Mechanism of action for current cancer therapies

Cancer represents a major worldwide health and economic burden with approximately 1 in 2-3 people diagnosed with a malignancy over their lifetime, with incidence rates increasing due to an ageing population. The leading causes of cancer in the developed world include prostate, breast, lung and bowel cancer. Surgery is the mainstay of treatment for many cancers, particularly well localized tumours. Post-operative (adjuvant) chemotherapy, radiation therapy (RT) or concurrent chemo-RT are often employed to sterilize suspected subclinical residual disease in the surgical bed or draining regional lymph nodes. Adjuvant chemotherapy is also used where there is suspected distant micro-metastases that have spread either through the circulation or lymphatics. In some circumstances pre-operative (neoadjuvant) chemotherapy and/or RT is used to reduce the size of the tumour and lessen the extent of surgery, or deal with micro-metastases early in the treatment course. In well-resourced countries, up to 40-60% of all cancer patients will receive some form of RT as either part of their local therapy, or to palliate symptoms due to recurrent or metastatic disease. Definitive (curative) RT as organ-preserving therapy, in place of surgery, is increasingly used in certain tumours, particularly locally advanced diseases such as lung cancer. Its mode of action is to damage the DNA either directly or through the production of hydroxy radicals, which in-turn damage the tumour cells nuclear DNA and prevent replication of cells, and ultimately cell death. Systemic therapy refers to a drug that is administered via any route (oral, intravenous, etc) and is transported through the circulation. The most common systemic therapy is chemotherapy, which exerts its effects through its cytotoxic (cell damaging) properties, mainly on rapidly turning over cells, namely cancers, but will have an effect on other rapidly turning over normal cells and tissues such as the gut and bone marrow. Chemotherapy, as a single modality, is only curative for about 3% of all cancers - germ cell tumours, haematological malignancies and some paediatric cancers. Another common form of systemic therapy is hormonal therapy. For example, breast cancers can express estrogen and/or progesterone receptors, which can be targeted by agents such as tamoxifen, while anti-androgen hormonal therapies can be used to halt the progression of prostate cancer.

Emerging methods of treatment

Over the past 2 decades there have been a number of major advances in the biological understanding of cancers, which have led to the development of better targeted therapeutics agents and a move toward “personalized therapy”. Molecular and genetic profiling is allowing us to understand the underlying genetic and molecular changes that have resulted in the development of a cancer, and the potential targets that may be used as therapy. Targeted Therapies differ in their action compared to chemotherapy agents. They tend to interact with specific targets or receptors expressed by tumours either on the cell surface or within the cell, and impair cell function. One of the more commonly used class of targeted therapies are known as Tyrosine Kinase Inhibitors (TKI’s). For cells (tumours) to survive and replicate they need to be switched “on” through a series of proteins. These proteins use a “phosphate group” as the “on” switch. The “phosphate group” is added to the protein by a tyrosine kinase enzyme. Normal cells turn on/off the enzyme as needed. Cancer cells loose this ability and stay “on”. TKI’s can block this “on” activity, by inhibiting the binding of the phosphate group to these transmembrane and/or intracellular proteins. One of the early and most impressive responses to a TKI has been the use of Imatinib in GastroIntestinal Stromal Tumours (GIST) which has led to a change in the median survival for these patients from 9 months to around 5 years. An exciting recent development in cancer therapy has been the emerging role of immunotherapies. These alter the immune system so as to enhance the body’s own response against tumours, or in some cases overcome the properties the tumour has developed to escape the body’s natural immune-surveillance. Both prevention and therapeutic vaccines have been developed toward cancers, particularly those cancers that are virally-mediated, such as the human papillomavirus (HPV). A class of immunotherapy drugs known as checkpoint inhibitors have shown dramatic improvements in survival for patients with metastatic disease such as melanoma. These drugs, such as anti-CTLA 4 (ipilumimab) and anti-PD1 (pembrolizumab), drive the immune system by removing negative feedback signaling that usually turns “off” the immune response.

In the surgical field, the use of robotic surgery, is an emerging modality, such as for head and neck cancers, where the use of trans-oral robotic surgery (TORS) allows for resection of tumours previously not accessable with conventional surgery that normally would require large resections.

There have been some striking gains in the delivery of RT. RT is commonly associated with substantial acute and long-term morbidity. The advent of computer based planning, coupled with improved tumour localization, has seen the ability to delivery highly conformal RT, such as volumetric intensity modulated RT and stereotactic radiosurgery/radiotherapy. In addition, the use of image-guided RT, means that adjustments can be made just prior to the delivery of RT, such as to account for the daily motion of the prostate gland, to further improve on the conformality of treatment. While most treatments are delivered using a linear accelerator, proton and heavy particle therapy and “Gammaknife” hold certain physical properties that makes them advantageous for certain tumours, such as those located intracranially. Other emerging areas of cancer therapy include radiofrequency ablation, hyperthermia and nanotechnology, but will not be covered in this session.

Practical limitations of current imaging methods in the treatment setting

Staging

The basis of cancer therapy begins with assessment of the TNM staging, which helps guide management. Along with the clinical examination, structural imaging such as CT and MRI usually provides sufficient information to help define the extent of the primary disease and inform the T-stage. However, structural imaging can be of limited value in the presence of associated surrounding inflammation or consolidation, such as in the case of distal collapse of the lung in the setting of a primary lung tumour. This is of particular relevance when chemo-RT is the planned treatment of choice. Differentiating between tumour and consolidation is of importance in order to limit the RT volumes and avoid whole lobe treatment. Fusing functional images using fluoro-deoxy-glucose positron emission tomography (FDG-PET) to either CT or MRI scans can assist in localizing disease versus consolidation and minimise RT volumes. One of the main issues with structural imaging is its lack of resolution in detecting nodal disease smaller than 5-10mm, N-stage. At present nodal positivity is presumed if nodes are morphologically abnormal and/or greater than 1cm. Once a node reaches this size it typically represents tumour burden of 10⁶ cells. In addition, its inability to differentiate between reactive or involved nodes creates a clinical dilemma. As a result a proportion of patients will have elective nodal treatment with either surgery or RT so as not to miss the therapeutic window of opportunity of cure. Attempts at identifying subclinical nodal disease to limit treatments include PET imaging, where the resolution of detecting nodal disease may be superior, or the use of sentinel lymph node biopsy. Our ability to detect mirco-metastases, M-staging, remains limited. Attempts at detecting sub-clinical disease, using other modalities, such as circulating tumour cells remains under investigation.

Therapeutic Monitoring

For patients receiving definitive RT, or RT and/or systemic therapy for metastatic disease often CT or MRI response to therapy may be delayed for some time. As a result patients may receive additional unwarranted treatment due to this delayed response. The use of functional imaging, or some form of biomarker may be used to assess tumour response and pre-empt structural imaging response, at an earlier time point.

Re-staging

The delay in treatment response or persisting residual abnormalities, particularly when RT + systemic therapy has been used, can often to lead to further therapies such as surgical salvage, where no pathologic residual disease may be found. An example of this is residual nodal abnormalities following chemo-RT for node positive head and neck squamous cell carcinoma, where approximately 30-40% of post-RT neck dissections performed for residual nodal abnormalities harvest no viable disease. These residual abnormities can take up to 3-6 months to resolve. Currently, PET imaging performed 8-12 weeks post-RT is used to determine if there is any residual PET avidity, suggesting persisting disease.

What clinicians would like to have but cannot currently get from imaging

The greatest challenge for clinicians remains the management of subclinical disease, either local, regional or distantly, hampering our ability to personalize therapy. Functional imaging can be useful but currently relies on a differential metabolic process, compared with surrounding normal tissues. In addition there can be a high level of false positives in the presence of inflammation, of false negatives when the uptake is below the resolution of the scanner. What clinicians require is the ability to move away from simply relying on size criteria for the detection of disease, so as to improve resolution. The concept of being able to “label” disease with a radio-bio-marker and detect disease structurally, and not solely rely on FDG-PET is appealing. Biologically characterizing tumours pre-treatment or, detecting biological changes during treatment would also be of great utility to the clinician. For example tumour hypoxia is a well known determinant of treatment outcome with chemoRT. Overcoming tumour hypoxia with some form of systemic hypoxic modifier has shown improvement in outcomes. Being able to assess hypoxia, and other characteristics, may help tailor therapies toward such characteristics. Assessing changes in the viable tumour fraction during treatment may allow changes in the dose of RT delivered to differing areas, a process known as ‘RT tumour dose painting”. One of the ongoing limitations with high conformal RT is the uncertainty of intra-fraction tumour motion. The ability to detect real-time movement of tumours, such as lung cancers during RT would be of value. MRI-Linac holds promise in this area, which will be discussed in greater detail later in this session.