1. Oncologic disorders
AD

2. Oncologic disorders
• Carcinogenesis is a multi-step process that includes
initiation, promotion, conversion, and progression.
– The growth of both normal and cancerous cells is
genetically controlled by the balance or imbalance of
oncogene (genes controlling cell growth and
multiplication), proto-oncogene (potential cancer
producing gene), and tumor suppressor gene protein
products.
– Multiple genetic mutations are required to convert
normal cells to cancerous cells.
– Apoptosis and cellular senescence (aging) are normal
mechanisms for cell death.

3. Oncologic disorders
• Cancer is a group of more than 100 different
diseases, characterized by uncontrolled
cellular growth, local tissue invasion, and
distant metastases.
Carcinogenesis
– The mechanism by which cancers occur is
incompletely understood.

4. Oncologic disorders
– Acancer, or neoplasm, is thought to develop from a
cell in which the normal mechanisms for control of
growth and proliferation are altered.
– Current evidence supports the concept of
carcinogenesis as a multistage process that is
genetically.
– The first step in this process is initiation, which
requires exposure of normal cells to carcinogenic
substances.
– These carcinogens produce genetic damage that, if
not repaired, results in irreversible cellular
mutations.

5. Oncologic disorders
• This mutated cell has an altered response to its
environment and a selective growth advantage,
giving it the potential to develop into a clonal
population of neoplastic cells.
• During the second phase, known as promotion,
carcinogens or other factors alter the
environment to favor growth of the mutated cell
population over normal cells.
• The primary difference between initiation and
promotion is that promotion is a reversible
process.

6. Oncologic disorders
• In fact, because it is reversible, the promotion phase
may be the target of future chemoprevention
strategies, including changes in lifestyle and diet.
• At some point, however, the mutated cell becomes
cancerous (conversion or transformation).
• Depending on the type of cancer, 5 to 20 years may
elapse between the carcinogenic phases and the
development of a clinically detectable cancer.
• The final stage of neoplastic growth, called
progression, involves further genetic changes leading
to increased cell proliferation.

7. Breast Cancer
Breast Cancer
DEFINITION
– Breast cancer is a malignancy originating from
breast tissue.
– This portion distinguishes between early stages,
which are potentially curable, and metastatic
breast cancer, which is usually incurable.

8. Breast Cancer
• PathophysiologY
– The development of malignancy is a multistep
process with preinvasive (or noninvasive) and
invasive phases.
– The strongest risk factors are female gender and
increasing age.
– Additional risk factors include endocrine factors
(e.g., early menarche, nulliparity, late age at first
birth (≥30 years), estrogen therapy), genetics (e.g.,
personal and family history, mutations of tumor
suppresser genes [BRCA1 and BRCA2]), and
environment (e.g., radiation exposure).

9. Breast Cancer
• Breast cancer spreads via the bloodstream early
in the course of the disease, resulting in relapse
and metastatic disease after local therapy.
– The most common metastatic sites are lymph nodes,
skin, bone, liver, lungs, and brain.
• The likelihood of developing metastatic disease
is related to prognostic factors as described
below.

10. Breast Cancer
CLINICAL PRESENTATION
• The initial sign in more than 90% of women with
breast cancer is a painless lump that is typically
solitary, unilateral, solid, hard, irregular, and
nonmobile.
– Less common initial signs are pain and nipple changes.
– More advanced cases present with prominent skin
edema, redness, warmth, and induration.
• Symptoms of metastatic breast cancer include bone
pain, difficulty breathing, abdominal enlargement,
jaundice, and mental status changes.

11. Breast Cancer
• Approximately 80% of women first detect some breast
abnormalities themselves.
• It is increasingly common for breast cancer to be detected
during routine screening mammography in asymptomatic
women.
DIAGNOSIS
• Initial workup for a woman presenting with a localized
lesion or suggestive symptoms should include a careful
history, physical examination of the breast, three-
dimensional mammography, and possibly other breast
imaging techniques such as ultrasound.
• Breast biopsy is indicated for a mammographic
abnormality that suggests malignancy or a mass that is
palpable on physical examination.

12. Breast Cancer
STAGING
• Stage is based on the size of the primary tumor
presence and extent of lymph node involvement
and presence or absence of distant metastases
(M).
– Simplistically stated, these stages may be
represented as follows:
• Early Breast Cancer
– Stage 0: Carcinoma in situ or disease that has not
invaded the basement membrane.
– Stage I: Small primary tumor without lymph node
involvement.

13. Breast Cancer
– Stage II: Metastasis to ipsilateral axillary lymph
nodes.
– Locally Advanced Breast Cancer
– Stage III: Usually a large tumor with extensive nodal
involvement in which node or tumor is fixed to the
chest wall; also includes inflammatory breast cancer,
which is rapidly progressive.
• Advanced or Metastatic Breast Cancer
– Stage IV: Metastases to organs distant from the
primary tumor.

14. Breast Cancer
PATHOLOGIC EVALUATION
• The pathologic evaluation of breast lesions
establishes the histologic diagnosis and
presence or absence of prognostic factors.
• Most breast carcinomas are adenocarcinomas
and are classified as ductal or lobular.
• Carcinoma in situ may be a preinvasive cancer or
a marker of unstable epithelium that represents
an increased risk for developing aggressive
cancer.

15. Breast Cancer
PROGNOSTIC FACTORS
• Tumor size and the presence and number of
involved axillary lymph nodes are primary
factors in assessing the risk for breast cancer
recurrence and subsequent metastatic disease.
• Hormone receptors are used as indicators of
prognosis and to predict response to hormone
therapy.
• The rate of tumor cell proliferation, nuclear
grade, and tumor (histologic) differentiation are
also independent prognostic research factors.

16. Breast Cancer
• Additional potential prognostic factors include
overexpression of erb-B2 oncogene (or HER-
2/neu), cathepsin-D, angiogenic growth factors,
and mutations in the tumor suppressor p53
gene.
– HER-2/neu status is of interest because targeted
therapy is available; however, the testing method is
controversial.
– The widely used method, immunohistochemistry
(IHC), can yield false-positive results at the 2+ level,
which should be confirmed by fluorescence in situ
hybridization (FISH) testing.

17. Breast Cancer
TREATMENT
• The treatment of breast cancer is rapidly
evolving.
– Specific information regarding the most
promising interventions can be found only in the
primary literature.
– Treatment can cause substantial toxicity, which
differs depending on the individual agent,
administration method, and combination
regimen.

18. Breast Cancer
EARLY BREAST CANCER
Local-Regional Therapy
– Surgery alone can cure most patients with in situ cancers
and approximately half of those with stage II cancers.
– Breast conservation is appropriate primary therapy for
most women with stages I and II disease; it is preferable
to modified radical mastectomy because it produces
equivalent survival rates with cosmetically superior
results.
– Breast conservation consists of lumpectomy (i.e.,
excision of the primary tumor and adjacent breast tissue)
followed by radiation therapy to prevent local recurrence.

19. Breast Cancer
• Primary systemic or neoadjuvant therapy, which is
administered before surgery, is gaining favor.
– Advantages include shrinking the tumor, making inoperable
tumors resectable, assessing in vivo response to
chemotherapy, and, in patients with complete pathologic
response, prolonging disease-free survival.
• Simple or total mastectomy involves removal of the entire
breast without dissection of underlying muscle or axillary
nodes.
– This procedure is used for carcinoma in situ where the
incidence of axillary node involvement is only 1%, for local
recurrence following breast conservation therapy, or to avoid
the inconvenience of radiation therapy and preserve the
option for future breast reconstruction.

20. Breast Cancer
• Axillary lymph nodes should be sampled for staging and
prognostic information.
– Lymphatic mapping with sentinel lymph node biopsy is a new,
less invasive alternative to axillary dissection; however, the
procedure is controversial because of the lack of long-term
data.
Systemic Adjuvant Therapy
• Systemic adjuvant therapy is the administration of
systemic therapy following surgery, radiation, or both.
– There is no evidence of metastatic disease but a high
likelihood of recurrence because of undetectable
micrometastases.
• The goal of such therapy is cure.

21. Breast Cancer
• The choice between chemotherapy and endocrine
therapy, or both, as adjuvant therapy is evolving.
• Essentially all women with stage I and stage II breast
cancer derive some benefit from chemotherapy, but
the absolute benefit is greater in premenopausal
women.
• The National Comprehensive Cancer Network (NCCN)
practice guidelines reflect the trend toward the use of
chemotherapy in all women regardless of
menopausal status, and the addition of endocrine
therapy in all women with receptor-positive disease
regardless of menopausal status.

22. Breast Cancer
• Adjuvant Chemotherapy
– Many combination regimens are used in the
adjuvant setting, which are typically derived
from those that produce the highest response
rate in advanced disease.
– Doxorubicin-containing regimens are popular
because they are superior to cyclophosphamide,
methotrexate, and fluorouracil (CMF) and require
only four cycles.

23. Breast Cancer
• Taxanes, docetaxel and paclitaxel, are a newer
class with activity against metastatic breast
cancer rivaling that of anthracyclines.
• When used in combination regimens or given
sequentially (e.g., doxorubicin and
cyclophosphamide followed by paclitaxel [AC
T]), taxanes increase disease-free survival in
women with node-positive breast cancer.
• Follow-up, however, is insufficient to assess
impact on the decisive endpoint, overall
survival.

24. Breast Cancer
• Clinical trials are being conducted to evaluate
newer agents (e.g., trastuzumab).
• Chemotherapy should be initiated within 3
weeks of surgical removal of the primary
tumor.
• The optimal duration of treatment is about 12
to 24 weeks.

25. Breast Cancer
• Dose intensity refers to the amount of drug
administered per unit of time, which can be
increased by increasing dose, decreasing time,
or both.
– Dose density is equivalent to dose intensity except
that it is increased only by decreasing time.
– Dose intensity, but not density, is an important
determinant of outcome in adjuvant therapy.

26. Breast Cancer
– Therefore, the dose of standard regimens should
not be reduced unless necessitated by severe
toxicity.
• The short-term toxicities of chemotherapy
are generally well tolerated in the adjuvant
setting, especially with the availability of
serotonin-antagonist antiemetics and colony-
stimulating factors.

29. Breast Cancer
• Adjuvant Endocrine Therapy
– Tamoxifen is the gold standard for adjuvant endocrine
therapy because of extensive trial experience showing
decreased recurrence and mortality.
– Additional benefits include estrogenic effects on lipids
and bone density.
• The optimal daily dose of tamoxifen is 20 mg,
beginning soon after completing chemotherapy
and continuing for five years.

30. Breast Cancer
• Tamoxifen is usually well tolerated.
– Symptoms of estrogen withdrawal (hot flashes
and vaginal bleeding) may occur but decrease in
frequency and intensity over time.
– Tamoxifen increases the risks of stroke, pulmonary
embolism, deep vein thrombosis, and endometrial
cancer, especially in women older than 50 years of
age.

31. Breast Cancer
• Other endocrine therapies show promise, but
trials have insufficient follow-up to assess
impact on survival.
– Such options included toremifene as an
alternative to tamoxifen; the luteinizing hormone-
releasing hormone (LHRH), goserelin, for
premenopausal women; and aromatase inhibitors,
either in place of or after tamoxifen, for
postmenopausal women.

32. Breast Cancer
• LOCALLY ADVANCED BREAST CANCER (STAGE III)
– Local-regional therapy with surgery, radiation, or both
does not cure locally advanced breast cancer.
– Primary or neoadjuvant or chemotherapy is the initial
treatment of choice.
• Benefits include rendering inoperable tumors resectable
and increasing the rate of breast-conserving surgery.
– Combination regimens used as primary chemotherapy
are similar to those used as adjuvant therapy and
generally include an anthracycline and taxane.

33. Breast Cancer
• METASTATIC BREAST CANCER (STAGE IV)
– The choice of therapy for metastatic disease is based
on the site of disease involvement and presence or
absence of certain characteristics, as described
below.
• Endocrine Therapy
– Endocrine therapy is the treatment of choice for
patients who have hormone receptor-positive
metastases in soft tissue; bone; pleura; or, if
asymptomatic.
• Compared with chemotherapy, endocrine therapy has an
equal probability of response and a better safety profile.

34. Breast Cancer
• Patients are sequentially treated with endocrine
therapy until they have rapidly growing metastatic
disease, at which time chemotherapy can be given.
• Because most endocrine therapies are equally
effective, the choice is based primarily on toxicity .
• Tamoxifen is usually the agent of choice in both
premenopausal and postmenopausal women whose
tumors are hormone-receptor positive, unless
metastases occur within a year of adjuvant tamoxifen.

35. Breast Cancer
• Maximal beneficial effects do not occur for 2
months or more.
• In addition to the side effects described for
adjuvant therapy, tumor flare or hypercalcemia
occurs in approximately 5% of patients with
metastatic breast cancer.
• This may be a positive indication that the patient
will have a response to endocrine therapy.

36. Breast Cancer
• New antiestrogens are being developed to maintain
tamoxifen's beneficial effects on breast cells, bone, and
lipids and avoid its effects on the endometrium.
– The new antiestrogen, toremifene, appears to have efficacy
and safety similar to that of tamoxifen, but it is not suitable for
tamoxifen-refractory disease because of cross-resistance.
• Ovarian ablation (oophorectomy) is considered by some
to be the endocrine therapy of choice in premenopausal
women and produces similar overall response rates as
tamoxifen.
– Medical castration with an LHRH analogue, goserelin,
leuprolide, or triptorelin, is a reversible alternative to ovarian
ablation.

37. Breast Cancer
• Aromatase inhibitors reduce circulating estrogens
by blocking peripheral conversion from an
androgenic precursor, the primary source of
estrogens in postmenopausal women.
– Newer agents are more selective and better tolerated
than the prototype, aminoglutethimide.
– As second-line therapy, anastrozole and exemestane
improve overall survival and tolerability compared
with progestins.

38. Breast Cancer
– As first-line therapy, anastrozole and letrozole
improve time to progression and tolerability
compared with tamoxifen.
• Progestins are generally reserved for third-line
therapy.
– They cause weight gain, fluid retention, and
thromboembolic events.

40. Breast Cancer
• SERM, selective estrogen receptor modulator
• SERD, selective estrogen receptor
downregulator
• LHRH, luteinizing hormone-releasing hormone.

41. Breast Cancer
• Chemotherapy
– Chemotherapy is preferred to endocrine therapy for
women with hormone receptor-negative tumors;
rapidly progressive lung, liver, or bone marrow
involvement; or failure of endocrine therapy.
– The choice of treatment depends on the individual.
Agents used as adjuvant therapy can be repeated
unless the cancer recurred within a year.
• Sequential single-agent regimens are less toxic than
combination regimens, but the latter are used to induce
rapid response for symptomatic bulky metastases.

42. Breast Cancer
• Combinations produce objective responses in
approximately 40% of patients previously
unexposed to chemotherapy, but complete
responses occur in less than 10% of patients.
– The median duration of response is 5 to 12 months;
the median survival is 14 to 33 months.
• Single agents are associated with lower response
rates, but time to progression and overall survival
are similar.
– Single agents are better tolerated, an important
consideration in the metastatic setting.

43. Breast Cancer
• Anthracyclines produce response rates of 50% to 60%
when used as first-line therapy for metastatic breast
cancer.
• Newer single agents, such as paclitaxel (50% to 60%),
docetaxel (54% to 68%), capecitabine (25%),
vinorelbine (30% to 50%), and gemcitabine (13% to
42%), produce impressive response rates in previously
untreated patients.
– Although response rates are lower in previously treated
patients, these agents are useful alternatives for
anthracycline-refractory breast cancer.
– Furthermore, some of these agents are moving to first-line
regimens, often in combination with anthracyclines.

44. Breast Cancer
• Different doses are available for single-agent
therapy of metastatic breast cancer (Table
bellow).
– Weekly paclitaxel administration causes less
myelosuppression and delayed onset of peripheral
neuropathy compared with paclitaxel given every 21
days.
– Trastuzumab, a monoclonal antibody that binds to
HER-2/neu protein, produces responses rates of 15%
to 20% when used as a single agent and prolongs
survival when combined with chemotherapy

47. Breast Cancer
• PREVENTION OF BREAST CANCER
– Tamoxifen, 20 mg daily, reduced the incidence of
estrogen-receptor-positive breast cancer by 48%
in a meta-analysis of women at risk for developing
breast cancer.
– Because adverse effects may be unacceptable
when tamoxifen is used as preventive therapy,
candidates should be informed of potential
benefits and risks.

48. Colorectal Cancer
• Colorectal Cancer
DEFINITION
– Colorectal cancer is a malignant neoplasm
involving the colon, rectum, and anal canal.
PATHOPHYSIOLOGY
– Development of a colorectal neoplasm is a
multistep process of genetic and phenotypic
alterations of normal bowel epithelium structure
and function leading to unregulated cell growth,
proliferation, and tumor development.

49. Colorectal Cancer
– Sequential mutations within colonic epithelium
result in cellular replication or enhanced
invasiveness.
– Genetic changes include mutational activation of
oncogenes and inactivation of tumor suppressor
genes.
– Adenocarcinomas account for more than 90% of
tumors of the large intestine.

50. Colorectal Cancer
• CLINICAL MANIFESTATIONS
– Signs and symptoms of colorectal cancer can be
extremely varied, subtle, and nonspecific.
– Patients with early-stage colorectal cancer are
often asymptomatic, and lesions are usually
detected by screening procedures.

51. Colorectal Cancer
• Blood in the stool is the most common sign; however,
any change in bowel habits, vague abdominal
discomfort, or abdominal distention may be a
warning sign.
• Less common signs and symptoms include nausea,
vomiting, and, if anemia is severe, fatigue.
• Approximately 20% of patients with colorectal cancer
present with metastatic disease.
– The most common site of metastasis is the liver, followed
by the lungs and then bones.

52. Colorectal Cancer
TREATMENT
GENERAL PRINCIPLES
• Treatment modalities are surgery, radiation
therapy (XRT), and chemotherapy and
biomodulators.
• Adjuvant therapy is administered after
complete tumor resection to eliminate
residual local or metastatic microscopic
disease.

53. Colorectal Cancer
• Adjuvant therapy differs for colon and rectal cancer
because their natural history and recurrence patterns
differ.
– Rectal cancer is more difficult to resect with wide margins, so
local recurrences are more frequent than with colon cancer.
– Adjuvant XRT plus chemotherapy is considered standard for
stage II or III rectal cancer.
– Adjuvant chemotherapy is standard for stage III colon cancer
and can be considered for high-risk stage II colon cancer.
– Adjuvant therapy is not indicated for stage I colorectal cancer
because most patients are cured by surgical resection alone.

54. Colorectal Cancer
• Neoadjuvant therapy is administered before
surgery to shrink the tumor, there- by making
it resectable.
– Neoadjuvant XRT may also prevent local
recurrence.
• Chemotherapy is the primary treatment
modality for metastatic colorectal cancer.
– Treatment options are generally similar for
metastatic cancer of the colon and rectum.

55. Colorectal Cancer
SURGERY
– Surgical removal of the primary tumor is the
treatment of choice for most patients with operable
disease.
– Surgery for colon cancer generally involves complete
tumor resection with an appropriate margin of
tumor-free bowel and a regional lymphadenectomy.
– Surgery for rectal cancer depends on the area
involved.
• Although less than 33% of these patients require
permanent colostomy, frequent complications include
urinary retention, incontinence, impotence, and local-
regional recurrence.

56. Colorectal Cancer
• Common complications of surgery for both
colon and rectal caner include infection,
anastomotic leakage, obstruction, adhesions,
and malabsorption syndromes.
• Surgery is rarely indicated for metastatic
colorectal cancer, except for discrete hepatic
and possibly other metastases that can be
resected.

57. Colorectal Cancer
RADIATION THERAPY
• XRT can be administered with curative surgical
resection to prevent local recurrence of rectal cancer,
before surgery to shrink a rectal tumor and make it
operable, or in advanced or metastatic disease to
alleviate symptoms.
– Adjuvant XRT, however, does not have a definitive role in
colon cancer because recurrences are usually extrapelvic.
• Acute adverse effects associated with XRT include
hematologic depression, dysuria, diarrhea, abdominal
cramping, and proctitis.
– Chronic symptoms may persist for months after XRT and
may involve diarrhea, proctitis, enteritis, small-bowel
obstruction, perineal tenderness, and impaired wound
healing.

58. Colorectal Cancer
CHEMOTHERAPY AND BIOMODULATORS
• Fluoropyrimidines
– Fluorouracil (5-FU) is the most widely used
chemotherapeutic agent for colorectal cancer.
– Biomodulators are usually added to 5-FU to modify its
activity and improve response rates, unless it is
administered by continuous intravenous (IV) infusion.
• Administration method affects clinical activity and
toxicity.
– 5-FU is administered by IV bolus once weekly or daily for 5
days each month, or by continuous IV infusion over 5 days.
– Continuous infusion appears to have better clinical activity,
but bolus administration is more popular in the United
States because of ease of administration and lower cost.

59. Colorectal Cancer
• Continuous IV infusion of 5-FU is generally well
tolerated but is associated with palmar-plantar
erythrodysesthesia or hand-foot syndrome.
– This distinct skin toxicity can be acutely disabling, but it is
reversible and not life-threatening.
– IV bolus administration is associated with leukopenia,
which is dose limiting and can be life-threatening.
– Both methods are associated with a similar incidence of
mucositis, diarrhea, nausea and vomiting, and alopecia.
• Oral cryotherapy reduces the incidence and severity of
stomatitis.
– Patients should chew and hold ice chips in the mouth for 5
minutes before, during, and for 30 minutes after bolus
administration of 5-FU.

60. Colorectal Cancer
• Capecitabine is an oral fluoropyrimidine,
which has efficacy and safety profiles similar
to those of IV infusion of 5-FU.
• Combined 5-FU and XRT results in severe
hematologic toxicity, enteritis, and diarrhea
compared with either chemotherapy or XRT
alone

61. Colorectal Cancer
Biomodulators
• Leucovorin improves 5-FU cytotoxicity.
– Toxicity depends on the regimen.
– High-dose leucovorin is associated with dose-limiting
diarrhea, whereas low-dose leucovorin is associated
with neutropenia and stomatitis.
• Levamisole is a synthetic, oral anthelmintic drug
with immunomodulatory properties.
– Toxicities are generally minimal and reversible.
– Toxicities include metallic taste, arthralgias, central
nervous system (CNS) toxicities (e.g., mood changes,
sleep disorders, or cerebellar ataxia), and hepatic
toxicity.

62. Colorectal Cancer
• Irinotecan
– Irinotecan is a topoisomerase I inhibitor.
– Irinotecan is associated with two distinct patterns
of diarrhea that require appropriate intervention.
– Early-onset diarrhea occurs 2 to 6 hours after
administration and is characterized by lacrimation,
diaphoresis, abdominal cramping, flushing, and/or
diarrhea.
– These cholinergic symptoms respond to atropine
0.25 to 1.0 mg IV or SC.

63. Colorectal Cancer
Oxaliplatin
– Oxaliplatin has a mechanism similar to that of
cisplatin and might have better activity against
colorectal cancer.
– Unlike other platinums, oxaliplatin is associated
with minimal renal toxicity, hematologic toxicity,
and nausea and vomiting.
– Oxaliplatin is associated with neuropathies.
• Acute neuropathy is reversible within 2 weeks, usually
occurs peripherally, and is precipitated by exposure to
cold.

64. Colorectal Cancer
• Monoclonal Antibodies
– Bevacizumab is a humanized monoclonal antibody
directed against vascular endothelial growth
factor (VEGF).
– Bevacizumab does not increase the frequency of
typical adverse events when added to
chemotherapy.
– Bevacizumab is associated with hypertension,
which is easily managed with oral
antihypertensive agents.

65. Colorectal Cancer
• Bevacizumab is also associated with
gastrointestinal perforation.
– This rare, but potentially fatal, complication
necessitates prompt evaluation of abdominal pain
associated with vomiting or constipation.
• Cetuximab is a chimeric monoclonal antibody
directed against epidermal growth factor
receptor (EGFR).
• Cetuximab is generally well tolerated.
– The most common adverse events are acne-like skin
rash, asthenia, lethargy, malaise, and fatigue.

66. Colorectal Cancer
ADJUVANT THERAPY FOR COLON CANCER
• 5-FU combined with leucovorin or levamisole
significantly reduces the risk of relapse and death
in patients with stage III colon cancer.
– 5-FU and leucovorin has become the standard
because a 6-month course is as effective as 12 months
of 5-FU and levamisole.
• The value of adjuvant therapy for stage II colon
cancer is less clear, but high-risk individuals will
probably benefit and should be offered adjuvant
therapy in a clinical trial.

67. Colorectal Cancer
• ADJUVANT AND NEOADJUVANT THERAPY FOR
RECTAL CANCER
– The goal of adjuvant XRT for rectal cancer is to
decrease local tumor recurrence after surgery,
preserve the sphincter, and, with preoperative
radiotherapy, improve resectability.
– 5-FU enhances the cytotoxic effects of XRT.
Compared with XRT alone, the combination
reduces local tumor recurrence and improves
survival in high-risk patients.

70. Lung Cancer
• DEFINITION
– Lung cancer is a solid tumor originating from
bronchial epithelial cells.
– This unit distinguishes between non-small cell
lung cancer (NSCLC) and small cell lung cancer
(SCLC) because they have different natural
histories and responses to therapy.

71. Lung Cancer
PATHOPHYSIOLOGY
• Lung carcinomas arise from pluripotent epithelial cells
after exposure to carcinogens, which cause chronic
inflammation that leads to genetic and cytologic
changes and ultimately to carcinoma.
• Activation of protooncogenes, inhibition or mutation of
tumor suppressor genes, and production of autocrine
growth factors contribute to cellular proliferation and
malignant transformation.
– Molecular changes, such as P53 mutations and
overexpression of epidermal growth factor receptor
(EGFR), also affect disease prognosis and response to
therapy.

72. Lung Cancer
• Cigarette smoking is responsible for about 83% of
lung cancer cases
• Exposure to asbestos, chloromethyl ethers, heavy
metals, polycyclic aromatic hydrocarbons, and
radon has also been implicated.
• The major cell types are SCLC (20% of all lung
cancers), adenocarcinoma (40%), squamous cell
carcinoma (less than 30%), and large cell
carcinoma (15%).
– The last three types are grouped together and
referred to as NSCLC.

73. Lung Cancer
CLINICAL PRESENTATION
• The most common initial signs and symptoms
include cough, dyspnea, chest pain, sputum
production, and hemoptysis.
– Many patients also exhibit systemic symptoms such
as anorexia, weight loss, and fatigue.
• Disseminated disease can cause neurologic
deficits from CNS metastases, bone pain or
pathologic fractures secondary to bone
metastases, or liver dysfunction from hepatic
involvement.

74. Lung Cancer
• Paraneoplastic syndromes commonly associated with
lung cancers include cachexia (A condition of severe
weight loss and decline in health), hypercalcemia,
syndrome of inappropriate antidiuretic hormone
secretion, and Cushing's syndrome
DIAGNOSIS
• In a patient with signs and symptoms of lung cancer,
chest x-ray, computed tomography (CT) scan, and
positron emission tomography (PET) scan are the most
valuable diagnostic tests.
– Integrated CT-PET technology appears to improve
diagnostic accuracy in staging NSCLC over CT or PET alone.

75. Lung Cancer
• Pathologic confirmation of lung cancer is
established by examination of sputum cytology
and/or tumor biopsy by fiberoptic bronchoscopy,
percutaneous needle biopsy, or open-lung biopsy.
• All patients must have a thorough history and
physical examination to detect signs and
symptoms of the primary tumor, regional spread
of the tumor, distant metastases, paraneoplastic
syndromes, and ability to withstand aggressive
surgery or chemotherapy.

76. Lung Cancer
STAGING
• The American Joint Committee on Cancer has
established a TNM staging classification for
lung cancer based
– on the primary tumor size and extent (T)
– regional lymph node involvement (N)
– the presence or absence of distant metastases
(M).

77. Lung Cancer
• A simpler system is commonly used to compare
treatments.
– Stage I includes tumors confined to the lung without
lymphatic spread
– stage II includes large tumors with ipsilateral
peribronchial or hilar lymph node involvement
– stage IIIA includes locally advanced disease
– stage IIIB includes bulky regional disease
– stage IV includes any tumor with distant metastases.

78. Lung Cancer
• A two-stage classification is widely used for
SCLC.
– Limited disease is confined to one hemithorax
and the regional lymph nodes.
– All other disease is classified as extensive.

79. Lung Cancer
TREATMENT
NON-SMALL CELL LUNG CANCER
Desired Outcome
– The goal of treating NSCLC depends on the disease
stage.
– Stages I, II, and possibly III disease can be cured with
appropriate therapy.
– In contrast, stage IV disease is not curable, but
chemotherapy can decrease symptoms and prolong
survival.

80. Lung Cancer
General Principles
• Surgery is the treatment of choice for localized
disease (stage I or IIA).
• Radiation therapy is used as adjuvant therapy
after surgery, as primary therapy if the tumor is
not operable or the patient is not a good surgical
candidate, and as palliative therapy for advanced
disease.
• Historically, NSCLC has been considered to be
insensitive to chemotherapy.

81. Lung Cancer
• New drugs and new combination regimens are
yielding promising results.
– For example, a 3-drug regimen was recently
shown to prolong survival when used as adjuvant
therapy after surgery for stages I, II, and III
disease.

82. Lung Cancer
• Management of locally advanced NSCLC (stages
IIB, IIIA, and IIIB) is controversial.
– Postoperative adjuvant and preoperative neoadjuvant
chemotherapy, with or without concurrent radiation
therapy, have been used.
• New combinations improve response and survival
rates in patients with stage IV disease.
– Patients most likely to benefit from chemotherapy
have a good performance status, no or minimal
weight loss, and less extensive disease.

83. Lung Cancer
• No single regimen is considered standard, so
selection should be based on the patient's
ability to tolerate expected toxicities and
likelihood of radiation therapy (and impact on
chemotherapy-induced toxicities).

84. Lung Cancer
Chemotherapy
• The most widely used and recommended regimens
include cisplatin or carboplatin combined with another
agent.
– Historically, cisplatin combined with etoposide was considered
to be the most active regimen for advanced NSCLC.
– Addition of a third drug does not appear to provide benefit
and can increase toxicity.
• Vinorelbine and cisplatin improves survival compared
with either agent alone.
– Vinorelbine has the advantage of minimal toxicity and is easily
administered in the outpatient setting over 6 to 10 minutes
followed by a 75- to 100-mL IV flush.

85. Lung Cancer
• More studies are needed to clarify how paclitaxel
should be combined with other agents, whether
the dose should be high or low, and whether the
dose should be infused over 1 or 3 hours or given
as a continuous 24-hour infusion.
– The 1-hour infusion is easy to administer in the
outpatient setting and causes minimal
myelosuppression, but it increases the rate of
peripheral sensory neuropathy.
– Studies are being conducted to determine whether
continuous infusion or high doses are more effective;
these approaches are more myelosuppressive and
require granulocyte colony-stimulating factor (G-CSF)
support.

86. Lung Cancer
• Docetaxel, a taxane without the schedule-
dependent efficacy and toxicity issues of
paclitaxel, is given IV over 1 hour every 3
weeks.
– Docetaxel is approved as a single agent after
failure of first-line therapy and in combination
with platinum as first-line therapy.
– The dose-limiting toxicity is neutropenia.

87. Lung Cancer
• Gemcitabine is approved as first-line therapy
when combined with cisplatin based on
studies showing prolonged survival compared
with cisplatin with or without etoposide.
– In a 4-way comparison of combination regimens,
gemcitabine combined with cisplatin was
associated with the least neutropenia but the
most thrombocytopenia and renal dysfunction.

88. Lung Cancer
• Irinotecan is being evaluated in many
combination regimens.
– Irinotecan is also being evaluated with chest
radiotherapy at a dose selected to avoid the
esophagitis, diarrhea, and unexpected severe
pneumonitis seen at higher doses.
• Two oral EGFR inhibitors are indicated as single-
agent therapy after failure of first-line therapy.
– Although not compared in a head-to-head study,
erlotinib appears to be more active because it
significantly prolonged survival whereas gefitinib did
not.

89. Lung Cancer
SMALL CELL LUNG CANCER
• Desired Outcome
– The goal of treatment is cure or prolonged survival, which requires
aggressive combination chemotherapy.
Surgery and Radiation Therapy
– Surgery is almost never indicated because SCLC disseminates early in
the disease.
– SCLC is very radiosensitive.
– Radiotherapy has been combined with chemotherapy to treat
tumors limited to the thoracic cavity.
– This combined-modality therapy prevents local tumor recurrences
but only modestly improves survival over chemotherapy alone.

90. Lung Cancer
Chemotherapy
• Aggressive combination chemotherapy
produces a four to fivefold increase in median
survival for patients with SCLC.
• Combination chemotherapy is clearly superior
to single-agent therapy.
– The most frequently used regimen is a platinum
combined with etoposide or, less frequently,
irinotecan

91. Lung Cancer
• Cisplatin-containing regimens yielded improved
survival and less life-threatening myelosuppression
than regimens without cisplatin.
– Carboplatin is frequently used in place of cisplatin because
it has similar efficacy and is less toxic.
• Alternating non-cross-resistant regimens and dose
intensity are theoretically attractive, but neither
provided substantial benefit in clinical studies.
– Dose-intensive regimens significantly increase toxicity
such as granulocytopenia, febrile neutropenia, mucositis,
and weight loss.

92. Lung Cancer
• Recurrent SCLC is usually less sensitive to
chemotherapy.
– If recurrence is more than 6 months after
induction chemotherapy, that regimen can be
repeated.
– If recurrence is less than 6 months, another
regimen should be used such as ifosfamide,
taxane, gemcitabine, topotecan, CAV
(cyclophosphamide, doxorubicin, and vincristine),
gemcitabine, oral etoposide, methotrexate, or
vinorelbine.

93. Lymphomas
Lymphomas
DEFINITION
– Lymphomas are a heterogenous group of
malignancies that arise from immune cells
residing predominantly in lymphoid tissues.
– Differences in histology have led to classification
as Hodgkin's and non-Hodgkin's lymphoma, which
are addressed separately in following slides.

94. Lymphomas
HODGKIN'S DISEASE
• PATHOPHYSIOLOGY
• Current hypotheses indicate that B-cell transcriptional processes
are disrupted, which prevent expression of B-cell surface markers
and production of immunoglobulin mRNA.
– Alterations in the normal apoptotic pathways favor cell survival and
proliferation.
• Malignant Reed-Sternberg cells overexpress nuclear factor-κ-B,
which is associated with cell proliferation and anti-apoptotic
signals.
– Infections with viral and bacterial pathogens upregulate nuclear
factor- κ-B.
– Epstein-Barr virus (EBV) is found in many, but not all, Hodgkin's
lymphoma tumors.

95. Lymphomas
CLINICAL PRESENTATION
• Most patients with lymphomas present with
adenopathy, which waxes and wanes and which is
painless and rubbery.
– Adenopathy is usually localized to the cervical region
but can also occur in the mediastinal, hilar, and
retroperitoneal regions.
• Up to 40% of patients with Hodgkin's disease
present with constitutional, or (B symptoms)
(e.g., fever, night sweats, weight loss, and
pruritus).

97. Con.

98. Lymphomas
Radiation Therapy
• Radiation therapy is an integral part of treatment and can be used
alone for selected patients with early-stage disease.
– Involved-field radiation therapy targets a single field of Hodgkin's
lymphoma.
– Extended-field or subtotal nodal radiation targets the involved
field and an uninvolved area.
– Total nodal radiation therapy targets all areas.
• Low-dose consolidative radiation therapy can be beneficial for
advanced-stage Hodgkin's disease if chemotherapy induces a
partial response.
• The major concern with radiation therapy is long-term effects
such as cardiovascular disease and secondary solid malignancies