Principle of oncology staging and management

1. Principles of Oncology II
Mod: Dr. Arjun Agarwal (MS, MCh Onco surgery)
By: Dr. Shruti Devendra
Department of Surgery, RMCH, Bareilly

2. Outline
• Staging
• Intent of treatment
• Curative
-Surgery: Primary, Lymph Node, Metastasis
-Radiotherapy
-Chemotherapy: Neoadjuvant chemotherapy, Adjuvant chemotherapy
• Palliative
-Best Supportive Care

3. TNM
T means size of the tumor
N lymph nodes
M metastasis
cTNM: clinical staging
pTNM: Pathologic
p(m)TNM: means multiple primary
ypTNM/ycTNM: y denotes patient have received systemic therapy
aTNM: Autopsy
rTNM: recurrent tumor
Tx or Nx or Mx: x means tumor cannot be assessed

4. Example breast cancer TNM
Primary tumor (T)
Tx cannot be assessed
T0 no evidence of primary tumor
Tis in situ
T1 <2 cm
T2 2 to <5 cm
T3 >5 cm
T4 direct extension to chest wall or
to the skin
Regional LNs (N)
cNx Cannot be assessed
cN0 no regional LN mets
cN1 movable ipsilateral level I, II
cN2 matted ipsilateral level 1 and II
cN3 ipsilateral level III, or with I,II
or supraclavicular
Metastasis (M)
Mx not accessible, M1, M0

5. Cancer staging
Cancer staging is a system used to describe the anatomic extent of a malignant
process in an individual patient.
Staging system may incorporate tumor size, location, extent, grade and
dissemination to regional lymph nodes or distant metastasis.
For the patient of breast cancer staging workup would include CXR, bone scan, and
liver USG or CT abdomen. To evaluate lung, bone and liver metastasis
Things done for cancer staging e.g. FNAC or biopsy of liver mets or bony mets,
ascitic fluid cytology for malignant cells.
In early operable breast cancer (Tl to 2, N0 to 1), there is no current evidence to support routine
screening for metastatic disease in asymptomatic women.

6. Indication of PET scan
Scar
Recurrence, relapse
Occult malignancy
High risk group for screening in young females
For assessing efficacy of the treatment

8. Breast
cancer
Staging
Stage T N M
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T0 N1mi M0
T1 N1mi M0
Stage IIA T0 N1 M0
T1 N1 M0
T2 N0 M0
Stage IIB T2 N1 M0
T3 N0 M0
T3 N2 M0
Stage IIIB T4 N0 M0
T4 N1 M0
T4 N2 M0
Stage IIIC AnyT N3 M0
Stage IV AnyT AnyN M1
Nmi: Micrometastasis 0.2mm to <2mm

9. Intent of underlying treatment
Curative
Radiotherapy, chemotherapy, or the
combination of the two, may be used
with curative intent.
Palliative
For symptomatic primary or secondary
tumor to improve quality of life.

10. Curative
-Surgery:
Primary,
Lymph Node (LN) basin,
Metastasis
-Radiotherapy
-Chemotherapy: Neoadjuvant chemotherapy, Adjuvant
chemotherapy

11. Schematic diagram to
show the spatial scope
of cancer
treatments.
Chemotherapy is
systemic, surgery is
mainly a local
treatment.
Radiotherapy is
usually local or
locoregional

12. 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.
If the primary tumor is not resectable with negative margins it is considered
to have unresectable disease.
Inoperable is when the tumor has distant metastasis stage IV disease
On occasions primary tumor are resected for palliative reasons such as
improving quality of life by alleviating pain, infection, or bleeding. Example,
toilet mastectomy for ulcerated breast tumor.

13. R0: Removal of all macroscopic disease and microscopically also the
margins are negative
R1: Macroscopically disease removed but microscopically margins are
positive
R2: Both macroscopic and microscopic margins are positive

14. Surgical management of LN basin
Most neoplasms have the ability to metastasize via the lymphatics.
Therefore, most oncologic operations have been designed to remove the
primary tumor and draining lymphatics en bloc.
This can be done where the primary site lies adjacent to the tumor bed.
Example, gastric cancer.
For tumors with the LN basin not adjacent. Surgery can be performed
from separate incision. Example, melanomas

15. Sentinel LN
Sentinel LN biopsy was first reported in 1977 by Cabanas for penile ca. Now widely used
for melanomas and breast cancer, endometrial cancer. Now being tried for head and neck
malignancy. In these cases false negative rate is <10% that’s why biopsy is done and in
other cases it is more than 10% so futile to attempt it.
First node to drain the tumor site is called sentinel LN. This is the node most likely to
contain metastases, if the metastasis to that regional LN basin is present.
Goal: of sentinel LN biopsy specimen is to identify and remove the LN most likely to
contain metastases in least invasive manner. This avoids the morbidity of LN dissection in
patients with negative nodes
Indications: breast lump with no evidence of lymph nodesin axilla, DCIS with mass or
DCIS with suspicion of synchronous malignancy or DCIS of >5 cms

16. Two Criteria to assess efficacy of sentinel LN biopsy 1. Sentinel LN
identification rate 2. The false negative rate

17. False negative rate could be due to identifying wrong (surgical error), or
first node not involved (biological variation), or inadequate histologic
evaluation .
Lymphatic mapping is performed by using Isosulfan blue dye,
technetium-labelled sulfur colloid or albumin or a combination of both.
Combination of both is considered superior. Isosulfan blue dye alone 7
% chance of false negative result, and when both together it is reduced
to 3 % and Tc sulfur colloid alone it is 5%.

18. Management of the patient with distant
metastases
Once the tumor has metastasized it is usually not curable with surgical
therapy, such surgery resulted in cure in selected cases with isolated
metastasis to liver, lung, or brain.
Example, Isolated liver metastases from colon cancer.
?Prechronous
The patients who have synchronous metastases do worse after
metastasectomy as compared to patients with metachronous metastases

19. Chemotherapy
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
Adjuvant therapy can be administered after surgery (post-operative
chemotherapy) or before surgery (Preoperative chemotherapy,
neoadjuvant chemotherapy, or induction therapy)

20. A portion or all of the planned chemotherapy can be administered before the
surgical removal of the primary tumor.
Pre-operative chemotherapy has three potential advantages
1. Preoperative regression of tumor (make it operable or to make
conservative surgery possible)
2. Treatment of micrometastases without the delay of post-operative
recovery (max time between surgery and chemo without affecting
prognosis or survival of the patient is 3 months)
3. The ability to assess a cancer’s response to treatment clinically to
chemotherapy and pathologically after surgical resection

21. Response to chemotherapy is measured with imaging studies and
clinical examination
Response is defined as
Complete response
Partial response
Stable disease
Progression
Using Response Evaluation Criteria in Solid Tumors (RECIST)

23. Principle of chemotherapy
Chemotherapy destroys cells by first-order kinetics, which
means that with the administration of a drug a constant percentage
of cells are 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).

25. Chemotherapeutic agents
Class Example MOA Side effects Tumor sensitive to
drug
Interfere with
mitosis
Vincristine
Vinblastin
Interfere with
formulation of
microtubules
SIADH, Peripheral
neuropathy
BMS
Lymphoma
Leukemias
Brain tumors
Paclitaxel Stabilize
microtubules
Breast cancer, non-
small cell lung ca,
ovarian, prostate ca

26. Class Example MOA Side effects Tumor sensitive to
drug
Interfere with DNA
synthesis
(antimetabolites)
5-FU Inhibition of
Thymidylate
synthase false
substrate
Hand foot disease Breast and GI
cancer
Capecitabine Orally active
prodrug which is
metabolised to 5-
FU.
Inhibition of
thymidylate
synthase, false
substrate
for both DNA and
RNA synthesis
Hand and foot
disease
Breast cancer
GI cancer
Folate analog Methotrexate Inhibition of
dihydrofolate
reductase
Megaloblastic
anaemia and
hepatotoxic
Breast cancer
Bladder cancer
Lymphomas
Cervical cancer

27. Class Example MOA Side effects Tumor sensitive to
drug
6-Mercaptopurine Inhibits de novo
purine synthesis
Hepatotoxic Leukaemias
6-Thioguanine Inhibits de novo
purine synthesis
Hepatotoxic Leukaemias
Cytosine
arabinoside
False substrate in
DNA synthesis
BMS Leukaemias
Lymphomas
Drugs which
directly
damage DNA or
interfere with its
function
Mitomycin C DNA cross-linking,
preferentially active
at sites of
low oxygen tension
(a bioreductive
drug)
Nausea, vomiting
and diarrhea
Anal cancer
Bladder cancer
Gastric cancer
Head and neck
cancer
Rectal cancer
Oxaliplatin Forms adducts
between DNA
strands and
interferes
with replication
BMS Colorectal cancer

28. Class Example MOA Side effects Tumor sensitive to
drug
Doxorubicin Intercalates between
DNA strands and
interferes
with replication
Cardiotoxic Breast cancer
Lymphomas
Sarcomas
Kaposi’s sarcoma
Cyclophosphamide A prodrug converted
via hepatic
cytochrome p450
to phosphoramide
mustard. Causes
DNA cross links
Hemorrhagic cystitis Breast cancer
Lymphomas
Sarcomas
Miscellaneous G2
Phase
Bleomycin DNA strand
breakage via
formation of metal
complex
Lung Fibrosis Germ cell tumours
Lymphomas
DNA gyrase II
inhibitor G2 phase
Etoposide Inhibits
topoisomerase 2,
prevents DNA
unwinding
Secondary
Leukemias
Small-cell lung
cancer
Germ cell tumours
Lymphomas

29. Class Example MOA Side effects Tumor sensitive to
drug
Actinomycin D Intercalation between DNA
strands, DNA strand
breaks
BMS, mouth ulcers Rhabdomyosarcoma
Wilm’s tumour
Hormones Tamoxifen Blocks oestrogen receptors Breast cancer
Anastrazole
Letrozole
Exemestane
An aromatase inhibitor than
blocks postmenopausal
(non-ovarian) oestrogen
production
Breast cancer
Leuprolide
Goserelin
Buserelin
Analogue of gonadotrophin-
releasing hormone,
continued use produces
downregulation of the
anterior pituitary with
consequent fall in
testosterone
levels
Prostate cancer

30. Combination chemotherapy
provide greater efficacy than single-agent therapy by three mechanisms:
(a) it provides maximum cell kill within the range of toxicity for each
drug that can be tolerated by the host,
(b) it offers a broader range of coverage of resistant cell lines in a
heterogeneous population, and
(c) 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.

31. Chemotherapy treatment is given in cycles
At any one time, some of the cancer cells will be resting. Chemotherapy
attacks cells that are dividing. So resting cells will not be killed.
Some of the cancer cells that were resting during first treatment will be
dividing by the time second treatment comes around. So they will be
killed off.
Normal cells usually repair the damage from chemotherapy more
effectively than cancer cells. So damage to cancer cells should
progressively build up without causing permanent damage to normal
cells.

32. Resistance
Tumors are heterogeneous, and, according to the Goldie-Coldman
hypothesis, tumor cells are genetically unstable and tend to mutate to
form different cell clones. This has been used as an argument for giving
chemotherapy as soon as possible in treatment to reduce the likelihood
that resistant clones will emerge.

33. Tumor size is another important variable. Large tumor, may have greater
heterogeneity, although heterogeneity may also differ based on
biological subtype. Moreover, according to the gompertzian model,
cancer cells initially grow rapidly (exponential growth phase), then the
growth slows down owing to hypoxia and decreased nutrient supply.
Because of the larger proportion of cells dividing, smaller tumors may
be more chemosensitive.

34. Radiation therapy
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.

36. 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.

37. 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.
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.

38. 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 G1 process referred to as reassortment.

39. Electromagnetic radiation is indirectly ionizing through the short-lived
hydroxyl radicals. Hypoxic cell are significantly less radiosensitive
because the presence of oxygen prolongs the half life of free radicals.
The radiation sensitive phase is G2 and M.
Protons and heavy particles are directly ionizing and directly damage
DNA and are independent of cellular oxygen levels. Less dependent on
cell-cycle phase.

40. 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.

41. Radiation therapy planning
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.
Conventional fractionation is 1.8 to 2 Gy/d, administered 5 days each
week for 3 to 7 weeks.

42. Unit of radiation
The amount of radiant energy absorbed in a certain amount of tissue. A
unit of absorbed radiation equal to the dose of one joule of energy
absorbed per kilogram of matter, or 100 rad = 1 Grays (Gy).

43. Brachytherapy
In Brachytherapy, unlike in external beam therapy, the radiation source
is in contact with the tissue being irradiated. Radiation source may be
cesium, gold, iridium, or radium.
Brachytherapy is administered to through temporary or permanent
implants such as needle, seeds, or catheters.
Post-op treatment with brachytherapy is of short duration, such as 1 to 3
days.

45. Intra-operative radiotherapy (IORT)
IORT is given in combination with external beam therapy.
IORT allows direct radiation to the target area while sparing normal
surrounding tissue. IORT is used to treat cancers that are difficult to
remove during surgery and when there is a concern that microscopic
amounts of cancer may remain.
Both Barchytherapy and IORT are short duration radiotherapy and the
oncologic consequence of limited volume and duration of these
therapies is not well understood.

47. Intensity modulated radiation therapy (IMRT)
IMRT is a complex technique for the delivery of radiation preferentially
to target structures while minimizing doses to adjacent normal critical
structures.
It is widely used for tumors of CNS, Head and neck, breast, prostate, GI
tract, and gynaecologic organs.

49. Chemoradiotherapy
Improves survival
Chemotherapy before radiotherapy reduces tumor burden
When given concurrently, may sensitize the tumor cells for radiation
therapy
Chemoradiation is being pursued in many tumor types, including rectal
cancer, pancreatic cancer, and esophageal cancer.

50. In Cochrane review of six randamized controlled trials. it was
demonstrated that in patients T3/4 rectal cancer, chemoradiation was
associated with a significantly lower local recurrence rate compared
with radiation therapy alone

53. Radiation therapy efficacy evaluated by 5 Rs
Repair (normal cells)
Reoxygenation
Repopulation (may stimulate cancer cell multiplication)
Redistribution (hit the sensitive phase)
Radiosensitivity (intrinsic sensitivity to radiation)
To decide on number of doses and number on cycles

54. End of life care or palliative care
Care given during last few months of patient’s life
Concept of “Good Death” in different cultures
Health care professionals deal with so many deaths and sometimes
forget that the patient who hopes for a good death has only one chance
to get it right!

55. Outline of palliative and supportive care
1. Symptoms (assessment and relief)
2. Psychosocial intervention (group therapy, counselling, music,
emotional support)
3. Physical and practical support (physiotherapy, speech therapy)
4. Nutritional support
5. Social support (family, relatives)
6. Financial support (grants)
7. Spiritual support

56. Thank You