Personalized Cancer Care

Introduction

The management of cancer patients has evolved exponentially over time. At the start of the 19th century surgery was the only available modality to treat cancer, and surgery itself was limited to superficial tumors such as breast and skin cancer due to the lack of anesthesia and the risk of sepsis. This resulted in surgery being a hazardous undertaking and the speed of surgery being the primary goal. The increasing availability of general anesthesia in the early 19th century, along with the introduction of aseptic techniques by Lister, opened the door to more invasive surgery and a number of surgeons across Europe and the United States, including Billroth, Kocher, Mayo, and Crile, developed new operations to treat malignancies. There was a progressive extension of both precision and radicality in approach, perhaps best personified by the work of William Halsted, who could perhaps be considered the “father” of cancer surgery. The development of the Halsted radical mastectomy, with the aim of removing all the areas of potential spread of breast cancer, led this mutilating surgery to become the standard of care for the next 75 years, even though the improvement in survival from breast cancer at that time had plateaued earlier with less radical surgery.

While surgery has remained the mainstay of cancer care, the introduction and development of other therapeutic pillars of cancer management have modified cancer care. The discovery of x-rays and radium by Roentgen and Curie led to the uptake of radiotherapy from the start of the 20th century, with varying efficacy across different tumors. The use of poisonous gas in the First World War led to the development of therapeutic drugs to treat cancer, initially “liquid” tumors such as leukemias and lymphomas, and then subsequently solid tumors. This has accelerated over the last 30 years as a result of the expansion of molecular biology and the increasing understanding of the molecular drivers of cancer, resulting in the development of targeted drug therapies aimed at specific molecular targets in a tumor type. More recently, the fourth pillar of cancer care has been the development of immunotherapy over the last decade. Immunotherapy, with drugs targeting CTLA-4 or PD-1 receptors, reducing immune suppression induced by the tumor has demonstrated dramatic results, predominantly in tumors with higher immunogenicity, such as melanomas, renal cell cancers, and microsatellite unstable tumors. The impact on other tumor types such as microsatellite stable bowel cancer has been far more limited, and research is in progress to explore how these drugs interact with standard chemotherapy, radiotherapy, and surgery.

The multiple available modalities of care pose challenges when determining the specific management of individual patients. The principle of utilizing all relevant modalities to deliver the best care and outcome for cancer patients is fundamental to modern cancer care and has been delivered through multidisciplinary care. The other principle has been the increased “tailoring” of care to the individual patient, rather than broad brushstroke care for particular tumor types. This “personalization” of cancer care has perhaps been the most significant change in management over the last 20 years. This chapter explores how this personalization has evolved and how it is delivered.

Multidisciplinary Care

The coordination of care across different modalities to deliver true multidisciplinary care poses several challenges. In the past this was undertaken through referral of patients from one clinician to another at varying stages of their treatment, without an integrated approach. This approach varied across different centers, with centers focused on cancer specifically having a more integrated approach; however, this was very specific to institutions and often the lack of integration led to inefficiencies in care and patient dissatisfaction. In the UK, the concept of multidisciplinary care first became more mainstream following the release of the Calman-Heine report in 1995. This report recommended that cancer care should specifically involve nonsurgical oncologic input into services and that a lead clinician with a specific interest in cancer care should organize and coordinate the entire range of cancer services provided within a cancer unit. The report also recommended the instigation of multidisciplinary team (MDT) meetings to facilitate the delivery of multidisciplinary care, which will be discussed later. Although for a number of cancer units, this was business as usual, for others this was a radical change, and this report led to a broad adoption of this approach across the UK. This broad uptake perhaps happened later in the United States and was driven by other factors. For example, the adoption of tumor boards for rectal cancer management in the United States has more recently been driven by the Optimizing Surgical Treatment of Rectal Cancer (OSTRiCh) group, a consortium of 18 health care institutions whose purpose is to transform the delivery of rectal cancer care in the United States. This is now supported by the American College of Surgeons, which has led to a significant uptake in a multidisciplinary approach to rectal cancer care in the United States.

The Multidisciplinary Team

The MDT is the collection of health care professionals across different disciplines, each providing specific services to ensure that the patient receives optimum care and management. While MDTs are now commonplace across a range of clinical areas, formal multidisciplinary meetings (MDMs) were initially instituted in a more general manner following the Calman-Heine report discussed earlier. The management of individual patients is discussed with representatives from all required specialties. Table 7.1 provides a summary of potential MDT members for a colorectal cancer MDT.

Table 7.1

Members of the Multidisciplinary Team for Colorectal Cancer

The multidisciplinary team may include the following members:

Care coordinator (as determined by multidisciplinary team members) ^a

Gastroenterologist with colorectal expertise ^a

General and/or colorectal surgeon ^a

Medical oncologist ^a

Nurse (with appropriate expertise) ^a

Pathologist ^a

Radiation oncologist ^a

Radiologist with expertise in MRI ^a

Stomal therapy nurse

Clinical psychologist

Clinical trials coordinator

Dietitian

Exercise physiologist

Fertility specialist

General practitioner

Geneticist or genetic counselor

Hepato-pancreatobiliary surgeon

Interventional radiologist

Nuclear medicine physician with PET expertise

Occupational therapist

Palliative care specialist

Pharmacist

Physiotherapist

Psychiatrist

Social worker

Spiritual/pastoral care

Thoracic surgeon.

^aDenotes core members. The core members of the multidisciplinary team are expected to attend most multidisciplinary team meetings, either in person or remotely. MRI , Magnetic resonance imaging; PET , positron emission tomography.

Coordination of care within an MDM has the potential to raise the quality of care for patients. For example, a study assessed the initiation of a colorectal cancer MDM in a hospital in the UK. Of the 310 patients, 176 were managed prior to the establishment of the MDT and 134 after establishment. There was a significant increase in the administration of adjuvant chemotherapy to node-positive patients following the initiation of the MDT, with a subsequent increase in the 3-year survival of these patients from 58% to 66%. Multidisciplinary management is also cost-effective. Fader et al. reported on the cost-effectiveness of multidisciplinary management of 104 patients with melanoma in Michigan as compared to a consecutive sample of 104 patients treated in the Michigan community, with a saving of $1600 per patient with multidisciplinary management.

The nature of a MDM is the focus on each individual patient. This facilitates the potential to shift from a protocolized management plan for a broad number of patients to a more tailored management plan for individual patients. Advances in imaging modalities have been the initial catalyst that has driven the individualization of care.

Imaging

The development of imaging techniques is an essential driver for the development of cancer care. The management of solid tumors is determined primarily by the stage of the tumor, both local extent and distant metastases. Detailed staging classifications are available for each tumor type through the Union for International Cancer Control (UICC), with tumor stage divided into T (tumor), N (nodal), and M (metastases). The specific imaging required for each tumor type will vary; however, determination of the tumor stage prior to any therapeutic intervention is essential.

Computed Tomography

Computed tomography (CT) scanning was invented in 1967 by Sir Geoffrey Hounsfield at the EMI laboratories in the UK, with the first CT scanners installed in the United States in 1973. By 1980, 3 million CT scans had been performed, and by 2005 that number had grown to 68 million CT scans performed annually. Shortened scan times and increased matrix size have been major developments allowing much greater resolution from the scanners. Hounsfield and McCormack were awarded the Nobel Prize for Medicine in 1979 for the development of computer-assisted tomography.

Cross-sectional imaging with a CT scan is the mainstay of cancer staging and is integral to cancer management. Cross-sectional imaging can be used to assess tumor response using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria. This provides a simple and pragmatic methodology to evaluate the activity and efficacy of new cancer therapeutics in solid tumors, using validated and consistent criteria to assess changes in tumor burden.

Magnetic Resonance Imaging

The first magnetic resonance imaging (MRI) was performed in a patient in 1977 by Damadian in Nottingham. Utilizing a magnetic field, rather than radiation, it detects energy release by protons in the various tissues that have been aligned by the generated magnetic field, with the release of energy determined by the different tissue types. It can provide detailed cross-sectional imaging with greater resolution of soft tissues when compared to CT scans. Lauterber and Mansfield were subsequently awarded the Nobel Prize for Medicine in 2003 for their work on MRI.

Positron Emission Tomography

While CT and MRI provide anatomic cross-sectional imaging, positron emission tomography (PET) scans provide functional imaging and measure the metabolic activity of tissues. Utilization of radionucleotide tracers and measurement of positron emission from the breakdown of the tracers allows metabolic activity in tissues to be assessed. Most commonly, fluorodeoxyglucose (FDG) is utilized as the tracer with more glucose taken up by metabolically more active tissues. The use of different tracers allows specific tissues to be targeted, such as neuroendocrine tumors (NETs) in the case of a Gatate tracer. PET scans are usually combined with a CT scan to allow the anatomic resolution of the PET scan. In addition to staging tumors, PET scans can be used in follow up to assess the response to treatment, such as radiation or chemotherapy, by measuring changes in metabolic activity. Quantitative measurement is made using PET Response Criteria in Solid Tumors (PERCIST).

Molecular Aspects and Personalized Therapy

There has been a revolution in cancer management over the last 20 years, and this has continued to accelerate. Management decisions have previously been determined by clinical parameters and variables, the specifics of which have been improved by the developments in imaging described earlier. Although this has led to treatment becoming more individualized, this remains a fairly unidimensional approach, driven by tumor stage and taking no account of the biological variables between individual tumors. Information on the biology of individual tumors is now becoming available and is beginning to influence and direct aspects of cancer management. This led to the term “personalized medicine” to be applied to this approach. It was first applied in 1999 in an article in the Wall Street Journal entitled “New Era of Personalized Medicine – Targeting Drugs for each unique Genetic Profile.” The article described the use of single-nucleotide polymorphism analysis for cancer drug development and generated significant excitement. Further advances in molecular biology and understanding of the hallmarks of cancer over the last 20 years have started to permeate and influence management across all modalities of treatment and even facilitated a new pillar of cancer management over the last decade in immunotherapy. It is a long way from the position where the biological and molecular tumor factors predominate over clinical factors such as tumor stage; however, the former definitely have an increasing impact on management. The “omic” information available for an individual tumor includes genomic, transcriptomic, and proteomic data that can now be obtained rapidly with readily available high throughput sequencers, allowing the molecular signature to be used in both a predictive and prognostic manner. The former allows identification of potential therapeutic targets and determining what therapy can be used, and the latter provides prognostic biomarkers that can provide information on the patients overall cancer outcome. The development of personalized or “precision” therapy is ongoing, and the degree of research and interest is reflected by the increasing number of publications on the subject. The degree and nature of personalization vary across different tumor types and treatment modalities. Some potential examples and the impact on therapies are considered in Fig. 7.1 .