Week 3: Tumor Biology & Clinical Behavior
LECTURE: SECOND MALIGNANCY RISK IN SURVIVORS OF HL & TESTICULAR CANCER Monday, 12/11/2018
Effects of cancer Tx = undesired consequence of Tx; risk of surviving cancer is increasing, however secondary cancer is also
possible to arise (e.g. breast cancer after lymphoma is it really secondary cancer?)
Somatic SE: second malignancy (mostly occur long after chemoTx, e.g. 10-20 years), cardiovascular disease, infertility, etc
HL & testicular cancer: 33% of new cancer in young adults, already occur at early age (high chance to reduce productivity),
excellent prognosis & high survival rate good models for late effects of cancer
Testicular cancer: (different origin)
a. Seminoma radiation-sensitive
b. Non-seminoma radiation-insensitive, requires combination chemoTx
Cause of second malignancy: aging long-term survival = risk of cancer >>, Tx consequence, lifestyle & environment, genetic
susceptibility (BRCA, Lynch, SNP variant)
Reasons for occurrence of 2 primary malignancies:
a. Host susceptibility (e.g. genetic predisposition, immunodeficiency, hormones, etc)
b. Common carcinogenic influences (smoking, obesity, alcohol use)
c. Tx of first tumor
d. Chance (unrelated to first cancer)
Tx related risk factor:
a. radioTx: any cancer, long-term increase risk of cancer in irradiated sites
b. chemoTx: systemic effect
AML & myelodysplastic syndrome d/t alkylating agents characterized by specific chromosome
rearrangements, short term occurrence/soon after Tx, e.g. 1-8 years after chemoTx, poorer prognosis!
Solid malignancy (d/t procarbazine, anthracyclines, cisplatin) new data emerging!
c. Hormonal agents (e.g. tamoxifen-related endometrial cancer following breast cancer Tx)
d. ImmunoTx
Determining factors of time to occurrence of secondary malignancy: dx, lifestyle, genetic alterations, tx approach (shorter
time span among patients treated with combination tx)
Radiotherapy in HL & testicular cancer
HL: large, extended radiation field involve many
Lnn, using high energy radiation Tx e.g. Linac
(“bombing” the tumor), allow prophylactic
irradiation to prevent disease progression; more
organ exposed = risk of SE >>
Testicular cancer: lower dose of radiation is
sufficient because seminoma is radiation sensitive;
for non-seminoma, the radioTx dose is greater
SIR = standardized incidence risk observed/expected incidence ratio; some cancer has increased risk to develop
secondary malignancy following Tx
Leukemia SIR = high, leukemia incidence = low (after 5 year follow up) leukemia is a rare disease in population, low cases
found compared to other cancers
, Week 3: Tumor Biology & Clinical Behavior
AER = absolute excess number of cases per 10000 patients/year burden of leukemia is low
Testicular cancer Tx: platinum based chemotx + orchidectomy current tx protocol: castration + observation (to alleviate the
risk of chemoTx), if needed: reduced cycles of cisplatin-based chemotx
SIR can also be affected by the choice of Tx & its side effects increased SIR for soft tissue sarcoma, pancreas, stomach cancer,
etc following non-seminoma testicular cancer Tx
Radiation dose-response for second solid cancer risk
Linear increase w/ higher dose for breast, lung, stomach, pancreas, esophagus & sarcoma
Not all tissue receive the same dose (radiation dose varies between regions of the cancer) affect the risk of secondary
malignancy; healthy organ is exposed to radiation waves at higher volume, using involved field radioTx reduce occurrence of
secondary cancer
Chemotherapy for HL & testicular cancer
Increased number of cycle = increased risk of SE adjust cycle protocol for reduction of SE (milder regimen), yet recurrence
still possible
Low radiation dose = less effect of chemoTx may reduce the risk of SE to healthy organ
Cisplatin: forming DNA adducts, platinum = heavy metal = slow to be eliminated (still traces of platinum after 20 years of
chemoTx), associated w/ long term effect
Tumor blocks of secondary malignancy following testicular cancer look for DNA adducts in tumor blocks (proving the
presence of cisplatin in the secondary tumor tissue)
What are the risks of decreased cisplatin elimination?
Environmental factors
Smoking increases risk of secondary malignancy following radioTx & chemoTx (e.g. lung cancer following HL) HL patients
who don’t smoke have less chance to develop lung cancer following HL tx
Future strategies:
Develop new Tx protocol with low toxicity & equal Tx effectiveness
Identification of high risk patients
Opportunities:
a. Adapted Tx
Lower volume/dose of radiotx
Lower dose of chemotx
Risk adapted tx (prognostic factor) based on genetic profile for late effects
Weighing benefit & harm risk prediction model from all the Tx possibilities (adjusted for age, Dx, sex, etc)
b. Lifestyle advice & chemoprevention
Smoking cessation
Low dose tamoxifen for childhood cancer survivor
c. Survivor monitoring
Identify high-risk group for SE (cancer/non-cancer)
Survivorship clinic
Screening (introduced much earlier than general population, e.g. several years after Tx irrespective of age)
, Week 3: Tumor Biology & Clinical Behavior
LECTURE: INTRAOPERATIVE FLUORESCENCE IMAGING (R. Meijer) Monday, 12/11/2018
Unmet needs in cancer treatment:
a. Surgery is mainstay of tx in solid cancer
Completeness of surgery improve prognosis
Prevent positive margin minimizing residual tumor to improve outcome
b. Intraoperative identification of tumor tissue is difficult
c. Need of intraoperative modalities that can identify tumor tissue
d. Improve intraoperative tumor detection by targeting specific surface receptor
Image-guided surgery modalities
a. (pre/intraoperative) Ultrasound tumor localization in liver
b. Contrast-guided surgery
Fluorescence guided surgery (FGS)
NIR camera + colour vid + collection optics + contrast
agent + light source (NIR: LED/laser, visible light)
Tumor is seen as green/coloured image (colour-NIR
merge)
Why optical imaging
a. Using NIR able to visualize areas invisible to
human eye
b. Fast acquisition
c. High tissue penetration
d. Easy to combine with contrast & camera system
Fluorescent contrast agent: clinically approved as off
label use (indocyanine green, methylene blue) time of
administration: depend on the substance; detecting
smaller lesions unseen to naked eye/CT/MRI
Improvement required for fluorescence-guided surgery:
a. Tumor-targeted contrast agent certain protein expressed in tumor surface
Make sure fluorescence bind to tumor only, leaving healthy tissue unmarked (healthy tissue vs. normal tissue)
b. Preclinical study
c. Clinical translation
Agent & tumor characteristics:
Overexpression of target in tumor tissue (multiple targets are possible) risk of spectral interference, reduce the
interference: 2 different agents, 2 different wavelength, 2 different time imaging
High probability of expression observed in all patients with that tumor
Cell surface target (close proximity to the tumor)
Homogenous upregulation (evenly expressed in all parts of the tumor)
LECTURE: SECOND MALIGNANCY RISK IN SURVIVORS OF HL & TESTICULAR CANCER Monday, 12/11/2018
Effects of cancer Tx = undesired consequence of Tx; risk of surviving cancer is increasing, however secondary cancer is also
possible to arise (e.g. breast cancer after lymphoma is it really secondary cancer?)
Somatic SE: second malignancy (mostly occur long after chemoTx, e.g. 10-20 years), cardiovascular disease, infertility, etc
HL & testicular cancer: 33% of new cancer in young adults, already occur at early age (high chance to reduce productivity),
excellent prognosis & high survival rate good models for late effects of cancer
Testicular cancer: (different origin)
a. Seminoma radiation-sensitive
b. Non-seminoma radiation-insensitive, requires combination chemoTx
Cause of second malignancy: aging long-term survival = risk of cancer >>, Tx consequence, lifestyle & environment, genetic
susceptibility (BRCA, Lynch, SNP variant)
Reasons for occurrence of 2 primary malignancies:
a. Host susceptibility (e.g. genetic predisposition, immunodeficiency, hormones, etc)
b. Common carcinogenic influences (smoking, obesity, alcohol use)
c. Tx of first tumor
d. Chance (unrelated to first cancer)
Tx related risk factor:
a. radioTx: any cancer, long-term increase risk of cancer in irradiated sites
b. chemoTx: systemic effect
AML & myelodysplastic syndrome d/t alkylating agents characterized by specific chromosome
rearrangements, short term occurrence/soon after Tx, e.g. 1-8 years after chemoTx, poorer prognosis!
Solid malignancy (d/t procarbazine, anthracyclines, cisplatin) new data emerging!
c. Hormonal agents (e.g. tamoxifen-related endometrial cancer following breast cancer Tx)
d. ImmunoTx
Determining factors of time to occurrence of secondary malignancy: dx, lifestyle, genetic alterations, tx approach (shorter
time span among patients treated with combination tx)
Radiotherapy in HL & testicular cancer
HL: large, extended radiation field involve many
Lnn, using high energy radiation Tx e.g. Linac
(“bombing” the tumor), allow prophylactic
irradiation to prevent disease progression; more
organ exposed = risk of SE >>
Testicular cancer: lower dose of radiation is
sufficient because seminoma is radiation sensitive;
for non-seminoma, the radioTx dose is greater
SIR = standardized incidence risk observed/expected incidence ratio; some cancer has increased risk to develop
secondary malignancy following Tx
Leukemia SIR = high, leukemia incidence = low (after 5 year follow up) leukemia is a rare disease in population, low cases
found compared to other cancers
, Week 3: Tumor Biology & Clinical Behavior
AER = absolute excess number of cases per 10000 patients/year burden of leukemia is low
Testicular cancer Tx: platinum based chemotx + orchidectomy current tx protocol: castration + observation (to alleviate the
risk of chemoTx), if needed: reduced cycles of cisplatin-based chemotx
SIR can also be affected by the choice of Tx & its side effects increased SIR for soft tissue sarcoma, pancreas, stomach cancer,
etc following non-seminoma testicular cancer Tx
Radiation dose-response for second solid cancer risk
Linear increase w/ higher dose for breast, lung, stomach, pancreas, esophagus & sarcoma
Not all tissue receive the same dose (radiation dose varies between regions of the cancer) affect the risk of secondary
malignancy; healthy organ is exposed to radiation waves at higher volume, using involved field radioTx reduce occurrence of
secondary cancer
Chemotherapy for HL & testicular cancer
Increased number of cycle = increased risk of SE adjust cycle protocol for reduction of SE (milder regimen), yet recurrence
still possible
Low radiation dose = less effect of chemoTx may reduce the risk of SE to healthy organ
Cisplatin: forming DNA adducts, platinum = heavy metal = slow to be eliminated (still traces of platinum after 20 years of
chemoTx), associated w/ long term effect
Tumor blocks of secondary malignancy following testicular cancer look for DNA adducts in tumor blocks (proving the
presence of cisplatin in the secondary tumor tissue)
What are the risks of decreased cisplatin elimination?
Environmental factors
Smoking increases risk of secondary malignancy following radioTx & chemoTx (e.g. lung cancer following HL) HL patients
who don’t smoke have less chance to develop lung cancer following HL tx
Future strategies:
Develop new Tx protocol with low toxicity & equal Tx effectiveness
Identification of high risk patients
Opportunities:
a. Adapted Tx
Lower volume/dose of radiotx
Lower dose of chemotx
Risk adapted tx (prognostic factor) based on genetic profile for late effects
Weighing benefit & harm risk prediction model from all the Tx possibilities (adjusted for age, Dx, sex, etc)
b. Lifestyle advice & chemoprevention
Smoking cessation
Low dose tamoxifen for childhood cancer survivor
c. Survivor monitoring
Identify high-risk group for SE (cancer/non-cancer)
Survivorship clinic
Screening (introduced much earlier than general population, e.g. several years after Tx irrespective of age)
, Week 3: Tumor Biology & Clinical Behavior
LECTURE: INTRAOPERATIVE FLUORESCENCE IMAGING (R. Meijer) Monday, 12/11/2018
Unmet needs in cancer treatment:
a. Surgery is mainstay of tx in solid cancer
Completeness of surgery improve prognosis
Prevent positive margin minimizing residual tumor to improve outcome
b. Intraoperative identification of tumor tissue is difficult
c. Need of intraoperative modalities that can identify tumor tissue
d. Improve intraoperative tumor detection by targeting specific surface receptor
Image-guided surgery modalities
a. (pre/intraoperative) Ultrasound tumor localization in liver
b. Contrast-guided surgery
Fluorescence guided surgery (FGS)
NIR camera + colour vid + collection optics + contrast
agent + light source (NIR: LED/laser, visible light)
Tumor is seen as green/coloured image (colour-NIR
merge)
Why optical imaging
a. Using NIR able to visualize areas invisible to
human eye
b. Fast acquisition
c. High tissue penetration
d. Easy to combine with contrast & camera system
Fluorescent contrast agent: clinically approved as off
label use (indocyanine green, methylene blue) time of
administration: depend on the substance; detecting
smaller lesions unseen to naked eye/CT/MRI
Improvement required for fluorescence-guided surgery:
a. Tumor-targeted contrast agent certain protein expressed in tumor surface
Make sure fluorescence bind to tumor only, leaving healthy tissue unmarked (healthy tissue vs. normal tissue)
b. Preclinical study
c. Clinical translation
Agent & tumor characteristics:
Overexpression of target in tumor tissue (multiple targets are possible) risk of spectral interference, reduce the
interference: 2 different agents, 2 different wavelength, 2 different time imaging
High probability of expression observed in all patients with that tumor
Cell surface target (close proximity to the tumor)
Homogenous upregulation (evenly expressed in all parts of the tumor)
