Mifamurtide (MTP-PE)

What is it?

Mifamurtide is the brand name for muramyl tripeptide phosphatidylethanolamine or MTP-PE for short. It is a synthetic derivative of muramyl dipeptide (MDP), which is an immune-stimulatory component of the bacterial cell wall. It’s advantage is that it has a longer half-life in plasma than MDP.

Mifamurtide is licensed for use as an adjunct in the treatment of high-grade resectable non- metastatic osteosarcoma after macroscopically complete surgical resection in children, adolescents and young adults. There has been much debate over the evidence to support it’s use but after much deliberation the National Institute for Health and Clinical Excellence (NICE) granted permission for it’s use in the UK in October 2011.  Read more about the NICE guidance.

How does it work?

Nucleotide-binding oligomerization domain-containing protein 2, or NOD2 for short, is a receptor found in monocytes and macrophages, which recognises bacterial peptidoglycan, stimulating an immune response. MTP-PE is recognised by NOD2 and thus simulates a bacterial infection, inducing an immune response and a cascade of cytokines including Tumour Necrosis Factor alpha (TNFα), which in turn generates a macrophage-mediated attack on the cancer cells.

The use of an immune stimulant like MTP-PE makes intuitive sense in the treatment of osteosarcoma, as post-resection infection has been shown to increase overall survival. Read more about infection in osteosarcoma.

The Evidence

There is one randomised controlled trial looking at the effect of Mifamurtide as an adjunct in the treatment of osteosarcoma. Meyers et al and the Children’s Oncology Group published the trial of 662 young people with localised, resectable osteosarcoma. They were randomly assigned to high-dose methotrexate, cisplatin, and doxorubicin plus or minus ifosfamide in a 2×2 factorial design, which also included a randomised evaluation of MTP. The study concluded that the addition of MTP to chemotherapy improved 6-year overall survival from 70% to 78% (P=0.03). The study has however generated much controversy. Read the paper for yourself in the Journal of Clinical Oncology.

Critics of the paper cite differences in the chemotherapy regimes in the different arms of the study, with cisplatin omitted from pre-operative chemotherapy in the ifosfamide-containing arm. Questions have also been raised about the apparent lack of effect of MTP on event-free survival (EFS) while at the same time overall survival (OS) is improved, as other studies suggest that EFS and OS are inextricably linked.

In defence of the paper it is pointed out that the trial was only powered to show a difference in effect from the MTP, which it does when the addition of MTP is looked at in isolation. It is also pointed out that MTP-containing arms of the trial had worse tumour necrosis at the time of resection, normally associated with a poorer prognosis, and yet those patients had the reported improvement in survival despite this.

You can read an eloquent commentary on some of the controversies in the Journal of Clinical Oncology.

You can read a riposte from the authors of the RCT of MTP, also in the Journal of Clinical Oncology.

  1. Meyers PA, Schwartz CL, Krailo MD, et al: Osteosarcoma: The addition of muramyl tripeptide to chemotherapy improves overall survival—A report from the Children’s Oncology Group. J Clin Oncol 26:633-638, 2008

Metastatic Bone Disease

Metastasis, or metastatic disease, is the spread of cancer from an initial or primary site in one organ or part of the body to a secondary non-adjacent organ or part.

Epidemiology

It is estimated that there are over 20,000 new cases of metastatic bone disease (MBD) in the UK each year.

Although any type of cancer can in theory spread to bone, MBD is most commonly seen in Breast, Prostate, Lung, Renal and Thyroid cancers.

In Breast and Prostate cancer in particular, the incidence of MBD is approximately 70% in advanced disease.

Presentation

The most common presenting feature is pain, usually exacerbated by weight-bearing and often worse at night.

Pathologic fracture occurs in about 20% of patients with MBD.

Patients may also present with symptoms of hypercalcaemia in about 20% of cases. Symptoms include generalised bone pain, nausea and vomiting, polyuria, abnormal heart rhythms, depression, cognitive dysfunction, and in extreme cases depressed consciousness.

Acute spinal cord or neural compression manifests in around 10% of patients, and bone marrow failure presenting as a pancytopaenia has been reported in up to 9% of patients with MBD.

Assessment 

Never assume that a solitary lesion is a metastasis!

A full medical history and examination must be performed and the general condition of the patient assessed.

Baseline blood tests, including a bone profile to look for hypercalcaemia, plasma electrophoresis to screen for myeloma, and tumour markers as indicated by the history and physical.

If the primary source of MBD is unknown, further investigations should be directed to finding it (CT chest/abdo/pelvis, mammogram, etc)

As a minimum, a full length radiograph of the affected bone must be obtained to rule out other lesions within the same bone. An isotope bone scan can help elicit other  sites of MBD, although it is often cold in myeloma.

If diagnostic doubt remains,  or the lesion is solitary, a biopsy is indicated. If done early, it can also help guide other investigations. Read more about the principles of how to biopsy a musculoskeletal tumour.

Assessing Fracture Risk

Mechanical or functional pain is a good indicator of imminent fracture risk, as are avulsion of the lesser trochanter, and >50% erosion through the cortex of a long bone on any view.

Mirels developed a scoring system to help rationalise the decision making process regarding the risk of pathological fracture and when to intervene with prophylactic fixation. The system has four categories scored 1-3, giving a maximum total of 12 points. Patients with scores of 8 and above are at high risk of fracture and should be considered for prophylactic fixation. The categories are:

  • Site: upper limb (1pt), lower limb (2pts), intertrochanteric (3pts).
  • Pain: mild (1pt), moderate (2pts), limits function (3pts).
  • Lesion: blastic (1pt), mixed (2pts), lytic (3pts).
  • Size: (maximal cortical destruction in any view) <1/3 (1pt), 1/3-2/3 (2pts), >2/3 (3pts).

Prognosis, pre-morbid functional status, and the likelihood that the lesion may respond to non-surgical treatment should also be taken into consideration.

Non-Surgical Treatment

Radiotherapy is usually palliative and is generally given in a single fraction. It may prevent a fracture from occurring  if the lesion subsequently heals.

Chemotherapy clearly has a role in chemo-sensitive tumours and should be discussed with oncologists in the setting of the MDT.

Bisphosphonates are a class of drug which block the mechanisms of bone resorption by stimulating apoptosis (programmed cell death) in osteoclasts, the cells which normally resorb bone. Their use is essential in cases of hypercalcaemia related to MBD. Critically, The addition of zoledronic acid to adjuvant endocrine therapy has been shown by Gnant et al to improve disease-free survival in premenopausal patients with estrogen-responsive early breast cancer. You can read the paper by Gnant et al in the New England Journal of Medicine.

Prophylactic Fixation

Read more about the principles for surgical treatment of metastatic bone disease.

References

British Orthopaedic Association Guidance on Metastatic Bone Disease.

Mirels H. Metastatic Disease in long bones. A proposed Scoring System for diagnosing impending pathologic fracture. Clin Orthop Rel Res 1989: 249; 256-264