Common strategy in tumour management

1. ManagementofTumors
Dr Shaurya Pratap Singh

2. Multidisciplinary
Team

3. Surgical
Management of
Primary Tumors
 A curative operation presupposes that the tumor is confined to the organ
of origin or to the organ and the regional lymph node basin. Patients in
whom the primary tumor is not resectable with negative surgical margins
are considered to have inoperable disease.
 On occasion, primary tumors are resected in these patients for palliative
reasons, such as improving the quality of life by alleviating pain, infection,
or bleeding. An example of this is toilet mastectomies for large ulcerated
breast tumors.
 In the past, it was presumed that the more radical the surgery, the better
the oncologic outcome would be. Over the past three decades, this has
been recognized as not necessarily being true, which has led to more
conservative operations, with wide local excisions replacing
compartmental resections of sarcomas, and partial mastectomies, skin-
sparing mastectomies, and breast conserving therapies replacing radical
mastectomies for breast cancer.
 Although it is clear that the surgical gold standard is negative surgical
margins, the appropriate surgical margins for optimal local control are
controversial for many cancer types.

4. Surgical
Management of
the Regional
Lymph Node
Basin
 For tumors in which the regional lymph node basin is not immediately
adjacent to the tumor (e.g., melanomas), lymph node surgery can be
performed through a separate incision. Unlike most carcinomas, soft
tissue sarcomas rarely metastasize to the lymph nodes (<5%); therefore,
lymph node surgery usually is not necessary.
 It is generally accepted that a formal lymphadenectomy is likely to
minimize the risk of regional recurrence of most cancers. For example, the
introduction of total mesorectal excision of rectal cancer has been
associated with a large decline in local-regional recurrence, and this
procedure has become the new standard of operative management.

5.  On the other hand, there have been two opposing views regarding the
role of lymphadenectomy in survival of cancer patients. The traditional
Halsted view states that lymphadenectomy is important for staging and
survival. The opposing view counters that cancer is systemic at inception
and that lymphadenectomy, although useful for staging, does not affect
survival.
 For most cancers, involvement of the lymph nodes is one of the most
significant prognostic factors. Interestingly, in some studies removal of a
larger number of lymph nodes has been found to be associated with an
improved overall survival rate for many tumors, including breast cancer,
colon cancer, and lung cancer. Although this seems to support the Halsted
theory that more extensive lymphadenectomy yielding of nodes reduces
the risk of regional recurrence, there may be alternative explanations for
the same finding.
Surgical
Management of
the Regional
Lymph Node
Basin

6.  For example, the surgeon who performs a more extensive
lymphadenectomy may obtain wider margins around the tumor or even
provide better overall care, such as ensuring that patients receive the
appropriate adjuvant therapy or undergo a more thorough staging
workup. Alternatively, the pathologist may perform a more thorough
examination, identifying more nodes and more accurately staging the
nodes. The effect of appropriate staging on survival is twofold.
Patients with nodal metastases may be offered adjuvant therapy, which
improves their survival chances. Further, the enhanced staging can
improve perceived survival rates through a “Will Rogers effect.”
Surgical
Management of
the Regional
Lymph Node
Basin

7.  Thus, identification of small metastases that had formerly been silent
and unidentified leads to stage migration for these patients and thus to a
perceived improvement in chances of survival for the higher stage. In
addition, there is improved survival for the lower stage, which is now
minus the patients with low volume nodal disease.
Surgical
Management of
the Regional
Lymph Node
Basin

8.  The first node to receive drainage from the tumor site is termed the
sentinel node. This node is the node most likely to contain metastases, if
metastases to that regional lymph node basin are present. The goal of
lymphatic mapping and sentinel lymph node biopsy specimen is to identify
and remove the lymph node most likely to contain metastases in the least
invasive fashion. The practice of sentinel lymph node biopsy specimen
followed by regional lymph node dissection for selected patients with a
positive sentinel lymph node avoids the morbidity of lymph node
dissections in patients with negative nodes. An additional advantage of
the sentinel lymph node technique is that it directs attention to a single
node, which allows more careful analysis of the lymph node most likely
to have a positive yield and increases the accuracy of nodal staging.
Surgical
Management of
the Regional
Lymph Node
Basin

9. Surgical
Management of
the Regional
Lymph Node
Basin

10.  Two criteria are used to assess the efficacy of a sentinel lymph node
biopsy specimen: the sentinel lymph node identification rate and the
false-negative rate.
 The nodes are evaluated with serial sectioning, hematoxylin and eosin
staining, and immunohistochemical analysis with S-100 protein and
homatropine methylbromide staining for melanoma and cytokeratin
staining for breast cancer. The utility of molecular techniques such as RT-
PCR to assess the sentinel nodes is still being explored.
 The nodes are evaluated with serial sectioning, hematoxylin and eosin
staining, and immunohistochemical analysis with S-100 protein and
homatropine methylbromide staining for melanoma and cytokeratin
staining for breast cancer.
Surgical
Management of
the Regional
Lymph Node
Basin

11.  Until recently, in breast cancer management, when sentinel node mapping
revealed a positive sentinel node, this was followed by a completion
axillary lymph node dissection. Results of the American College of
Surgeons Oncology Group Z0011 trial, challenged this practice. ACOSOG
Z11 was a phase 3 multicenter noninferiority trial conducted to
determine the effects of complete axillary lymph node dissection on
survival of patients with sentinel lymph node metastasis of breast cancer.
Patients were women with clinical T1-T2 invasive breast cancer, no
palpable adenopathy, and 1 to 2 SLNs containing metastases identified by
frozen section, touch preparation, or hematoxylin-eosin staining on
permanent section. All patients underwent breast conserving surgery
and tangential whole-breast irradiation.
Surgical
Management of
the Regional
Lymph Node
Basin

12.  Those with sentinel node metastases identified by sentinel node biopsy
specimen were randomized to undergo axillary lymph node dissection or
no further axillary treatment. At a median follow-up of 6.3 years, 5-year
overall survival was 91.8% (95% confidence interval [CI], 89.1%–94.5%)
with axillary lymph node dissection and 92.5% (95% CI, 90.0%–95.1%) with
sentinel node alone. The 5-year disease-free survival was 82.2% (95% CI,
78.3%–86.3%) with axillary lymph node dissection, and 83.9% (95% CI,
80.2%–87.9%) with sentinel node alone. Thus, ACOSOGZ11 demonstrated
that among breast cancer patients with limited sentinel node metastasis
treated with breast conservation and systemic therapy, the use of
sentinel node alone compared with axillary lymph node dissection did
not result in inferior survival. This study challenges the traditional
surgical dictum of regional management, and has led to a selective
utilization of completion axillary lymph node dissection in breast cancer
patients undergoing breast conservation.
Surgical
Management of
the Regional
Lymph Node
Basin

13.  The role of completion lymph node dissections in melanoma is under
investigation. In the MSLT-II clinical trial, melanoma patients with sentinel-
node metastases were randomized to immediate completion lymph-node
dissection or nodal observation with ultrasonography. The primary end
point of this study was melanoma-specific survival. Immediate completion
lymph-node dissection led to increased regional disease control and
provided prognostic information but did not increase melanoma-specific
survival among patients with intermediate-thickness melanoma and
sentinel-node metastases.
Surgical
Management of
the Regional
Lymph Node
Basin

14. Surgical
Management of
the Regional
Lymph Node
Basin

15.  Patient selection is the key to the success of surgical therapy for distant
metastases. The cancer type is a major determinant in surgical decision
making. A liver metastasis from a colon cancer is more likely to be an
isolated and thus resectable lesion than a liver metastasis from a
pancreatic carcinoma. The growth rate of the tumor also plays an
important role and can be determined in part by the disease-free
interval and the time between treatment of the primary tumor and
detection of the distant recurrence.
Surgical
Management of
Distant
Metastasis

16.  Patients who have synchronous metastases (metastases diagnosed at the
initial cancer diagnosis) do worse after metastasectomy than patients
who develop metachronous metastases (metastasis diagnosed after a
disease-free interval).
 The natural history of metastatic disease is so poor for some tumors
(e.g., pancreatic cancer) that there is no role at this time for surgical
metastasectomy. In cancers with a more favorable outlook, observation for
several weeks or months, potentially with initial treatment with systemic
therapy, can allow the surgeon to monitor for metastases at other sites.
 In curative surgery for distant metastases, as with surgery for primary
tumors, the goal is to resect the metastases with negative margins.
Surgical
Management of
Distant
Metastasis

17.  In patients with documented distant metastatic disease, chemotherapy is
usually the primary modality of therapy. The goal of therapy in this
setting is to decrease the tumor burden, thus prolonging survival. It is
rare to achieve cure with chemotherapy for metastatic disease for most
solid tumors.
 Chemotherapy administered to a patient who is at high risk for distant
recurrence but has no evidence of distant disease is referred to as
adjuvant chemotherapy. The goal of adjuvant chemotherapy is
eradication of micrometastatic disease, with the intent of decreasing
relapse rates and improving survival rates. The goal of adjuvant
chemotherapy is eradication of micrometastatic disease, with the
intent of decreasing relapse rates and improving survival rates.
 Adjuvant therapy can be administered after surgery (postoperative
chemotherapy) or before surgery (preoperative chemotherapy,
neoadjuvant chemotherapy, or induction therapy).
 A portion or all of the planned adjuvant chemotherapy can be
administered before the surgical removal of the primary tumor.
Clinical use of
Chemotherapy

18. Clinical use of
Chemotherapy
 Preoperative chemotherapy has three potential advantages.
 The first is that preoperative regression of tumor can facilitate
resection of tumors that were initially inoperable or allow more
conservative surgery for patients whose cancer was operable to
begin with.
 The second advantage of preoperative chemotherapy is the
treatment of micrometastases without the delay of postoperative
recovery.
 The third advantage is the ability to assess a cancer’s response
to treatment clinically, after a number of courses of chemotherapy,
and pathologically, after surgical resection. This is especially
important if alternative treatment regimens are available to be
offered to patients whose disease responded inadequately.
Molecular characterization of the residual disease may also give
insight into mechanisms of chemoresistance and possible
therapeutic targets.

19. Clinical use of
Chemotherapy
 There are some potential disadvantages to preoperative chemotherapy,
however. Although disease progression while the patient is receiving
preoperative chemotherapy is rare in chemotherapy-sensitive tumors
such as breast cancer, it is more frequent in relatively chemotherapy-
resistant tumors such as sarcomas. Thus, patient selection is critical to
ensure that the opportunity to treat disease surgically is not lost by giving
preoperative chemotherapy. Often, rates of postoperative wound
infection, flap necrosis, and delays in postoperative adjuvant therapy
do not differ between patients who are treated with preoperative
chemotherapy and patients who are treated with surgery first. However,
preoperative chemotherapy can introduce special challenges to tumor
localization, margin analysis, lymphatic mapping, and pathologic staging.

20. Clinical use of
Chemotherapy
 Response to chemotherapy is monitored clinically with imaging studies as
well as physical examinations. Response usually is defined as complete
response, partial response, stable disease, or progression. Response
generally is assessed using the Response Evaluation Criteria in Solid
Tumors (RECIST) criteria. Objective tumor response assessment is critical
because tumor response is used as a prospective endpoint in clinical
trials and tumor response is a guide to clinicians regarding continuation of
current therapy.

21. Response
Evaluation
Criteria inSolid
Tumours
 At baseline, tumour lesions/lymph nodes will be categorised measurable
or non-measurable as follows:
 Measurability of tumour at baseline
 At baseline, tumour lesions/lymph nodes will be categorised measurable
or non-measurable as follows:
 Measurable Tumour lesions: Must be accurately measured in at least one
dimension (longest diameter in the plane of measurement is to be recorded)
with a minimum size of:
 10mm by CT scan (CT scan slice thickness no greater than 5 mm; see Appendix
II on imaging guidance).
 10mm caliper measurement by clinical exam (lesions which cannot be
accurately measured with calipers should be recorded as non-measurable).
 20mm by chest X-ray.

22.  Malignant lymph nodes:
 To be considered pathologically enlarged and measurable, a lymph node
must be 15mm in short axis when assessed by CT scan (CT scan slice
thickness recommended to be no greater than 5mm). At baseline and in
follow-up, only the short axis will be measured and followed.
 Non-measurable
 All other lesions, including small lesions (longest diameter <10 mm or
pathological lymph nodes with 10 to <15mm short axis) as well as truly
non-measurable lesions.
 Lesions considered truly non-measurable include:
 leptomeningeal disease, ascites, pleural or pericardial effusion,
inflammatory breast disease, lymphangitic involvement of skin or lung,
abdominal masses/abdominal organomegaly identified by physical exam
that is not measurable by reproducible imaging techniques.
Response
Evaluation
Criteria inSolid
Tumours

23.  Special considerations regarding lesion measurability
 Bone lesions, cystic lesions, and lesions previously treated with local
therapy require particular comment:
 Bone lesions:
 Bone scan, PET scan or plain films are not considered adequate imaging
techniques to measure bone lesions. However, these techniques can be
used to confirm the presence or disappearance of bone lesions.
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue
components, that can be evaluated by cross sectional imaging techniques
such as CT or MRI can be considered as measurable lesions if the soft
tissue component meets the definition of measurability described above.
 Blastic bone lesions are non-measurable.
Response
Evaluation
Criteria inSolid
Tumours

24.  Cystic lesions:
 Lesions that meet the criteria for radiographically defined simple cysts
should not be considered as malignant lesions (neither measurable nor
non-measurable) since they are, by definition, simple cysts.
 ‘Cystic lesions’ thought to represent cystic metastases can be considered
as measurable lesions, if they meet the definition of measurability
described above. However, if noncystic lesions are present in the same
patient, these are preferred for selection as target lesions.
 Lesions with prior local treatment:
 Tumour lesions situated in a previously irradiated area, or in an area
subjected to other loco-regional therapy, are usually not considered
measurable unless there has been demonstrated progression in the lesion.
Study protocols should detail the conditions under which such lesions
would be considered measurable.
Response
Evaluation
Criteria inSolid
Tumours

25.  Response criteria
 Complete Response (CR):
 Disappearance of all target lesions. Any pathological lymph nodes (whether
target or non-target) must have reduction in short axis to <10 mm.
 Partial Response (PR):
 At least a 30% decrease in the sum of diameters of target lesions, taking as
reference the baseline sum diameters.
 Progressive Disease (PD):
 At least a 20% increase in the sum of diameters of target lesions, taking as
reference the smallest sum on study (this includes the baseline sum if that is
the smallest on study). In addition to the relative increase of 20%, the sum
must also demonstrate an absolute increase of at least 5 mm. (Note: the
appearance of one or more new lesions is also considered progression).
 Stable Disease (SD):
 Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify
for PD, taking as reference the smallest sum diameters while on study.
Response
Evaluation
Criteria inSolid
Tumours

26. Principles of
Chemotherapy

27.  Chemotherapy destroys cells by first-order kinetics, which means that
with the administration of a drug a constant percentage of cells is killed,
not a constant number of cells. If a patient with 1012 tumor cells is
treated with a dose that results in 99.9% cell kill (3-log cell kill), the tumor
burden will be reduced from 1012 to 109 cells (or 1 kg to 1 g). If the
patient is retreated with the same drug, which theoretically could result
in another 3-log cell kill, the cells would decrease in number from 109 to
106 (1 g to 1 mg) rather than being eliminated totally.
 Chemotherapeutic agents can be classified according to the phase of
the cell cycle during which they are effective. Cellcycle phase-nonspecific
agents (e.g., alkylating agents) have a linear dose-response curve, such
that the fraction of cells killed increases with the dose of the drug.
 In contrast, the cell-cycle phase-specific drugs have a plateau with respect
to cell killing ability, and cell kill will not increase with further increases in
drug dose.
Principles of
Chemotherapy

28. Anticancer
Agents
 Alkylating Agents
 Alkylating agents are cell-cycle– nonspecific agents, that is, they are
able to kill cells in any phase of the cell cycle. They act by cross-linking
the two strands of the DNA helix or by causing other direct damage
to the DNA. The damage to the DNA prevents cell division and, if severe
enough, leads to apoptosis. The alkylating agents are composed of three
main subgroups:
 classic alkylators,
 nitrosoureas, and
 miscellaneous DNA-binding agents.

29.  Antitumor Antibiotics
 Antitumor antibiotics are the products of fermentation of microbial
organisms. Like the alkylating agents, these agents are cell-cycle
nonspecific. Antitumor antibiotics damage the cell by interfering with
DNA or RNA synthesis, although the exact mechanism of action may
differ by agent.
 Antimetabolites
 Antimetabolites are generally cell-cycle specific agents that have their
major activity during the S phase of the cell cycle and have little effect on
cells in G0. These drugs are most effective, therefore, in tumors that have
a high growth fraction. Antimetabolites are structural analogues of
naturally occurring metabolites involved in DNA and RNA synthesis.
Therefore, they interfere with normal synthesis of nucleic acids by
substituting for purines or pyrimidines in the metabolic pathway to inhibit
critical enzymes in nucleic acid synthesis. The antimetabolites include
 folate antagonists,
 purine antagonists, and
 pyrimidine antagonists.
Anticancer
Agents

30.  Plant Alkaloids
 Plant alkaloids are derived from plants such as the periwinkle plant,
Vinca rosea (e.g., vincristine, a vinca alkaloid), or the root of American
mandrake, Podophyllum peltatum (e.g., etoposide, a podophyllotoxin).
 Vinca alkaloids affect the cell by binding to tubulin in the S phase. This
blocks microtubule polymerization, which results in impaired mitotic
spindle formation in the M phase.
 Taxanes such as paclitaxel, on the other hand, cause excess
polymerization and stability of microtubules, which blocks the cell cycle
in mitosis.
 The epipodophyllotoxins (e.g., etoposide) act to inhibit a DNA enzyme
called topoisomerase II by stabilizing the DNA-topoisomerase II complex.
This results in an inability to synthesize DNA, and thus the cell cycle is
stopped in the G1 phase.
Anticancer
Agents

31. Anticancer
Agents

32. Anticancer
Agents

33. Combination
Chemotherapy
 Combination chemotherapy may provide greater efficacy than single-
agent therapy by three mechanisms:
 it provides maxi-mum cell kill within the range of toxicity for each drug that
can be tolerated by the host,
 it offers a broader range of coverage of resistant cell lines in a heterogeneous
population, and
 it prevents or delays the emergence of drug-resistant cell lines.
 When combination regimens are devised, drugs known to be active as
single agents usually are selected. Drugs with different mechanisms of
action are combined to allow for additive or syn-ergistic effects.
Combining cell-cycle–specific and cell-cycle–nonspecific agents may be
especially advantageous. Drugs with differing dose-limiting toxic effects
are combined to allow for each drug to be given at therapeutic doses.
Drugs with differ-ent patterns of resistance are combined whenever
possible to minimize cross-resistance. The treatment-free interval
between cycles is kept to the shortest possible time that will allow for
recovery of the most sensitive normal tissue.

34. Drug toxicity
 Tumors are more susceptible than normal tissue to chemotherapeutic agents,
in part because they have a higher proportion of dividing cells. Normal tissues
with a high growth fraction, such as the bone marrow, oral and intestinal
mucosa and hair follicles are sensitive to chemotherapeutic effects.
Therefore, treatment with chemotherapeutic agents can produce toxic effects
such as bone marrow suppression, stomatitis, ulceration of the GI tract, and
alopecia.
 Toxic effects usually are graded from 0 to 4 on the basis of World Health
Organization standard criteria.
 Significant drug toxicity may necessitate a dosage reduction. A toxic effect
requiring a dose modification or change in dose intensity is referred to as a
dose-limiting toxic effect.
 Because maintaining dose intensity is important to preserve as high a tumor
cell kill as possible, several supportive strategies have been developed, such as
 administration of colony-stimulating factors and erythropoietin to treat poor
bone marrow reserve and
 administration of cytoprotectants such as mesna and amifostine to prevent
renal dysfunction.
 Some toxicities, such as neuropathy, are not as easily reversible, and their
potential effects on lifestyle must be considered when evaluating a patient
prior to the initiation of chemotherapy.

35. Administration
of
Chemotherapy
 Chemotherapy usually is administered systemically (IV, IM, SC, or PO).
Systemic administration treats micrometastases at widespread sites and
prevents systemic recurrence. However, it increases the drug’s toxicity to a
wide range of organs through-out the body. One method to minimize
systemic toxicity while enhancing target organ delivery of chemotherapy is
regional administration of chemotherapy.
 Many of these approaches require surgical access, such as intrahepatic
delivery of chemo-therapy for hepatic carcinomas or metastatic colorectal
cancer using a hepatic artery infusion pump, limb perfusion for extremity
melanoma and sarcoma, and intraperitoneal hyperthermic perfusion for
pseudomyxoma peritonei. Alternately, percutaneous access may be
utilized, such as limb infusion with percutaneously placed catheters.

36. Types of
Chemotherapy
Agents

37. Types of
Chemotherapy
Agents

38. Types of
Chemotherapy
Agents

39. Hormonal
Therapy
 Some tumors, most notably breast and prostate cancers, originate from
tissues whose growth is under hormonal control. The first attempts at
hormonal therapy were through surgical ablation of the organ producing
the hormones involved, such as oophorectomy for breast cancer.
 Currently, hormonal anticancer agents include androgens, antiandrogens,
antiestrogens, estrogens, glucocorticoids, gonadotropin inhibitors,
progestins, aromatase inhibitors, and somatostatin analogues.
Hormones or hormone-like agents can be administered to inhibit tumor
growth by blocking or antagonizing the naturally occurring substance,
such as with the estrogen antagonist tamoxifen. Other substances that
block the synthesis of the natural hormone can be administered as
alternatives. Aromatase inhibitors, for example, block the peripheral
conversion of endogenous androgens to estrogens in postmenopausal
women. Hormonal therapy provides a highly tumor-specific form of
therapy in sensitive tissues. In breast cancer, estrogen and progesterone
receptor status is used to predict the success of hormonal therapy.
Androgen receptor is also being pursued as a therapeutic target for breast
cancer treatment.

40. Targeted
Therapy
 The basic principle of molecular therapeutics is to exploit the molecular
differences between normal cells and cancer cells to develop targeted
therapies. Thus, targeted therapies usually are directed at the processes
involved in tumor growth rather than directly targeting the tumor cells.
The ideal molecular target would be exclusively expressed in the cancer
cells, be the driving force of the proliferation of the cancer cells, and be
critical to their survival.
 The major groups of targeted therapy agents are
1. inhibitors of growth factor receptors,
2. inhibitors of intracellular signal transduction,
3. cell-cycle inhibitors,
4. apoptosis-based therapies, and
5. anti-angiogenic compounds.

41.  Protein kinases have come to the forefront as attractive therapeutic
targets with the success of imatinib mesylate (Gleevec) in treating chronic
myelogenous leukemia and GI stromal tumors, and trastuzumab
(Herceptin) in treating breast cancer, and vemurafanib in treating
melanoma. These drugs work by targeting bcr-abl and c-kit (imatinib) and
HER2 and BRAF, respectively.
 Potential targets like HER2 can be targeted via different strategies, such as
transcriptional down regulation, targeting of mRNA, RNA inhibition,
antisense strategies, direct inhibition of protein activity, and induction of
immunity against the protein. Most of the compounds in development are
monoclonal antibodies like trastuzumab or small-molecule kinase
inhibitors like imatinib or vemurafanib. Some other agents, such as
sunitinib, are multitargeted kinase inhibitors.
Targeted
Therapy

42.  Development of molecularly targeted agents for clinical use presents
several unique challenges. Once an appropriate compound is identified
and confirmed to have activity in preclinical testing, predictive markers
for activity in the preclinical setting must be defined. Expression of a target
may not be sufficient to predict response because the pathway of
interest may not be activated or critical to the cancer’s survival. Although
in traditional phase 1 trials the goal is to identify the maximum
tolerated dosage, the maximum dosage of biologic agents may not be
necessary to achieve the desired biologic effect. Thus, assays to verify
modulation of the target need to be developed to determine at what
dosage the desired effect is achieved. When phases 2 and 3 clinical
trials are initiated, biomarker modulation studies should be integrated
into the trial to determine whether clinical response correlates with target
modulation and thus to identify additional parameters that impact
response. Rational dose selection and limitation of study populations to
patients most likely to respond to the molecular therapy as determined by
predictive markers are most likely to lead to successful clinical translation
of a product..
Targeted
Therapy

43.  Rational dose selection and limitation of study populations to patients
most likely to respond to the molecular therapy as determined by
predictive markers are most likely to lead to successful clinical translation
of a product..
 Finally, most biologic agents are cytostatic, not cytotoxic. Thus, rational
combination therapy mixing new biologic agents with either established
chemotherapeutic agents that have synergy or with other biologic agents
is more likely to lead to cancer cures.
Targeted
Therapy

44. Targeted
Therapy

45. Immunotherapy
 The aim of immunotherapy is to induce or potentiate inherent antitumor
immunity that can destroy cancer cells. Central to the process of
antitumor immunity is the ability of the immune system to recognize
tumor-associated antigens present on human cancers and to direct
cytotoxic responses through humoral or T-cell–mediated immunity.
 Overall, T-cell–mediated immunity appears to have the greater potential
of the two for eradicating tumor cells. T cells recognize antigens on the
surfaces of target cells as small peptides presented by class I and class II
MHC molecules.
 One approach to antitumor immunity is nonspecific immunotherapy,
which stimulates the immune system as a whole through administration of
bacterial agents or their products, such as bacille Calmette-Guérin. This
approach is thought to activate the effectors of antitumor response such
as natural killer cells and macrophages, as well as polyclonal lymphocytes.

46.  Another approach to nonspecific immunotherapy is systemic
administration of cytokines such as interleukin-2, interferon-α, and
interferon-γ.
 Interleukin-2 stimulates proliferation of cytotoxic T lymphocytes and
maturation of effectors such as natural killer cells into lymphokine-activated
killer cells.
 Interferons, on the other hand, exert antitumor effects directly by inhibiting
tumor cell proliferation and indirectly by activating host immune cells,
including macrophages, dendritic cells, and natural killer cells, and by
enhancing human leukocyte antigen (HLA) class I expression on tumor cells.
Immunotherapy

47.  Antigen-specific immunotherapy can be active, as is achieved through
antitumor vaccines, or passive. In passive immunotherapy, antibodies to
specific tumor-associated antigens can be produced by hybridoma
technique and then administered to patients whose cancers express these
antigens, inducing antibody-dependent cellular cytotoxicity. The early
attempts at vaccination against cancers used allogeneic cultured cancer
cells, including irradiated cells, cell lysates, and shed antigens isolated
from tissue culture supernatants. An alternate strategy is the use of
autologous tumor vaccines. These have the potential advantage of being
more likely to contain antigens relevant for the individual patient but have
the disadvantage of requiring a large amount of tumor tissue for
preparation, which restricts eligibility of patients for this modality.
Strategies to enhance immunogenicity of tumor cells include the
introduction of genes encoding cytokines or chemokines, and fusion of
the tumor cells to allogeneic MHC class II-bearing cells. Alternatively, heat
shock proteins derived from a patient’s tumor can be used because heat
shock protein peptide complexes are readily taken up by dendritic cells for
presentation to T cells.
Immunotherapy

48.  Identification of tumor antigens has made it possible to perform antigen-
specific vaccination. For example, in the case of melanoma, several
antigens have been identified that can be recognized by both CD8+
cytotoxic T cells and CD4+ helper T cells, including MART-1, gp 100,
MAGE1, tyrosinase, TRP-1, TRP-2, and NY-ESO-1.151
Immunotherapy

49.  Several different vaccination approaches have been studied, including
tumor cell-based vaccines, peptide-based vaccines, recombinant virus-
based vaccines, DNAbased vaccines, and dendritic cell vaccines.
 In adoptive transfer, antigen-specific effector cells (i.e., cytotoxic T
lymphocytes) or antigen-nonspecific effector cells (i.e., natural killer cells)
can be transferred to a patient. These effector cells can be obtained
from the tumor (tumor-infiltrating lymphocytes) or the peripheral blood.
Immunotherapy

50. Immunotherapy
 Tolerance to self-antigens expressed in tumors is a limitation in
generating antitumor responses. Recently, several pathways that modulate
tolerance and approaches to manipulating these pathways have been
identified: pathways that activate professional antigen-presenting cells
such as Toll-like receptors, growth factors, and the CD40 pathway;
cytokines to enhance immunoactivation; and pathways that inhibit T-cell
inhibitory signals or block the activity of immune-suppressive regulatory T
cells (Tregs).
 A new and highly effective strategy to activate the T-cell arm of
anticancer immunity is the use of monoclonal antibodies to block
inhibitory signaling pathways employed by the immune system to prevent
T cell over activation and the development of auto-immunity. CTLA-4 and
PD-1 are two important inhibitory T-cell checkpoints that can be blocked
with neutralizing antibodies and result in an effective antigen-specific anti-
tumor response.

51. Immunotherapy
 The FDA-approved CTLA-4 blocking antibody ipilimumab has shown
efficacy in patients with metastatic melanoma.156,157 Nivolumab and
pembrolizumab are antibodies that target PD-1, whereas blockade of PD-
L1 is accomplished with agents such as atezolizumab.
 Cancers for which checkpoint inhibitors have found utility include
melanoma, renal cell carcinoma, bladder carcinoma, squamous cell
carcinoma of the head and neck, and carcinoma of the lung. These agents
produce durable shrinkage of advanced disease in 20% to 40% of patients,
and combination strategies that employ checkpoint inhibitors with
cytokines, vaccines, cellular therapies, and other targeted agents are
under active investigation.

52. GeneTherapy
 One of the main difficulties in getting gene therapy technology from the
laboratory to the clinic is the lack of a perfect delivery system. An ideal
vector would be administered through a noninvasive route and would
transduce all of the cancer cells and none of the normal cells.
Furthermore, the ideal vector would have a high degree of activity, that is,
it would produce an adequate amount of the desired gene product to
achieve target cell kill. Unlike genetic diseases in which delivery of the
gene of interest into only a portion of the cells may be sufficient to achieve
clinical effect, cancer requires either that the therapeutic gene be
delivered to all of the cancer cells or that a therapeutic effect be achieved
on nontransfected cells as well as transfected cells through a bystander
effect.
 However, treatment of a metabolic disease requires prolonged gene
expression, whereas transient expression may be sufficient for cancer
therapy.

53.  One of the promising approaches to increase the number of tumor
cells transduced is the use of a replication-competent virus like a
parvovirus, human reovirus, or vesicular stomatitis virus that selectively
replicates within malignant cells and lyses them more efficiently than it
does normal cells. Another strategy for killing tumor cells with suicide
genes exploits tumor-specific expression elements, such as the MUC-1,
PSA, CEA, or VEGF promoters, that can be used to achieve tissue-specific
or tumor-specific expression of the desired gene.
 Because the goal in cancer therapy is to eradicate systemic disease,
optimization of delivery systems is the key to success for gene therapy
strategies. Gene therapy is likely to be most successful when combined
with standard therapies, but it will provide the advantage of customization
of therapy based on the molecular status of an individual’s tumor.
GeneTherapy

54. Mechanisms of
Intrinsic and
Acquired Drug
Resistance

55. Radiation
Therapy
 Physical Basis of Radiation Therapy
 Ionizing radiation is energy strong enough to remove an orbital electron
from an atom. This radiation can be electromagnetic, like a high-energy
photon, or particulate, such as an electron, proton, neutron, or alpha
particle. Radiation therapy is delivered primarily as high-energy photons
(gamma rays and X-rays) and charged particles (electrons). Gamma rays
are photons that are released from the nucleus of a radioactive atom.
X-rays are photons that are created electronically, such as with a
clinical linear accelerator.
 Currently, high-energy radiation is delivered to tumors primarily with
linear accelerators. X-rays traverse the tissue, depositing the maximum
dose beneath the surface, and thus spare the skin. Electrons are used to
treat superficial skin lesions, superficial tumors, or surgical beds to a depth
of 5 cm. Gamma rays typically are produced by radioactive sources used in
brachytherapy.

56. Radiation
Therapy

57.  Biologic Basis of Radiation Therapy
 Radiation deposition results in DNA damage manifested by single- and
double-strand breaks in the sugar phosphate backbone of the DNA
molecule. Cross-linking between the DNA strands and chromosomal
proteins also occurs. The mechanism of DNA damage differs by the type of
radiation delivered. Electromagnetic radiation is indirectly ionizing through
the actions of short-lived hydroxyl radicals, which are produced primarily
by the ionization of cellular hydrogen peroxide (H2O2). Protons and other
heavy particles are directly ionizing and directly damage DNA.
 Radiation damage is manifested primarily by the loss of cellular
reproductive integrity. Most cell types do not show signs of radiation
damage until they attempt to divide, so slowly proliferating tumors may
persist for months and appear viable. Some cell types, however, undergo
apoptosis.
Radiation
Therapy

58.  Biologic Basis of Radiation Therapy
 The extent of DNA damage after radiation exposure is dependent on
several factors. The most important of these is cellular oxygen. Hypoxic
cells are significantly less radiosensitive than aerated cells. The
presence of oxygen is thought to prolong the half-life of free radicals
produced by the interaction of X-rays and cellular H2O2, and thus
indirectly ionizing radiation is less efficacious in tumors with areas of
hypoxia. In contrast, radiation damage from directly ionizing radiation is
independent of cellular oxygen levels.
 The extent of DNA damage from indirectly ionizing radiation is dependent
on the phase of the cell cycle. The most radiation-sensitive phases are G2
and M, whereas G1 and late S phases are less sensitive. Thus, irradiation
of a population of tumor cells results in killing of a greater proportion of
cells in G2 and M phases.
Radiation
Therapy

59.  Biologic Basis of Radiation Therapy
 However, delivery of radiation in divided doses, a concept referred to as
fractionation, allows the surviving G1 and S phase cells to progress to
more sensitive phases, a process referred to as reassortment. In contrast
to DNA damage after indirectly ionizing radiation, that after exposure to
directly ionizing radiation is less dependent on the cell-cycle phase.
 Several chemicals can modify the effects of ionizing radiation. These
include hypoxic cell sensitizers such as metronidazole and misonidazole,
which mimic oxygen and increase cell kill of hypoxic cells.

A second category of radiation sensitizers are the thymidine analogues
iododeoxyuridine and bromodeoxyuridine. These molecules are
incorporated into the DNA in place of thymidine and render the cells
more susceptible to radiation damage; however, they are associated with
considerable acute toxicity. Several other chemotherapeutic agents
sensitize cells to radiation through various mechanisms, including 5-
fluorouracil, actinomycin D, gemcitabine, paclitaxel, topotecan,
doxorubicin, and vinorelbine. The development of novel radiosensitizers is
an active area of research and multiple small molecules as well as novel
nanomaterials are under investigation.
Radiation
Therapy

60. Radiation
Therapy

61. Radiation
Therapy:
Planning

62.  Radiation therapy is delivered in a homogeneous dose to a well defined
region that includes tumor and/or surrounding tissue at risk for subclinical
disease. The first step in planning is to define the target to be irradiated as
well as the dose-limiting organs in the vicinity. Treatment planning
includes evaluation of alternative treatment techniques, which is done
through a process referred to as simulation. Once the beam distribution
that will best achieve homogeneous delivery to the target volume and
minimize the dose to the normal tissue is determined, immobilization
devices and markings or tattoos on the patient’s skin are used to ensure
that each daily treatment is given in the same way. Conventional
fractionation is 1.8 to 2 Gy/d, administered 5 days each week for 3 to 7
weeks.
 Radiation therapy may be used as the primary modality for palliation in
certain patients with metastatic disease, primarily patients with bony
metastases. In these cases, radiation is recommended for symptomatic
metastases only. However, lytic metastases in weight-bearing bones such
as the femur, tibia, or humerus also are considered for irradiation. Another
circumstance in which radiation therapy might be appropriate is spinal
cord compression due to metastases to the vertebral body that extend
posteriorly to the spinal canal.
Radiation
Therapy:
Planning

63.  The goal of adjuvant radiation therapy is to decrease localregional
recurrence rates. Adjuvant radiation therapy can be given before surgery,
after surgery, or, in selected cases, during surgery. Preoperative radiation
therapy has several advantages. It may minimize seeding of the tumor
during surgery and it allows for smaller treatment fields because the
operative bed has not been contaminated with tumor cells. Also, radiation
therapy for inoperable tumors may achieve adequate reduction to make
them operable.
 The disadvantages of preoperative therapy are an increased risk of
postoperative wound healing problems and the difficulty in planning
subsequent radiation therapy in patients who have positive surgical
margins. If radiation therapy is given postoperatively, it is usually given 3 to
4 weeks after surgery to allow for wound healing.
Radiation
Therapy:
Planning

64.  The advantage of postoperative radiation therapy is that the surgical
specimen can be evaluated histologically and radiation therapy can be
reserved for patients who are most likely to benefit from it. Further, the
radiation therapy can be modified on the basis of margin status.
 The disadvantages of postoperative radiation therapy are that the volume
of normal tissue requiring irradiation may be larger owing to surgical
contamination of the tissue planes and that the tumor may be less
sensitive to radiation owing to poor oxygenation. Post laparotomy
adhesions may decrease the mobility of the small bowel loops, increasing
the risk for radiation injury in abdominal or pelvic irradiation. Given the
potential advantages and disadvantages of both approaches, the roles of
preoperative and postoperative radiation therapy are being actively
evaluated and compared for many cancer types.
Radiation
Therapy:
Planning

65.  Another mode of postoperative radiation therapy is brachytherapy. In
brachytherapy, unlike in external beam therapy, the radiation source is
in contact with the tissue being irradiated. The radiation source may be
cesium, gold, iridium, or radium. Brachytherapy is administered via
temporary or permanent delivery implants such as needles, seeds, or
catheters. Temporary brachytherapy catheters are placed either during
open surgery or percutaneously soon after surgery. The implants are
loaded interstitially, and treatment usually is given postoperatively for a
short duration, such as 1 to 3 days. Although brachytherapy has the
disadvantages of leaving scars at the catheter insertion site and requiring
special facilities for inpatient brachytherapy, the advantage of patient
convenience owing to the shorter treatment duration has made
intracavitary treatment approaches popular for the treatment of breast
cancer.
Radiation
Therapy:
Planning

66.  Another short delivery approach is intraoperative radiotherapy (IORT),
often used in combination with external beam therapy. The oncologic
consequences of the limited treatment volume and duration associated
with brachytherapy and IORT are not well understood. Accelerated
partial breast irradiation with interstitial brachytherapy, intracavitary
brachytherapy (MammoSite), IORT, and three-dimensional conformal
external beam radiotherapy is being compared with whole breast
irradiation in an intergroup phase 3 trial (NSABP B-39/Radiation Therapy
Oncology Group 0413). Several additional studies of adjuvant IORT also are
ongoing internationally.
Radiation
Therapy:
Planning

67.  There has also been increased interest in utilizing intensity-modulated
radiation therapy (IMRT). IMRT is a complex technique for the delivery of
radiation therapy preferentially to target structures while minimizing
doses to adjacent normal critical structures. It is widely utilized for the
treatment of a variety of tumor types, including the central nervous
system, head and neck, breast, prostate, gastrointestinal tract, and
gynecologic organs, as well as in patients where previous radiation
therapy has been delivered.
Radiation
Therapy:
Planning

68.  Stereotactic radiosurgery uses extremely accurate image-guidance and
patient positioning to deliver a high dose of radiation to a small tumor
with well-defined margins. In this manner, the dose of radiation being
applied to normal tissues can be minimized. It is most commonly used
for the treatment of brain and spinal tumors. Protons are a charged
particle that can be also used in external beam radiation therapy. Proton
therapy employs a beam of protons as a means of delivering radiation to a
tumor. In contrast to photons, which deposit energy continuously during
their passage through tissue, protons deposit a large amount of their
energy near the end of their path (known as the Bragg peak) and release
less energy along the way. Thus, proton therapy could theoretically reduce
the exposure of normal tissue to radiation, allowing the delivery of higher
doses of radiation to a tumor.
Radiation
Therapy:
Planning

69.  It is thought that chemotherapy given concurrently with radiation
improves survival rates. Chemotherapy before radiation has the advantage
of reducing the tumor burden, which facilitates radiation therapy. On the
other hand, some chemotherapy regimens, when given concurrently with
radiation, may sensitize the cells to radiation therapy. Chemoradiation is
being investigated in many tumor types, including rectal cancer, pancreatic
cancer, and esophageal cancer.173-175 In a Cochrane review of six
randomized controlled trials, it was demonstrated that in patients with
T3/4 rectal cancer, chemoradiation was associated with a significantly
lower local recurrence rate compared with radiation therapy alone (OR
0.56, 95% CI 0.42–0.75, P <0.0001) but was not associated with improved
survival.

Radiation
Therapy:
Planning

70. Radiation
Therapy:Side
Effects

71. Thank you😁