Transcript Slide 1

Surgical
Management of
Cancer
Principles of Surgery
Suzie Harriman
Sept 10, 2013
Outline
• Overview
• Epidemiology
• Cancer Biology
• Cancer Etiology
• Cancer Screening
• Cancer Diagnosis
• Surgical Approach
• Cancer Prevention
• Trends in Surgical Therapy
Picture from: www.stjameshospital.com
Overview- Oncology and
Surgeons
• Multidisciplinary
• Surgeons, medical onc, radiation onc, reconstructive plastic
surgeons, radiologists, pathologist and primary care
physicians.
• Primary (definitive) surgical therapy
• En bloc resection of tumor with adequate margins and
regional LNs
• Goal for local and regional control
• Adjuvant therapy
• Radiation therapy and systemic therapies (chemo,
immunotherapy, hormonal and biologic)
• Goal for systemic control by tx of distant foci to prevent
recurrence
Q:Epidemiology
• What are the top three cause of cancer death
in females worldwide?
1.
2.
3.
4.
Lung, breast and CRC
Lung, breast and ovarian
Lung, CRC and ovarian
Breast, ovarian and cervical
Q:Epidemiology
• What are the top three cause of cancer death
in females worldwide?
1.
2.
3.
4.
Lung, breast and CRC
Lung, breast and ovarian
Lung, CRC and ovarian
Breast, ovarian and cervical
Epidemiology
• 2008  1.44 million new cancer cases
• Cause of cancer death in men:
• Lung and bronchus, prostate and colorectal cancer
• Women
• Lung and bronchus, breast and colorectal cancer
• Cancer is leading cause of death in women 40-79 and men
60-79.
• Worldwide:
• New cases per yr: Lung, Breast
• Deaths per yr: Lung, Gastric, Colorectal, Liver, Breast
Cancer Biology
Malignant growth dictated by 6 steps:
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CANCER INITIATION:
3 Steps in Tumorigenesis:
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Initiation
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Promotion
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Field effect: numerous cells in
target organ undergone the
initiating genetic event = normal
cells have malig potential
Progression
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Picture from: Schwartz’s
Oncogenes gain function
Tumor-suppressor genes lose
function
•
Arise from single cell and
accumulate mutations =
aggressive behavior
benign lesion  in situ 
invasive CA
Ie. Atypical ductal hyperplasia 
ductal carcinoma in situ
invasive ductal
Cancer Biology:
Oncogenes
Oncogene: normal cellular genes that contribute to cancer when abnormal
• HER2 (growth factor receptor)
• The protein overexpressed in breast, ovarian, lung,
gastric and oral cancers
• Associated with increased cell proliferation,
resistance to apoptosis, increases cell migration and
in vitro invasiveness
• RAS (intracellular signal transduction molecules)
• Increase proliferation
• Induce cell-cycle regulators which suppress cell-cycle
inhibitors like p27, and enhance survival signaling
Cancer Biology
• Cancer Invasion
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•
In situ: above BM
Invasive cancer: breach BM
• Angiogenesis
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New blood vessels from pre-existing vascular bed for tumor growth and
metastasis
• Metastasis
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Access blood or lymphatics, circulating cells extravasate in new organ
• Cancer Stem Cells
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Ability to self-renew and to generate mature cells of a particular tissue
through differentiation
?tumor growth and mets driven by small # of stem cells
•
Therapies fail to kill stem cells?
Cancer Etiology
• Cancer genetics
• Environmental (60-90% of cancers)
• Chemical carcinogens
• Physical carcinogens
• Viral carcinogens
Cancer Genetics
• Factors suggesting the presence of hereditary
cancer:
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Tumor development at a much younger age
Bilateral disease
Multiple primary malignancies
Clustering of the same type in relatives
Presentation in the less affected sex (ie. Male
breast CA)
• Cancer associated with mental retardation or
pathognomonic skin lesions etc.
Cancer Genetics
• Why do we care as surgeons?
• Implications on patient counseling, planning of
surgical therapy, and cancer screening and
prevention
Cancer Genetics
• P53 – Tumor suppressor gene
• Most commonly mutated gene in CA
• Regulates cell-cycle progression and apoptotic death to stress (ie. UV,
hypoxia, chemo etc)
• APC gene – Tumor suppressor gene
• Identified in FAP and 80% sporadic colon CA
• BRCA1, BRCA2 – Tumor suppressor gene
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5-10% of breast CA hereditary (10% with onset <40)
Increased risk of breast and ovarian CA
BRCA1 – colon CA and prostate CA
BRCA2 – gallbladder and bile duct CAs, pancreatic CA, gastric CA and
melanoma
• MSI – Mismatch repair gene
• Majority with HNPCC; 15% with sporadic CRC
Q: Cancer Genetics
• Approximately 70% of Li-Fraumeni Syndrome
families have been shown to have a germline
mutation in:
1.
2.
3.
4.
HCHK2
P53
BRCA2
PTEN
Q: Cancer Genetics
• Approximately 70% of Li-Fraumeni Syndrome
families have been shown to have a germline
mutation in:
1.
2.
3.
4.
HCHK2
P53
BRCA2
PTEN
Chemical Carcinogens
• International Agency for Research on Cancer
• Five groups:
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Group 1. Proven human carcinogens
Group 2. Probable human carcinogen
Group 2B. Possible carcinogens
Group 3. Not classifiable as to carcinogenicity in
humans
• Group 4. Probably not carcinogens
Chemical Carcinogens
• Examples of Group 1 Chemical Carcinogens
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Afatoxins  liver cancer
Arsenic  skin cancer
Benzene  Leukemia
Nickel  Lung cancer, nasal cancer
Tobacco smoke  Lung cancer, oral cancer,
pharyngeal cancer, esophageal cancer
(squamous cell), pancreatic cancer, liver cancer,
RCC, cervical cancer, leukemia
Physical Carcinogens
• Inflammation and cell proliferation over a
period of time or through exposure to physical
agents that induce DNA damage
• H. pylori – gastritis and gastric CA
• Asbestos fibers and silica -- lung CA and
mesothelial cancers
• Radiation
• Nonionizing UV radiation
Viral Carcinogens
• ~15% of humun tumors worldwide are caused by
viruses
• Cause/increase risk through several mechanisms
• Direct transformation
• Expression of oncogenes that interfere with cellcycle checkpoints or DNA repair
• Expression of cytokines or other growth factors
• Alteration of the immune system
• Viral orgin for some tumors has lead to
vaccinations as a preventative strategy
Q: Viral Carcinogen
• Epstein-Barr Virus is associated with all but
which predominant tumor type?
1.
2.
3.
4.
Hodgkin’s disease
Burkitt’s lymphoma
Nasopharyngeal carcinoma
Cervical cancer
Q: Viral Carcinogen
• Epstein-Barr Virus is associated with all but
which predominant tumor type?
1.
2.
3.
4.
Hodgkin’s disease
Burkitt’s lymphoma
Nasopharyngeal carcinoma
Cervical cancer
Cancer Screening
• Early detection is key!
• Allow more conservative surgical therapies
• Improve surgical cure rates
• Screening guidelines based on:
• Cancer prevalence
• Risk associated with screening measure
• Outcome with early detection
Note: Cancer screening has not shown to increase
survival in breast CA
Cancer Diagnosis
• Biopsy for tumor histology and grade
• Endoscopically (colonoscopy, bronchoscopy,
cystoscopy)  mucosal
• Punch biopsy or excisional biopsy  skin/easily
palpable
• CT or US guided biopsy  deep seated
• Needle biopsy vs open biopsy
Cancer Diagnosis
• FNA, core-needle biopsy
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Advantage:
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Disadvantage:
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FNA: safe, performed under direct palpation
Core: safe, performed under palpation or image guided
FNA: can’t give enough info on tissue architecture (aspiration of breast mass may make
dx of malignancy, but no differentiation of invasive and non invasive)
Core: introduces sampling error (19-44% of atypical ductal hyperplasia on core bx are
found to have carcinoma on excision)
If inconsistent with clinical scenario  rpt needle bx or proceed to open bx
• Incisional biopsy (large lesions, definitive dx can’t be made by needle bx)
• Excisional biopsy (curative intent)
•
Markings for pathologist for negative surgical margins and orientation for re-excision
***biopsy incision should directly overlie area being removed and adequate
hemostasis is important to prevent contamination***
Cancer Staging
• Why is it important?
• Treatment decisions/Prognosticates
• Allows for evaluation of screening and
treatment programs
• Facilitates information between centers
• Financial decisions and improvement of quality
control
• Crucial for the success and interpretation of
both prospective and retrospective clinical trials
Cancer Staging
• Staging Work-up
• LN basin
• Imaging based of preferential metastasis for cancer type
• FDG PET to assess rate of glycolysis
• FDG uptake increased in most malignant (inflammation,
trauma, infection)
• TNM staging system
• (T) tumor size; (N) nodal involvement  presence of LN
vs number vs size; (M) metastasis  M0 to M1
• Note in new AJCC guidelines – clinically evident nodes =
more advanced stage (N).
Q: Cancer Staging
• Which of the following is the most important
prognostic determinant of survival after
treatment of colorectal cancer?
1.
2.
3.
4.
5.
LN involvement
Transmural extension
Tumor size
Histologic differentiation
DNA content
Q: Cancer Staging
• Which of the following is the most important
prognostic determinant of survival after
treatment of colorectal cancer?
1.
2.
3.
4.
5.
LN involvement
Transmural extension
Tumor size
Histologic differentiation
DNA content
Surgical Approach to
Cancer
• Multidisciplinary Approach to Cancer
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Surgical technique
Alternatives to surgery
Reconstructive options
Indications for and complications of preop and
postop chemotherapy and radiation
• Appropriate adjuvant therapy/Sequence of
therapy
***Multidisciplinary approach***
Surgical Mgmt of Primary
Tumors
• Goal: Achieve widely negative margins with no evidence of macroscopic
or microscopic tumor at the surgical margins
• Operability of tumor is best determined with preop imaging (ie. Size/tumor
extension; distant mets?)
• Inking margins, orientation, frozen section analysis
• Bigger isn’t better?
• Sarcoma: wide local instead of compartmental rsxns
• Breast CA: partial mastectomies, skin sparing and breast conserving
replacing radical mastectomies
• -ve microscopic surgical margins for survival and local control (rectal, breast,
sarcomas and pancreatic CA)
• Optimum surgical margins for each cancer type??
• Melanomas: <1mm thick=1cm margins; >1mm thick=2cm margins
• Adjuvant radiation and systemic therapy if increased risk of local recurrence
• Adjuvant therapy ≠ adequate surgery
Surgical Mgmt of
Regional LNs
• Remove the primary and draining lymphatics
en bloc
• CRC, gastric cancers  Primary tumor site
adjacent to tumor bed
• LN resection through a different incision
• Melanomas  LN basin not immediately
adjacent
Lymphadenectomy
• Halsted view: lymphadenectomy is important for
staging and survival
• Opposing view: lymphadenectomy is useful for
staging, but doesn’t affect survival.
• Removal of larger number of LNs = improved
overall survival for many tumors
• ?surgeon performs wider margins
• ?Pathology examination more extensive
Lymphatic
Mapping/Sentinel LN
• First reported in 1977 by Cabanas for penile CA
• Sentinel node biopsy  standard of care in melanoma
and breast cancer
• First node to receive drainage from the tumor site
• Predicts the status of the remaining regional LNs
• Avoids morbidity of LN dissections in –ve nodes
• False negative rates: 0-11%
• ?D/t surgical error vs cancer cells not metastasizing to
first node encountered?
• Increase in identification and decrease in false negative
as surgical experience is gained
Sentinel Node Concept
Picture from: Schwartz’s
Lymphatic
Mapping/Sentinel LN
• Combination of isosulfan blue and technetiumlabeled sulfur colloid or albumin
• “hot” or blue nodes identified with gamma
probe and nodal exploration
• Manual palpation also decreases false-negative
rate
• Lymphoscintigraphic imaging
is usually done several hours
prior to biopsy
Picture from: Schwartz’s
SLNB in Breast CA
• SLNB is used as an alternative to ALND for the diagnosis of
axillary mets in pts with clinically node-negative early breast CA
• SLN identified ~96% of cases
• Predicts the status of the remaining axillary LNs ≥95% of cases
• False negative result 5-10%, but lower rates attainable by
experienced surgeons
• Decreases risk of lymphedema and other arm morbidity by avoid
ALND
• Lymphedema 2% after SLNB; 13% after ALND (ACOSOG)
Q: Breast CA
• With regard to the natural history of breast cancer,
which of the following statements in true?
1.
2.
3.
4.
5.
Virtually all patients with untreated breast CA die
within 2 years of their diagnosis
The likelihood of distant mets is related to the size of
the primary tumor and involvement of the axillary
nodes
The most common initial site for distant mets is the
liver
Stage for stage, the survival rate for breast cancer in
males is lower than that in females
Survival is longer in patients who undergo mastectomy
than in patients who undergo breast conservation for
stage I and II breast carcinoma
Q: Breast CA
• With regard to the natural history of breast cancer,
which of the following statements in true?
1.
2.
3.
4.
5.
Virtually all patients with untreated breast CA die
within 2 years of their diagnosis
The likelihood of distant mets is related to the size of
the primary tumor and involvement of the axillary
nodes
The most common initial site for distant mets is the
liver
Stage for stage, the survival rate for breast cancer in
males is lower than that in females
Survival is longer in patients who undergo mastectomy
than in patients who undergo breast conservation for
stage I and II breast carcinoma
Lymphatic Mapping and
SLNB in Melanoma
• Metastasize through LN, most important
prognostic factor for primary disease
• Lymphatic mapping useful to identify LN
basins draining from primary sites with
possible multiple nodal basin drainage
• ie. Head, neck, distal extremities and trunk
• Mapping and SLNB accepted for
extremity and truncal, but the role in
H&N still evolving.
Picture from: Schwartz’s
Surgical Mgmt of Distant
Mets
• Number and sites of mets, cancer type, rate of growth, previous txs and
responses
• Patient selection – age, physical condition, desires
• Cancer type
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ie. Liver mets from colon CA more likely isolated and resectable then
pancreatic liver met
• Growth rate of the tumor
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Disease-free interval
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Longer interval have higher survival after surgical metastasectomy than those
with a short disease free interval
Mets at time of diagnosis worse prognosis then after a disease free interval
• Goal: resection of metastases with negative margins
Q: Cancer Prevention
• Which is an example of primary cancer
prevention?
1.
2.
3.
4.
5.
Removal of polyp with colonoscopy
Tamoxifen for breast cancer chemoprevention
Celecoxib to reduce polyp number/burden in FAP
Pap smear to detect cervical cancer
Mammography to detect non-palpable breast
cancer
Q: Cancer Prevention
• Which is an example of primary cancer
prevention?
1.
2.
3.
4.
5.
Removal of polyp with colonoscopy
Tamoxifen for breast cancer chemoprevention
Celecoxib to reduce polyp number/burden in FAP
Pap smear to detect cervical cancer
Mammography to detect non-palpable breast
cancer
Cancer Prevention
• Primary prevention
• Prevention of initial CA in healthy adults
• Tamoxifen for breast cancer chemoprevention
• Prophylactic surgery
• Secondary prevention
• Prevention of cancer in pts with premalignant conditions
• Celecoxib reduces polyp number and burden in FAP
• Tertiary prevention
• Prevention of second primary cancers in those cured of initial
• 13-cis-retinoic acid reverse oral leukolakia and reduce second primary tumor
development
• Surgeons will likely be involved in diagnosis of premalignant and
malignant conditions so should be aware of chemopreventative options
Cancer Prevention
• High risk of cancer  surgical prevention
• Hereditary breast-ovarian syndrome (BRCA1
BRCA2)
• Hereditary diffuse gastric cancer
• Multiple endocrine neoplasia 2
• Familial adenomatous polyposis
• Hereditary nonpolyposis colorectal cancer
• Ulcerative colitis
Trend in Surgical Therapy
• Screening and Diagnosis
• Serum markers, improved imaging  earlier detection
• Conservative resections
• Early identification allows for conservative surgery
• Goal always to remove tumor en bloc with negative margins
• Destruction of tumors
• Radiofrequency ablation, lasers etc
• Experimental
• Systemic Therapy
• Transcriptional profiling to understand molecular properties that
respond to certain agents
• Spare some patients toxicity of drugs in known to have poor
response
Questions:
• Genomic instability increases the chance of specific
gene mutations ultimately responsible for the various
phenotypes of cancer cells. Which of the following
statements about genomic instability is TRUE?
1.
2.
3.
4.
The tumor suppressor gene p53 plays a critical role in
genomic stability
The presence of the ras-oncogene causes genetic
instability
Local over expression of TGF-B may lead to genomic
instability in areas of chronic inflammation
DNA mismatch repair genes (MMR) can compensate
for most causes of genetic instability
Questions:
• Genomic instability increases the chance of specific
gene mutations ultimately responsible for the various
phenotypes of cancer cells. Which of the following
statements about genomic instability is TRUE?
1.
2.
3.
4.
The tumor suppressor gene p53 plays a critical role in
genomic stability
The presence of the ras-oncogene causes genetic
instability
Local over expression of TGF-B may lead to genomic
instability in areas of chronic inflammation
DNA mismatch repair genes (MMR) can compensate
for most causes of genetic instability
Questions:
• Regarding the biology of malignant neoplasms, which
of the following statements are TRUE?
1.
2.
3.
4.
Most malignant neoplasms arise from a single cell that
has undergone transformation to form a malignant
clone
Cancer cells proliferate faster than normal cells and the
rate of proliferation increases as the tumor mass
increases
Malignant cells are characterized by reversion to more
primitative cell types, cellular monomorphism, and
increased cohesion
Tumors double in size at least every 20 days and
therefore essentially all human neoplasms are clinically
detectable within one year after the inception of
neoplastic transformation
Questions:
• Regarding the biology of malignant neoplasms, which
of the following statements are TRUE?
1.
2.
3.
4.
Most malignant neoplasms arise from a single cell that
has undergone transformation to form a malignant
clone
Cancer cells proliferate faster than normal cells and the
rate of proliferation increases as the tumor mass
increases
Malignant cells are characterized by reversion to more
primitative cell types, cellular monomorphism, and
increased cohesion
Tumors double in size at least every 20 days and
therefore essentially all human neoplasms are clinically
detectable within one year after the inception of
neoplastic transformation
Questions:
• A 60 year old man has unresectable pancreatic
carcinoma. This has resulted in gastric outlet
obstruction and obstructive jaundice. He has no other
co-morbid factors. When considering palliative
treatment, which of the following statements is NOT
true?
1.
2.
3.
4.
Percutaneous biliary drainage will relieve his obstrutive
jaundice and lessen his pruritis
The patient should participate in the choice of
treatment plan after being informed of the options and
risks
If the patient desires, the family may assist him in
making decisions
Palliative operation is not indicated because his
estimated survival is less than three months.
Questions:
• A 60 year old man has unresectable pancreatic
carcinoma. This has resulted in gastric outlet
obstruction and obstructive jaundice. He has no other
co-morbid factors. When considering palliative
treatment, which of the following statements is NOT
true?
1.
2.
3.
4.
Percutaneous biliary drainage will relieve his obstrutive
jaundice and lessen his pruritis
The patient should participate in the choice of
treatment plan after being informed of the options and
risks
If the patient desires, the family may assist him in
making decisions
Palliative operation is not indicated because his
estimated survival is less than three months.
Questions:
• Which of the following viruses are not
associated with malignancy?
1.
2.
3.
4.
5.
HBV
HCV
EBV
CMV
HTLV-1
• Which of the following viruses are not
associated with malignancy?
1.
2.
3.
4.
5.
HBV
HCV
EBV
CMV
HTLV-1
References
• Schwart’s Principles of Surgery
• UptoDate
• RUSH University Medical Center Review of
Surgery
Thank you