July 22, 2001
BREAST CANCER - Richards Adeleye Afonja, MD
Miss AXT is a 25-year old female with a family history of breast cancer. She is a journalist. The mother, maternal grandmother and maternal great-grandmother had breast cancer and they all died in their forties. She noticed a fullness in her right breast. She consulted a physician who told her this was due to her menstrual cycle. She became worried after three months of persistent breast swelling. She traveled to Lagos on a business trip. She decided to see another physician who did a fine needle aspiration. The pathology report came back positive for infilterating ductal carcinoma of the breast.
Mrs. BJK is an eighty-year old female with anemia, back pain, headaches and jaundice. She was examined and found to have a breast lump. Chest x-ray and CAT scans showed that the cancer has spread to the lungs, liver, spine, brain and bone marrow. Breast biopsy was positive for breast cancer.
Mr. KJK is fifty-nine years old with a small lump in the left breast. Biopsy reveals lobular carcinoma.
The most prevalent type of cancer in females but it is the second leading cause of death.
- Family history - two to four fold increase in risk for breast cancer among women with one or more first-degree relatives with the disease. First degree families could be paternal or maternal
1. Hereditary Breast/Ovarian Cancer Syndrome (BRCA1) gene: found on the longer arm of chromosome 17
a. BRCA2 Gene:
- localized to the long arm of Chromosome 13
- Also associated with male breast cancer
- prostate and pancreatic cancers
b. Li-Fraumeni Syndrome:
- associated with breast cancer (1%)
- childhood sarcomas
- brain tumors
- leukemias (cancer of the blood)
- adrenocortical carcinomas.
- Inheritance is autosomal dominant
c. Cowden Syndrome:
1. Associated with skin manifestations
2. Breast cancer
3. Gastrointestinal cancers
4. Thyroid disease
5. Caused by mutation in the PTEN (Protein Tyrosine Phosphates with homology to tensin) gene located on chromosome 10
- Previous history of breast , ovarian and endometrial cancers
- Geographical location - highest incidence in N. America
- Age - Over age 45 common in whites; under age 40 common in blacks
- Early menstruation and late menopause. Abortion does NOT increase risk of breast cancer.
- Oral contraceptives and breast cancer have no known association with the development of this cancer
- Obesity increases the risk of breast cancer. There is increased production of estrogen in fat cells.
- Exposure to radiation
a. Patients treated for Hodgkins's disease using mantle radiation tend to have breast cancer development in inner part of the breast (the part of the breast nearest to the midline) which is part of the area covered by the radiation.
- Diet - high fat diet increases breast cancer risk
- Alcohol - There are conflicting reports on this issue
- Short duration of breast feeding or none at all increases risk.
Screening Guidelines National Comprehensive Cancer Network Guidelines for Familial Breast Cancers
- Annual mammography starting at age 20-25 (30 years in patients with Cowden Syndrome)
- Semi-annual clinical breast exam starting at 20-25 years.
- Training in self-breast examination starting at age 25
- Prophylactic care to be discussed with patients on a case by case basis
- Annual comprehensive examination starting at age 20-25 years (18 years in patients with Cowden's Syndrome)
- Target surveillance based on family histories
- Prophylactic mastectomy/oophorectomy confers about 90% reduction in the incidence of breast cancer.
- Male patients with a family history of breast cancer require annual mammogram and clinical breast examinations like women with the same situation.
- 85% of newly diagnosed cases are detected as breast lumps
- Some breast cancers are detected on routine mammography
- Bloody breast discharge, skin dimpling, nipple refractions are other forms of presentations
- Some breast cancers present with metastases at diagnosis
- General screening guidelines include
a. Self breast examinations
b. Clinical examinations
c. Radiological imaging techniques, e.g., mammography (especially useful in reducing breast cancer mortality in women over 50 years).
Pathologic Classification of Breast Cancer
- Two broad terms
d. Non-invasive breast cancer
e. Invasive breast cancer
Non-invasive Breast Cancer
- Two main sub-divisions:
f. Lobular carcinoma in-situ (LCIS)
i. Cancer is confined to one or more mammary lobules without basement membrane invasions
ii. Common in pre-menopausal women
iii. It is usually multi-centric
iv. Risk of bilateral breast involvement is high
v. May progress to invasive carcinoma
g. Ductal Carcinoma in-situ (DCIS)
i. Ductal proliferation of cancer cells without invasions
ii. The "comedo" type of DCIS has a central tissue lesions and this histology portends a poorer prognosis (increased incidence of recurrence).
iii. Maxillary lymph node involvement is lower
Invasive Breast cancer
- The most common type is invasive ductal cancer
- Paget's disease of the nipple is a form of invasive DCIS in which case there is invasion of the ducts and the epidermis of the areola
POOR PROGNOSTIC FACTORS IN BREAST CANCER
- Lymph node involvement - the most important factor
- Tumor size - prognosis is worse with increased tumor size
- Vascular invasion
- Negative estrogen and progesterone receptor status
- Increased cell proliferation indices (S-phase, K1-67, Thymidine labeling index) Increased growth factors/receptors: Her2/neu, EGRF (epidermal growth factor), TGF (Tumor growth factor), however increased Her2/neu factor is predictive of response to anthracycline based regimen. Somatostation receptor, if present is indicative of better prognosis Angiogenesis: Growing cancer cells require a rich network of blood vessels to supply nutrient. If there is increased density of microvessels in the malignant tissue, prognosis is worse.
- The role of Ca15-3 (or CA27-29) as tumor markers, if considered separately is not clear. It may be used as a baseline marker and when considered in conjunction with the other biological, clinical and pathological factors, could be important in making decisions in the follow-up of these patients.
MANAGEMENT OF BREAST CANCER
- Consists of the following treatment modalities:
- Treatment in any patient may involve the use of one or more of these modalities: A). Surgical Management
- An initial biopsy is required to make a diagnosis
- This could be in the form of fine needle aspiration (FNA), excisional biopsy of the breast or biopsy of metastatic sites
- Definitive surgical procedures include:
1. radical mastectomy, modified radical mastectomy
2. axillary lymph node dissection (total).
3. Sentinel node concept is fast gaining popularity and this may obviate the need for unnecessary radical lymph node dissection.
4. Breast preservation procedures e.g. lumpectomy, tumorectomy, quandrantectomy.
Note: Breast conservation procedures and mastectomy plus axillary lymph node dissection have equivalent end points in terms of survival in clinical trials. However, radiation therapy must be given in patients with breast conservation procedures. In patients with mastectomy/lumpectomy margins of resection should be negative for tumor. If not, additional therapy will be required (e.g. mastectomy in a patient with previous lumpectomy, wider excision if cosmetically possible, radiation therapy, chemotherapy, hormonal therapy, etc.)
1. Radiation Therapy (RT)
- RT is mandatory in patients with breast conservation procedures (lumpectomy, quadrantectomy)
- May also be used in patients with local recurrence
- The effect of RT in patients with multiple lymph node involvement on survival is yet to be seen but it reduces local recurrence
- For palliative treatment of metastatic deposits in bones, soft tissues, brain
- Cord compression requires RT in addition to the use of steroids and pain medications
- Upfront chemotherapy in patients with Stage III breast cancer before definitive surgery is performed
- CMF (cyclophosphamide, methotrexate, 5-fluoruracil) is preferred in none-negative patients. Six cycles of CMF is equivalent to 4 cycles of CAF (Cyclophosphamide, Adriamycin and 5-Fluorouracil)
- High dose chemotherapy with peripheral blood stem cell transplant is evolving but there is no effect on prolongation of survival , according to a recent report.
- Taxanes are being increasingly used (paclitaxel and Docetaxel). These drugs produce significant nerve toxicity causing tingling sensation, hair loss, bone marrow suppression, severe anaphylactic reactions that may be fatal. The use of steroid, Benadryl and H-2 blockers like Zantac given before infusing prevents anaphylaxis.
- Taxanes are being used as single agents (weekly, monthly and three-weekly schedules) or in combination with antrhacyclines
3. Hormonal Therapy
- The first line hormonal agent is Tamoxifen
- Used in ER/PR receptor positive post-menopausal and pre-menopausal patients
- ER/PR receptor negative pre-menopausal patients should be given chemotherapy
- Elderly patients benefit from hormonal therapy whether they are ER/PR receptor positive or negative.
- FEMARA (brand name) is the only drug that has been documented to be better than Tamoxifen in terms of efficacy and side effect profiles.
- Second line hormonal agents include: a. Aromatase inhibitors which may be either Reversible non-steroidal inhibitors of Aromatase e.g., Letrozole and Anastrazole or Irreversible aromatase inhibitors, e.g. Exemestane
4. Other Agents
- Angiogenesis inhibitors a. Thalidomide - given in low doses was tried in breast cancer patients. These drugs prevent the formation of new blood vessels thereby ‘starving’ the cancer cells thus decreasing the chances of growing.
b. AE-941 is another agent being tried in Canada
- HER-2 Receptor Antibody (HERCEPTIN) produces a 15% response rate as a single agent. Use is indicated in patients who express HER-2 receptors Combinations of Herceptin + Taxol ± Carboplatin and Herceptin + Anthracyclines have to be evaluated in randomized, double blinded controlled trials. The use of Herceptin in recurrent breast cancer is mainly for palliation (make the patient comfortable) but it does not produce a cure of the cancer.
FOLLOW - UP AND WAYS TO DETECT BREAST CANCER EARLY
- Monthly self breast examination while taking a shower
- Annual clinical breast examination.
- Annual chest xray, mammogram, pap smear ( in patients who are on hormonal therapy).
- The question one would like to ask is : Would the use of Tamoxifen reduce the incidence of cancer in healthy people who have a family history of breast cancer or in people with a previous breast cancer? In patients who are menopausal (stopped menstruating) and have breast cancer lesions that exhibit positive oestrogen or progesterone receptors, Tamoxifen has been documented to reduce the incidence of recurrence of cancer on affected site and also in the other non-affected breast by up to 25 to 30 percent of cases if the medication is taken daily for at least five years. On the other hand, people with familial occurrences of breast cancer who exhibit BRCA1 genes do not benefit from the protective effect of this drug. The reason for this is that these patients tend to have cancer cells that do not exhibit receptors for oestrogen or progesterone. Healthy individuals with BRCA2 genes, however, exhibit positive receptors and are thereby protected to the tune of 62 percent reduction in the development of breast cancer.
- The use of Tamoxifen in patients who have estrogen receptor negative breast cancer may paradoxically reduce survival in these patients.
The lessons to be learnt from the above is that there are a lot of factors that come into play when anyone is diagnosed of breast cancer. The use of appropriate diagnostic tools to obtain the correct information on surgical specimens is the starting point to delivering appropriate medical care in patients with breast cancer.
Richards Adeleye Afonja, MD
Diplomate, American Board of Internal Medicine
Diplomate, American Board of Hematology
Diplomate, American Board of Oncology.
June 18, 2001
LUNG CANCER - Richards Adeleye Afonja, MD
Scenario 1: Mr. X is a 67 year-old male with a six-month history of cough with
bloody sputum, shortness of breath, weight loss, chest pain and bone pains.
He has a history of smoking two packs per day for forty-five years.
Scenario 2: Ms. Y is a 50 year-old female with a history of neck swelling, facial puffiness, shortness of breath, persistent cough with sore throat and hoarseness of voice. She is not a smoker but her husband smokes three packs per day.
Scenario 3: Mr. Z is a 36 year-old male with a history of alcohol and tobacco abuse that presented with left shoulder pain, shortness of breath and left upper chest wall pain.
All the three patients described above were tested and the tissue biopsies
(specimens taken from various parts of the body to be viewed under the
microscope) were read by the pathologists as “Lung cancer”.
Lung cancer has remained the most frequent cause of cancer in men (although the number is decreasing) in North America and it has, in the last few years has displaced breast cancer as the most frequent cause of death in women. Lung cancer remains the main cause of death worldwide. Lung cancer kills more people than colon, breast and prostate cancer combined.
The list of potential causes of lung cancer is endless but both active and passive smoking account for about 80% of cases. More men have stopped smoking recently thus explaining the decrease in the incidence in men but increasing number of women are taking up the habit of smoking which explains why there is an increasing incidence of lung cancer in women. A lot of steps have been taken the United States, which includes severe monetary fines imposed on tobacco companies and banning advertisements of cigarettes. Peer pressure also
contributes significantly to initiating smoking since adolescents and young adults think it is “cool” to be seen as a smoker which makes the individual smoker looks “more matured” and “independent” depending on the group of people present at these various functions. Poverty, stress, depression and people of poor educational background tend to be more active smokers than people who are better educated.
Cultural acceptance is also a significant factor in the acceptance or resentment of smoking habits. With the more westernized cultural influence in our society along with strategic advertisements aimed at increasing sales of tobacco, more and more people ignorantly take up the habit with the resulting dire consequences. It is a known fact that cigarette production and consumption of tobacco is markedly increasing and this is evident in the very attractive financial gains achieved by investing in these companies. Adenocarcinoma of the lung is rapidly increasing in incidence in women, especially of Chinese origin, who have no history of smoking.
Cessation of smoking after treatment reduces the chances of SPT (second primary tumors) according to a paper published by Kawahara, M et al in British Journal of Cancer 78: 409-412, 1998.
It is important to stress that non-smokers may also have lung cancer.
Other predisposing factors are as follows:
Exposure to asbestos. The effect is worse in smokers than in non-smokers.
Most buildings in Nigeria still use asbestos for roofing!
Occupational hazards like Uranium mining and exposure to Radon, which is
encountered in hard rock mining.
Genetic factors: Patients who metabolize Debrisoquin at a high rate may be
at high risk for the development of lung cancer. Chromosome 3 abnormality
has been associated with lung cancer, whether or not there is a direct
causative effect is yet to be seen. The MU phenotype of an enzyme,
Gluthathione transferase is found in high quantity in smokers without lung
Other forms of air pollution may be contributory factors
Diets that consist of fruits and fish have been suggested to be protective
based on studies conducted in Greece and Australia respectively.
Studies are ongoing to determine whether Vitamin A or its derivatives protect
individuals who have been treated with lung cancer from developing recurrent
or synchronous cancers in the lung and head and neck areas.
TYPES OF LUNG CANCERS
For the sake of simplicity, lung cancers may be divided into two broad categories:
1.Non-small cell lung cancer (NSCLC) which may be pathologically divided into the following:
squamous cell type
Only 20% of NSCLC are potentially curable with surgical resection or removal
but only 40% of these are alive in 5 years.
2.Small cell lung cancer (SCLC)
The natural course, symptoms, treatment and response to the modalities are
different in each of these types of lung cancers.
Signs and symptoms:
There may be no complaint whatsoever and the lung mass might have been
picked up on chest x-rays performed during a routine check-up or
Cough which may be persistent with or without brownish phlegm production
Hemoptysis – coughing up blood.
Loss of appetite
Complaints arising from spread to other parts of the body – bone pains,
headaches, nausea, vomiting, visual disturbance, neurological problems due
to direct compression or invasion of nerves by the tumor, seizures, hormonal
imbalance, liver dysfunction etc.
Screening techniques like annual chest x-rays in double-blinded controlled
trials have not been found to be significantly useful in decreasing deaths due
to lung cancer.
Spiral CAT scan of the chest is increasingly being used as a screening tool to detect small tumors in the lungs.
Molecular markers like k-ras mutation, bcl-2, p53 statement, c-erbB-1
statement, c-erbB-2, MIA 15-5 statement are not useful predictors of survival
in patients with NSCLC according to a report by Greatens TM et al in the
American Journal of Resp. Critical Care Medicine 157: 1093 – 1097, 1998.
An initial chest x-ray is mandatory after which CT scans of the chest with
intravenous contrast (including the upper abdomen to determine involvement
of the adrenals which occurs in 33% of cases).
Sputum collection and examination looking for cancer cells are routinely
ordered but the yield is low.
Bronchoscopy – a procedure that is done under light sedation. It involves the
passage of a tube down the airway of the patient into the lungs to determine
whether the cancer is invading the airway, which renders the tumor more
accessible and a biopsy (a small portion of the tumor is taken for inspection
under the microscope) can be performed. Some tumors are peripherally
placed in the lung and this procedure may not be found useful.
A CT-scan guided needle biopsy of the lung may be performed if
bronchoscopy is not appropriate due to the reason given above.
Mediastinoscopy (inspection and biopsy of lung tissue or lymph nodes
achieved by passing a scope through an incision made in the chest) and
open lung biopsy may be necessary in problematic cases before a diagnosis
can be obtained.
Full blood counts and electrolytes may show anemia (due to myelophthisis –
invasion of the bone marrow by cancer cells) or by direct suppression of the
bone marrow by factors produced by the tumor. Elevated calcium level with its various symptoms and signs like giddiness, change in mental status,
drowsiness, coma and death may be present.
Bone scans to detect involvement of the bones
CAT scan or MRI of the brain to detect any involvement of the brain.
The concept of “field carcinogenesis”: any areas exposed to nicotine and the
other products of tobacco may develop cancer and the sites that may be
potentially involved are: mouth, tongue, larynx (voice box), esophagus, bladder etc. These sites must be checked for coexisting cancers or a direct spread from the lung cancer.
- Lung cancers are advanced at diagnosis and cure is almost always
impossible. Cure rate in the 1960s was 8%, now it is 14%.
Chest surgeons suspected that most of lung cancer cures are in incidentally
detected tumors on chest x-rays.
The development of the cancer starts in the cells lining the bronchus and in the air sacs with subsequent spread. The pattern of spread depends on the type of lung cancer.
For localized (small) tumors of NSCLC variety, surgery is the treatment of
choice. For more advanced lesions, surgery alone is not adequate and a
combination of chemotherapy and radiation therapy given concurrently is
Chemotherapy is the mainstay of treatment with small cell lung cancer (SCLC) and in patients with limited stage disease with a potential for cure, brain irradiation is necessary to prevent recurrence.
External beam radiation therapy may be used to treat patients with
post-obstructive pneumonitis or to treat pain at different parts of the body
involved with cancer especially the brain, bone pains, liver involvement etc.
Brachytherapy (implantation of radiation seeds) in the lungs may also be
necessary in patients who had received external beam radiation therapy.
Cancer spread to other parts of the body is incurable and it, ultimately, leads
to the demise of the patient.
Educating the patient and the family about the extent of the disease and the
fact that the disease is incurable once it spreads is necessary to avoid
unnecessary and wasteful spending on new cares that have not proven to be
beneficial on the long run.
Chemotherapeutic agents (drugs) presently being used are:
Platinum-compounds, Taxanes (paclitaxel and docetaxel), Etoposide,
Gemcitabine etc. in various combinations.
Most of these drugs are highly emetogenic (cause severe vomiting) and
medications that prevent this must be given prior to their infusion.
Other side effects caused by these drugs are numbness, kidney dysfunction,
imbalance of sugar and electrolyte regulation, soreness in the mouth, hearing
dysfunction, nerve toxicity, hair loss, bone marro suppression, low white count, infection, anemia and heart dysfunction.
Various tests are necessary to prevent some of these side effects and the
use of Amifostine is known to reverse the renal (kidney) and neurological side
effects of some of the drugs. Transfusion of Packed red blood cells and the
use of erthropoietin and granulocyte-colony stimulating factors may be
Efforts should be directed at modifying advertisement of tobacco and tobacco
products and there should be a plan to curb sales of tobacco to minors.
Class act litigation of tobacco companies by patients who picked up smoking
as a habit without knowing that nicotine is addictive would go a long way to
reduce impressive ads in the newspapers and on the television.
Till then, thanks!
Richards Adeleye Afonja, MD
Diplomate, American Board of Internal Medicine
Diplomate, American Board of Hematology
Diplomate, American Board of Oncology.
May 12, 2001
EARLY DETECTION OF CANCER: MYTH OR REALITY?
The newly diagnosed cancer patient is often faced by a complex situation and no matter how strong an individual is, he or she often finds out that there are a lot of complex situations that surround the event. The initial reaction, no matter what stage of development, is anger and this prompts the question "why me". There is a common fear of the six Ds: death, dependency on the family, spouse or physician, disfigurement, disability, disruption of
interpersonal relationships and discomfort or pain in the later stages of development.
Knowing that there is significant morbidity and mortality attached to this dreaded disease, it is important to know what guidelines to follow in order to detect cancers early to prevent death. Most tests are designed to detect cancerous and pre-cancerous lesions that would help in making decisions to initiate treatment. The important question is: "Is there a single test available that would diagnose any cancer(s) in any individual at an early stage?" The answer is "NO".
There are different types of cancers and various tests are available for each type of disease depending on the site involved. When to initiate these tests and future surveillance depend on the type of cancer, the site involved, family history, previous diagnosis, other co-morbid conditions, and the potential advantage that could be derived from the tests.
Various agencies, institutions and organizations, financed by different institutions, conduct various tests with the objective of disseminating the information derived from the analysis of the results of the test to the public but the issue is what guidelines to follow to prevent a delay in diagnosis which may be ultimately fatal.
The outcome of certain cancers cannot be altered despite utilizing various screening tests but , luckily, a change in habit may help to prevent some of these cancers.
To learn more about the American Cancer Society Guidelines in ensuring early detection of cancers of the:
Please click Here
April 15, 2001
BREAKTHROUGH DRUG -"GLIVEC" (ST1571) FOR GASTRO-INTESTINAL TUMORS
The April 5th report from Cancer Press Releases shows that: "GLIVEC" (ST1571) is a unique drug produced and supplied by Novartis that has been shown to induce a 'significant improvement in patients with "Unresectable or Metastatic Gastro-intestinal Stromal Tumors" (GIST)'. GIST affects 4 out of 1 million patients. This drug functions by altering the function of the gene responsible for the development of the disease. Whether the drug is useful in other types of cancers is unknown but it was stated by one of the trial coordinators that the drug may be useful in patients with CML (chronic myelogenous leukemia). It is an investigational drug so far and it is only available in centers participating in the trials.
For more information please click here..
April 7, 2001
SIDE EFFECTS OF TAMOXIFEN: Tamoxifen is a drug that is antiestrogenic and it is approved by the FDA for the treatment of metastatic breast cancer, for use in the adjuvant setting after the initial surgical, radiation or chemotherapy, mastalgia, gynecomastia, malignant melanoma, cancers of the liver, pancreas and endometrium. In the adjuvant setting , tamoxifen is usually given for a period of five years. The medication is given orally but various side effects have limited the compliance of patients. The side effects include, but are not limited to anemia, low platelets, leukopenia, nausea, vomiting, anorexia, diarrhea, constipation, rash, mild hair loss, increased liver enzymes, hot flashes, dizziness and depression, headaches, blood clots and inflammation of the veins, vaginal bleeding , vaginal discharge, itch, cataracts, optic neuritis, decreased vision, tumor flare or worsening of symptoms of bone pains at the beginning of the treatment.
These various side effects along with the MYTH that it causes decreased sexual functioning (because it is antiestrogenic) in women when taken for a prolonged period of time constitute a significant cause for concern. A recent publication (Tamoxifen for the prevention of Breast Cancer: Psychosocial Impact on Women Participating In Two Randomized Controlled Trials; by Lesley Fallowfield, Dphil, et al.; Cancer Research Campaign Psychosocial Oncology Group, University of Sussex, Brighton, United Kingdom. Vol. 19, No 7 (April 1) 2000: pp1885-1892)has however shed some lights on the fact that mood swings and decreased libido are not associated with prolonged use of Tamoxifen. If this is case there will be an increased compliance to this drug use. The writer summarise that Tamoxifen may also have an estrogenic effect on certain parts of thus explaining the above findings.
To find out more, please CLICK HERE
THE WILL TO SURVIVE: AN ESSENTIAL INGREDIENT IN CANCER TREATMENT
Many of us would have heard of instances where a patient was given less than six months to live yet more than five years later, the patient still lives to tell the story.
What makes these group of people different from the rest of the population? Is it a special divine intervention, guardian angel or the patient's spiritual belief that gives this precious gift of life? Everyday is precious to a sick person and his family and the sleep-wake cycle that we often take for granted is very valuable to every cancer patient. Are some people born with the innate ability to withstand the stress of the ravaging effects of cancer?
The sum of a person's life experience determines the ultimate strength and determination with which a person tackles a problem as 'gigantic' as cancer. Carmen Dorso is one of such persons. The story of how he fought leukemia to a standstill is worthy of emulation. Where there is a will there is a way! The series of events that took place were chronologically narrated in February 2001 issue of Hem/Onc Today (a clinical news in hematology and oncology).
To learn more about this incredible feat performed by Carmen Dorso.....
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