CA BREAST METASTATIC

1. Management of Metastatic
Breast Cancer
Presenter Dr. Jyoti Sharma

2. Metastatic breast cancer : It is defined by tumor spread beyond the breast, chest
wall, and ipsilateral regional lymph nodes.
MBC remains virtually an incurable disease with a median overall survival (OS) of 3
years and a 5-year survival of only 25%
Most common sites for breast cancer metastasis :
Bone
Lung
Liver
lymph nodes
chest wall
Brain
Hormone receptor–positive tumors are more likely to spread to bone as the initial
site of metastasis;
Hormone receptor–negative and/or HER2-positive tumors are more likely to recur
initially in viscera

3. • Lobular (as opposed to ductal) cancers are more often associated with
serosal metastases to the pleura and abdomen
• 10% of patients with newly diagnosed breast cancer in the United States
have metastatic disease at presentation
• Symptoms of metastatic breast cancer relate to the location and extent of
the tumor /Non Specific like :
• bone discomfort,
• lymphadenopathy,
• skin changes,
• cough or shortness of breath
• fatigue
• When radiologic or clinical findings are equivocal, tissue biopsy is
imperative. If a biopsy is performed, ER, PR, and HER2 should be
redetermined

4. Treatment goals in women with advanced
breast cancer
• Treatment of metastatic breast cancer is based on consideration of :--
• Tumor biology
• Clinical history.
• ER, PR, and HER2 status is critical for all patients
• detailed assessment of past treatment
• Timing of therapies & patient symptoms
• Functional assessment
• Prolongation of life
• Control of tumor burden
• Reduction in cancer-related symptoms or complications
• Maintenance of quality of life and function.
Therapy is not generally considered curative

5. Patients with
endocrine-sensitive tumors+ minimal symptoms and limited visceral
involvement, are candidates for initial treatment with
endocrine therapy alone
(Initial treatment using combined chemo-endocrine therapy has not been shown
to improve survival compared with sequential treatment programs).
Patients with hormone receptor–negative tumors/hormone receptor–positive
tumors progressing despite the use of endocrine therapy are candidates for
chemotherapy.
If the tumor is HER2 positive, then anti-HER2 treatment is employed in
combination with chemotherapy.

6. Patients who have received
less therapy;
longer disease-free interval since
initial diagnosis, soft tissue or bone
metastases
fewer symptoms,
better performance status;
hormone receptor positive or HER2
positive are
likely to experience longer survival
with metastatic disease
more heavily treated patients
with shorter intervals since treatment,
visceral metastases
greater symptoms
Vs

7. Art of treating patients with metastatic breast cancer
• Careful, thoughtful repetition of a process of treatment initiation
• Evaluation including assessment of patient functional status and symptom
profile;
• Serial measurement of tumor burden and response to therapy (through
multiple lines of therapy)
• Clinical guidelines for the management of metastatic carcinoma are often quite
open-ended, acknowledging the multiple treatment pathways that might be
legitimately pursued, arguing for judicious use of clinical decision making and
treatment selection based on tumor biology, and focusing clinicians on the
continuous considerations of patient preference and illness experience.

8. Endocrine Therapy for Metastatic Breast Cancer
• It is the key intervention for women with hormone receptor–positive +
metastatic breast cancer.
• Various therapies are :--
• Ovarian suppression/ablation (premenopausal women)
• Selective estrogen receptor modulators (tamoxifen, toremifene)
• Aromatase inhibitors (anastrozole, letrozole, exemestane; postmenopausal
women)
• Antiestrogens (fulvestrant; postmenopausal women)
• Progestins (megestrol and medroxyprogesterone)
• Other steroid hormones (high-dose estrogens, androgens; principally of
historical interest)

10. Tamoxifen
• Tamoxifen was the historic standard as treatment for ER-positive metastatic
breast cancer, associated with a 50% response rate and median duration of
response of 12 to 18 months among treatment-naïve patients.
“Tamoxifen flare” reaction,
typically characterized by
intensification of bone pain
transient tumor
progression, and
hypercalcemia,
5% to 10% of patients within the first days
or weeks of tamoxifen treatment.
Flare reactions are often harbingers of
exquisite tumor sensitivity to endocrine
manipulation but must be distinguished
from overt tumor progression.
Not frequently seen with other endocrine
therapies such as AIs or fulvestrant

11. Types of ovarian ablation
• Oophorectomy
• Hormonal therapy to 'shut down' the ovaries-Ovarian suppression drugs such
as leuprolide or goserelin (LHRH agonists)- By interrupting the normal pulsatile
stimulation of, and thus desensitizing, the GnRH receptors, it downregulates the
secretion (LH) and (FSH).
Some of the benefits of chemotherapy in premenopausal women are attributed
to its effect in causing ovarian failure.
• Radiotherapy- Trials evaluating radiotherapy for ovarian ablation have used
doses ranging from a single 450 cGy fraction up to 1,000–2,000 cGy divided in
five or six fractions.

12. • EBCTG overview
• Ovarian Ablation included 12 trials that compared OA by surgery or
radiation to control and encompassed 2012 women with early breast
cancer.
• This meta-analysis concluded that OA was associated with both DFS and OS
advantages when compared to observation.
• At 15 years, 52% were alive in those who underwent OA, compared to 46%
who did not (p = 0.001), and 45% were disease-free, compared to 39% (p =
0.0007).

13. Premenopausal women with metastatic breast cancer, combined endocrine
therapy + ovarian suppression and tamoxifen
Improve survival compared with treatment with either alone.
Postmenopausal women are candidates for tamoxifen /AI/ fulvestrant/
progestational agents as palliation for metastatic breast cancer.
AIs appear to be the preferred initial agents for women who received prior
tamoxifen treatment in the adjuvant setting and may have modest clinical
advantages over tamoxifen as initial treatment for metastatic disease.
Fulvestrant appears to have comparable activity to AIs in women previously
treated with tamoxifen.

14. • Several studies have examined the combined use of an AI with fulvestrant for de
novo or progressive, ER-positive, metastatic breast cancer.
• In treatment-naïve patients SWOG 0226 trial suggested that combining
anastrozole with fulvestrant improved progression-free survival and OS
• (By contrast, in patients who had received prior tamoxifen in the SWOG the
combination of fulvestrant plus an AI was not superior to monotherapy
approaches)
• In Fulvestrant and Anastrozole Compared in Hormonal Therapy-Naïve Advanced
Breast Cancer (FALCON) trial, either fulvestrant or AI therapy afforded
comparable outcomes in first-line therapy of ER-positive metastatic breast
cancer.
• Thus, first-line endocrine choices include an AI, a fulvestrant, or, particularly in
women with endocrine-naïve cancers, a combination of the two.

15. • Progression on Hormone therapy and Resistance
• Eventually, most women with hormone receptor–positive metastatic breast
cancer will progress despite first line endocrine therapy and be candidates
for second-, third-, and even subsequent lines of endocrine therapy.
• Resistance to treatment does not seem to be associated with loss of
hormone receptor expression by the tumor cells.
• Resistance to AI therapy can arise through acquired mutations in the ER
gene (ESR1), which constitutively activate the receptor even in the absence
of estrogen.
• Such mutations are rare in primary breast cancers but have been identified
in up to 40% of tumors recurring or progressing on AI therapy and are
associated with resistance to ongoing AI treatment but not to therapy with
selective ER degraders (SERDs) such as fulvestrant.

16. • Combining endocrine therapy+targeted treatments inhibiting other important
cell growth and regulatory pathways
useful strategy for enhancing the efficacy of endocrine treatments.
• Cell cycle regulation, of which the cyclin-dependent kinases (CDKs) are an
important component, is normally tightly controlled. In breast cancer, this
process is often disrupted.
• Two approaches are widely used :---
• CDK4/6 inhibitors + AIs as first-line treatment for ERpositive metastatic breast
cancer
• CDK4/6 inhibitors + fulvestrant as second-line treatments.
In both settings, the addition of CDK4/6 inhibition dramatically
improved the progression-free survival compared to outcomes for
endocrine therapy alone

17. Phase III Trials of CDK4/6 Inhibitors in ER-Positive, HER2-
Negative Metastatic Breast Cancer
Line of
Therapy
Study Name Schema Median PFS (mo)
1st PALOMA-2 Letrozole +/- palbociclib 14.5 vs. 24.8
1st MONALEESA-2 Letrozole +/- ribociclib 14.7 vs. < 26
1st MONARCH-3 AI +/- abemaciclib 14.7 vs. <25
2nd PALOMA-3 Fulvestrant +/- palbociclib 3.8 vs. 9.2
2nd MONARCH-2 Fulvestrant +/- abemaciclib 9.3 vs. 16.4
Side Effects :--
Palbociclib and ribociclib are associated with greater risks of neutropenia;
Abemaciclib is more likely to cause diarrhea
CDK4/6 inhibitors have not yielded benefits in OS but have been shown to delay initiation
of palliative chemotherapy by about 1 year.

18. • Mammalian target of rapamycin inhibitor (mTOR) everolimus has also
been shown to enhance the activity of endocrine therapy in the setting of
resistant, ER-positive tumors.
• In a randomized clinical trial (BOLERO-2 trial ) patients with advanced
disease resistant to letrozole or anastrozole were assigned to exemestane
plus everolimus or placebo.
• The combination of exemestane and everolimus extended median
progression-free survival to 11.0 months compared with 4.1 months
(hazard ratio, 0.38; P < .0001)
• It was associated with significant side effects, including
• Stomatitis
• Hyperglycemia
• Pneumonitis.

19. • After several lines of endocrine therapy, most patients will develop disease refractory to
endocrine manipulations and will transition to chemotherapy.
• Indications for chemotherapy:--
• Symptomatic tumor progression
• Impending visceral crisis
• Resistance to multiple endocrine therapies.
• Patients presenting with extensive visceral metastases or profound symptomsfrom
breast cancer may benefit from
induction chemotherapy
followed with
endocrine therapy

20. Chemotherapy for Metastatic Breast Cancer
• Cytotoxic chemotherapy : Mainstay of treatment for women with metastatic
breast cancer, irrespective of hormone receptor status, and is the backbone of
many novel treatments incorporating biologic therapy
• Chemotherapy has substantial side effects:--
• Fatigue
• nausea, vomiting,diarrhoea
• myelosuppression
• neuropathy
• Alopecia,
• Making trade-offs between cancer palliation Vs toxicities of therapy.
• Chemotherapy is used in patients with hormone-refractory or hormone-
insensitive tumors

21. • Tumor response to chemotherapy = longer cancer control & survival
• 1st line chemotherapy is associated with higher response rates and longer tumor
control than 2nd line chemotherapy, and so forth.
• Chemotherapy treatment can be interrupted in patients who have had
significant response or palliation following initiation of therapy and reintroduced
when there is tumor progresssion or symptom recurrence.
• Single-agent sequential treatment Vs combination treatment ??
• Combination chemotherapy : higher response rates and improved time to
progression compared vs single-agent therapy
• Extensive visceral disease/pending visceral crisis may preferentially require
initiation of combination chemotherapy, (not demonstrated in prospective
studies)
• Single-agent chemotherapy facilitates better understanding of which drugs are
contributing to benefit /side effects and is generally associated with less
toxicity, it remains the preferred approach.

22. Common Chemotherapy Agents and Combinations for Advance Breast Cancer
Single Agents Combination Regimens
Anthracyclines : doxorubicin, epirubicin,
pegylated liposomal doxorubicin
Cyclophosphamide/anthracycline ± 5-
fluorouracil regimens AC, EC, CEF, CAF,FEC,FAC)
Taxanes : paclitaxel, docetaxel, nanoparticle
albumin-bound paclitaxel (NAB Paclitaxel)
Anthracyclines/taxanes (such as
doxorubicin/paclitaxel or doxorubicin/docetaxel)
5-Fluorouracil (5-fluorouracil by IV infusion or
oral capecitabine)
Docetaxel/capecitabine
Vinca alkaloids (vinorelbine, vinblastine) Gemcitabine/paclitaxel
Gemcitabine Taxane/platinum regimens (such as
paclitaxel/carboplatin or docetaxel/carboplatin)
Platinum salts (cisplatin, carboplatin) xabepilone/capecitabine
Ixabepilone
Cyclophosphamide
Eribulin

23. • A single “best” approach for all patients with metastatic cancer is not supported
by the literature.
• Anthracycline + taxane-based treatments : Most active in treatment of
metastatic breast cancer, their utility has led to their incorporation into adjuvant
chemotherapy regimens.
• Thus, many women with metastatic breast cancer will already have been treated
with anthracyclines and/or taxanes
Diminishing the utility of these agents in the palliation of metastatic disease

24. • Capecitabine
• orally available fluoropyrimidine
• metabolized in tissues into 5-fluorouracil
• Clinical activity in anthracycline- and taxane-resistant breast cancer
• Improves response and survival as 1st line treatment when added to single-agent docetaxel
• Gemcitabine (Antimetabolite)
• higher response rates and survival when paired with paclitaxel compared with paclitaxel
therapy alone.
• Ixabepilone,
• Epothilone chemotherapy agent,
• substantial activity as a single agent /combination with capecitabine in patients previously
treated with anthracyclines and taxanes.
• Eribulin
• Synthetic analog of halichondrin B
• Nontaxane microtubule dynamics inhibitor that was evaluated against physician’s choice of
chemotherapy in a randomized phase III study,
• Improved OS in patients with locally recurrent or metastatic breast cancer with at least two
prior regimen

25. The study met its primary endpoint with a significant improvement in OS
by a median of 2.5 mo with Eribulin vs. TPC. Eribulin demonstrated a
manageable tolerability profile, acceptable for a CT agent used as
monotherapy in this late-line setting.

26. • Dose escalation of taxane therapy with paclitaxel has not been shown to result in
clinically important improvements.
• Weekly administration of paclitaxel therapy
• Improve response rate
• Improved time to progression Vs every-3-week administration.
Strategy to overcome chemotherapy resistance
High-dose chemotherapy with autologous bone marrow or stem cell support
Preliminary studies : favorable clinical outcomes = widespread use of high-dose
chemotherapy in clinical practice and randomized trials for patients with either
metastatic or high-risk, node-positive breast cancer.
Clinical trials found no difference in outcome between standard chemotherapy
followed by treatment with either high-dose chemotherapy and autologous stem
cell rescue or maintenance chemotherapy at conventional doses.
There is no current role for bone marrow or stem cell transplant in management of
either early- or late-stage breast cancer.

27. Anti-HER2 Therapy for Metastatic Breast Cancer
• First-line Treatment
• AntiHER2 treatment revolutionized outcomes for patients with HER2-positive
breast cancer
• Trastuzumab, the humanized anti-HER2 monoclonal antibody, was the first anti-
HER2 agent to enter clinical practice.
• 1st line chemotherapy for HER2-positive metastatic breast cancer + trastuzumab
improved response rates, time to progression, and OS
• Cardiomyopathy is a known side effect of trastuzumab therapy,
• Concurrent administration of trastuzumab+anthracyclines = Avoided.
• Serial determinations of LVEF should be performed to screen for changes related
to trastuzumab.

28. • Pertuzumab
• It binds HER2 + human epidermal growth factor receptor 3 (HER3) proteins and
is believed to prevent dimerization of those receptors.
Trial :--
(CLEOPATRA) study Clinical Evaluation of Pertuzumab and Trastuzumab
• Docetaxel and Trastuzumab Vs Docetaxel, Trastuzumab, and pertuzumab
• (as 1st line treatment for HER2-positive breast cancer)
• showed improvement in both progression-free survival and OS with the
addition of pertuzumab

29. Refractory, HER2-Positive Breast Cancer
• Continuation of trastuzumab treatment beyond progression : associated with
improvements in time to progression and justifies the practice of continued anti-
HER2 blockade in association with multiple lines of treatment for HER2-positive
metastatic breast cancer.
• Lapatinib is a dual-kinase inhibitor that targets both the HER2 and the EGFR
tyrosine kinase signaling pathways.
• 2nd anti-HER2 therapy for patients with disease progression after chemotherapy
and trastuzumab.
• In comparison with the administration of capecitabine chemotherapy alone, the
combination of lapatinib+capecitabine = Longer period of tumor control and
improvement in response rate but not survival.

30. • Ado-trastuzumab emtansine (T-DM1)
• antibody–drug conjugate in which the trastuzumab antibody has been linked
chemically to a potent chemotherapy moiety
• Substantial activity in trastuzumab-refractory breast cancer, without the
traditional side effects of chemotherapy, such as neutropenia or alopecia
• In a Randomized trial (EMILIA Trial) of trastuzumab-resistant breast cancer TDM1
was found to be superior to the combination of lapatinib and capecitabine with
respect to progression-free survival, OS, and tolerability

31. Emerging Options for BRCA1- or BRCA2-Associated Breast Cancer
• PARP Inhibitors
• Drugs that inhibit the poly (adenosine diphosphate–ribose) polymerase (PARP)
enzyme, are emerging as potentially valuable drugs in treatment of advanced breast
cancer, particularly in hereditary breast cancer.
• In a proof-of-principle, open-label, phase II study, the PARP inhibitor olaparib was
studied in patients with BRCA1- or BRCA2-associated cancers. This select group of
patients was chosen because of preclinical data that suggested that tumors with BRCA
deficiency might be particularly dependent on the DNA repair function of the PARP
enzyme complex and thus suitable targets for PARP inhibition.
• Initial observations have suggested robust responses among BRCA-associated breast
cancers when patients are given single-agent therapy with olaparib.
• In a randomized trial comparing the PARP inhibitor olaparib vs standard chemotherapy
choices for refractory, BRCA-associated metastatic breast cancer,
• olaparib : improved response rate
progression-free survival,
with fewer side effects than standard chemotherapy

32. • Talazoparib :Shown single-agent activity in BRCA-associated cancers and, in
comparison against standard chemotherapy options, showed superior time to
progression and response rates
• Platinum-based chemotherapy has a clinical role in hereditary breast cancers
• Treating to New Targets (TNT) trial compared
docetaxel Vs carboplatin
(as first-line treatment for triple-negative metastatic breast cancer)
Overall : docetaxel yielded higher response rates and better PFS
Subset of BRCAassociated tumors : Carboplatin had better RR & PFS .
BRCA status affects the treatment options for metastatic breast cancer and is an
indication for platinum-based chemotherapy and PARP inhibitor treatment

33. Immunotherapy in Advanced Breast Cancer
• Immunotherapy : Actively investigated in the palliation of advanced breast
cancer
• Checkpoint inhibitors either alone or in combination with chemotherapy have
been studied
• Triple-negative cancers : Area of focus because of :
• Lack of existing targeted treatments
• Greater mutational burden in triple-negative breast cancer vs other subtypes
• Frequency of tumor infiltrating lymphocytes in TNBC.
• Single-agent therapy with the programmed cell death protein 1 (PD-1) inhibitor
Pembrolizumab has shown response rates of approximately 10% to 20% in
previously treated triple-negative breast cancer.

34. • Single-agent treatment with the programmed cell death protein ligand 1
(PD-L1) inhibitor Avelumab showed lower response rates among a cohort
of patients with previously treated ER-positive and triple-negative tumors.
• Strategies combining chemotherapy + PD-1/PDL1 inhibition have
suggested improved activity in the neoadjuvant treatment of triple-negative
breast cancer.
• Preliminary data suggest that adding anti-PDL1 antibody therapy to first-
line chemotherapy may improve outcomes in metastatic, triple-negative
breast cancer.
• But specific regimens / biomarkers for identifying successful treatment with
immunotherapy are not yet well established in breast cancer

37. Special Metastatic Sites in Patients with Breast
Cancer
Bone metastasis
Pathophysiology :
Batson described the high-flow, low-pressure, valveless plexus of veins that
connects the visceral organs to the spine and pelvis.
Recent research has focused on the multistep cellular process of metastases.
1st cancer cell must disengage from its primary site.
The loss of expression of E-cadherin, a cell-surface adhesion molecule, has been
demonstrated as an early step in cellular disengagement.
After invasion of the vascular or lymphatic system, the cancer cell must survive the
immune system and then arrest at its final destination.
At the distant site, the malignant cell must adhere to the basement membrane,
invade the surrounding tissue, induce angiogenesis, and develop into a secondary
mass.

38. • Tumor cells in the bone marrow require interaction with normal bone cells to
establish a metastatic lesion in bone.
• Disseminated tumor cells have the ability to reside within hematopoietic,
osteoblastic, or vascular niches within the bone marrow where they may enter a
prolonged dormant state, often for years.
• Subsequently, for reasons that are poorly understood, the cells can awaken from
this dormant state, proliferate, and begin the process of establishing overt
metastases.
• Growth Factor and cytokine expression of the tumor cells leads to an interaction
with osteoclasts and osteoblasts, the balance of which determines the nature of
the lesion and its corresponding radiographic appearance.

39. • Osteoclastic activity : increased expression of growth factors,cytokines that
further lead to bone resorption.
• This leads to release of BONE derived growth factors (transforming growth factor
β) which in turn may react with receptors on the tumor cells.
• Vicious cycle sets up whereby the stimulation of bone cell activity produces a
favourable microenvironment for the neighbouring tumor cells and facilitates the
metastatic process.
• Osteoblastic activity :New bone formation associated with osteoblastic lesions
has been associated with endothelin 1 and insulin-like growth factor stimulation
of osteoblasts, but typically even in osteoblastic lesions, there is also an
associated increase in osteoclastic bone resorption.

40. DIAGNOSTIC EVALUATION :
• Radiographs and bone scans are
the 1st Lines of imaging
supplemented by :--
• CT
• MRI
• PET
• Documents :Presence/absence of
an osseous lesion and to identify
whether these are solitary or
multiple lesions.
• In the spine, plain films classically
show absence of a pedicle with the
“winking owl sign”

41. Bone Scan
• Technetium-99m bone scintigraphy is the best method for screening patients at
risk for bone metastasis who may not present with bone pain.
• Evaluates the extent of metastatic disease in the bone
• Indicator of osteoblastic activity.
• Not specific for metastatic disease, and positive findings must often be confirmed
using other imaging studies Especially important in a weight-bearing bone such
as the proximal femur
• False-positive readings may be seen in areas of arthritis, trauma, prior fractures,
or Paget’s disease.
• False-negative readings may occur in fast-growing, highly aggressive tumors,
especially if these are mainly osteolytic.

43. CT scan
It is most useful to evaluate aspects of bony stability as measured by pedicle
and/or posterior body wall integrity.
Important in establishing risk of burst fracture and for planning and assessing the
safety of vertebroplasty as a treatment alternative.
Defines the extent of cortical destruction and helping to assess the risk of a
pathologic fracture.
CT-guided biopsy can be used for obtaining tissue samples.
More sensitive than plain radiographs and may be better able to localize the lesion
within the bone.
More expensive and more time-consuming and may not be useful as a screening
tool for skeletal metastasis.
Limited usefulness in detecting marrow involvement but are much better than
plain radiographs at evaluating soft tissue extension of disease.

44. An example of metastatic breast
cancer, in this case illustrated on
CT and bone scan. The CT clearly
depicts multiple sclerotic lesions in
vertebrae and the sacrum, which
show corresponding increased
uptake on the bone scan

45. MRI
• Evaluates marrow disease
• most sensitive in identifying metastatic deposits in the spine and pelvis. MRI
scans may be more sensitive than bone scintigraphy in the vertebral body region.
The sensitivity of MRI scanning has been reported as 91% to 100%, compared
with 62% to 85% for bone scintigraphy
• In patients with neurologic compromise, MRI is best for assessing epidural
disease and extent of vertebral involvement (solitary versus multifocal)
• Magnetic resonance imaging (MRI) is better than plain radiography or nuclear
medicine bone scintigraphy at assessing the involvement of trabecular bone and
bone marrow, especially in the vertebral bodies The findings are typically best
seen on T1 contrast-enhanced images and short tau inversion recovery (STIR)
images
• MRI images : Distinguish whether a vertebral body compression fracture is from
malignancy or from osteoporosis

47. Treatment of bone metastasis
• Systemic Therapy : As discussed
• Bisphosphonates for Metastatic Bone Disease :
• Bisphosphonates : Analogs of pyrophosphate
• Characterized by a phosphorus-carbon phosphorus–containing central structure
that binds to bone and a variable side chain that determines the relative potency,
side effects, and precise mechanism of action.
• Bisphosphonates bind avidly to exposed bone mineral, and during bone
resorption, bisphosphonates are internalized by the osteoclast and subsequently
cause apoptotic cell death.
• After intravenous administration of a bisphosphonate, the kidney excretes
approximately 25% to 40% of the injected dose, and the remainder is taken up by
bone where it is retained for months or even years.
• Poor bioavailability when given by mouth and must be taken on an empty
stomach, as they bind to calcium in the diet.

48. • Osteoclast activation :Key step in the establishment and growth of bone
metastases.
• Biochemical data indicate that bone resorption is of importance not only in
classic “lytic” diseases such as myeloma and breast cancer but also in prostate
cancer.
• Osteoclast is a key therapeutic target for skeletal metastases irrespective of the
tissue of origin.
• Radiotherapy : is the treatment of choice for localized bone pain, the
bisphosphonates provide an additional treatment approach for the relief of bone
pain across a range of tumor types.
• Oral Bisphosphonates : oral Clodronate and Ibandronate
• Intravenous Bisphosphonates : zoledronic acid, pamidronate, and ibandronate

49. • In randomized trial of 1,130 patients with advanced breast cancer, an additional 20%
reduction in the risk of SREs was seen with zoledronic acid compared with pamidronate
• Ibandronate was licensed in Europe for the treatment of metastatic bone cancer after a
placebo-controlled trial of monthly infusions showed a significant reduction in skeletal-
related morbidity.
Denosumab :
• Fully human monoclonal antibody that binds and neutralizes RANK ligand with high
affinity and specificity to inhibit osteoclast function and bone resorption
• Denosumab does not adversely affect renal function
• Acute-phase reactions are also less common with denosumab
• Hypocalcemia is more frequent = Vitamin D deficiency should be corrected, and all
patients should be encouraged to take calcium and vitamin D supplements throughout
the course of their treatment.
• Most important adverse event associated with denosumab in the oncology setting is
osteonecrosis of the jaw
• Frequency in patients treated with denosumab or zoledronic acid, affecting 0.5% to 1%
of patients per year on treatment.

50. • NEW TARGETED THERAPIES : Number of targeted agents have entered clinical
development.
• A radioactive isotope that is a βemitter or low-energy γ-source will allow localized
treatment in the areas in which the radiopharmaceutical accumulates, thus
minimizing side effects and giving an excellent therapeutic ratio
• First radiopharmaceutical used for treatment of bone metastases was
phosphorous-32
• Radium-223, inhibitors of cathepsin K, an osteoclast-derived enzyme that is
essential for the resorption of bone, and Src kinase, a key molecule in
osteoclastogenesis
• Radium-223 is a calcium mimetic that preferentially targets bone metastases and
emits high-energy alpha particles, resulting in highly localized cytotoxic effects
with minimal myelosuppression
• This agent is now being studied earlier in the course of metastatic prostate
cancer, both as a single agent and in combination with endocrine or cytotoxic
agents, as well as in breast cancer.

51. • Other Radiopharmecological agents : --
• Sr-89 is a pure β-emitter with an energy of 1.4 MeV and a half-life of 50.6 days.
• Samarium-153 (Sm-153) is primarily a βemitter but also has a component of
gamma emission
• Surgical treatment :
• Prophylactic surgery for stabilization should be considered in medically
appropriate candidates with weight-bearing pain in the long bones, particularly
the femur.
• Spinal decompression surgery should be strongly considered for patients with
spinal involvement and neurologic compromise.
• Patients with frank long bone or pelvic fractures should be considered for
stabilization of fractures or joint-replacing surgery

52. EXTERNAL-BEAM RADIATION THERAPY
Radiation : helps in
• relieving bone pain
• preventing impending fractures
• promoting healing in pathologic fractures.
Radiation Therapy Oncology Group (trial 74-02)
• A total of 90% of patients experienced some relief of pain, and 54% achieved eventual
complete pain relief.
• This trial concluded that the low-dose, short-course schedules were as effective as the
high-dose protracted programs
• Criticized for using physician-based pain assessment.
• A reanalysis of the same set of data, grouping solitary /multiple bone metastases, using
the end point of pain relief, and taking into account analgesic intake and retreatment,
Concluded that the number of radiation fractions was statistically significant related
to complete combined relief (absence of pain and use of narcotics).
• The conclusion was that protracted dose fractionation schedules were more effective
than short-course schedules. This reanalysis was contrary to the initial report,
highlighting that the choice of end points is important in defining the outcomes of
clinical trials.

53. • United Kingdom Bone Pain Trial Working Party randomized 765 patients
with bone metastases to either an 8-Gy single fraction or a multifraction
regimen (20 Gy in 5 fractions or 30 Gy in 10 fractions).
• There were no differences in the time to first improvement in pain, time to
complete pain relief, or time to first increase in pain at any time up to 12
months from randomization
• The study concluded that a single 8-Gy fraction is as safe and effective as a
multifraction regimen for the palliation of metastatic bone pain for at least
12 months

54. • Wide-Field or Half-Body External-Beam Radiation
• Wide-field or half-body irradiation (HBI) differs from localized external-beam
radiation mainly in the volume of tissues and bone metastases covered as a
single treatment field.
• It is more useful for patients with multiple painful bone metastases.
• HBI is usually delivered either to the upper half or to the lower half of the body.
• Single-fraction HBI has been shown in retrospective and prospective phase I and
II studies to provide pain relief in 70% to 80% of patients.
• Pain relief is apparent within 24 to 48 hours, suggesting that cells of the
inflammatory response pathway may be the initial target tissue, as tumor cell
activities are unlikely to be halted so quickly.
• Toxicities: Minor bone marrow suppression and gastrointestinal side effects such
as nausea and vomiting in upper abdominal radiation and may be controlled
with ondansetron or dexamethasone

55. Lung metastasis
Pulmonary metastases from breast cancer are common, patients rarely present
with isolated pulmonary disease
Despite the relative infrequency, metastasectomy for isolated pulmonary
metastases has been described as a means to augment the moderate success of
chemotherapy, hormonal therapy, and radiation therapy
Studies of metastasectomy demonstrate 5-year survival rates between 30% and
50%, with 5- year survival in excess of 80% in highly selected patients
Factors associated with prolonged survival include
• long DFI (>36 months)
• R0 resection
• hormone receptor positivity
• fewer than four metastases

56. • These four factors were recently assessed in a large meta-analysis of breast
cancer patients undergoing metastasectomy;
• Negative hormone status was the strongest negative prognostic factor.
• The importance of hormone receptor status on survival after metastasectomy
reiterates the need for individualized therapy in breast cancer care, and to that
end, pulmonary metastasectomy is often used to obtain tissue to further guide
treatment due to changes in molecular profile.

58. Brain metastasis
• The true incidence of brain metastases,
which develop in nearly 30% of cancer
patients is not known, although autopsy
estimates are as high as 170,000 cases
annually in the United States.
• Brain metastases are solid or ring-
enhancing lesions, pseudospherical in
shape, and multiple in number; occur in
the gray–white junction; and occur most
frequently in the cerebral hemispheres
(80%) followed by the cerebellum (15%)
and brain stem.
• Primary Breast : 5%–20% of brain
metastasis
• 2nd most common after lung cancer.

61. Treatment of Brain Metastasis
• Initial treatment of brain metastases is influenced by lesion number, location,
size, and upon the status of a patient's systemic disease
• Supportive :
• Corticosteroids : for patients with symptomatic edema
• Anticonvulsants : for patients with a history of seizures. In patients without a
seizure history, the routine use of prophylactic anticonvulsants is not
recommended
• Radiation
• WBRT : WBRT continues to be a standard of care in select patients with diffuse
brain metastasis (≥5 brain metastases). It is well known to provide improvement
in neurologic symptoms with overall response rates of 70% to 93%.
• reduces the risk of intracranial recurrence but does not appear to affect overall
survival

62. Surgery
• In patients with single or solitary brain lesions, good performance status, and
stable extracranial disease, surgical resection or SRS is recommended.
• Surgery is preferred for lesions with symptomatic mass effect, larger lesions, and
when the risk of operative morbidity is acceptably low.
• Surgical resection can aid in obtaining a pathologic diagnosis of intracranial
lesions, provide immediate relief of tumor mass effect and may cure a small
percentage of patient with single or solitary lesions.
• On the other hand, radiation typically takes several days to work.
Radiobiologically, 30 Gy in 10 fractions to a solid tumor (excluding
radiosensitive tumors) is not adequate to achieve long-term tumor control.

63. Radiosurgery
• Provides a suitable alternative to conventional surgery
• No randomized trials have been performed comparing surgery vs SRS,
• SRS boost appears to provide at least comparable, if not improved, local control
rates (80% to 90% when combined with WBRT).
• Therefore, in the setting of limited intracranial disease burden, unless emergent
surgery is warranted, SRS alone or as a boost can serve as a noninvasive
alternative

70. Thank you