CONCURRENT CHEMO RADIATION IN CARCINOMA BREAST WITH ISOLATED SUPRACLAVICULAR NODE METASTASIS.
A dissertation submitted to
The Tamilnadu Dr. M.G.R. Medical University, Chennai,
in partial fulfilment of the requirements for the award of the degree of
DOCTOR OF MEDICINE (M.D.) IN RADIOTHERAPY
April 2012
CERTIFICATE
This is to certify that this dissertation titled, “CONCURRENT CHEMO RADIATION IN CARCINOMA BREAST WITH ISOLATED SUPRACLAVICULAR NODE METASTASIS ” is a bonafide record of the work done by Dr. Murugesh linga perumal. S.K.P.P, in the Division of Radiation Oncology, Cancer Institute (W. I. A), Chennai, during the period of his postgraduate study for the degree of M.D. (Branch IX – Radiotherapy) from 2009 - 2012 under my direct guidance and supervision.
Date:
Place:
Dec , 2011 Chennai
Dr. G. Selvaluxmy., Professor and H.O.D., Division of Radiation Oncology, Cancer Institute (W.I.A.), Chennai
ACKNOWLEDGEMENT
I am ever-grateful to Late. Dr. S. Krishnamurthi, Advisor, Dr. V. Shanta, Chairman, Cancer Institute (WIA), Adyar, for providing me all the facilities for this study.
I express my gratitude to Dr. A. Vasanthan, Professor and Chairman, Division of Radiation Oncology, for his support and guidance throughout my postgraduate career.
I thank Dr. G. Selvaluxmy, Professor and H.O.D., Division of Radiation Oncology, for her encouragement, constant support and advice throughout my post-graduate days and in this study.
I am also thankful to Late. Dr. D. V. L. N. Sastry, Dr. Faith Viswanathan, Dr. Alexander John, Dr. K. Satish Srinivas, Dr. Ananthi, Dr. P. Selvarani, Dr. M. N. Arun kumar for their support.
I thank all the other faculty members, my colleagues, physicists, radiotherapy technologists and tumour registry staff without whom this study would not have materialised.
I express my gratitude to all the patients who form the most important part of this study.
I thank my parents and all my family members all of whom have been the greatest sources of motivation and support for me.
CONTENTS
TITLE PAGE NO
1. INTRODUCTION 01
2. AIM OF THE STUDY 38
3. ORIGIN OF THE STUDY 39
4. MATERIALS AND METHODS 40
5. RESULTS 48
6. DISCUSSION 50
7. CONCLUSION 55
8. BIBLIOGRAPHY 56
1
INTRODUCTION
Mammary glands are a distinguishing feature of mammals. Breast feeding offers many advantages to the mother both physiologically and psychologically. It helps in the involution of uterus in the immediate postpartum period, helps in the transfer if passive immunity and helps in bonding. Mammary glands can also harbor malignancy which is now the most common cancer in females. Breast cancer is one of the tumors for which there is conclusive evidence that screening can substantially decrease mortality. . Patients who develop breast cancer have a longer survival now due to the advent of new treatment options. In addition, hormonal and surgical interventions are able to prevent some breast cancer within high-risk populations. Isolated supraclavicular metastasis in breast cancer is a unique scenario in which patient stands at the border between loco regional and metastatic disease. Last few decades have witnessed changing scenario in understanding the disease, improved methods of early detection and establishment of combined modality of treatment for this cancer.
I ANATOMY:
The adult breast is situated between the second and sixth ribs vertically and horizontally between the mid-axillay line and the edge of the sternum. Breast tissue also extends into axilla which is called as the axillary tail of Spence. Breast is made of breast tissue, subcutaneous tissue, and the skin, the breast tissue has two parts (Stroma and Parenchyma) Parenchyma is usually divided into 15 to 20 segments which converge at the nipple. (1)
2
Anatomy of the breast
3
1. Perforating branches from internal mammary artery and vein;
2. Pectoral branches from thoraco acromial artery and vein;
3. External mammary branch from lateral thoracic artery and vein;
4. Branches from sub scapular and thoraco dorsal arteries and veins;
5. Lateral branches of third, fourth, and fifth intercostal arteries and veins;
6. Internal mammary artery and veins;
7. Sternocostal head of pectoralis major muscle;
8. Clavicular head of pectoralis major muscle;
9. Axillary artery and vein;
10. Cephalic vein;
11. Axillary sheath;
12. Latissimus dorsi muscle;
13. Serratus anterior muscle;
14. External abdominal oblique muscle.
4
Breast has numerous lobes, each lobe is made of 20 to 40 lobules, and there are numerous alveoli in each lobule. Each duct drains a lobe and finally extends to collecting duct in nipple.
The stroma and subcutaneous tissues of the breast contain fat, connective tissue, blood vessels, nerves, and lymphatics. (1)
Lymphatic anatomy:
Lymphatic anatomy:
The lymphatic drainage of the breast is of great importance in the spread of cancer of the breast. The sub epithelial lymphatics of the breast are continuous with the sub epithelial lymphatics in the surface of the skin. They don’t have valves and merge with the subareolar plexus of sappy. (2). Lymph flow in breast is unidirectional. It starts from the superficial plexus, reach the deep plexus and from the subareolar plexus to the peri lobular and deep subcutaneous plexus through the lymphatic vessels of the lactiferous ducts. The periductal lymphatic vessels lie just outside the myoepithelial layer of the duct wall (3). The deep sub cutaneous and intra- mammary lymphatic vessels drain towards the axillary and internal mammary lymph nodes. In some of the studies which employed radio labeled colloid injection (4, 5) physiology of lymph flow has been very well studied. 97 % of lymph flow from breast is towards axillary nodes and the remaining flows to the internal mammary nodes. (6).
New insight into lymphatic anatomy and the physiology of lymph flow has been gained from sentinel lymph node studies. It has been observed that the dermal and parenchymal lymphatics drain to the same axillary lymph nodes that are the main basin for lymph draining from the breast (1) Lympho scintigraphic studies have also shown that deeper parenchymal or
5
retro mammary lymphatics preferentially drain to the internal mammary lymph nodes when compared to intradermal or subdermal injection (1). There has been controversy over the direction of parenchymal lymph flow in relation to the sub areolar plexus. Isotope injection of technetium Tc 99m–labeled sulfur colloid into the sub areolar region results in localization of isotope in the axillary sentinel lymph node (1). A detailed isotope study of sub areolar injection and the lymphatic channels leading to the sentinel lymph node showed that in 90% of cases a single channel exited the areolar margin superiorly or laterally and terminated in an axillary sentinel lymph node (7). Secondary lymphatic channels exited the areola in 75% of cases. None entered the internal mammary lymph node chain.
Suami et al. (8) studied 24 breasts in 14 fresh human cadavers to examine the lymphatic drainage. Lymph collecting vessels were found evenly spaced at the periphery of the anterior upper torso draining radially into the axillary nodes. As identified in cross-section analysis, as these collecting vessels reached the breast some passed over and some through the breast parenchyma. Perforating lymph vessels that coursed beside the branches of the internal mammary vessels and drained into the ipsilateral internal mammary lymphatics were also found.
Some of these findings are discordant with current knowledge and may explain some of the false-negative rates of sentinel lymph node biopsy.
Supraclavicular lymph nodes:
Supraclavicular lymph nodes are located in the supraclavicular fossa, a triangle defined by the omohyoid muscle and tendon (lateral and superior border), the internal jugular vein
6
(medial border), and the clavicle and subclavian vein (lower border). Adjacent lymph nodes outside of this triangle are considered to be lower cervical nodes (M1).
Axillary Lymph Nodes:
The axillary lymph nodes are the major root of regional spread of breast cancer. The lymphatic drainage has been studied extensively by various people. Pickren (9) studied it in a very detailed manner and showed the pathway of tumor spread.
Axillary lymph nodes are classified into many groups:
1) Apical or subclavicular nodes, (They lie medial to pectoralis minor)
2) Axillary vein nodes, (they extend from lateral limit of axilla to the pectoralis minor muscle)
3) Rotter nodes also called as interpectoral nodes (They lie along lateral pectoral nerve between pectoralis minor and major muscles), (10, 11);
4) Scapular group (they include nodes lying along the subscapular vessels)
5) Central group ( lies below pectoralis minor)
6) External mammary nodes (lying over axillary tail).
7) Intra mammary lymph nodes, (which are found in 28% of breasts)
7
(8) Paramammary nodes (over upper, outer quadrant of the breast in the subcutaneous fat)
Berg JW divided axillary lymph nodes into three levels (12).
Level I - lateral to the lateral border of the pectoralis minor muscle,
Level II - behind the pectoralis minor muscle,
Level III- located medial to the medial border of the pectoralis minor muscle.
These levels can be determined accurately only by marking them with tags at the time of surgery.
Internal Mammary Lymph Nodes:
The internal mammary nodes are located in the para - sternal region in the intercostal space close to the internal mammary vessels. The number of nodes and location is highly variable.
• In first and second intercostal space it lies medial to internal mammary vessels in 88%
and 76% of patients.
• They lie in the third intercostal space lateral to the vessels in 79% of patients.
The prevalence of lymph nodes in each intercostal space is shown below: (13).
• First intercostal space 97%;
• Second intercostal space 98%;
• Third intercostal space 82%;
8
• Fourth intercostal space 9%;
• Fifth intercostal space 12%;
• Sixth intercostal space 62%.
Handley and Thackray (14) and Urban and Marjani (15) described the pathologic pathways of spread of breast cancer. Alternative pathways become important when there is nodal metastasis causing obstruction to the flow of lymphatics.
The alternative pathways are cross drainage to the contra lateral internal mammary chain via substernal and deep lymphatics; mediastinal drinage; superficial presternal crossover and lateral intercostal drinage; spread to subdiaphragmatic and subperitoneal plexus to rectus abdominis muscle sheath ( Gerotas's pathway).
The Gerotas pathway is the pathway through which the tumor spreads directly to retroperitoneal nodes and liver.
9
Lymph node groups in breast cancer
10 II PATHOLOGY
WHO CLASSIFICATION OF CARCINOMA BREAST Noninvasive carcinoma
· DCIS (Ductal carcinoma in situ)
· LCIS (Lobular carcinoma in situ) Invasive carcinoma
· Invasive ductal carcinoma
· Invasive lobular carcinoma (ILC)
· Mucinous carcinoma
· Medullary carcinoma
· Papillary carcinoma
· Tubular carcinoma
· Adenoid cystic carcinoma
· Secretory carcinoma
· Apocrine carcinoma
· Metaplastic carcinoma (Carcinoma with metaplasia)
· Inflammatory carcinoma
Others
· Paget’s disease of nipple
11
Almost all the breast cancers arise from the glandular element of the breast (adenocarcinoma). More than 80 % of the breast cancers are of ductal type. Approximately 10 % is constituted by infiltrating lobular carcinoma. Other less frequent histologies are Medullary, mucinous, or tubular histologies and they have a good prognosis. Other tumors which are found in breast are cystosarcoma phylloides, carcinosarcomas, squamous cell carcinomas and sarcomas. Ductal carcinoma in situ (DCIS) is a non invasive carcinoma in which there are malignant epithelial cells in mammary ductal system without invasion. It is either treated with breast conserving surgery or mastectomy followed by adjuvant Tamoxifen. Lobular carcinoma in situ (LCIS) usually is an incidental finding on breast biopsy performed for other reasons. LCIS is considered as a marker of increased risk of breast cancer if it is not properly treated. The risk is more both in the ipsilateral and contralateral breast.
III EPIDEMIOLOGY AND RISK FACTORS
When we analyze the epidemiologic studies we can infer that the incidence is mostly influenced by hormonal, familial and other environmental factors. Other important risk factors are previous personal history of breast cancer or benign proliferative breast disease. However most breast cancer patients have no identifiable risk factor except being female and having advanced age. Female to male ratio is for breast cancer in approximately 100:1. Table I shows the surveillance, Epidemiology, and End Result Program (SEER) lifetime risk assessment of breast cancer based on age of diagnosis for women.
12 TABLE I
SEER Lifetime risk Breast cancer Diagnosed by Age
By Age Risk of breast cancer
30 1 out of 2212
40 1 out of 235
50 1 out of 54
60 1 out of 23
70 1 out of 14
80 1 out of 10
Ever 1 out of 8
Mathematical models of risk assessment have been created; the most commonly used is the Gail model.
The Gail et al model which calculates a woman’s risk of developing breast cancer is based on age at menarche, age at first child birth, number of previous breast biopsies, the presence or absence of atypical hyperplasia and the number of first degree female relatives with breast cancer. (16)
The Claus et al model takes into account both first and second degree relatives. (17)
13 A. Genetic
A very important risk factor for developing breast cancer is family history of breast cancer. There are two types of breast cancer risk associated with family history of breast cancer.
First type is the one in which there is a germ line mutation derived either paternally or maternally; the second type is the one without germ line mutation. Approximately five to ten percentages of patients with breast cancer have mutation in either of the two genes BRCA1 and BRCA2. There is a risk of 40 to 85% for developing breast cancer if there is mutation in either of those genes. They are commonly found in Ashkenazi Jews, associated with other cancers other than breast cancer and affect both sexes. Patients with familial syndrome (ex; Li- Fraumani) and mutations in tumor suppressor genes (e.g.: P53) also have an increased risk for breast cancer.
Those patients in which there is a strong suspicion of genetic mutation of family history should be referred for genetic counseling and genetic testing.
B. Endocrine
Uninterrupted exposure to estrogen (39) is a very important risk factor and patients who come under the following categories have a high risk for developing breast cancer.
1. Early menarche (< 12 yrs), 2. Late menopause (> 55 yrs),
3. First pregnancy after 30 yrs of age,
4. Nulliparity, Hormonal replacement therapy for a long period,
5. BRCA1 BRCA2 mutation patients who have received oral contraceptives for long period which has high estrogen content (38),
14 6. Exposure to DES (Diethylstilbestrol).
The mechanism of estrogen producing cancer is still incompletely understood.
C. Environmental
Certain countries have low incidence of breast cancer. This may be related to dietary influences; mainly fat intake. There is already a randomized clinical trial of low fat intervention among breast cancer patients – the result is yet awaited. There is a lot of interest regarding phyto- estrogens nowadays. Phytoestrogens are found in soy proteins and can act as SERM (Selective Estrogen Receptor Modulators) by competing with endogenous estrogens. It is also postulated that they can also increase the risk of cancer by being estrogenic in post-menopausal women.
Further investigations regarding this product are must before using this as a dietary supplement.
Ionizing radiation is a very important risk factor and it is well proved that patients who have received mantle field RT for Hodgkins disease at a younger age are at increased risk. Also patients who survived atomic bombs in II world war and Chernobyl nuclear accident had increased risk of breast cancer.
Studies which have analyzed physical activity as a risk factor for breast cancer have produced inconsistent results. Analysis of six cohort studies has proved that there is a 40 percent increased risk for breast cancer if a person is taking more than 30 to 60 grams of alcohol per day (36). Overall recommendations are to have a healthy diet, lower alcohol intake and regular exercise (37).
15 IV PREVENTION:
Tamoxifen is proved to reduce the risk of breast cancer. Tamoxifen is a Selective Estrogen Receptor Modulator (SERM) and is used for more than 2 decades for the treatment of breast cancer.
NSABP P-1 (18) trial demonstrated the effectiveness of Tamoxifen as a chemo preventive agent. Patients in this trial were randomized into two groups; one group received tamoxifen and other group received placebo. First group had approximately 50% reduction in both invasive and non invasive caner. Overall survival was not proved in this study. There were two other European studies which analyzed the effect of tamoxifen as chemo-preventive agent, but they did not produce similar results because they were underpowered; had higher noncompliance rates; and some patients were using hormonal replacement during the study period.
Raloxifene was studied as a agent which prevents breast cancer in the STAR trial (NSABP P2) (19). In this trial tamoxifen was compared with raloxifene and they concluded that tamoxifen is usually recommended in pre - menopausal age group and Raloxifene in post- menopausal age group.
Prophylactic mastectomy reduces the risk of breast cancer by 90% in women with a strong family history (40). Prophylactic mastectomy procedure is similar to therapeutic mastectomy technically and this should be offered to patients with a high risk for breast cancer.
But this procedure is not well accepted by patients.
16 V GENETIC SCREENING
Only 5-10% of breast cancer patients have germ line mutations, showing an autosomal dominant inheritance pattern in familial cancer
BRCA1, BRCA2 and p53 genes are affected mainly, of which the first two are mainly important.
In women with BRCA1 and BRCA2 mutation, lifetime risk of breast cancer 65-75 %
No definite screening recommendations in those with proved germ line mutations
VI. EVALUATION A. Asymptomatic (Screening)
Screening for disease is a rapidly evolving concept in oncology and breast cancer is the one which has gained much from screening. It provides the opportunity for earlier detection and so the morbidity and mortality associated with advanced disease is reduced.
The main methods for detecting breast cancer in earlier stages are,
1. Self breast examination 2. mammography and
3. Clinical breast examination.
Self breast examination is very useful in detecting early caners but it has not been demonstrated to reduce the mortality. But if self breast examination is routinely practiced more breast cancers will be detected. Also patients who detect breast cancer by self breast examination usually presents with earlier stage and have less involvement of axillary lymph nodes.
17 Mammogram:
There are two types of mammogram.
Screening mammography - usually done in general population who are asymptomatic and
Diagnostic mammography. - done on patients who have a breast abnormality.
Mammogram has about 80 -85 % sensitivity. There is a chance also that it may miss remaining 10-15 percent of tumors. So even if a mammogram is negative in a patient who presents with breast lump, further evaluation should be done.
The risk of false positivity leading to further evaluation is also a problem. In a retrospective study women were screened for over a period of 10 years using mammogram;
approximately 33% of women screened required an additional evaluation, but no breast cancer was found (33).
Most of the cancer associations recommend screening to begin at an age of 40. Screening mammograms has definitely been proved useful in women between age group 50 and 75; but its role is controversial in women of young age and age more than 75.
Women who have first degree relative diagnosed with breast cancer should start the screening at least 5 to 10 years before the youngest age of onset in the family. Mammogram is difficult to interpret in younger women because of the increased density of breast tissue.
18
TABLE II
American cancer society screening guidelines (34)
Age in years Recommendations Benefit
20-39
SBE every month.
CBE every 3 years.
High-risk patients: consider additional screening.
No data
40-49
SBE every month.
CBE every year .
Mammogram every year.
Reduce risk of dying from breast cancer by 18%
>50
SBE every month.
CBE every year .
Mammogram every 1 year
Reduce risk of dying from breast cancer by 30%
SBE – Self breast examination.
CBE – Clinical breast examination.
Digital mammography is a new technique which displays infinite scale of gray tones which leads to enhanced quality of imaging; also magnification is also possible for designated area.
Ultrasound is being explored as a screening tool although it is most commonly used to define cystic breast structures and for doing breast biopsied under guidance.
19
Magnetic resonance imaging (MRI) can be used as a screening modality; but it is routinely recommended only in those patients who are at high risk of developing breast carcinoma.
Other techniques such as ductal lavage, nipple aspiration, fiber optic ductoscopy are under investigation for breast screening. The main concept in these techniques is to obtain cells for cytology from the ducts of the breast.
B. Presenting Symptoms and Signs
The main complaints with which the patient presents to physician include
Mass in the breast
skin changes
nipple discharge
breast pain
change is size of breast
axillary lymphadenopathy.
When the history and features of the mass is suggestive of a cyst and aspiration of the lesion should be done which can be done with or without ultrasound guidance.
If the aspirate is clear and the cytology is negative and the lesion disappears completely;
no further evaluation is needed; but follow-up is a must to confirm that the lesion has resolved completely.
If the cyst recurs or bloody aspiration is there then biopsy has to be done.
20
Evaluation of a solid mass requires FNAC / Biopsy; if a biopsy is being planned mammogram should be done prior to that so that post biopsy changes won’t interfere with the interpretation of the mammogram.
Before labeling a mass as benign, all clinical; cyto - pathological ; radiological examination should have been done.
Fibroadenoma:
Fibroadenomas are usually rounded, lobulated; may feel rubbery; freely mobile and non tender. They constitute about 50%of breast biopsies. They are benign but they carry a small risk (about 1.2- 3 relative risk) for development of breast cancer.
Two options can be offered to patients diagnosed with fibroadenoma; either close follow- up of the lesion over time (or) excision . Excision offers the opportunity for histo - pathological examination of the lesion which is considered the gold standard for diagnosis in fibroadenoma.
If the physical of radiological findings are not consistent with fibroadenoma then tissue diagnosis should be attempted. Tissue diagnosis can be carried out with fine needle aspiration cytology (FNAC); Core needle biopsy; incisional (or) excisional biopsy.
If the lesion is not palpable then it may need needle localization (or) stereotactic biopsy.
After biopsy also radiological assessment is required to confirm that the abnormality has been removed.
Before definite treatment; both the breasts should have been examined to rule out additional foci of malignancy.
21 VII DIAGNOSIS
Most of the breast biopsies will be benign; 30% of biopsies will have no disease; 40% of biopsies will show fibrocystic changes; 7% show fibroadenoma; 13% chow miscellaneous lesions and only 10% will have carcinoma.
Benign proliferative lesions confer an increased risk of breast cancer particularly when atypia is present. It is noted in a recent study that hospitals in which more than 25 breast cancer patients are treated in a year have better survival rate when compared to the centers which treat less than 25 cases (35). Once cancer is diagnosed the next step is the staging of cancer.
A. Staging
Before definitive treatment is planned all patient s should undergo a thorough physical examination; histo - pathological and radiological examination to rule out any distant metastasis;
and if possible breast conservation treatment and breast reconstruction should be offered to suitable patients. The routine investigations which should be done include complete blood count, renal function test, liver function test, x-ray chest and mammogram. Additional tests may be indicated depending on the results of basic investigations and the extent of disease. For example if alkaline phosphatase is increased then bone scan may be warranted.
The most widely used staging system is AJCC staging system (American Joint Committee on cancer classification ) which is based on the T-Tumor size, N-Nodal status and M- Metastasis.
The latest AJCC is as follows.
22 TNM staging of breast cancer (AJCC 2010) (20) PRIMARY TUMOR (T):
TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ
Tis (DCIS) Ductal carcinoma in situ Tis (LCIS) Lobular carcinoma in situ Tis (Paget’s) Paget’s disease of the nipple .
T1 Tumor ≤ 20 mm in greatest dimension T1mi Tumor ≤ 1 mm in greatest dimension
T1a Tumor >1 mm but ≤ 5 mm in greatest dimension T1b Tumor >5 mm but ≤ 10 mm in greatest dimension T1c Tumor >10 mm but ≤ 20 mm in greatest dimension T2 Tumor >20 mm but ≤ 50 mm in greatest dimension T3 Tumor >50 mm in greatest dimension
T4 Tumor of any size with direct extension to the chest wall and/or to the skin (ulceration or skin nodules)
T4a Extension to the chest wall, not including only pectoralis muscle adherence/invasion
T4b Ulceration and/or ipsilateral satellite nodules and/or edema (including peau d'orange) of the skin which do not meet the criteria for inflammatory
carcinoma
T4c Both T4a and T4b
23 T4d Inflammatory carcinoma.
Regional lymph nodes:
N1 Metastases to movable ipsilateral level I, II axillary lymph node(s)
pN1 Micrometastases; or metastases in 1 to 3 axillary lymph nodes; and/or in internal mammary nodes with metastases detected by sentinel lymph node biopsy but not clinically detected
pN1mi Micrometastases (greater than 0.2 mm and/or more than 200 cells, but none greater than 2.0 mm)
pN1a Metastases in 1 to 3 axillary lymph nodes, at least one metastasis greater than 2.0 mm
pN1b Metastases in internal mammary nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected
pN1c Metastases in 1 to 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected
N2 Metastases in ipsilateral level I, II axillary lymph nodes that are clinically fixed or matted; or in clinically detected. ipsilateral internal mammary nodes in the absence of clinically evident axillary lymph node metastases
pN2 Metastases in 4 to 9 axillary lymph nodes; or in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases
N2a Metastases in ipsilateral axillary lymph nodes fixed to one another (matted) or to other structures
24
pN2a Metastases in 4 to 9 axillary lymph nodes (at least one tumor deposit greater than 2.0 mm)
N2b Metastases only in clinically detected ipsilateral internal mammary nodes and in the absence of clinically evident axillary lymph node metastases.
pN2b Metastases in clinically detected internal mammary lymph nodes in the absence of axillary lymph node metastases.
N3 Metastases in ipsilateral infraclavicular (level III axillary) lymph node(s) with or without level I, II axillary lymph node involvement; or in clinically detected ipsilateral internal mammary lymph node(s) with clinically evident level I, II axillary lymph node metastases; or metastases in ipsilateral supraclavicular lymph node(s) with or without axillary or internal mammary lymph node involvement pN3 Metastases in 10 or more axillary lymph nodes; or in infraclavicular (level III
axillary) lymph nodes; or in clinically detected ipsilateral internal mammary lymph nodes in the presence of 1 or more positive level I, II axillary lymph nodes;
or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected; or in ipsilateral supraclavicular lymph nodes
N3a Metastases in ipsilateral infraclavicular lymph node(s)
pN3a Metastases in 10 or more axillary lymph nodes (at least one tumor deposit greater than 2.0 mm); or metastases to the infraclavicular (level III axillary lymph) nodes N3b Metastases in ipsilateral internal mammary lymph node(s) and axillary lymph
node(s)
25
pN3b Metastases in clinically detected ipsilateral internal mammary lymph nodes in the presence of 1 or more positive axillary lymph nodes; or in more than 3 axillary lymph nodes and in internal mammary lymph nodes with micrometastases or macrometastases detected by sentinel lymph node biopsy but not clinically detected
N3c Metastases in ipsilateral supraclavicular lymph node(s).
Distant metastasis (M)
M0 No clinical or radiographic evidence of distant metastases (no pathologic M0;
clinical M is used to complete stage group)
cMo(i+) No clinical or radiographic evidence of distant metastases, but deposits of molecularly or microscopically detected tumor cells in circulating blood, bone marrow or other non-regional nodal tissue that are no larger than 0.2 mm in a patient without symptoms or signs of metastases
M1 Distant detectable metastases as determined by classic clinical and radiographic means and/or histologically proven larger than 0.2 mm
AJCC STAGE GROUPING
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T0 N1mi M0 T1 N1mi M0
26 Stage II A T0 N1 M0,
T1 N1 M0,
T2 N0 M0
Stage II B T2 N1 M0,
T3 N0 M0
Stage III A T0 N2 M0,
T1 N2 M0,
T2 N2 M0,
T3 N1 M0,
T3 N2 M0
Stage III B T4 N0 M0,
T4 N1 M0,
T4 N2 M0
Stage III C Any T N3 M0
Stage IV Any T Any N M1
27 B. Prognostic and Predictive Factors
A prognostic factor is defined as a measurement taken at the time of diagnosis or surgery that is associated with outcome.
A predictive factor is a measurement that predicts response or lack of response to a specific treatment.
The important prognostic factors are:
1. Tumor size
2. Axillary lymph node status.
3. ER,PR receptor status.
4. HER 2/ neu protein over expression.
Other factors which are used to predict the outcome are,
1. Mitotic index
2. Lympho - vascular invasion 3. S-Phase fraction
4. Ploidy
5. P53 , P27 status 6. Cathepsin D
7. micro vascular density.
28 VIII. TREATMENT
A. Optimization:
Treatment involves selecting the optimal sequence of procedures and interventions to minimize the toxicity and to maximize the treatment outcome. In the past the sequence is usually surgery followed by adjuvant chemotherapy, adjuvant radiotherapy and hormonal therapy as indicated. When a patient is not a suitable candidate for upfront surgery such as inflammatory carcinoma; neo - adjuvant treatment is employed.
Neo adjuvant chemotherapy is also used nowadays to reduce the tumor size and to bring the patient into the purview of surgery. The sequence of treatment is based on patients general condition and attitude towards treatment.
B. Surgery
1. Primary Treatment
The type of surgery depends on multiple factors such as histology (invasive vs. non- invasive); margin status; co morbidities and adjuvant treatment and patients preference. Due consideration should be given to neoadjuvant treatment and local control should be accomplished by least invasive means. Sentinel lymph node dissection is an evolving concept and it should be considered whenever feasible. Sentinel lymph node dissection is an evolving concept and it should be considered whenever feasible. Sentinel lymph node dissection is a demanding procedure which needs lots of expertise. They should be carried out in a very well equipped center with lots of expertise for the procedure. This method has been proved to be equivalent to standard axillary dissection in a recent Z001 trial (30) although some controversies still exist. IF there is no evidence of invasion then a clinically negative axilla need not be explored.
29 Breast conservation surgery:
This must be offered to all eligible patients as BCT has been proved to be equivalent to radical mastectomy in many trials.
Absolute contraindication to BCS:
Diffuse micro calcifications
First and second trimester of pregnancy
Multi focal disease with involvement of separate quadrants of breast.
Prior breast irradiation.
Relative contraindication to BCS:
Collagen vascular disease.
Tumor location beneath nipple
Large tumor to breast ratio
Large breast size which may limit radiation dose homogeneity.
2. Reconstruction
All patients who undergo modified radical mastectomy should be offered immediate of delayed reconstruction. There are various options for reconstruction which depends on the patients preference. Some of the options are
Placement of an implant
Transposition from lattismus dorsi or rectus abdominus muscle.
Contra lateral breast surgery to obtain symmetry.
30 C. Adjuvant Therapy for Early Stage Breast Cancer
To improve the survival rate both local and distant control of the disease must be obtained. As breast cancer is considered a systemic disease occult micro metastasis may be present at the time of diagnosis. Systemic therapy is a must in most of the breast cancer patients to eradicate micro metastasis. Adjuvant systemic therapy includes chemotherapy and hormonal therapy. This should be started as soon as the wound heals, which is usually between 4 to 8 weeks after definitive surgery.
A Meta analysis of numerous randomized trials by Early Breast Cancer Trialists Collaborative Group (EBCTG (21)) has demonstrated that Hormonal therapy and Chemotherapy may alter the natural history of breast cancer, the magnitude of which depends on the patient and tumor specific characteristics.
1. Adjuvant Chemotherapy
Chemotherapy substantially increases the long term, overall and relapse free survival in both pre - menopausal and post menopausal patients with node positive and nose negative breast cancer.
All patients with lymph node metastasis and primary tumor mot\re than 1 cm should be offered adjuvant chemotherapy. Poly chemotherapy regimens are superior to single agent regimens. (32). There are lots of chemotherapy regimens such as CMF / FAC / FEC /AC followed by Taxol / TE etc.; Anthracycline containing regimens are proved too be superior to non - anthracycline containing regimens. Selection of a particular regimen depends on the
31
general condition, tolerability and presence and absence of co morbidities such as Ischemic heart disease etc.
Usually chemotherapy is administered for 6 cycles and EBCTG (21) Meta analysis has proved that there is no added benefit for prolonged (> 1 year) poly chemotherapy regimens.
Newer regimens are evaluating the role of taxanes and Herceptin (Transtuzumab) in the adjuvant setting. The concept of dose density and dose intensity is also being explored. There is no evidence to prove that dose intense treatment regimens which require stem cell support results in prolonged survival when compared to the standard poly chemotherapy regimens (37). But improved DFS (disease free survival) has been observed in some studies.
2. Adjuvant Hormonal Therapy
The decision on adjuvant hormonal therapy is based on the demonstration of hormonal receptors on the tumor. Those tumors which are ER, PR positive will have benefit from adjuvant hormonal manipulation irrespective of age, lymph node status, tumor size and menopausal status.
Although hormonal therapy is used in some centers for patients with negative hormonal status, there is no evidence to prove the benefit.
The main aim of hormonal manipulation is to prevent estrogen form stimulating the tumor cell with positive estrogen or progesterone receptor. Because estrogen acts like a growth factor for tumor cells which express either of the receptors.
Estrogen deprivation is achieved by hormonal agents and also in pre menopausal women by ovarian ablation either surgically / chemically or by using radiation.
32
Tamoxifen is commonly used in the adjuvant setting and many new drugs are evaluated in clinical trials. Tamoxifen is usually preferred in the pre - menopausal age group and aromatase inhibitors in the post menopausal age group. Trials have proved that 5 years of tamoxifen usage is better than 1 – 2 years; However the optimal duration is still unknown. The EBCTCG (21) meta analysis has showed that with the use of tamoxifen for 5 years the proportional reduction in mortality and recurrence were 26% and 47%; There is also a reduction in incidence of contra lateral breast cancer by 50%. Tamoxifen should not be administered simultaneously with chemotherapy because of the increased risk of thrombo embolic events without no known additional benefit. So hormonal therapy is usually started after the completion of chemotherapy.
3. Adjuvant Radiation Therapy
Adjuvant radiation therapy is indicated in
Breast conservation therapy
Post- mastectomy patients with
◦ tumor size > 5cm.
◦ T3, T4 tumors.
◦ > 4 positive lymph nodes,
◦ positive or close margins.
Post-mastectomy patient s with 1-3 positive nodes may also benefit from post- mastectomy radiotherapy. The role of radiotherapy in this setting is now being evaluated.
When a patient needs both adjuvant chemotherapy and radiotherapy the sequence is sequential chemotherapy followed by radiotherapy. But in our institute we follow concurrent
33
chemo radiation for high risk patients as we believe that concurrent chemo radiotherapy is better than sequential therapy in breast cancer patients.
IX. TREATMENT OF RECURRENT AND METASTATIC DISEASE
A. Loco regional Relapse
Those patients who have loco regional relapse will be difficult to salvage because it is usually associated with a 25% chance of systemic disease. However re-excision of the lesion;
irradiation; chemotherapy; change of hormonal agents should be considered.
B. Metastatic Disease
Metastasis may be present initially at presentation (or) it may develop after primary treatment; when metastasis develop in breast cancer, it is rarely if ever 'curable'. In treating a metastatic breast cancer the main objective are to optimize response to treatment, improve the survival with maintaining the quality of life.
The evaluation should include physical examination; complete blood count; blood chemistries; imaging studies such as CT chest; Ultrasound abdomen and pelvis; bone scan etc.
PET scan may also be considered. Treatment should be tailored based on patients predictive markers; extent of metastasis and patients general condition.
34 1. Hormonal Therapy for Metastatic Disease
Patients who have ER, PR positivity must be considered for hormonal therapy as it is less toxic than chemotherapy. Response may be slow; also patients may experience a flare up of symptoms such as increased pain; increased level of tumor markers, increased uptake in bone scan etc. The agent chosen depends on the menopausal status as well as prior exposure to hormonal agents.
The treatment options include:
Anti- Estrogens (Tamoxifen, Raloxifene etc.)
Aromatase inhibitors (Letrazole, Anastrazole )
Steroidal aromatase inhibitors (Exemestane)
Androgens (Fluoxymesterone)
Progestins (Medroxyprogesterone acetate) etc.
Pre - menopausal patients must be made menopausal by either of the following.
Oopherectomy
LHRH analogues
Radio ablation of ovaries.
Then all treatment options available for postmenopausal women should be considered for them.
A Meta analysis by Klijn (31) and colleagues showed that combined estrogen blockage with both LHRH analogues and Tamoxifen is superior to LHRH analogue alone which results in significant decrease in the risk of dying or progressive disease. Hormonal agents are used sequentially; with trial of single drug in each class at a time till there is progression or drug
35
toxicity. They are usually very well tolerated; it is usually associated with mild thrombophlebitis, hot flashes, nausea etc. Tamoxifen can also cause increased risk of uterine cancer. So those patients on tamoxifen therapy should be followed for dysfunctional uterine bleeding.
2. Chemotherapy for Metastatic Disease
Patients who are symptomatic (secondary to visceral involvement), rapidly progressing disease, and bulky disease may not be appropriate for hormonal agents.
The choice of agents depends on the patient’s prior exposure to chemotherapy in the adjuvant setting and time from adjuvant therapy. Chemotherapeutic agents which may be effective in metastatic breast cancer include anthracyclins and taxanes. Other drugs such as 5- Fluro-uracil, capecitabine, vinorelbine, cyclophosphamide, gemcitabine are also useful. In chemotherapy naïve patients cisplatin and carbopaltin will be having significant activity.
Combination chemotherapy will have a good response rate and may act faster but it will be having more toxicities also. There is no evidence as of now that high dose chemotherapy with stem cell rescue will have improved outcome over standard therapy. When patient progresses with a regimen (or) when a regimen produces unacceptable toxicity then the treatment may be shifted to second or third line therapy.
36 3. Monoclonal Antibody Therapy
Transtuzumab (Herceptin) is an emerging treatment option in a patient with breast cancer. It targets a transmembrane tyrosine kinase receptor which is a gene product of HER2/
neu. The receptor is structurally related to human epidermal growth factor receptor. About 30%
of breast cancers have amplification (or) over expression of HER2/ neu and the presence of this is considered to be a poor prognostic factor. It has activity as a single agent and also it has been shown that it improves overall survival and response rate when used with combination chemotherapy regimens. The use of anthracycline with tanstuzumab is contraindicated as it produces significant cardiac toxicity.
4. Supportive Therapies
Supportive therapies may be necessary when the patient become symptomatic either from the disease or from the treatment toxicity. These measures include palliative radiation for painful metastasis; local therapy to site of relapse; bisphosphonate therapy in patients with multiple bone metastasis; analgesics and narcotics for pain control. Other measures are anti emetics for nausea either related to disease or treatment; antidepressants for mood disturbance; Granulocyte – colony stimulating factor; erythropoietin support. Apart from this social and psychological support is a must in any supportive treatment.
X. FOLLOW-UP OF BREAST CANCER PATIENTS
Follow-up is very important in oncology care as it helps to identify disease recurrence as well as it gives data for the study of disease. During follow-up specific attention should be paid to recurrence and treatment complications. Most of the breast cancer recurrences are within 5
37
years but recurrences after this is not uncommon. Each women with breast cancer has an approximate 0.5 to 1 % per year risk of developing second primary breast cancer.
Patients may also have got problems due to breast cancer therapy such as pain due to reconstruction, cardiac dysfunction, lymphedema, menopausal symptoms, cognitive changes, osteoporosis, secondary malignancies etc. Recommended follow-up include a complete history;
physical examination every 3 to 6 months for first 3 years, Every 6-12 months for next 2 years then annually for the entire life. The patient should be instructed to have self breast examination monthly and mammogram annually. Additional investigations should be carried out if necessary.
Screening for other cancers is also recommended as appropriate during follow-up.
38
AIM OF THE STUDY
To study retrospectively carcinoma breast patients with histologically proven supraclavicular node metastasis, without distant metastasis, at presentation, treated with initial chemoradiation.
39
ORIGIN OF THE STUDY
Tumor involvement of the supraclavicular lymph nodes is a very unfavorable prognostic indicator in several studies. Nonetheless, it remains debatable as to whether these patients should be treated as patients with disseminated disease and receive palliative treatment or with curative intent. Randomized clinical data are not much in this setting and so optimal treatment approaches should be deduced from the observation of retrospective data. Historically all patients were treated with neoadjuvant chemotherapy followed by radiation. But in our institute we use Neoadjuvant chemoradiation protocol for isolated supraclavicular metastasis patients. As chemoradiation is proved to be superior to sequential regimens in many sites including head and neck we analyzed retrospectively the patients presented with isolated supraclavicular metastasis and presenting the results.
40
MATERIALS AND METHODS
All the patients who presented with ipsilateral supraclavicular metasiatis at presentation from the year 2004 to 2007 were taken retrospectively analysed and specific inclusion and exclusion creiteria were designed to carry out the analysis.
SELECTION CRITERIA
The inclusion criteria were:
1. Patients with any T tumor with SCL node presentation.
2. Pathologically confirmed infiltrating ductal carcinoma of the breast 3. Histological proof of SCL node.
4. Patients planned for neoadjuvant chemoradiation.
5. All metastatic workup negative.
Exclusion criteria
The exclusion criteria were:
1. Patients who had already undergone surgical removal of tumor in the form of excision biopsy, wide local excision or mastectomy.
2. Other histologies.
3. Patients who did not complete the planned treatment of neoadjuvant concurrent chemo- radiation.
4. Patients who received only chemotherapy.
41
There were totally 2898 patients diagnosed with carcinoma breast and treated at our institute between 2004 and 2007, out of them 144 patients presented with isolated supraclavicular metastasis. Out of 144 patients 86 had systemic metastasis on further evalustion and so excluded from the analysis . Of the remaining 58 patients with isolated supraclavicular metastasis only 24 patients had histological proof of metastasis and so only those patients were taken for analysis.
Initial workup:
1. History
2. Physical examination
3. Staging according to AJCC staging system.
4. Hemogram 5. RFT 6. LFT
7. Coagulation profile 8. Viral markers 9. ECG
10. ECHO 11. X-ray-chest
12. USG-Abdomen and pelvis 13. CT-Chest.
14. Bonescan
15. Histopathological examination 16. Hormone receptor status.
42 Age wise distribution:
AGE GROUP(Yrs) NO OF PATIENTS
21-30 3
31-40 6
41-50 9
51-60 4
>61 2
Distribution according to T stage:
T STAGE NO OF PATIENTS
T1 0
T2 4
T3 9
T4 11
43 Distribution according to N stage:
NODAL SIZE (cm) NO OF PATIENTS
<3 14
>3 10
Distribution as per Hormone receptor status:
HORMONAL STATUS (ER/PR)
NO OF PATIENTS
POSTIVE 10
NEGATIVE 14
44 TREATMENTPROTOCOL:
All patients received chemotherapy using either of the following schedules - CMF /FAC /FEC / Taxol - Epirubicin. The chemotherapy was repeated every 3 weeks. After the patient complete the first cycle of chemotherapy; radiotherapy to the breast and nodal regions were started. Radiation to the breast / axilla/ supraclavicular regions were delivered using cobalt beam therapy and was given 5 days a week i.e from Monday to Friday. A dose of 40 Gy was delivered in 180-200 cGy per fraction. Patients were treated even on chemotherapy day. All the patients were assessed once a week during Radiotherapy and Total count was checked twice a week and whenever necessary, patients were also assessed weekly, before each cycle and at the end of radiotherapy for acute toxicity. Subsequently patients were followed up at 6 weeks then once in 3 months. Normal tissue reactions were graded according to RTOG toxicity criteria. Patients were also checked for disease status during each follow up, if metastatic workup is negative after 1 year patients were taken up for mastectomy.
Radiotherapy:
Radiotherapy was delivered using cobalt 60 beam. The treated areas include involved breast, ipsilateral axilla and supraclavicular regions. Treatment was delivered at a source skin distance of 80 cm.
45 Breast RT:
The arm was kept in abducted position. Two tangential medial and lateral fields were used for breast irradiation at an angle of 60 degrees and 120 degrees. The upper border was inferior border of the clavicle, medial border is midline, lateral border is mid- axillary line, inferior border is 2 cm below the infra mammary fold. Dose is prescribed at the center of the tumor, computing the dose from medial and lateral fields. Total dose was 40Gy in 20 fractions, 5 days per week.
SCL and Axillary RT:
Usually a combined field was used for SCL and axilla. Single direct field of size 15 x 10 cm (approximate) was used. Dose is calculated at 3 cm depth for SCL RT. Daily dose was 200cGy/day and Total dose was 40Gy in 20 fractions, 5 days per week.
For irradiating the axilla, the dose contribution from the both tangential fields is measured at the midpoint of axilla and 3 cm from the tangentialfield’s superior border. Posterior axillary boost was given with the patient in prone position, approximate field size is 8 x 10 cm and Total dose was 40Gy in 20 fractions, 5 days per week.
Field size changes and bolus requirement was decided on individual basis.
Internal mammary RT:
For those patients in whom internal mammary RT was required a standard field size of 6x15 cm 2 was used and the field was from supra sternal angle upto xiphi sternum. The field width was 6 cm which crossed the midline for about 1 cm.
46 Chemotherapy schedules:
Taxol/Epirubicin
Inj Epirubicin 60 mg/m2 iv D1 Every 3 weeks
Inj Paclitaxel 175 mg/m2 iv D1
CMF
Inj Cyclophosphomide 600 mg/m2 iv D1 Every 3 weeks
Inj Methotrexate 50 mg/m2 iv D1
Inj 5 FU 600 mg/m2 iv D1
FEC
Inj Cyclophosphomide 600 mg/m2 iv D1 Every 3 weeks
Inj Epirubicin 60 mg/m2 iv D1
Inj 5 FU 600 mg/m2 iv D1
FAC
Inj Cyclophosphomide 600 mg/m2 iv D1 Every 3 weeks
Inj Adriamycin 40 mg/m2 iv D1
Inj 5 FU 600 mg/m2 iv D1
47 Hormonal therapy:
All premenopausal patients received Tamoxifen 10mg BD after completing chemotherapy, while postmenopausal patients received Letrazole 2.5 mg OD after completing chemotherapy.
48 RESULTS
11 patients achieved clinical complete response to chemoradiation.
13 patients achieved clinical partial response to chemoradiation.
Those patients who had a nodal size of less than 3cm fared better than the patients with node size >3cm.
Hormone positive patients had better disease control and survival.
Grade 3 tumors had bad outcome.
4 year survival for patients treated with Neoadjuvant chemoradiation
Period Dead Alive Survival (in %)
1 Year 0 24 100
2 Year 2 22 96
3 Year 6 18 75
4 Year 8 16 66
49
4 Year Progressive disease free survival
Period Local and distant failure
No failure Progressive disease free survival (in %)
1 Year 8 16 66.7
2 Year 11 13 54
3 Year 14 10 41.6
4 Year 16 8 33
Failure rate:
At end of four years
7 patients failed systemically
10 patient s failed both locally and systemically
1 patient failed in local site alone.
50 DISCUSSION
Patients with breast cancer who has supraclavicular metastasis at presentation have a poor prognosis, especially when treated alone with either surgery or Radiation (22-24). There is 50%
mortality at 3 years. Haagensen and Stout identified the presence of supraclavicular disease as inoperable condition. Patients with supraclavicular metastasias has a poor prognosis, so the TNM staging system released in 1987 changed SCL metastasis into from N3 to distant metastasis.
Brito et al (26) in his article which analyzed supraclavicular metastasis showed that isolated supraclavicular metastasis patients have a good prognosis when compared to patients who have visceral metastasis. In 2002, AJCC revised the staging system and included the patients with isolated supraclavicular metastasis into stage III C
AJCC 2009 (20) staging also has kept ipsilateral supraclavicular metastasis at Stage III C.
This implies that the isolated supraclavicular metastasis can be considered as a locally advanced disease rather than metastatic disease.
Most of the trials that studied the treatment regimens in patients with Isolated Supracalvicular Lymph node Metastasis included neoadjuant chemotherapy followed by local therapy in the form of surgery and RT. S. Pergolizzi et.al.(27) in his trial published in Annuls of Oncology 2001 concluded that “ patients with isolated Supracalvicular Lymphnode Metastasis can have a better event free survival with induction chemotherapy and radiotherapy. It also produced improved survival which is not statistically significant. They stressed the importance of RT as it is necessary to eliminate the cancer cells in supra clavicular region which can act as a
51
source for further new distant metastasis. They also proved that increasing local control will improve the disease free survival. Our institute policy for locally advanced breast cancer in earlier years when chemotherapy was not yet systematized, and had not come into clinical practice, was preoperative radiotherapy in an attempt to reduce the physical proportions of the tumor and to diffuse its biological aggressiveness, followed by definitive surgery. Locoregional tumor regression after radiotherapy was very much satisfactory and brought approximately 45 percentages of patients within the scope of surgery, with a disease free survival of 45 percentage at 5 years.
In the 1970’s chemotherapy was introduced worldwide in an adjuvant setting for operable tumors. Because our institute had a practice of using preoperative RT with acceptable results for LABC’s and the major problem was loss to systemic disease, our institute added preoperative chemotherapy to the radiation therapy in what is today referred as neoadjuvant. The results clearly demonstrated the value of multimodality approach in the management of LABC.
The same principle was used in the treatment of isolated supraclavicular metastasis also as we considered it as a locally advanced stage and not a metastatic disease. In isolated supraclavicular metastasis also we got good results using concurrent chemo radiation.
Kiricuta IC et.al (28) at their analysis of 59 patients who initially presented with isolated supraclavicular metastasis and treated with chemotherapy surgery and RT reported a 2 year survival of 52% and a five year survival of 34%.
52
Ivo A.Olivotto et. Al. ( 29 ), analyzed long term survival of patients with supraclavicular metastasis at the time of diagnosis of breast cancer treated mainly with initial chemotherapy followed by local therapy; they had an overall survival of 33% at 5 years.
M.D. Anderson cancer center's experience (26) was published in 2001 in the Journal of clinical oncology. They analyzed patients who received neo-adjuvant chemotherapy for stage IIIC breast cancer. It was a meta-analysis of three prospective trials. Patients received upfront chemotherapy followed by local therapy. Follow up period was 11.6 years. They had an overall survival of 41 and 31 percent at 5 and 10 years respectively. They concluded that patients with isolated supraclavicualr metastasis should be treated with combined modality therapy with curative intent. They had an overall response rate (including complete response and partial response) of 89%.
Our institute analysis showed a clinical complete response in 11 / 24 patients and partial response in 13/24 patients. i.e. overall response rate is 100%. This shows that better response can be achieved with concurrent chemoradiation than achieved with neoadjuant chemotherapy alone.
The survival rate in our study is compared with other studies in the table III.
53
TABLE III
CENTER NO.OF.PTS SURVIVAL
Dr.Kiricuta, Urzburg university 59 34% ( 5 yr) Ivo A. Olivotto, Canada 51 33% ( 5 yr)
M.D. Anderson cancer center experience
70 33% ( 5 yr)
Cancer institute 24 66% ( 4 yr)
23 patients who received concurrent chemoradiation had grade II skin reaction. Only one patient had grade III skin morbidity. As against expectations Adriamycin didn’t produce morbid skin reactions in these patients. Grade II skin reactions didn’t produce treatment breaks and patients were compliant with the treatment.
16 out of 24 patients (66%) survived more than 4 years. (Kiricuta IC et.al, 5 year survival is 34%, Ivo A. olivotto 5 year survival is 33%, M.D. Anderson cancer centre experience is 33%
at 5 years).
We could not compare the efficacy between different chemo regimens as the number of patients was small. This is a short term study with only 24 patients so we won’t be able to offer
54
any suggestion regarding weather chemoradiation will offer survival advantage. Randomized, well controlled clinical trials, with long follow up, may be required before this question can be answered definitely.
55
CONCLUSION
Isolated supraclavicular metastasis in carcinoma breast is a part of locally advanced breast cancer and Neoadjuvant chemoradiation will definitely be a better option than neoadjuvant chemotherapy with comparable acute toxicity and this has to be proved by randomized, well controlled clinical trials, with long term follow up.
BIBILOGRAPHY
1) Harris, Jay R.; Lippman, Marc E.; Morrow, Monica; Osborne, C. Kent. Diseases of the Breast,
4th Edition, Publishers Lippincott Williams & Wilkins., 2010.
2) Spratt JS. Anatomy of the breast. Major Probl Clin Surg 1979;5:1.
3) Bonsor GM, Dossett JA, Jull JW. Human and experimental breast cancer. Springfield, IL: Charles
C Thomas, 1961.
4) Turner-Warwick RT. The lymphatics of the breast. Br J Surg 1959;46:574
5) Sappey MPC. Injection preparation et conservation des vasseaux lymphatiques. These pour le
doctorat en medicine, no 241. Paris: Rignoux Imprimeur de la Faculte de Medecine, 1834.
6) Hultborn KA, Larsen LG, Raghnult I. The lymph drainage from the breast to the axillary and
parasternal lymph nodes: studied with the aid of colloidal Au198. Acta Radiol 1955;43:52.
7) Kern KA. Lymphoscintigraphic anatomy of sentinel lymphatic channels after subareolar injection
of technetium 99m sulphur colloid. J Am Coll Surg 2001;193:601.
8) Suami H, Wei-Ren P, Mann GB, et al. The lymphatic anatomy of the breast and its implications
for sentinel lymph node biopsy: a human cadaver study. Ann Surg Oncol 2008;15:863.
9) Pickren JW. Lymph node metastases in carcinoma of the female mammary gland. Bull Roswell
Park Mem Inst 1956;1:79.
10) Grossman F. Ueber die axillaren lymphdrusen. Dissert. Berlin: 1896.
11) Rotter J. Zur topographic des mammacarcinoms. Arch F Klin Chir 1899;58:346.
12) Berg JW. The significance of axillary node levels in the study of breast carcinoma. Cancer
1955;8:776.
13) Stibbe EP. The internal mammary lymphatic glands. J Anat 1918;52:257.
56
14) Handley RS, Thackray AC. Invasion of internal mammary lymph nodes in carcinoma of the
breast. BMJ 1954;1:161.
15) Urban JA, Marjani MA. Significance of internal mammary lymph node metastases in breast cancer. AJR Am J Roentgenol 1971;111:130.
16) Gail MH, Brinton LA, Byar DP et al. Projecting individualised probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989; 81: 1879.
17) Claus EB, Schildkraunt JM, Thompson WD et al. The genetic attributable risk of breast and ovarian cancer. Cancer 1996; 77: 2318.
18) Fisher B, Costantino JP, Wickerham DL et al (2005) Tamoxifen for the prevention of breast cancer: current status of the National Surgical Adjuvant Breast and Bowel Project P-1 study. J Natl Cancer Inst 97:1652–1962.
19) Vogel VG, Costantino JP, Wickerham DL et al (2006) Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes:
the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727–
2741.
20) Edge SB, Byrd DR, Compton CC et al (2009) American Joint Committee on Cancer, American Cancer Society. AJCC cancer staging manual, 7th edn. Springer, Berlin Heidelberg New York.
