Session 10: The Incidence, Prognosis and Treatment of Malignant Tumours

Incidence of new cancer diagnoses in the UK

In 2017, new diagnoses in England continued to increase from 303,135 in 2016 to 305,683 new cancer diagnosis.

Changes in the rate of people dying from cancer in England

The rate of people dying from cancer in England has decreased from 275.2 deaths per 100,000 in 2016 to 270.1 deaths per 100,000 in 2017.

Although the incidence of cancer is increasing, the cancer survival rate is at its ___ ever

Although the incidence of cancer is increasing, the cancer survival rate is at its highest ever

Significant improvements over the past 15 years

Most common cancers in the UK

Breast and prostate cancer

What is the gold standard for survival rate (cancer)

The percentage of people alive 5 years since their diagnosis is gold-standard

Clinical endpoints for survival data (cancer)

- Overall survival

- Progression free survival

- Event free survival

- Death

- Remission

- Clinical response

- Disease progression

Factors to consider include when predicting outcome of cancer

- Age and performance status

- Comorbidities

- Genetic mutations, including targetable demographics e.g., race/ethnicity

- Tumour site

- Tumour type

- Grade (differentiation)

- Tumour stage

- Availability of effective treatment

- Socioeconomic factors

- Economic and healthcare considerations

- Drug availability/licensing

- Clinical trials - active & accessibility

What type of prognostic indicators can be found in a cancer report

Grading

Staging

Margin status

Hormonal or gene status (as in breast cancers)

Why are the prognostic indicators in a cancer report necessary?

Valuable information to the patient and clinician

Helps to guide treatment

ECOG performance scale

0 (fully active) - 5 (dead)

What is a prognosis

Likely course of a disease or diagosis

Biopsy

Small amount of material used to give primary diagnosis.

A preliminary grading of the tumour is also given at this stage.

Resection of specimen

Large tissue which is resected surgically with curative intent.

The tumour extent & assessment of metastasis in the tissue provided helps in staging the tumour (including lymphatic spread)

Grading vs staging

Grading = how close tumour correspond to normal cells (done by a pathologist).

Staging = how far has it spread (done by a clinician)

Pleomorphism

Increasing variation in the size and shape of cells and nuclei

What are the histological characteristics of malignancy (pleomorphism)

- Increased nuclear size

- Increased nuclear to cytoplasmic ratio

- Clumping of chromatin in nuclei

- Increase in mitotic figures including abnormal mitosis

Dysplasia

Abnormal development or growth of cells, tissues, or organs

CIN

Cervical Intraepithelial neoplasia

Squamous cell carcinoma

Malignant tumor of the squamous epithelial cells in the epidermis

Grading

A method for evaluating a tumor based on microscopic examination of the cells

This is broadly based on how a tumour resembles its parent tissue

G1 = well differentiated

G2 = moderately differentiated

G3 = poorly differentiated

G4 = anaplastic carcinoma

Staging of the cancer (TNM)

Tumour staging is a measure of the malignant neoplasm's overall burden.

Size of primary tumor = (T)

Involvement of regional lymph nodes = (N)

Spread (metastasis) of tumor =(M)

All three then constitute the TNM stage which is further divided into stage 1 to stage 4

Colorectal cancer staging

Dukes staging

Lymphoma staging

Ann Arbor staging

How is the T status of malignant melanoma described?

Described by Breslow's thickness (expressed in mm)

Lymph node (N) status

Regional lymph nodes

All organs have a specific lymphatic drainage - often the first sites to be involved by tumour metastasis

Sentinel lymph node

First node that receives draining from a body area suspected of having a tumor

Sentinel lymph node biopsy

Injection of blue dye and/or radioactive isotope (labelling substance) used to identify the sentinel lymph nodes (sentinel lymph node absorbs labelling substance)

This procedure helps give lymph node (N) status

Distant metastasis (M) status

Affects other organs distant to the primary tumour site

Lymphoma uses Ann Arbor staging.

Briefly describe each of the stages in this criteria...

Stage 1

Lymphoma in single node region

Stage 2

Two separate regions on one side of diaphragm

Stage 3

Spread to both sides of the diaphragm

Stage 4

Diffuse or disseminated involvement of one or more extra-lymphatic organs such as bone marrow or lungs.

Colorectal cancer uses Duke's staging.

Briefly describe each of the stages in this criteria...

Dukes' A

Invasion into but not through the bowel

Dukes' B

Invasion through the bowel wall

Dukes' C

Involvement of lymph nodes

Dukes' D

Distant metastases

Preferred staging system worldwide for cancer

TNM staging

Tumour stage is a measure of...

Tumour stage is a measure of the malignant neoplasm's overall burden

Neoadjuvant treatment

Treatment provided BEFORE primary cancer treatment (surgery)

Adjuvant treatment

Short course of high-dose of drug treatment AFTER surgery to destroy residual cells and prevent recurrence

Aimed at eradicating subclinical and residual disease

Radiotherapy

Treatment of tumors using doses of radiation; radiation oncology

Focused on the tumour with shielding of surrounding healthy tissue

Shrink tumour as part of neoadjuvant treatment

Why is radiotherapy given in fractionated doses

Minimise damage to normal healthy tissue

When may radiotherapy be the main form of treatment for cancer?

Anal squamous cell carcinoma

When may radiotherapy be used in the palliative care setting?

Controlling bleeding

Pain relief

The radiation oncologist must select the ___ ___ ___. This must be large enough to cure the cancer but avoid acute and long-term toxicity to the healthy parts of the patient.

The radiation oncologist must select the field of radiation. This must be large enough to cure the cancer but avoid acute and long-term toxicity to the healthy parts of the patient.

There are different types of radiotherapy, give some examples

- Brachytherapy

- Internal

- ARC

- Proton beam

Radiation treatment can have side effects that might not be seen until long after treatment has ended.

Name some examples of these effects...

Cardiac damage after breast cancer

Cognitive/behavioural changes in children

Chemotherapy can be used in the neo-adjuvant or adjuvant setting.

What does this mean?

Neo-adjuvant setting

Prior to surgery to shrink the tumour

Adjuvant setting

Follows surgery and aimed at eradicating the subclinical disease

Different types of chemotherapeutic agents

1) Antimetabolites

2) Alkylating and platinum-based drugs

3) Antibiotics

4) Plant-derived drugs

How do antimetabolite chemotherapeutic drugs act?

Mimic normal substrates involved in DNA replication

E.g., Fluorouracil

How do alkylating and platinum-based chemotherapeutic drugs act?

Cross-link the two strands of the DNA helix

E.g., Cyclophosphamide and Cisplatin

How do antibiotic chemotherapeutic agents act?

Act in several ways...

Doxorubicin = inhibits DNA topoisomerase which is needed for DNA synthesis

Bleomycin = causes double-stranded DNA breaks

How do plant-derived chemotherapeutic agents act?

Vincristine blocks microtubule assembly and interferes with mitotic spindle formation

Hormonal treatment for cancer

Mostly used to treat tumours that are driven by hormones such as oestrogen and testosterone

They are non-toxic but have side effects

Give examples of hormonal treatment for hormone receptor-positive breast cancer

Selective oestrogen receptor modulators (SERMs) such as Tamoxifen bind to oestrogen receptors and prevent oestrogen from binding

Give examples of hormonal treatment for prostate cancer

Androgen blockage used for prostate cancer

What is targeted cancer therapy?

These are drugs which specifically act against specific molecular targets in cancer cells.

Targeted therapy is split into two main categories...

1) Antibody drugs = manmade versions of immune system proteins, targeting receptors e.g., rituximab

2) Small molecules = target abnormal proteins or enzymes that form on or inside of cancer cells and promote uncontrolled tumour growth e.g., imatinib

Molecular Therapy

If the patient (metastatic colorectal disease) has a mutated form of Kras, the patient does not respond to ___ ___ such as cetuximab and other forms of treatment are required

If the patient (metastatic colorectal disease) has a mutated form of Kras, the patient does not respond to EGFR inhibitors such as cetuximab and other forms of treatment are required

Molecular Therapy

If the patient (metastatic colorectal disease) has the wild-type Kras, ____ is an option

If the patient (metastatic colorectal disease) has the wild-type Kras, EGFR is an option

Personalised treatments aim at giving patients the best treatment according to...

1) Personal medical history

2) Physiological status

3) Molecular characteristics of their tumours

4) Their genome

Personalised medicine demands an increased understanding of genomics, including the risk of adverse drug effects and identifying patients who will survive with reduced treatment

Tumour markers

Tumour markers are released by cancer cells into the blood circulation.

Tumour markers can be used for...

1) Diagnosing conditions

- PSA

- AFP

2) Monitoring tumour burden during treatment & follow-up

- CEA

- AFP

- hCG

- Ca-125

Screening programmes in the UK for cancer

In the UK, screening programmes exist for cervical, breast and bowel cancer

Cervical screening

- PAP smear

- Liquid based cytology

- HPV testing

Breast screening

- Mammogram

Bowel cancer screening

- Faecal occult blood

Bowel scope screening programme

- Flexible sigmoidoscopy

How does the targeted therapy Imatinib (Gleevec) work to treat Chronic Myeloid Leukemia (CML)?

CML shows a chromosomal rearrangement (t9:22) creating an abnormal Philadelphia chromosome in which an oncogenic fusion protein (BCR-ABL) is encoded.

Imanitib (Gleevec) inhibits the fusion protein (BCR-ABL).

Regarding carcinoma of the breast, answer true or false to the following statements...

a) Is the most commonly of ductal type

b) Tubule formation is assessed in grading

c) Occurs between ages of 40-50

d) Abnormalities of retinoblastoma gene may be identified in some cases

e) Is familial in 50% of cases

Regarding carcinoma of the breast, answer true or false to the following statements...

a) Is the most commonly of ductal type = true

b) Tubule formation is assessed in grading = true

c) Occurs between ages of 40-50 = false

d) Abnormalities of retinoblastoma gene may be identified in some cases = true

e) Is familial in 50% of cases = false (these famiial cases are much less common)

Regarding colorectal cancer, answer true or false to the following statements...

a) May be associated with defected DNA mismatch repair genes

b) Occurs most commonly between 40-50 years of age

c) The extent of spread is incorporated into Dukes' staging

d) Is usually a squamous cell carcinoma

e) Has a 95% five year survival rate if confined to the bowel wall

Regarding colorectal cancer, answer true or false to the following statements...

a) May be associated with defected DNA mismatch repair genes = true

b) Occurs most commonly between 40-50 years of age = false (peak age is older than 40-50)

c) The extent of spread is incorporated into Dukes' staging = true

d) Is usually a squamous cell carcinoma = false

e) Has a 95% five year survival rate if confined to the bowel wall = true

Regarding the treatment of malignancy, answer true or false to the following statements...

a) Castration may be helpful in treating prostatic cancer

b) Hormonal manipulation is of little value in the treatment of carcinoma of the breast

c) The major effect of radiotherapy is on tumour cell membranes

d) Most chemotherapeutic drugs affect cell division

e) Neoadjuvant treatment is given after surgery

Regarding the treatment of malignancy, answer true or false to the following statements...

a) Castration may be helpful in treating prostatic cancer = true

b) Hormonal manipulation is of little value in the treatment of carcinoma of the breast = false (tamoxifen is an anti-oestrogen)

c) The major effect of radiotherapy is on tumour cell membranes = false

d) Most chemotherapeutic drugs affect cell division = true

e) Neoadjuvant treatment is given after surgery = false (neoadjuvant treatment is given BEFORE surgery)