly diagnosed patient.

Indolent Haematological Malignancies The principal considerations in deciding whether watch and wait is appropriate are the natural history of the patient’s condition and the 4 | WWW.PRIMARYCAREREPORTS.CO.UK

evidence base for benefit (or harm) from early treatment. On the basis of their natural history, haematological malignancies can be broadly divided into aggressive and indolent conditions. Acute leukaemias and certain forms of nonHodgkin lymphoma (NHL) tend to develop rapidly and, if not effectively treated, will progress rapidly. Before the development of effective treatments patients with these conditions rarely survived longer than a few months. Int contrast, indolent malignancies develop slowly and, even without treatment, they progress slowly with patients commonly surviving for years or even decades. The indolent group includes; • Chronic lymphocytic leukaemia, • Low-grade NHL, • Smouldering myeloma • Most cases of myelodysplastic syndromes (MDS) and • Most cases of myeloproliferative neoplasms (MPN). Watch and wait is appropriate for many patients with indolent malignancies; a proportion of patients with more aggressive disease may also qualify for watch and wait. The essence of the treatment approach is not therapeutic nihilism; it is to only treat early where clinical trials have shown benefit from so doing. Both myeloma and chronic lymphocytic leukaemia are preceded by clinically silent prodromal conditions, monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-lymphocytosis (MBL) respectively. Although monitoring of these conditions is not defined as watch and wait, they are briefly described here for completeness and because there may be some overlap with early stage myeloma or CLL respectively.

Leukaemia Although there are many sub-types of leukaemia, these all fall within four major groups: • Acute lymphoblastic leukaemia • Acute myeloid leukaemia • Chronic lymphocytic leukaemia • Chronic myeloid leukaemia Acute leukaemia may be managed palliatively if a patient is frail elderly or has co-morbidities which would preclude offering definitive therapy; it is never managed on a watch and wait basis. If the patient is fit enough to receive treatment then this will commence soon after diagnosis. An attempt to manage acute leukaemia by watch and wait would result in early and severe morbidity; even if palliative care may not extend survival it can mitigate morbidity due to the leukaemia. Chronic myeloid leukaemia is also never managed by watch and wait, even though the natural history of the disease is indolent – prior to the introduction of effective definitive

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Typical morphology of CLL cells in peripheral blood (http://www.flickr.com/photos/euthman/2869815349)

chemotherapy using imatinib median survival was on the order of 7 years. The reason for not delaying therapy is the fact that, when left untreated, the disease will enter a more aggressive phase which is less responsive to chemotherapy. It is not possible to predict when an individual patient’s condition will progress. Disease transformation may occur within the first year after diagnosis – for this reason it is normal to start treatment very soon after diagnosis. The side-effect profile of imatinib and related drugs is sufficiently mild that even frail patients will usually be given definitive treatment. Chronic lymphocytic leukaemia (CLL) is the most common form of leukaemia in the Western population and is the only form of leukaemia for which watch and wait is recommended. There are about 3 300 cases each year in the UK. Most patients with CLL have an indolent form of the disease and a significant proportion of patients never require treatment. An oft-used description of CLL is that, “Many patients die with CLL, not from it.” A number of studies have reported that there is no survival benefit from early treatment. A recent review in Blood1 by John Gribben offers a detailed description of management of newly diagnosed CLL. Gribben describes CLL thus, “CLL is extremely heterogeneous in its clinical course; some patients live for decades with no need for treatment for their disease, whereas others have a rapidly aggressive clinical course.” One of the questions posed in this review was whether watch and wait should continue to be the preferred management for most newly diagnosed patients. A metaanalysis of trials enrolling more than 2 000 patients showed no benefit from early vs. deferred treatment; there was a slight trend to poorer survival in the early treatment group2. A

caveat to this finding is that the patients in the trials analysed were treated with alkylating agents whereas the preferred up front treatment now uses newer drugs with lower systemic toxicity. A second consideration is the developing use of biomarkers to predict which patients will experience early progression – a discussion of this is beyond the scope of this article – see the recent reviews by Bockstaele et. al. and Butler and Gribben.3 Treatment is normally initiated in response to; • Symptomatic disease, • Bulky lymphadenopathy and/or splenomegaly, • Risk of local compressive disease, • Marrow compromise, or • Rapid disease progression. It is possible that practice will change with increasing availability of prognostic screening tests which may enable earlier recognition of patients who disease is likely to progress rapidly. In Europe the most widely used staging system is called the Binet system and the earliest recognized is stage A, in the US the Rai system is more widely used, in which the earliest stage is stage 0. Watch and wait would be reserved for stages A or 0; some stage A/0 patients would now be identified as having MBL rather than CLL – MBL is discussed below as a prodromal condition. Patients who have CLL and are being managed on watch and wait are normally seen around every 3 to 4 months initially, then less frequently if their condition remains stable. Between haematology consultations the primary care health team should be alert for any indications that their condition may be progressing. Gribben specifically mentions: • development of night sweats, • increasing adenopathy at one site, or • elevated lactate dehydrogenase

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Many clinicians would offer all eligible patients an opportunity to take part in a clinical trial if they are eligible.

Cut surface of lymph node replaced by follicular lymphoma (http://en.wikipedia.org/wiki/File:Lymphoma_macro.jpg)

Non-Hodgkin Lymphoma Non-Hodgkin lymphoma is the fifth most common cancer in the developed world – in the UK there are about 9000 newly diagnosed patients with NHL each year. A broad, clinically based, classification of the many sub-types is between indolent (low-grade) and aggressive (high-grade). • Indolent – Slow onset; often diagnosed at late stage – Long survival period without therapy (many years) – Frequently a rapid response to treatment – Typically relapses with shortening duration of intermission – Not curable in the majority of cases • Aggressive – Rapid onset; commonly presents at early stage – Progress rapidly without effective therapy – High probability of cure if chemo/ radio-sensitive The WHO classification of blood cancers4 is the most widely used; within this schema the indolent forms of NHL are: • Follicular lymphoma • Small lymphocytic lymphoma • Marginal zone B-cell lymphoma, mucosa-associated lymphoid tissue type • Marginal zone B-cell lymphoma, nodal type • Lymphoplasmacytic lymphoma Together, indolent forms make up about one-third of all NHL. The standard of care for patients with newly diagnosed indolent NHL is “expectant 6 | WWW.PRIMARYCAREREPORTS.CO.UK

management for asymptomatic patients with low-bulk disease”; and to “initiate treatment in patients with symptomatic disease, bulky lymphadenopathy or splenomegaly or both, risk of local compressive disease, marrow compromise, or rapid disease progression”5. Many clinicians would offer all eligible patients an opportunity to take part in a clinical trial if they are eligible. It may be confusing for patients that their options may consist of “do nothing” or undergo relatively high-risk treatment such as a stem cell transplant; support from the primary care team can be of great value. Patients on expectant management would typically be reviewed in clinic at 3-monthly intervals with history, physical examinations and bloods including LDH. Clinical indicators of possible transformation from indolent to aggressive NHL include fast growing of lymph nodes, pleural effusions or superior cave vein syndrome6. Transformation is an indication for immediate initiation of treatment so the primary care team should treat any suspicion of this as grounds for an immediate emergency referral.

Myeloma Myeloma is about as common as indolent NHL with about 3 500 new cases in the UK each year. As with several other conditions, there is an increasing trend for early, incidental diagnosis as more people undergo “well-person” medical reviews, which means that many patients are asymptomatic at diagnosis. A recent “review of reviews” stated that “The results from the overview show that early treatment does not offer survival benefit.”7 The crucial considerations for initial management of myeloma are whether the patient is symptomatic and whether there is

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

Plasma cells in peripheral blood (http://en.wikipedia.org/wiki/File:PCL.jpg)

evidence of myeloma related organ or tissue damage (ROTI). ROTI includes hypercalcaemia, renal damage, anaemia and bone lesions – easily remembered by the acronym CRAB. Standard management for a patient who is asymptomatic and has no ROTI is watch and wait8. Monitoring is usually at three-monthly intervals. Symptoms which may indicate progression, and therefore justify emergency referral include: • Bone disease • Impaired renal function • Anaemia • Hypercalcaemia • Recurrent or persistent bacterial infection • Hyperviscosity Spinal cord compression, hypercalcaemia and renal failure are medical emergencies requiring immediate investigation and treatment. Signs of spinal cord compression include9: • pain (both local and radicular), • weakness, • paraesthesias,

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• loss of bladder or bowel function • ataxia

Myelodysplastic Syndromes and Myeloproliferative Neoplasms The myelodysplastic syndromes are “…clonal bone marrow disorders that lead to underproduction of normal blood cells. The consequent cytopenias result in infections and bleeding complications. MDS transform to acute myeloid leukemia in one-third of patients.”10 Almost all MDS patients will require transfusional support at some supportive rather than disease-oriented. The deciding factor for a change from watch and wait to treatment is, therefore, usually the development of anaemia severe enough to impinge upon performance status. The myeloproliferative neoplasms (MPN) are essential thrombocythaemia (ET), polycythaemia vera (PV) and primary myelofibrosis (MF). For both PV and ET thrombosis is the primary MPN

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SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

The wider use of laboratory testing of apparently healthy individuals is likely to lead to an increasing number of patients being diagnosed with precursor syndromes or early stages of a haematological malignancy.

related causes of death11; for this reason, even asymptomatic patients are likely to be started on prophylactic medication and thus cannot be considered to be on watch and wait. Patients with MF are dealt with in essentially the same way as MDS patients; at such time as they develop anaemia which limits activities of daily living (ADL) they are started on a transfusion regimen. Until transfusion becomes necessary, which it almost always does, they are actively monitored.

Prodromal Conditions As mentioned, both CLL and myeloma are preceded by non-malignant clonal proliferations; monoclonal B cell lymphocytosis (MBL) and monoclonal gammopathy of undetermined significance (MGUS) respectively. It is part of the definition in both MBL and MGUS that the condition is asymptomatic at the time of diagnosis.12;13 There is a degree of overlap between MBL and early CLL and between MGUS and early myeloma; despite this it is not normally considered that MBL or MGUS patients are on watch and wait. It is recommended that patients with prodromal syndromes should be monitored as there is a rate of conversion to clinically frank disease of about 1% per annum in each case. For each condition there is a recent review which discusses the clinical implications and follow-up.

Practice Points Psychological Considerations Many patients being managed on watch and wait are, understandably, often very anxious. As such, they may benefit from reassurance that the deferment of treatment is based on clinical grounds. The primary care team should offer explicit reassurance that neither cost nor availability of treatment has played any part in their treatment planning. It is possible that, with the introduction of new systems for commissioning, patients may be more likely to fear that treatment decisions are based on cost. In this case the GP can explain that the issue of payment for treatment has not arisen because the evidence base supports watch and wait. Again, it may help to assure the patient that there will be no problem with funding payment if, and when, this is indicated. Availability hints at another reason for patient anxiety, the perception that they are not being treated because there is nothing that can be done. This can best be dealt with using positive rather than negative assurances; it should be made clear that, if and when treatment becomes necessary, there are options available. In the case of particularly anxious patients the primary care team may be able to act as go-betweens; this will involve liaison with 8 | WWW.PRIMARYCAREREPORTS.CO.UK

the haematology care team. A primary care practitioner, with a long-standing therapeutic relationship with the patient, may be better able to communicate clinical information in an understandable and reassuring fashion. Infection Prophylaxis and Management Patient with haematological malignancy commonly suffer some degree of immunoparesis, even when not being treated; evidence is equivocal on whether, despite this, they benefit from prophylaxis such as flu vaccination. Despite the lack of definitive evidence it is generally recommended that they should be included in vaccination programs. Indications for Referral As previously indicated, the wider use of laboratory testing of apparently healthy individuals is likely to lead to an increasing number of patients being diagnosed with precursor syndromes or early stages of a haematological malignancy. It is likely that most practices will have at least one patient being managed on a watch and wait basis for haematological malignancy. A prudent approach would be to develop a protocol for referral of such patients between planned reviews.

SPECIAL REPORT: HAEMATOLOGICAL MALIGNANCY

References: 1

Gribben, J. How I treat CLL up front. Blood 115, 187-197. 20102010.

CLL Trialistsâ&#x20AC;&#x2122; Collaborative Group. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. J Natl Cancer Inst. 91(10), 861-868. 19991999.

Butler T, Gribben JG. Biologic and clinical significance of molecular profiling in Chronic Lymphocytic Leukemia. Blood Rev. 2010;24:135-141.

Swerdlow SH, Campo E, Harris NL et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Lyon: IARC; 2008.

Gribben JG. How I treat indolent lymphoma. Blood 2007;109:4617-4626.

Gine E, Montoto S, Bosch F et al. The Follicular Lymphoma International Prognostic Index (FLIPI) and the histological subtype are the most important factors to predict histological transformation in follicular lymphoma. Ann.Oncol. 2006;17:1539-1545.

Kumar A, Galeb S, Djulbegovic B. Treatment of patients with multiple myeloma: an overview of systematic reviews. Acta Haematol. 2011;125:8-22.

British Committee for Standards in Haematology in conjunction with the UK Myeloma Forum (UKMF). Guidelines on the diagnosis and management of multiple myeloma. 20102010.

Chakraborti C, Miller KL. Multiple myeloma presenting as spinal cord compression: a case report. J Med.Case. Reports. 2010;4:251.

Barzi A, Sekeres MA. Myelodysplastic syndromes: a practical approach to diagnosis and treatment. Cleve.Clin.J Med. 2010;77:37-44.

Guglielmelli P, Vannucchi AM. Recent advances in diagnosis and treatment of chronic myeloproliferative neoplasms. F1000.Med.Rep. 2010;2:

Rawstron AC, Hillmen P. Clinical and diagnostic implications of monoclonal B-cell lymphocytosis. Best.Pract.Res.Clin. Haematol. 2010;23:61-69.

Landgren O. Monoclonal gammopathy of undetermined significance and smoldering myeloma: new insights into pathophysiology and epidemiology. Hematology.Am.Soc.Hematol.Educ.Program. 2010;2010:295-302.

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