Cancer detection and treatment Flashcards
What are the objectives of cancer treatment?and what are the Indications?
- It is important that the goal of treatment is clear in order to manage the expectations of the patient, their relatives and the treating team
- It is a requirement in the UK that the goal of treatment is recorded in the medical notes of the patient
- The goal can be either with curative intent or for palliation and there are four main indications for therapy
Indications
Metastatic disease(improve quality life,palliation)
The goal of treatment is an improvement in symptoms with a focus on improving quality of life and survival increments are secondary
As a result the treatment should be well-tolerated and aim to minimise adverse effects
Accept limited toxicity but not at the expense of performance status
Adjuvant therapy(In addition to surgery)
Adjuvant therapy is in addition to another intervention, often surgery (first) that is designed to cytoreduce the tumour bulk and removes all macroscopic disease
Focus is on achieving an improvement in disease-free and overall survival
Intention is on eradicating the micrometastatic disease that remains
Greater toxicity is accepted as the patient is chasing cure of their cancer
May have increased morbidity and mortality associated with the treatment
Primary therapy (neoadjuvant)-Chemo first to reduce tumour size,then surgery)
Primary medical therapy, is where chemotherapy is administered first before a planned cytoreductive procedure (usually surgery)
Can result in a reduced requirement for surgery, increase the likelihood of successful debulking, reduce the duration of hospitalisation and improve the fitness of the patient prior to interval debulking
This approach has the same goals as adjuvant treatment but creates opportunity for translational research to measure responses to treatment and correlate with subsequent specimens removed at the time of surgery.
Most commonly used for an inoperable patient (technical or fitness factors)
Can be used to determine adjuvant goals
Chemoprevention-eg.Tamoxifen
Treatment used in selective at risk groups to prevent the development of cancer
Agents used are to modify risk and improve survival
Only accept very low incidence of toxicity
Many chemotherapy agents are themselves carcinogenic
Impact on overall survival needs careful evaluation
What are the different treatment approaches?
The dosing schedule and interval is determined by the choice of drugs and recovery of the cancer and normal tissues
For most common chemotherapy regimens, the treatment is administered every 21 or 28 days, which defines one cycle
A course of treatment often uses up to 6 cycles of treatment
An increase in effectiveness can be achieved by changing the approach to treatment
In some cases this will increase toxicity too, but it can change the nature of the toxicity and such developments are evaluated in clinical trials
Low-dose therapy is the standard approach and most palliative chemotherapy is given in this manner
The next cycle is started once the bone marrow function has recovered sufficiently to start the treatment (neutrophils >1.0x109/L and platelets >100x109/L)
High-dose therapy uses a higher individual drug dose to achieve a higher cell kill but results in more bone marrow toxicity
This can be minimised by using G-CSF
This approach allows more drug to be delivered within the same schedule of administration but the total received dose can be less than the intended dose due to limitations of non-haematological toxicity
Dose dense therapy involves fractionating the intended dose of drug and administering each fraction on a more frequent basis (often weekly)
Each individual dose produces less toxicity but the anticancer effect is related to the accumulative dose over time
Such an approach can overcome drug resistance, produce a greater cell kill and in some cases produce a response with weekly administration when the 3-weekly schedule demonstrates a lack of response or even disease progression
Alternating therapy involves giving different drugs in an alternating manner
This is most commonly used with haematological malignancies and is designed to treat different subpopulations of cancer cells where individual clones of cells might be resistant to one or more of the agents
How can toxicity be assessed?
Most anticancer treatment is given at the maximum dose tolerated by the patient and adverse effects are inevitable
There are common toxicity criteria (CTC) scales that rate the severity of several hundred side-effects on a four-point scale
This allows an objective measurement and comparison over time throughout treatment
Detailed information and the current version of the CTC is maintained by the National Cancer Institute and is available at http://ctep.cancer.gov/reporting/ctc.html
How can treatment be evaluated?
The evaluation of treatments includes an assessment of overall survival duration, response to treatment, remission rate, disease-free survival and response duration, quality of life, and treatment toxicity
Uniform criteria have been established to measure these, including the response evaluation criteria in solid tumours (RECIST)
This allows clinicians to accurately inform patients of the prognosis, effectiveness and toxicity of chemotherapy and empowers patients to take an active role in treatment decisions
Overall survival rate is the percentage of patients in a study or treatment group that are alive for a certain period of time after the diagnosis of cancer
This is usually stated as a 5-year survival rate, which is the percentage of patients in a defined group that are alive five years after diagnosis or treatment
Remission rate is the percentage of patients that achieve a state where the cancer is no longer detectible
This is complete remission where all signs and symptoms of cancer have disappeared, although cancer still may be in the body
In partial remission, some, but not all, signs and symptoms of cancer have disappeared
Disease-free survival is the length of time after treatment for cancer during which a patient survives with no symptoms or signs of the disease
Disease-free survival may be used in a clinical trial to measure how well a new treatment works
Response is usually assessed by RECIST 1.1 criteria with pre-treatment documentation of target and non-target lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, representative of all involved organs should be identified as target lesions and measured at baseline
Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repeated measurements (either by imaging techniques or clinically)
A sum of the longest diameter (LD) for all target lesions will be calculated and recorded as the baseline sum LD, used as a reference to characterise the objective response. All other lesions (or sites of disease) should be identified as non-target lesions and be recorded at baseline
Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter (LD) to be recorded)
Each lesion must be >10mm when assessed by CT and MRI (if the slice thickness is ≤5mm), and clinical examination; or >20mm when measured by plain X-ray
(For CT and MRI scans where the slice thickness is >5mm, measurability is defined as a lesion with LD > 2x the slice thickness)
For malignant lymph nodes, short axis diameter must by >15mm to be considered pathological and measurable
Non-measurable disease includes aspects that are more subjective in their assessment and based upon factors such as tumour marker levels, presence of ascites or effusions
Residual disease is that left at completion of planned treatment and if present indicates resistance to the treatment and is therefore an adverse prognostic factor
In some circumstances it may be difficult to distinguish residual disease from normal tissue, particularly in patients with post-operative changes following abdominal or pelvic surgery
When the evaluation of complete response depends on this determination, it is recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the complete response status
What is the Future of Cancer Chemotherapy?
Targeted therapies are now integrated with conventional chemotherapy
Treatment may be optimised to the individual patient
Combinations will be important
Sequencing may be crucial
More targets-not only cancer cells
Rethink the process of screening and clinical trials
What Investigations can be done for anaplastic carcinoma in cervical nodes
CXR; sputum cytology (most reliable in small cell lung cancer)
Thyroid scan + needle biopsy
Nasopharyngeal assessment
Consider diagnosis of undifferentiated lymphoma (exclude with immunophenotyping)
What Investigations are done for squamous cell carcinoma in inguinal nodes
Careful examination of legs, vulva, penis, perineum for primary tumour
Pelvic examination (exclude vaginal/cervical cancer)
Proctoscopy/colposcopy (exclude anal/cervical cancer)
Which positive immunohistochemical staining on material obtained from a cervical biopsy would imply the presence of human papillomavirus infection?
p21
How common is bowel cancer and what are the risk factors?
Colorectal cancer is the third most common cancer and second most common cause of cancer death in the UK. Occurrence is strongly related to age, with 90% of cases occurring in people aged 50 years and over. It is significantly more common in the developed world, occurring most frequently in New Zealand, Canada, USA and UK and lower in Asia, Africa (among blacks), and South America (except Argentina and Uruguay).
Gender: Overall, the incidence of colorectal cancer and mortality rates are higher in men than in women; tumours of the colon are slightly more frequent in women than in men (1.2:1), whereas rectal carcinomas are more common in men than in women (1.7:1).
Increasing age is the most important risk factor for most cancers. Other risk factors for colorectal cancer include the following:
- Family history of colorectal cancer in a first-degree relative.[[2]
- Personal history of colorectal adenomas, colorectal cancer, or ovarian cancer.[[3]
- Hereditary conditions, including familial adenomatous polyposis (FAP) and Lynch syndrome (hereditary nonpolyposis colorectal cancer [HNPCC]).[[6](
- Personal history of long-standing chronic ulcerative colitis or Crohn colitis.[[7](
- Excessive alcohol use.[[8]
- Cigarette smoking.[[9]
- Race/ethnicity: African American.[[10](
- Obesity.
What is the pathogenesis of bowel cancer?
Over 70% of all colorectal cancers are adenocarcinomas arising in the mucosa from benign adenomatous polyps. Adenomas are typically slow growing, with a minority progressing to malignancy if they are not surgically removed. This risk of malignant transformation is increased with increasing size of the adenoma and with the length of time it has been present. Once a tumour has become established, it can spread through the layers of the bowel wall and may eventually metastasise to the liver, lungs, bone, brain and skin. Several genetic alterations have been implicated in the progression of benign adenomas to invasive adenocarcinomas.
Approximately 5% of all colorectal cancer cases occur as a consequence of genetic syndromes, the most common of which is hereditary non-polyposis colorectal cancer (HNPCC or Lynch syndrome type I). HNPCC develops as a consequence of germ-line mutations in one of several DNA mismatch repair genes and carries a 40% lifetime risk of developing colorectal cancer. The condition is transmitted in an autosomal dominant pattern. Patients with HNPCC typically develop colorectal cancer in the fourth decade of life. Other malignancies such as ovarian, endometrial, gastric, urinary and hepatobiliary cancer, may occur and these are recognised as Lynch syndrome type II.
Familial adenomatous polyposis (FAP) is a more rare type of hereditary colorectal cancer. It is inherited in an autosomal dominant pattern and arises as a result of germ-line mutations in the tumour suppressor geneAPC.From a young age,affected patients develop numerous benign colonic polyps, which will eventually transform into cancerous lesions, typically in the third and fourth decades of life. Prophylactic colectomy is therefore strongly advised.
The molecular pathogenesis and multistep development of colorectal cancer is covered in the presentation on Carcinogenesis and you should review this if not done already.
Histological types of colon cancer include:
- Adenocarcinoma - most colon cancers - (mucinous (colloid) adenocarcinoma & signet ring adenocarcinoma
- Scirrhous tumours
- Neuroendocrine: Tumours with neuroendocrine differentiation typically have a poorer prognosis than pure adenocarcinoma variants
How can the features of a left sided bowel cancer be differentiated from those of a right-side?
In its early stages, colorectal cancer is often asymptomatic and hence 55% of patients present with advanced disease. Patients with right-sided cancer typically present with a palpable mass in the right iliac fossa, diarrhoea, weight loss, anaemia and occult gastrointestinal bleeding. The clinical features of a left-sided cancer include a palpable mass in the left iliac fossa, change in bowel habit (most commonly constipation), tenesmus, rectal bleeding and signs and symptoms of bowel obstruction. Patients with left-sided cancer typically present earlier than those with right-sided cancer.
What factor Contributes to the highest risk of Cancer in UC?How can they screened?
Pancolitis
Screening-Colonoscopy with multiple biopsies
What is the most likely explanation for the left iliac fossa mass?
Clinical presentation of bowel cancer?
a)Cancer, Diverticulitis
Clinical presentation of bowel cancer?-think and check notion
What complication can occur with a bowel tumour and If distant sites of disease are present, which sites are most likely?
Bowel obstruction, rupture of bowel causing peritonitis
Sites-Liver,kidney,bladder,brain,bone
What Investigations can be done for bowel cancer and how can they be staged?
Laboratory tests
Routine bloods should be performed for all suspected cases. A full blood count (FBC) may show a microcytic anaemia (an iron-deficiency anaemia), as well as LFTs and clotting.
The tumour marker Carcinoembryonic Antigen (CEA) should not be used as a diagnostic test, due to poor sensitivity and specificity, however it is used to monitor disease progression and should be conducted both pre- and post-treatment, screening for recurrence.
Imaging
The gold standard for diagnosis of colorectal cancer is via colonoscopy with biopsy. If a colonoscopy is not suitable for the patient, such as from frailty, co-morbidities, or intolerance, a flexible sigmoidoscopy or CT colonography can be performed for initial diagnosis.
Once the diagnosis is made, several other investigations are required (primarily for staging):
CT scan (Chest/Abdomen/Pelvis) to look for distant metastases and local invasion A full colonoscopy or CT colonogram is required to check for a 2nd (synchronous) tumour if not used initially MRI rectum (for rectal cancers only) to assess the depth of invasion and potential need for pre-operative chemotherapy Endo-anal ultrasound (for early rectal cancers, T1 or T2 only) to assess suitability for trans-anal resection
Teatment decisions can be made with reference to the TNM (tumour, node, metastasis) classification rather than to the older Dukes or the Modified Astler-Coller classification schema.
Dukes’ Staging
Like many other tumours, colorectal cancers are staged according to the TNM system. This stages the cancer according to the depth the tumour invades the bowel wall (T stage), the extent of spread to local lymph nodes (N stage), and whether or not there are distant metastasis (M stage). The Duke’s staging system has now been largely superseded but is still used at some centres for additional staging detail.
Stage Description 5 Year Survival
A Confined beneath the muscularis propria 90%
B Extension through the muscularis propria 65%
C Involvement of regional lymph nodes 30%
D Distant metastasis <10%
What screening is available for colorectal Ca?What is referral criteria
Colorectal Cancer Screening
In the UK, screening is offered every 2 years to men and women aged 60-75 years. For most of the UK, a faecal immunochemistry test (FIT) is used, superseding the faecal occult test, which utilises antibodies against human haemoglobin to detect blood in faeces.
If any of the samples are positive, patients are offered an appointment with a specialist nurse and further investigation via colonoscopy. Since its introduction in 2006, the NHS Bowel Cancer Screening Programme has increased detection of colorectal cancer in people aged 60-69 by 11%
In the UK, NICE guidance recommends that patients should be referred for urgent investigation of suspected bowel cancer if:
≥40yrs with unexplained weight loss and abdominal pain
≥50yrs with unexplained rectal bleeding
≥60yrs with iron‑deficiency anaemia or change in bowel habit
Positive occult blood screening test.
How can bowel cancer be treated and what is use of CEA?
Whilst this patient has a raised serum CEA, this is not diagnostic in isolation but could be used to correlate response to subsequent therapeutic intervention. Whilst microscopic disease cannot be detected using conventional imaging, the high value of the CEA suggests that there may be a greater risk of more widespread microscopic disease but the treatment stratification relies on staging the patient and for that, the primary tumour and nearby lymph nodes need to be surgically removed. Cystic structures in the liver can be a normal variant and MR imaging is best to distinguish the features of metastatic disease from simple cysts. This may be important as pre-operative chemotherapy for metastatic disease and resection of solitary liver metastasis can be considered in selected patients.
All patients should be discussed with the multidisciplinary team (MDT). The only definitive curative option is surgery, although chemotherapy and radiotherapy have an important role as neoadjuvant and adjuvant* treatments, alongside their role in palliation.
Surgical
Surgery is the mainstay of curative management for localised malignancy in the bowel. The general plan in most surgical management plans is suitable regional colectomy, to ensure the removal of the primary tumour with adequate margins and lymphatic drainage, followed either by primary anastomosis or formation of a stoma:
Right Hemicolectomy or Extended Right Hemicolectomy
The surgical approach for caecal tumours or ascending colon tumours, with the extended option performed for any transverse colon tumours. During the procedure the ileocolic, right colic, and right branch of the middle colic vessels (branches of the SMA) are divided and removed with their mesenteries.
Left Hemicolectomy
The surgical approach for descending colon tumours. Similar to the right hemicolectomy, the left branch of the middle colic vessels (branch of SMA/SMV), the inferior mesenteric vein, and the left colic vessels (branches of the IMA/IMV) are divided and removed with their mesenteries.
Sigmoidcolectomy
The surgical approach for sigmoid colon tumours. In this instance, the IMA is fully dissected out with the tumour in order to ensure adequate margins are obtained.
Anterior Resection
The surgical approach for high rectal tumours, typically if >5cm from the anus. This approach is favoured as leaves the rectal sphincter intact if an anastomosis is performed (unlike AP resections). Often a defunctioning loop ileostomy is performed to protect the anastomosis and reduce complications in the event of an anastomotic leak, which can then be reversed electively four to six months later.
Abdominoperineal (AP) Resection
The surgical approach for low rectal tumours, typically <5cm from the anus. This technique involves excision of the distal colon, rectum and anal sphincters, resulting in a permanent colostomy.
*Elective colectomies are often performed laparoscopically, as this offers faster recovery times, reduced surgical site infection risk, and reduced post-operative pain, with no difference in disease recurrence or overall survival rates when compared to open surgery
Hartmann’s Procedure
This procedure is used in emergency bowel surgery, such as bowel obstruction or perforation. This involves a complete resection of the recto-sigmoid colon with the formation of an end colostomy and the closure of the rectal stump
Chemotherapy
Chemotherapy is indicated typically in patients with advanced disease (adjuvant chemotherapy in Dukes’ C colorectal cancer has been found to reduce mortality by 25%).
An example chemotherapy regime for patients with metastatic colorectal cancer is FOLFOX, comprised of Folinic acid, Fluorouracil (5-FU), and Oxaliplatin, which has been demonstrated to significantly improvement in 3-year disease-free survival for patients with advanced colon cancer.
Radiotherapy
Radiotherapy can be used in rectal cancer (it is rarely given in colon cancer due to the risk of damage to the small bowel), most often as neo-adjuvant treatment.
It is of particular use in patients with rectal cancers which look on MRI to have a “threatened” circumferential resection (i.e. within 1mm). They can undergo pre-operative long-course chemo-radiotherapy to shrink the tumour, thereby increasing the chance of complete resection and cure.
Palliative Care
Very advanced colorectal cancers will be managed palliatively, focusing on reducing cancer growth and ensuring adequate symptom control. Whilst a large variety of palliative care options are available to such patients, important surgical options that can offered include:
Endoluminal stenting can be used to relieve acute bowel obstruction in patients with left-sided tumours
The main side-effects of stents are perforation, migration, and incontinence
Stoma formation can be performed for patients with acute obstruction, usually with either a defunctioning stoma or palliative bypass
Resection of secondaries, not commonly performed but can done with adjuvant chemotherapy for any liver metastases
What are the factors associated with recurrence?
the degree of red and processed meat intake before diagnosis was associated with a higher risk of death
Aspirin may reduce risk?check notion
What are the different imaging techniques used to view the colon?
So a colonoscopy examines from the anus all the way to the ceacum, and can also enter the small intestine to view the terminal ileum.
Colonoscopy v flexisigmoidoscopy v rigid sigmoidoscopy:
There are couple of procedures similar to a colonoscopy, however there are key difference
Colonoscopy– views of the full colon, from rectum to terminal ileum
Flexi-sigmoidoscopy– used to view pathology on left side of colon, from the rectum to splenic flexure
Rigid sigmoidoscopy– used to view rectal pathology, from the rectum to approximately 25cm along the bowel. This is less popular now as usually a flexisigmoidoscopy would be done instead
Proctoscopy– used to view the rectum, often to carry out minor haemorrhoid procedures
CT colonography– a specific type of CT scan used if a patient is unable to have colonoscopy, Gas is used to inflate the colon, which allows the bowel wall to be imaged, therefore creating a ‘virtual’ colonoscopy
What are Indications for colonoscopy?
Diagnostic > surveillance > therapeutic (of these diagnostic is the commonest reason)
Bowel cancer screening:The NHS invites all people for bowel screening at the age of 55. This is usually a flexi-sigmoidoscopy rather than a colonoscopy. Although this does occasionally diagnose a cancer, the main purpose is to look and remove polyps, which can develop into a cancer if left untreated.
Most colonoscopies will involve biopsies to be taken. This allows the bowel to be examined from a histopathology point of view, which aides diagnosis and surveillance.
Diagnostic:
Symptoms…
- PR bleeding / faecal occult blood
- Change in bowels habit (constipation / diarrhoea, usually for >6 weeks)
- Weight loss
- Iron deficient anaemia (microcytic anaemia can be the first sign of a right sided colon cancer)
Commonest differentials…
- Cancer (if there is a concern that the diagnosis might be a cancer, the patient should be referred via the 2-wee-wait pathway to receive an urgent colonoscopy)
- Inflammatory bowel disease
- Diverticular disease
Surveillance:
- Polyps
- Previous cancer
- IBD
Therapeutic:
- Polypectomy (removal of polyps
- Colonic stenting (used most commonly in palliative treatment of colorectal cancers)
- Colonic dilatation (used most commonly in strictures of the colon)
What are Indications for colonoscopy?
Main risks:
- Pain
- Bleeding
- Perforation
- Requirement for major operation
- Missing lesion
- Complications of sedation
These should all be included on a written consent form that is signed by the patient and the endoscopist before the procedure.
What preparation is needed before colonoscopy?
Do a mosler
Medication: certain medications should be stopped before the procedure, these include anticoagulants, medications containing iron, and codeine
Diet: Patients are advised to drink plenty of fluids and have a low fibre diet for 2-3 days beforehand
Bowel prep: usually requires the patient to take strong laxative sachets the day before or on the day of the procedure. This varies slightly between hospitals, but patients are always given clear instructions of how to take it. The commonest types used are citrafleet, picolax, klean-prep, and moviprep
After the procedure:
·The patient is monitored and is usually able to go home after an hour or so
·The images and pathology are reviewed, and then the patient is contacted with the results. Depending on the findings the patient is informed via letter or is brought back to hospital for a face-to-face appointment.
How common is cancer?
- Cancer represents a significant economic burden for the global economy and is now the third leading cause of death worldwide
- By 2030, it is projected that there will be 26 million new cancer cases and 17 million cancer deaths per year
- The developing world is disproportionately affected by cancer and in 2008 developing nations accounted for 56% of new cancer cases and 75% of cancer deaths
What are the most common cancer associated with Smoking?
Tobacco contributes to the development of 3 million cancers (lung, oropharynx, larynx, bladder, kidney), which could be prevented by smoking cessation
What are the common cancers associated with obesity?
Like tobacco, obesity, physical inactivity and poor nutrition are established causes of several types of cancer
Diet contributes to 3 million cancer deaths per year (gastric, colon, oesophagus, breast, liver, oropharynx and prostate) and diet modification could reduce these by avoiding animal fat and red meat, increasing fibre, fresh fruit and vegetable intake, as well as avoiding obesity
What are challenges for Cancer care?
- Prevention with vaccination against certain cancers could reduce the cancer burden with protection against HBV and HPV
- Education is important as low rates of literacy are associated with regions of poverty
- Education about cancer could result in earlier diagnosis, better engagement with screening, and acceptance of diagnostic and treatment services
- Such approaches need to reflect the local cultural requirements
- Access to treatment is resource limited as treatment for cancer relies on surgery, radiotherapy and chemotherapy, all of which remain expensive and often unavailable in developing nations
- New targeted therapies will be too expensive and therefore the newest developments in therapy will be unavailable without successful engagement of the pharmaceutical industry to negotiate reimbursement schemes which might make new drugs more affordable and accessible
- Cure the curable: with a greater understanding of the hallmarks of cancer, specific features of cancers can be used as targets for treatment and could be used to reclassify the cancers
- Understanding the microenvironment of the cancer cell is vital to delivering successful future therapies but open access to research findings for all nations should be a key principle for funding research
- Provide palliation whenever it is required as the majority of cancer treatment is not aimed at cure, more to control symptoms of the patient
- Access to analgesia is often poor with only 9% of the world’s morphine used in developing nations which have 83% of the world’s population
- In some regions of Africa, patients have to walk for more than a day in each direction to and from a pharmacy to receive only 5 days supply of medication
- There are persisting misconceptions about the problems of strong opioid analgesia that have yet to be overcome
- End of life care is not expensive but requires involvement of the family and other care givers
- It can be improved by access to better training and education and provision of community-based services that understand the diversity and requirements of the local population
What is performance status and why is it checked?
§ One of the most important factors that impacts on the planning of treatment and prognosis is the performance status of the patient
§ This requires an assessment of their functional capacity, ability to self-care and mobility
§ The performance status correlates with prognosis and tolerance of treatment and a number of different scales are used; the more common being the ECOG and Karnofsky scales
§ Patients with performance status 3 or 4 do not tolerate treatment as well and indeed some systemic chemotherapy may shorten their life
What cancers can cause lymphadenopathy in Supraclavicular fossa?
When considering a patient with lymphadenopathy in the supraclavicular fossa or axilla, consider the anatomical sites that drain to those locations. In this case, breast, lung, oesophagus and stomach.
How to identify the primary cancer in a patient presenting with metastatic disease?How can it be managed?
For most patients who present with metastatic disease, routine examination and investigation will quickly disclose the underlying primary tumour. However, for 1-5% of patients, the primary site remains undisclosed because it is too small to be detected or has regressed. The usual histological diagnosis in these patients with unknown primary site is adenocarcinoma or poorly differentiated carcinoma (see case 7).
Important considerations:
- What is the rationale for establishing primary tumour site?
- Diagnosing treatable disease (see table below)
- Avoiding over treating unresponsive disease (iatrogenic morbidity in resistant disease)
- Preventing complications related to occult primary, e.g. bowel obstruction, pathologic fracture
- Prognostic clarification
The most important first investigation to aid diagnosis is to biopsy or excise the lymph node in the neck. Histology of the lymph node in this case demonstrated squamous cell carcinoma.
“Five highly treatable subsets of unknown primary site have been identified which have more favourable outcomes and require distinct management.”
What are the risk factors for cervical cancer?
“Increasing age is the most important risk factor for most cancers. The primary risk factor for cervical cancer is human papillomavirus (HPV) infection.
Other risk factors for cervical cancer include the following:
- High parity and HPV infection
- Smoking cigarettes and HPV infection
- Long-term use of oral contraceptives and HPV infection
- Immunosuppression
- Having first sexual encounter at a young age
- High number of sexual partners
- Exposure to diethylstilbestrol (DES)in utero
Human papillomavirus (HPV) infection
HPV infection is a necessary step in the development of virtually all precancerous and cancerous lesions. Epidemiologic studies convincingly demonstrate that the major risk factor for development of preinvasive or invasive carcinoma of the cervix is HPV infection, far outweighing other known risk factors.”1”Transient HPV infection is common, particularly in young women, while cervical cancer is rare. The persistence of an HPV infection leads to increased risk of developing precancerous and cancerous lesions.
The strain of HPV infection is also important in conferring risk. There are multiple subtypes of HPV that infect humans; of these, subtypes 16 and 18 have been most closely associated with high-grade dysplasia and cancer. Studies suggest that acute infection with HPV types 16 and 18 conferred an 11-fold to 16.9-fold risk of rapid development of high-grade CIN. Further studies have shown that infection with either HPV 16 or 18 is more predictive than cytological screening of high-grade CIN or greater disease, and that the predictive ability is seen for up to 18 years after the initial test.
There are two commercially available vaccines that target anogenital-related strains of HPV. The vaccines are directed towards HPV-naïve girls and young women, and although penetration of the vaccine has been moderate, significant decreases in HPV-related diseases have been documented.”1
What are the clinical features and prognostic factors?
“Early cervical cancer may not cause noticeable signs or symptoms. Possible signs and symptoms of cervical cancer include:
- Vaginal bleeding
- Unusual vaginal discharge
- Pelvic pain
- Dyspareunia
- Postcoital bleeding”1
Prognostic factors
- “HIV status: Women with HIV have more aggressive and advanced disease and a poorer prognosis
- C-mycoverexpression: A study of patients with known invasive squamous carcinoma of the cervix found that overexpression of the C-myconcogene was associated with a poorer prognosis
- Number of cells in S phase: The number of cells in S phase may also have prognostic significance in early cervical carcinoma
- HPV-18 DNA: This has been found to be an independent adverse molecular prognostic factor. Two studies have shown a worse outcome when HPV-18 was identified in cervical cancers of patients undergoing radical hysterectomy and pelvic lymphadenectomy
- A polymorphism in the Gamma-glutamyl hydrolase enzyme, which is related to folate metabolism, has been shown to decrease response to cisplatin, and as a result is associated with poorer outcomes.”
What are the poor prognostic factors associated with adenocarcinoma?
Poor prognosis is associated with adenocarcinoma, lymph node involvement, advanced clinical stage, large primary tumour and early recurrence. Relapse after 5 years is unusual.
How can cervical cancer be treated?
Optimum treatment is determined by the stage of the disease, age and general health of the woman and plans for future fertility.
- Local excision using loop diathermy is performed for CIN 2/3 confined to the visible ectocervix
- Loop biopsy is performed for CIN 3 with disease extending into cervical canal
- Simple hysterectomy is performed for micro-invasive disease
- Stage IB or 2 cervical cancers are treated by radical hysterectomy with pelvic lymphadenectomy or pelvic radiotherapy. Both methods are equally effective
- Stage 2B and 3 should be treated with pelvic radiotherapy and patients treated with curative intent typically receive chemoradiotherapy with cisplatin as a radiation sensitizer
- Stage 4 and recurrent disease are treated with chemotherapy. Radiotherapy can be used to treat specific site of metastasis.
- Chemotherapy alone has no role in the adjuvant treatment of cervical cancer
What Investigation are done for Suspected cervical cancer and how it be staged?
n a woman presenting with symptoms suggestive of cervical cancer, the initial investigation depends on age:
Pre-menopausal – test for chlamydia trachomatis infection
If positive; treat for chlamydia infection. If symptoms persist after treatment, refer for colposcopy and biopsy.
If negative; a colposcopy and biopsy is usually performed.
Post-menopausal – urgent colposcopy and biopsy.
A colposcopy is where a colposcope (modified microscope) is used to produce a magnified view of the cervix. Acetic acid is used to stain dysplastic areas, and a biopsy is taken.
If the diagnosis of cervical cancer is confirmed, further investigations are required:
Basic blood tests – such as full blood count, liver function tests and urea & electrolytes
CT Chest-Abdomen-Pelvis – looking for metastases.
Further staging scans – e.g. MRI pelvis, PET.
+/- examination under anaesthesia with further biopsies.
The International Federation of Gynaecology and Obstetrics (FIGO) staging system is used for cervical cancer:
Stage 0 – Carcinoma in-situ
Stage 1 – Confined to cervix
A) Identified only microscopically.
B) Gross lesions, clinically identifiable.
Stage 2 – Beyond cervix but not pelvic sidewall/ involves vagina but not lower 1/3
A) No parametrial involvement.
B) Obvious parametrial involvement.
Stage 3 – Extends to pelvic sidewall/ involves lower 1/3 vagina/ hydropnephrosis not explained by another cause.
A) No extension to sidewall.
B) Extension to sidewall and/or hydronephrosis.
Stage 4 – Extends to bladder or rectum, or metastases
A) Involves bladder/rectum.
B) Involves distant organs
How is screening done for Cervical cancer?
Cervical cancer is very rare in women younger than 25. But changes in the cells of the cervix are quite common in this age group. These changes often return to normal and are less likely to develop into cancer
Using Cervical smear test
How may Lung cancer present?
- A small proportion of patients will have no presenting symptoms
- Most patients will present with intrathoracic symptoms (e.g. cough, dyspnoea, chest pain, haemoptysis, recurrent chest infections)
- Dysphagia may result from extrinsic compression by the primary tumour
- A hoarse voice suggests invasion of the recurrent laryngeal nerve
- Extrathoracic symptoms may include anorexia, weight loss, malaise and lethargy
What are the most typical clinical features of Lung Cancer?
- Hands: nicotine staining, clubbing
- Neck: lymphadenopathy
- Chest: signs of pulmonary collapse or consolidation
- Superior vena caval obstruction
- Pancoast’s syndrome (Chest wall pain, Horner’s syndrome (miosis, anhydrosis, partial ptosis and enophthalmos) and pain in T1 dermatomal distribution due to apical tumour invading chest wall, interrupting sympathetic chain and invading T1 nerve root)
- Non-metastatic manifestations: haematological (e.g. anaemia), neuromuscular (e.g. Eaton-Lambert syndrome), cutaneous (e.g. acanthosis nigricans), due to ectopic hormone production (e.g. hypercalcaemia), etc
What is the Epidemiology of Lung Cancer?
- Lung cancer is the commonest malignant solid tumour in the UK (excluding non-melanomatous skin cancer)
- Causes approximately 35,000 deaths per year in the UK
- In the UK 7% of patients are alive and disease-free 5 years from diagnosis
- The incidence of lung cancer is approximately 42,000 cases per year in the UK
- Peak incidence is at 60-70 years
- The incidence has paralleled trends in cigarette smoking after a 20- to 50-year lag period
- Among the major histological subtypes of lung cancer, the association between the extent of tobacco exposure and risk is particularly strong for squamous cell and SCLC (small-cell lung cancer)
- Male to female ratio is approximately 3:1
- In males the incidence is decreasing, in females it is increasing
- Incidence is greater than prevalence
What are the different types of Lung cancer?
- Spread is circumferential and longitudinal along the bronchus of origin
- Tumours frequently involve regional lymphatics
- Spread is to ipsilateral peribronchial and hilar nodes, followed by mediastinal, contralateral hilar and supraclavicular nodes
- There is a propensity to disseminate widely via the bloodstream and virtually any site may be involved
Small cell lung cancer(SCLC) accounts for 20% of all lung cancers and arises in the larger airways and tends to be a more central tumour. Most patients present with systemic disease and it frequently metastasises, via haematogenous spread, to the liver, skeleton, bone marrow, brain and adrenal glands. The small cells contain dense neurosecretary granules which can produce ectopic biological substances resulting in Cushing’s syndrome (ACTH) and SIAD. Mutations inRB1andTP53are found in 80% of patients with SCLC and abnormal DNA methylation of the cyclin D2 gene is common.
Non-small cell lung cancers(NSCLC) (80% of lung cancers) arise from the epithelial cells of the lung from the central bronchi to the terminal alveoli. It can be divided into 3 main types:
- Squamous cell carcinoma (50%) is the commonest histological diagnosis, often presenting as an obstructive lesion of the bronchus causing infection. They can cavitate on a chest radiograph and tend to grow slowly, spreading locally and disseminating late
- Adenocarcinoma (15%) arises from the bronchial mucosal glands, and tends to occur in the periphery. As such findings can represent a metastasis from a distant site, careful patient assessment is required. There is less association with smoking, but they can originate in scar tissue and carry a high risk of metastatic spread, often to mediastinal lymph nodes and pleura producing an effusion
- Large cell carcinoma (10%) often presents as a large peripheral mass on a chest radiograph and can have neurosecretory elements that produce paraneoplastic features. They tend to be poorly differentiated, can grow rapidly and metastasise early
Genetics
There is a 2.5-fold increased risk of lung cancer where there is a significant family history, despite their own smoking history and rarely lung cancers develop in patients with germ line mutations in genes such as inRbandTP53.
What are the risk factors for Lung Cancer?
“Increasing age is the most important risk factor for most cancers but other risk factors for lung cancer include:
- History of or current tobacco use: cigarettes, pipes, and cigars
- Exposure to cancer-causing substances in secondhand smoke
- Occupational exposure to asbestos, arsenic, chromium, beryllium, nickel, and other agents
- Radiation exposure from any of the following:
- Radiation therapy to the breast or chest
- Radon exposure in the home or workplace
- Medical imaging tests, such as computed tomography (CT) scans
- Atomic bomb radiation
- Living in an area with air pollution
- Family history of lung cancer
- Human immunodeficiency virus infection
- Beta carotene supplements in heavy smokers
The single most important risk factor for the development of lung cancer is smoking. For smokers, the risk for lung cancer is on average tenfold higher than in lifetime non-smokers (defined as a person who has smoked <100 cigarettes in his or her lifetime). The risk increases with the quantity of cigarettes, duration of smoking, and starting age.
Smoking cessation results in a decrease in precancerous lesions and a reduction in the risk of developing lung cancer. Former smokers continue to have an elevated risk of lung cancer for years after quitting. Asbestos exposure may exert a synergistic effect of cigarette smoking on the lung cancer risk.”1
What Investigations are done in Lung Cancer?
The aim of investigation is to gain a histological diagnosis and determine the extent of spread (stage), in order to determine the most appropriate treatment plan.
All patients with known or suspected lung cancer should have:
- History
- Examination
- CXR
- FBC
- Biochemical profile (including U&Es, LFTs, LDH and serum calcium)
Sputum cytology can be unreliable and a biopsy is preferable. CT imaging is used to assess the tumour size and spread, determine lymph node involvement or identify chest wall invasion or metastasis to other sites.
Tissue for diagnostic testing is usually obtained during a bronchosocopy but a fine needle aspiration sample from an involved lymph node or CT-guided transthoracic biopsy may be considered. Fluid cytology from a pleural effusion can be useful if present at diagnosis. If bone pain is present, plain X-rays and bone scan imaging are required to exclude metastasis.
MRI scan of the chest can determine lymph node involvement but PET/CT is increasingly being used as an alternative to an invasive mediastinoscopy to determine operability of the patient.
Patients with small cell lung cancer should have imaging of the upper abdomen, as the cancer can often spread to the liver and adrenal glands
Patients with non-small cell lung cancer being considered for radical treatment may require:
- pulmonary function tests
- contrast CT scan of the thorax and upper abdomen
- V/Q scan
- MRI scan
- ultrasound scan
- mediastinoscopy, laryngoscopy, PET-CT
- additional investigation if clinical, biochemical or radiological suspicion of metastatic disease.
What are the Prognostic factors?
Multiple studies have attempted to identify the prognostic importance of a variety of clinicopathologic factors and those that correlate with adverse prognosis include:
Presence of pulmonary symptoms
- Large tumor size (>3 cm)
- Nonsquamous histology
- Metastases to multiple lymph nodes within a TNM-defined nodal station
- Vascular invasion
For patients with inoperable disease, prognosis is adversely affected by poor performance status and weight loss of more than 10%. These patients have been excluded from clinical trials evaluating aggressive multimodality interventions.
What are the complications of Lung cancer?
Disease-related complications in NSCLC
- Local invasion
- SVC obstruction
- Pleural effusion
- Distant metastasis
- Brain, liver, bone
- Non-metastatic
- Hypercalcaemia
- Cushing syndrome
- SIAD
- Neurological syndromes
How does SVC present?
SVC obstruction
- SVC syndrome is the clinical expression of obstruction of blood flow through the SVC
- Characteristic symptoms and signs may develop quickly or gradually
- Caused by compression, invasion, or thrombosis in the superior mediastinum
- Symptoms and signs may be aggravated by bending forward, stooping, or by lying down
- Treatment is directed at the underlying cause
- Prognosis of patients with SVC syndrome strongly correlates with the prognosis of the underlying disease
Common symptoms and signs of SVC obstruction
Dyspnoea Facial swelling Head fullness Cough Arm swelling Chest pain
Primary pathologic diagnoses for SVC Obstruction
Lung cancer Lymphoma Other malignancies (Primary or secondary) Nonneoplastic Undiagnosed
Chest X-ray findings of SVC obstruction
Superior mediastinal widening Pleural effusion Right hilar mass Bilateral diffuse infiltrates Cardiomegaly Calcified paratracheal nodes Anterior mediastinal mass Normal
How can brain mets present?how can they be managed?
Increasingly diagnosed
- Patients living longer
- Better imaging modalities
Frequency
- Lung (50%)
- Breast (15-20%)
- CUP (10%)
- Melanoma (10%)
- GI (5%)
Presenting features of brain metastasis
- Headache (70-80%)
- Cognitive dysfunction (40%)
- Neurological deficit (40%)
- Seizures (15-20%)
Treatment for brain metastasis
Steroids: first described in 1961, can:
- decrease peritumoral oedema
- minimal mineralocortocoid activity
- can double overall survival
- no single optimal dose or schedule known, but 10 mg stat iv, followed by 16 mg per 24 hours is a generally accepted
Anticonvulsants:
- choice of IV or PO: tailor it to the patients needs
- traditionally phenytoin is the agent of choice, but many centres use sodium valproate, although there are problems with the enzyme inducing effect and erythema multiforme
- No evidence for prophylactic anticonvulsive therapy
Surgery:
- Evidence is limited - Series are usually small and often retrospective
- Role of surgery clear for solitary brain mets or singular brain mets with quiescent extra cranial disease
- Generally, post surgical Whole Brain Irradiation recommended
Radiotherapy:
- RT has been postulated to increase survival, however role of XRT in poor PS patients remains undefined and there is no RCT against best supportive care
- No optimal dose schedule have been established, but 30Gy/10# or 20Gy/4-5# is quite normal
Chemotherapy:
- Role of chemotherapy is generally disappointing, due to inability for chemotherapy to pass blood brain barrier despite disease
- More role in germ cell and small cell tumours as these are particularly sensitive to treatment
What is cellular communication and control?and how does What is cellular communication and control?
Signalling at the cell surface
Signalling pathways that control gene activity
Integration of signals and gene controls
Regulating the cell cycle
Cell birth, development and death
Mean of communication and coordination for cancer cells to exploit and use this for their advantage
Cell signalling is part of a complex system of communication that governs basic cellular activity and coordinates cell actions
Used in development, tissue repair and immunity
Essential for normal tissue homeostasis
Errors cause cancer, autoimmunity and diabetes
Signal transduction-Occurs when an extracellular signalling molecule binds to and activates a cell surface receptor
The receptor alters intracellular molecules creating a response
A second messenger transmits the signal into the cell, eliciting a physiological response
How does Hormonal signalling work?
Induce a specific response or alter the activities of the target tissue
Act specifically via receptors located on, or in, target tissue
A substance may be released by one cell and recognized by different target cells producing heterogenous responses
Endocrine signalling
Paracrine signalling
Autocrine signalling
Contact-dependent signalling (juxtacrine)
Same signal, different response
Different combinations, different response
What factors determine Specificity of biosignalling ?
Molecular complementarity between signal and receptor
multiple non-covalent interactions similar to substrate-enzyme, solute-transporter, and antigen-antibody interactions
Cell-specific expression of receptors
only cells with receptors specific for the signal can respond
Cell-specific expression of signal transduction proteins
same signal-receptor may activate or inhibit depending on other signal transduction proteins present
Cell-specific expression of effector proteins
differential response of liver, skeletal muscle and adipose cells to epinephrine depends on expressed enzymes
What are second and third signals?
Small molecules synthesised in cells in response to an external signal and are responsible for the intracellular signal transduction
Ca2+ ions DG, ceramide lipid derivatives IP3 carbohydrate derivatives cAMP, cGMP nucleotides Ras, JAK, Raf proteins
Third messengers are the molecules which transmit message from outside to inside of nucleus or from inside to outside of nucleus
Also called DNA binding protein
What are the 4 mechanism of signal transduction pathways?
There are 4 types of mechanism
1. Direct ligand-gated channel type
Nicotinic acetylcholine, GABA
receptors, neurotransmitters
Acts as a gate when the receptor changes shape
When a signal molecule binds as a ligand to the receptor, the gate allows specific ions, such as Na+ or Ca2+ through a channel in the receptor
- G-protein-coupled type
Muscarinic acetylcholine, adrenergic receptors
Constitute a large protein family of receptors that are also called seven-transmembrane receptors because they pass through the cell membrane seven times
Found only in eukaryotes, including yeast, choanoflagellates and animals
The ligands that bind and activate these receptors include light-sensitive compounds, odours, pheromones, hormones and neurotransmitters, varying in size from small molecules to peptides and large proteins
Involved in many diseases and are the target of approximately 40% of all modern medicinal drugs such as Hydrocodone and Lisinopril - Tyrosine kinase-linked type
Epidermal growth factor, VEGF - Nuclear receptor super family
Ligand-sensitive transcription factor
Steroid and thyroid hormones
Intracellular receptor proteins are found in the cytosol or nucleus of target cells
Small or hydrophobic chemical messengers can readily cross the membrane and activate receptors
Examples of hydrophobic messengers are the steroid and thyroid hormones
An activated hormone-receptor complex can act as a transcription factor, turning on specific genes
What physiological processes are controlled by G-protein coupled receptors?
Two principal signal transduction pathways involve the G protein–coupled receptors
cAMP signal pathway
phosphatidylinositol signal pathway
The human genome encodes thousands of G protein-coupled receptors, about 350 of which detect hormones, growth factors, and other endogenous ligands
Approximately 150 of the GPCRs found in the human genome have unknown functions
Involved in a variety of physiological processes:
Vision: The opsins use a photoisomerization reaction to translate electromagnetic radiation into cellular signals
Taste: GPCRs in taste cells mediate release of gustducin in response to bitter- and sweet-tasting substances
Smell: Receptors of the olfactory epithelium bind odorants (olfactory receptors) and pheromones (vomeronasal receptors)
Behavioural and mood regulation: Receptors in the mammalian brain bind several different neurotransmitters, including serotonin, dopamine, GABA, and glutamate
Homeostasis modulation: e.g., water balance
Inflammation: Chemokine receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as histamine receptors bind inflammatory mediators and engage target cell types in the inflammatory response
Immune system regulation: involved in suppression of TLR-induced immune responses from T cells.
Autonomic nervous system transmission: Both the sympathetic and parasympathetic nervous systems are regulated by GPCR pathways, responsible for control of many automatic functions of the body such as blood pressure, heart rate, and digestive processes
Cell density sensing: A novel GPCR role in regulating cell density sensing
What is the role of EGFR in human cancers?
EGFR can influence the regulation of tumour cell cycle progression, repair, and survival, and is involved in tumour metastasis
Binding of specific ligands to EGFR (e.g. EGF, TGF-) activates the receptor and triggers signal transduction cascades that affect cell proliferation
Many human cancers express EGFR on the cell surface
Inhibition of EGFR on tumour cells may inhibit the growth or progression of EGFR-positive tumours
Many point mutations are recognised within EGFR and these correlate with response to therapy
Development of monoclonal Abs
Binds to the extracellular domain of the EGFR
Blocks growth factor binding and signal transduction
Combined treatment of mAbs with cytotoxic drugs increases anti-tumour activity in tumour xenograft models
Development of recombinant humanized and chimeric mouse-human antibodies
Examples:
trastuzumab
cetuximab
Tyrosine kinase inhibitor
Binds to the intracellular tyrosine kinase domain and inhibits tyrosine autophosphorylation and downstream intracellular signalling
Compete with ATP for binding with the intracellular catalytic domain of TK
Examples:
gefitinib
erlotinib
Immunoconjungates
Binds to the extracellular domain of the receptor
Activate receptors and when internalised the isotope or toxin kills the cell
Examples:
Rhenium186 anti-EGFR Ab h-R3
Pseudomonas exotoxin A
Antisense approach
Binds to EGFR or ligand mRNA
Prevents transcription and receptor or ligand production
What are mechanisms of EGFR activation in tumour cells?
1) Overexpression of EGFR protein
2) Increase autocrine ligand loop
3) heterodimerisation and cross-talk
4) reduce phosphatase
5) mutant EGFR
What is Carcinogenesis?
The process by which normal cells are transformed into cancer
It is clear that changes in the host genome are the final common pathway in the process of carcinogenesis, whatever the initial aetiology
A multi-step process resulting from the accumulation of errors in vital regulatory pathways
Can be initiated in a single cell which then multiplies and acquires additional changes providing a survival advantage over its neighbours
Altered cells must be amplified to generate billions of cells that constitute a cancer
Therefore as this takes time, the longer one lives, the more likely one is to develop cancer
The smallest detectable tumour is approximately 1cm in diameter and already contains 1 billion (1,000,000,000) cells
What is contact inhibition?
Contact inhibition is recognised by cells following reproduction and so switch off division (due to the presence of glycoprotein on the cell surface)
What is the aetiology of Carcinogenesis?
Environmental factors Chemicals and occupational hazards Physical (radiation) Ionising radiation Ultraviolet radiation Biological Viruses Bacteria Parasitic infections Drugs and hormones Nutritional and lifestyle Genetic factors
How can hormones cause Carcinogenesis?
Cancer can be induced by overproduction of endogenous hormones as well as exogenous substances as contained within the combined oral contraceptive pill (COCP) and hormone replacement therapy (HRT)
Risk of breast cancer is related to the duration of exposure to oestrogens, with risk increased by low parity, early menarche, late menopause and prolonged exposure to oestrogens by the use of HRT
The COCP does not increase risk as it is used at a time in the life cycle when oestrogen is naturally present
Ovarian cancer is related to the number of ovulations; therefore the risk is increased by nulliparity but reduced by the COCP, reducing by 50% in those taking the COCP for 10 or more years
The risk of endometrial cancer in postmenopausal women is increased by using oestrogen-only HRT or tamoxifen
What is Li Fraumeni syndrome and how is it inherited?
A rare syndrome characterised by premenopausal breast cancer childhood sarcoma brain tumours leukaemia and lymphoma adrenocortical carcinoma Associated with a germline mutations in the TP53 gene on chromosome 17p Inheritance is autosomal dominant with a penetrance of at least 50% by age 50
