Intro to Clinical Oncology

Question 1

Most common malignancies and most common causes of death

Answer 1

Most common malignancies:

1. Prostate/breast
2. Lung/Bronchus
3. Colon

Most common causes of death

1. Lung/bronchus
2. Prostate/breast
3. Colon

Question 2

How does cancer present?

Answer 2

1. Local symptoms of disease:
   - Interference with normal organ function –> bowel obstruction, cough
   - Direct extension into adjacent organ/structures –> chest wall pain
2. Symptoms of metastatic disease:
   - Pain or organ dysfunction from disease that has pread to other organs –> bone pain, seizures, headache
3. Paraneoplast:
   - Abnormal hormone production
4. Incidental or screening

Question 3

Presentations of hematologic malignancies

Answer 3

1. Bone marrow failure
   - anemia –> weakness, fatigue, dyspnea
   - thrombocytopenia –> bleeding, bruising
   - leucopenia –> infection
2. Bone marrow proliferation
   - erythrocytosis (PCRV) –> headache, plethora
   - thrombocytosis –> thrombosis, bleeding
   - leukocytosis –> dyspnea, confusion
   - splenomegaly
3. Lymphadenopathy
4. B-symptoms: fever, night sweats, weight loss
   - due to elaboration of cytokines
5. Thrombosis

Question 4

Signs (physical findings) and symptoms (what the patient reports)

Answer 4

Local symptoms:

• pain
• mass
• organ dysfunction –> symptoms depend on the organ
• direct extension to adjacent organs –> e.g. difficulty swallowing due to a tumor in the bronchus obstructing the esophagus

Metastatic disease:

• lumps, bumps
• pain
• symptoms referable to disruption of normal organ function –> obstruction, seizure, paralysis, fracture

Question 5

Paraneoplastic symptoms

Answer 5

Symptoms that result from various substances secreted by the tumor or as a response to the tumor –> not a direct effect of malignancy

• weight loss without GI tract obstruction
• hypercalcemia
• hyponatremia
• “clubbing”

DVT and pulmonary embolism = common presentation and/or complication due to hypercoagulability

• requires immediate diagnosis and anticoagulation
• potentially fatal

Clubbing

Cutaneous signs of malignancy –> can be direct extension, paraneoplastic or metastatic
- cutaneous metastases generally associated with poor prognosis

Cancer anorexia and cachexia –> weight loss is common (>10%)

• frequent presenting sign
• usually associated with advanced disease
• etiology is controversial

Question 6

Difference between incidental finding and screening

Answer 6

Incidental = patient evaluated for another reason

• frequently, an unsuspected radiologic finding
• major source of medicolegal problems

Screening

• recommended for breast, colon, cervical, lung in certain patients (sprial CT)
• prostate (PSA blood test) is controversial
• more complex than most appreciate

Question 7

Screening for cancer

Answer 7

Detecting cancer before symptoms and signs

• basic premise is that smaller/earlier is better –> proven to be true in some disease, but not in others
• level of benefit varies –> best where the site of tumor is directly sampled (e.g. pap smear or colonoscopy); less effective when radiologic imaging is used (e.g. mammography or CT scan)

Question 8

Current recommended screening for standard risk population

Answer 8

• Breast cancer –> mammography after age 50
• Colon cancer –> colonoscopy after age 50
• Cervical cancer –> pap smears
• Head and neck cancer –> evaluation during dental exam
• Prostate cancer –> PSA testing in males >50 (controversial)
• Lung cancer (as of 2011) –> low dose helical CT for patients with significant smoking history, >55, only at institutions with substantial expertise

Question 9

Diagnosis of cancer

Answer 9

There must be histologic or cytologic proof of disease –> rare exceptions

• biopsy should be from the most accessible, least dangerous place –> generally, if you prove a cancer from a distant site, you do not need to biopsy the primary tumor unless curable approaches to both sites would be changed
• the biopsy should come before the rest of the evaluation, however a certain degree of radiographic evaluation is frequently performed simultaneously

Example of biopsy dilemmas:
1 41 y.o female presents with a breast lump and a single bony swelling in the distal femur. Biopsy of breast = infiltrating ductal cancer
- should the leg also be biopsied? –> YES! if low grade chondrosarcoma, patient could have two ultimately curable neoplasms
2. 50 y.o. male smoker presents with pancytopenia and a lung mass apparent on chest x ray. Bone marrow biopsy = diagnostic of small cell lung cancer
- can proceed with tx for small cell lung cancer

Question 10

The diagnostic biopsy

Answer 10

• need a diagnosis –> “suspicious” and “possible” are not good enough, need the definitive proof for diagnosis
• need enough tissue to perform special stains and other analysis –> FNA usually not enough
• immunohistochemistry –> can distinguish tissue of origin in difficult cases
• molecular analysis –> for therapeutic decisions (Her2/neu, EGFR, k-ras, etc.)

Question 11

Staging

- clinical vs. pathological staging

Answer 11

How extensive is the cancer?

• TMN system
• other factors –> tumor markers
• therapy is stage directed but not mandated
• staging systems do not incorporate all known variables –> therefore, therapy is determined by stage in addition to other factors (physiology, patient preferences, local expertise)
• staging does not incorporate performance status

Clinical vs. pathological staging

• clinical stage = stage determined after complete clinical assessment (physical exam, laboratory, radiologic, biopsy, mediastinoscopy, etc.) –> clinical stage frequently underestimates the extent of disease
• pathological stage = stage determined after resection (or attempted resection) OR pathological determination of metastatic disease

Question 12

Tumor board

Answer 12

Organized meeting of internal medicine, surgical, and radiation oncologists –> include radiologists and pathologists

• review all evidence and assign clinical and/or pathologic stage
• recommend treatment approaches
• OK to use staging manuals –> guidelines change frequently
• important to have in mid the clear staging criteria for curative intent in each tumor type

Question 13

Performance status

Answer 13

Considers the general ability of a patient to do things –> 2 major scales

1. Karnofsky –> percentage score, more detailed
2. Eastern Cooperative Oncology Group
   - -> 0 = no limitations
   - -> 1 = OOB all day, capable of a full day of work
   - -> 2 = OOB > 50% of the day, limited ability to work
   - -> 3 = OOB < 50% of day –> capable of self care
   - -> 4 = requires nursing assistance with ADL
   - ->5 = dead

Question 14

How is staging accomplished?

Answer 14

• History and physical
• Radiographic studies
• Laboratory evaluation
• Invasive and surgical
• Clinical vs. surgical staging

Question 15

Radiographic studies in cancer diagnosis

Answer 15

1. Plain films = chest X ray –> easy, inexpensive, useful for initial assessment and follow up
2. CT = best method for many disease –> excellent imaging of most organs
   - need IV contrast (iodinated) for best assessment usually
   - easy and relatively inexpensive
3. MRI = best method for imaging the brain and spinal cord
   - useful in certain special situation in chest and liver
   - cannot use in patients with ferrous metals in the body
   - slightly more difficult to obtain and more expensive than CT
4. PET scans = assessment of undiagnosed masses to determine malignant potential
   - useful as part of staging evaluation for lung and other cancers
   - requires 18FluoroDeoxyGlucose isotope
   - expensive, limited availability
   - may ultimately prove valuable in follow up
   - currently overutilized –> PET avidity and value in each cancer has yet to be established
5. PET/CT
6. Ultrasound

Question 16

Surgical staging

Answer 16

Occurs prior to definitive procedure

• provides information regarding lymph node status (primarily in lung cancer)
• mediastinoscopy
• other methods are gaining favor –> e.g. endoscopic bronchial ultrasound

Question 17

Treatment of cancer

Answer 17

Stage directed

Goals of therapy –> vary depending upon disease, extent, and patient

For solid tumors –> must control both the local disease (i.e. primary disease) and the systemic disease

Local therapy for local disease:

• surgery
• radiation
• adjuvant therapy
• others –> radiofrequency ablation, cryotherapy

Locally advanced disease –> combined modality therapy

Advanced disease:

• chemotherapy
• hormonal therapy –> breast/prostate cancer
• immunotherapy

Question 18

Stage directed therapy –> localized disease

Answer 18

Confined to tissue or origin, no invasion of adjacent structures, at most local lymph node

• treat with localized therapy –> surgery or radiation
• adjuvant chemotherapy

Question 19

Stage directed therapy –> locally advanced disease

Answer 19

Regional lymph node involvement, large tumors, invades adjacent structures
- treat with combined modality therapy –> chemotherapy, radiation, surgery

Question 20

Stage directed therapy –> advanced diseases = metastases

Answer 20

Distant spread

• treat with systemic therapy –> chemo, hormonal
• radiation + surgery to relive/prevent specific local complications, occasionally to remove residual disease for cure (e.g. testicular cancer)

Question 21

Surgical treatment

Answer 21

Can you operate vs. should you operate

Various goals of surgery:

• diagnostic
• curative
• staging procedures –> e.g. mediastinoscopy
• “debulking” to optimize use of other treatments
• palliative –> treatment and prevention of complications

For cure, goal should be complete removal of the tumor with clear margins in an anatomically appropriate fashion
- potentially curative procedure should not be undertaken until after completion of non-surgical staging

Resectable vs. operable

Question 22

Principles of radiation therapy

Answer 22

Maximize dose to the target (tumor or areas at risk) while minimizing exposure to normal cells

• precise target localization
• reliable target immobilization
• conformal treatment delivery

Use a fractionated dose that causes lethal damage to cancer cells but only sublethal damage to nearby normal cell populations

Question 23

Radiation biology

Answer 23

Photons

• gamma rays = photons produced from radiation decay –> cobalt-60, cesium-137, iridium-192, etc.
• X-rays = man made
• –> diagnostic radiology = kilovoltage energy
• –> radiation oncology = megavoltage energy

Electrons, protons, neutrons, etc

Question 24

Radiation dose

Answer 24

Uses radiation of a certain type (ionizing) to cause tissue damage by ions release from target molecules and from DNA
- gray = gy: a unit of energy delivered per mass of tissue (cGy = 1 rad)

Fractionated dosing:

• 1.25 - 8 Gy daily fraction x a total dose dictated by organ tolerance
• 1.8 - 2 Gy for curative cases
• palliative cases usually 3 gy per day –> can be 8 Gy for those with very poor performance status

Total dose = a complex balance between giving enough radiation to kill the primary and subclinical tumor and avoiding normal tissues

• stage I seminoma: 25 Gy in 1.25 Gy fxn
• high risk prostate cancer: 75.6-84.4 Gy

Question 25

Systemic cancer treatment = chemotherapy/biological therapy

Answer 25

Chemotherapy: - cytotoxic "small molecule" drugs - targeted "small molecule" Biological therapy: - antibodies/antibody drug complexes - ligand directed proteins - cytokines - cellular therapies - gene therapies

Question 26

Principles of chemotherapy

Answer 26

- drug sensitivity is specific to disease - log-kill hypothesis = fractional kill - growth kinetics --> small tumors are more sensitive to chemo - overlapping toxicities are additive - cytotoxicity is usually dose dependent

Question 27

Combination chemotherapy principles

Answer 27

- individual drugs should be effective - combinations should "make sense" --> be synergistic, etc. - repeated dosing > single high doses - low stage disease responds better - avoid cross resistant combinations - toxicities should not overlap - use each drug at optimum dose

Question 28

Utilization of antineoplastic agents

Answer 28

Increase life expectancy/palliative treatment in advanced disease --> breast, colon, lung, prostate, bladder, pancreas Curative therapy of advanced disease - hematologic malignancies --> hodgkins, NHL, acute myelogenous leukemia, acute lymphoblastic leukemia - solid tumors --> testicular cancer + choriocarcinoma Chemoradiotherapy for curative treatment of locally advanced disease --> bulky hodgkins, stage III NSCLC, limited SCLC, rectal cancer Preservation of organ function --> laryngeal cancer, lung cancer, anal carcinoma Adjuvant therapy in early stage disease --> breast, colon, lung, prostate, bladder

Question 29

The decision to use chemotherapy

Answer 29

- should be evidence based - drug/regiment to be utilized should be employed in a patient who could have been enroled in a trial which demonstrated a positive outcome for that particular treatment plan - decisions require that the patient be carefully staged

Question 30

Stage I and II disease - the decision to utilize adjuvant chemotherapy

Answer 30

Adjuvant treatment: therapy administered after all known disease is removed because there is a statistical possibility of relapse - requires large studies to prove benefit - must balance the risks of exposing cured patients to potentially toxic agents - proven benefit in all major solid tumors --> lung, breast, colon, prostate

Question 31

Decision to use chemo as part of multimodality treatment

Answer 31

Locally advanced disease is frequently unresectable or has poor long term outcome due to both local and systemic relapse - chemo can improve the outcomes of radiotherapy - risk of increased toxicity

Question 32

Decision to utilize chemo in advanced cancer

Answer 32

With a few notable exceptions, most metastatic cancers are incurable - chemo can improve both quality and quantity of life in many patients - factors beyond classic staging frequently come into play --> performance status, co-morbidities, patient attitude

Question 33

Future of chemotherapy

Answer 33

Improved understanding of the molecular basis of cancer will lead to better therapy --> "targeted agents" - more narrowly targeted agents will result in fewer side effects - patient selection --> prognostic and predictive markers

Question 34

Individualization of therapy

Answer 34

Not a new concept --> we have individualized based upon patient factors including performance status, organ function, toxicity, etc. for a long time New examples: - Bcr-abl --> imatinib - ER --> tamoxifen - Her2-neu --> trasztusumab, lapatanib - RAR alpha --> all trans retinoic acid - Ras mutation --> cetuximab

Question 35

Prognostic vs. predictive

Answer 35

Prognostic --> marker that indicates how the patient will do irrespective of therapy (unless specifically directed) Predictive --> marker that indicates how a patient will respond to treatment Examples: - ER is a positive prognostic and positive predictive marker (tamoxifen) in breast cancer - Her 2-neu is a negative prognostic and positive predictive marker (trastuzumab) in breast cancer - Ras is a negative prognostic and negative predictive marker (cetuximab) in colon cancer - ERCC1 is a positive prognostic and negative predictive (cisplatin) marker in lung cancer

Question 36

Important points of lecture

Answer 36

- Cancer can present in a myriad of ways. - Symptoms can be a direct or indirect effect of the malignancy. - Screening for asymptomatic disease has been demonstrated to improve survival in some cancers. - Diagnosis requires tissue. - Staging is the extent of the cancer and is based upon history, exam, labs and radiologic studies (depending upon the malignancy). - Treatment is stage directed