General Information about the Lungs:

The paired lungs develop from lung buds in the human embryo during a period of rapid cell division. The main type of cell in the lungs is called"epithelial", meaning a lining cell. Mucous is formed by "adeno" cells which fold into glands. Another type of cell, called the"type II" cell, secretes "surfactant" which provides the stiffness for lung tissue. All of these cells divide quickly during womb life, infancy and puberty, but growth slows dramatically by adulthood. In adults, the cells only divide to replace ones lost to injury or old age.

Air breathed in passes though the throat into the larynx, where the vocal cords can form sounds. Below the larynx is the trachea, a tube ringed with cartilage which helps keep it from collapsing. The trachea splits ("bifurcates") in an upside-down "Y" with the arms of the "Y" going into each lung. The part of the trachea that actually enters each lung is called the"mainstem bronchus" ; there is a right and a left one to correspond with each lung. The area where the mainstem bronchi enter is called the "hilum" of each lung, the main blood vessels also enter at the hilum. The main bronchi branch out into smaller"lobar" and"segmental" bronchi to carry the air into the lungs. The right lung is made up of 3 lobes, and the left lung of 2 lobes. Each lobe is made up of smaller segments. The air breathed into the lungs ultimately gets to the tiny air sacs, called"alveoli", which provides the surface for the oxygen in air to mix with the blood. Also, the alveoli allow the carbon dioxide in the blood to be released into the lungs to get exhaled. The lungs are surrounded by an outer membrane called the "pleura" -- it is composed of 2 parts, an inner "visceral" pleura and an outer"parietal" pleura. There are bean-sized filters, called "lymph nodes" along the bronchi, which connect to each other via "lymph channels" . The lymph nodes contain lots of white blood cells and make up part of the immune system to help purify the blood. The lungs have a very rich blood supply, both from the blood they are oxygenating from the heart, which will be circulated to the rest of the body, and from the aorta, which provides nourishment for the lungs themselves. Thus, disease in the lungs, such as infection or cancer, can spread through the lymph channels and/or bloodstream to other areas of the body.

When people smoke tobacco over many years, the lungs lose their softness and start to become stiff. Then the lungs are more prone to infection and inflammation of the bronchi, called "bronchitis", and produce soothing sputum. The air sacs are gradually destroyed, and stale air gets trapped in the lungs. This is called "emphysema" . It gradually destroys the interface between the air sacs and the bloodstream, compromising the ability of the lungs to oxygenate the blood and to release the built up carbon dioxide waste product. About 1 in 5 people with emphysema will eventually develop lung cancer.

What is Lung Cancer?

Normally, the division of cells in the adult lung to make new cells is under very tight control. This control is exerted by the"genes" inside each cell, which are housed in long clumps forming"chromosomes", which are visible under a light microscope. The genes themselves are made up of DNA, the master genetic code material. If the genes are damaged, say by chemicals or radiation, the control over cell division may be lost in one particular cell. Ultimately, cancer is considered a disease of the DNA. Lung cancer starts in a single lung cell . That cell starts dividing haphazardly, making millions and billions of copies of itself. It takes up the nourishment needed by other cells, depriving them so the cancer can continue to grow. Quickly growing cells can clump up to form a"tumor" . A tumor simply means a swelling, it can be caused by inflammation or infection. A "benign" tumor only grows in it's local area (although it may get quite large)-- it cannot spread and is not cancer. By contrast, a tumor which can spread to other body areas is called "malignant" and this is cancer . The process of cancer spread to other areas is called "metastasis", so only malignant tumors (i.e. cancer) can metastasize. Theoretically, cancer can spread to any area of the body, and it often grows better in it's area of spread than in it's area of origin ("primary site") . It is this capacity for spread that makes cancer so dangerous. If not treated successfully, it ultimately kills by debility, anemia, infection, compromise of other organs and interference with normal body functions.

What are the Types of Lung Cancer?

Depending on which type of cell in the lung goes awry, different types of lung cancer may arise. Although mixed types may occur, lung cancer is commonly broken down into 4 basic categories, and a smattering of much less common types. The most common type is Squamous Cell Carcinoma (35% of cases). It starts from the cells lining the bronchi, especially when they have been repeatedly damaged by smoke or other irritation. Normally, squamous cells are the type that line the mouth, anus, vagina and skin-- they are resistant to abrasion and heal quickly. Fascinatingly the normal "cuboidal" epithelium of the lung can start to turn into squamous cells with repeated irritation, a process called "dedifferentiation" . If this conversion is not totally successful, a cancerous squamous cell may arise.

The second most common type of lung cancer is Adenocarcinoma (30% of cases) which arises from glands, and the cells lining the air sacs. It is usually found in the periphery of the lungs, as opposed to squamous cell which commonly has a more central location along the bronchioles (that is arises in the middle of the chest). This is the type common in non-smokers.

The third most common type is Small Cell Carcinoma, also called "oat cell" (20% of cases). It seems to arise from"neuroendocrine" cells, which produce small amounts of local hormones. The specific cell that small cell lung cancer arises from appears to be the"Kulchitsky" cell, a neuroendocrine cell within the lining of the bronchioles. There are 3 subtypes of small cell cancer--"Oat Cell", "Intermediate" and "Combined" (mixed type). Over 90% of cases are the Oat Cell type, and it is the type that best responds to chemotherapy (although the others do also). The determination of which type of Small Cell cancer is present is made by a pathologist using a microscope, to see what the cells look like. A pathologist is a physician who specializes in diagnosing disease from tissue samples. However, pathologist's won't always agree on the exact subtype. However, over 90% of pathologists will concur that a "Small Cell component" exists when shown a questionable specimen, and if any exists, the patient should be treated for small cell cancer. Treatment is much different than for the other types of "epithelial" lung cancer.

The fourth most common type isLarge Cell carcinoma (15% of cases) which is actually a form of adenocarcinoma. Since the cells look much larger under a light microscope, however, it is given a separate category. It generally occurs in the periphery of the lung. Sometimes, the cancer does not look exactly like any of the above types, the cells are very primitive and aggressive looking. This is called"undifferentiated" cancer but careful analysis can often reveal the particular subtype. Nearly 30% of cancers may be "mixed", especially if advanced. As mentioned, if there is any Small Cell Cancer present, it should be treated as such.

It is possible for other rare types of cancer to arise in or around the lungs. Examples are Lymphoma from the immune cells in the lung, SarcomaMesothelioma from the pleural lining of the lungs. These conditions are all separate topics, with their treatment following that the the areas where they more commonly arise. Cancers from other areas may spread to the lungs, especially adenocarcinomas and sarcomas from other organs. The lungs are rich in blood and are a fertile area for other cancers to spread to. These are dealt with when considering the treatment for metastasis of these particular cancers.

How Common is Lung Cancer?

Each year there are about170,000 new cases of lung cancer in the U.S.A. and 150,000 deaths attributable to this disease. Lung cancer is the most frequent fatal cancer, for both men and women, in the United States. Men are affected somewhat more frequently (100,000 cases/year) than women (70,000 cases/year). Worldwide, there are 1 million new cases per year. Over the past 5 decades the number of yearly cases has been increasing, and the worldwide incidence may double to 2 million per year in the coming decade. The average patient is 60 years old, and only 1% of cases are under 40 years old. Small Cell Cancer is the most rapidly increasing form of lung cancer and accounts for about 37,000 cases per year in the U.S.A . The proportion designated as Small Cell Cancer will vary in different studies depending on the methods of detection; in surgically treated patients the percentage is just 8% and in those diagnosed by fluid aspiration ("cytology") of the lungs, 30%. This is because surgery is inappropriate for most Small Cell Cancer patients. About 90% of patients have historically died from their disease but survivals are improving with the latest effective therapy as we will see.

What Causes, or Increases the Risk For Small Cell Cancer?

Tobacco Smoking is the greatest risk factor for getting Small Cell Cancer, In large series of patients, fewer than 2% deny a history of heavy smoking. The risk begins to decline 5 years after quitting, and approaches normal at 20 years after quitting (but never exactly goes back to normal). Patients who quit smoking, even after diagnosis, tend to do better in treatment and live longer than those who continue smoking.

Radon Inhalation is associated with an increase in lung cancer. The radon breaks down into radioactive particles in the bronchi of the lungs, irritating the cells there, causing genetic damage, and leading them to divide. Radon tends to build up in unventilated Basements and Mine Shafts, uranium miners get more lung cancer; it is an occupational hazard.

Asbestos Inhalation in Mine workers, Pipe fitters, Shipbuilders, and people who worked with asbestos in insulation materials. The risk is especially high if patients both smoke tobacco and have asbestos exposure.

Can Small Cell Lung Cancer be Prevented?

Quitting smoking, and not being in close proximity of those who do, is the best way to prevent Small Cell Cancer. Even patients who have smoked for many years will see a decreased risk of heart attack from the day they quit smoking, and decreased risk of lung cancer after several years. A diet high in natural vitamins "A" and"E", and relatively low in fat, may be preventative for many "aero-digestive" cancers (those arising in the nose, mouth, throat, lungs and digestive system). Regular screening Chest X-rays do succeed in diagnosing lung cancer at earlier "stages", but have not been proven to increase survival from lung cancer. Nonetheless, it is reasonable for a person with high risk factors to get a chest X-ray as part of their annual physical, and to get one without delay if symptoms of lung cancer manifest.

What are the Symptoms of Small Cell Lung Cancer?

Like any cancer,very early Small Cell lung cancer has no symptoms, since there are too few cancer cells to interfere with normal body functioning. "Symptoms " are things that the patient "feels", such as pain and dizziness,"Signs" are things that can be measured, such as fever and weight loss. As the cancer gets larger, the following commonly occur:

Persistent Cough, and sputum tinged with flecks of blood("hemoptysis") must always be evaluated to rule-out cancer. Cough is triggered by small "receptors" in the bronchi which send an instruction to cough to the brain-stem. Small Cell cancer is less likely to "present" initially with hemoptysis than other types, since the disease starts in cells under the inner lining ("submucosal cells" ) instead of right on it. The cancer can block of a bronchiole, causing obstructive pneumonia . This pneumonia is less likely to "cavitate" (produce apparent holes) than that caused by "Non Small Cell" cancer. It is important for a follow-up X-ray to be taken after a pneumonia is treated, to make sure no tumor was lurking behind it.

Shortness of Breath will be seen if bronchi are blocked off by the tumor, and so prevent the inspired oxygen from mixing with the blood. The effort in breathing will also increase if a fluid collection("effusion") develops due to the cancer. This puts more stress on the heart pumping blood through the lungs, which in turn leads to more shortness of breath andfatigue . Fatigue also can be due to a buildup of the waste-product carbon dioxide in the lungs-- it's exit blocked by the tumor. Progressive shortness of breath ("SOB") must always be evaluated.

Weight Loss is very common with lung cancer, as the body's resources are shunted into the growing cancer, andappetite decreases. Sometimes an unexplained weight loss is the first sign of lung cancer. The cancer itself can produce substances that interrupt appetite and metabolism, as seen below

Paraneoplastic Syndromes ("PNS") are especially common to Small Cell Cancer patients, with 14% of patients developing them (compared to 2% in other lung cancers). PNS means the cancer actually produces some chemical which alters normal body function causing signs and symptoms. Patients who get PNS only get some of them as a rule. Examples Include:
a) SIADH means "syndrome of inappropriate anti-diuretic hormone"-- the kidneys retain the body water are dilute the blood sodium, causing "hypo- natremia". This is usually only picked up on lab tests.
b) Eaton Lambert Syndrome means a progressive weakness on using one's muscles, much like the disease "Myesthenia Gravis". The muscles will "recharge" after a rest, then fail again.
c) Ectopic Cushing's Syndrome means overproduction of steroids by the body leading to masculization, hair growth on the face, redistribution of fat to the abdomen and thinning of the limbs, bone brittleness, a "moonlike" rounded face, and development of a fat pad ("Buffalo Hump") on the upper back.
d) Cerebellar Ataxia means a degeneration of the hindbrain with balance problems, unfortunately this may be permanent. e) Neuro-Muscular degeneration (like muscular dystrophy) and severe weight loss may be caused by substances released from the tumor. PNS will usually improve or disappear with successful therapy of the underlying cancer. Thus these symptoms can be monitored to gauge therapy success.

Chest Pain will manifest as the cancer invades into bone and nerves. Many patients have almost no pain until late in the disease, or only "pleuritic" (stabbing) pain on deep inspiration. The pain may radiate to the back.

Hoarseness can occur if the cancer invades the middle portion of the chest ("mediastinum") and damages the "recurrent laryngeal nerve", which normally controls the voicebox. The voice may also change to be higher pitched. The hoarseness may be progressive, or occur all at once.

Superior Vena Cava Syndrome ("SVC") means the cancer has grown large in the middle of the chest ("mediastinum) and is compressing the blood vessels returning blood from the upper body to the heart. Patients get facial and arm swelling, short of breath, and wheeze. The veins on the neck stand out since blood can't drain from the head ("jugular venous distension"). If SVC is promptly treated, it does not adversely effect a patient's chance of cure.

Signs of Distant Spread include mental changes, strength and sensory loss owing to spread to the brain, and bone pain and fractures due to distant spread to bone. About 10% of the time, these "late signs" are the first indication of lung cancer. Any symptom is possible, since the cancer can spread to any body area. The most common areas of spread are to lymph glands, the other lung, liver, brain, bone marrow, bone, skin, and adrenal glands (on top of each kidney).

How Does Small Cell Cancer Start and Spread?

As mentioned, the cancer starts in a single cell. This cell divides over and over again to make million, then billions of copies("clones") of itself. When the tumor contains about 1 billion cells, it is 1 cm. (1/2 inch) across if it is a sphere. Small Cell Cancer normally starts in the lung's air tubules ("bronchi) under the inner lining ("mucosa"), in the"submucosa", It can cause the overlying squamous cells to look abnormal ("dysplastic") . Ultimately the bronchiole becomes blocked("obstructed") by the growing tumor leading to shortness of breath, wheezing, and possibly pneumonia forming behind the blockage ("post-obstructive pneumonia") . The cancer can spread in the lymphatic channel in the submucosa to local lymph nodes, and enlarge them ("lymphadenopathy") . It can get into the bloodstream and spread via the blood("hematogenously") to any area of the body, mostly bone marrow, brain, liver, and adrenal glands. In the meantime, the original tumor ("primary tumor") can continue to grow, press upon the blood vessels in the chest, and cause Superior Vena Cava Syndrome and Hoarseness. It can cause weight loss and Paraneoplastic Syndromes. If not successfully treated, patients succumb to anemia, debility, infection, and organ failure from spread of disease.

How Is Small Cell Cancer Diagnosed and Evaluated?

It is important to note that any of the above symptoms are more likely caused by something other than lung cancer. However, they shouldn't be ignored. If a patient comes to their doctor with problems suggestive of lung cancer, the doctor will do:

Complete Physical Examination includes checking weight, temperature and blood pressure, and the skin surface. The heart and lungs are carefully listened to ("auscultated") and any wheezes or lack of breath sounds are noted. Tapping on the back to listen for dullness ("percussion") can tell if fluid is building up in the lungs. The even expansion of the chest with each breath is observed. The quality of the voice is noted for hoarseness. The fingernails are checked for curving which indicates chronic lung disease. Examination of the lymph glands in the neck, shoulder and armpit region may show swelling there. The abdominal organs (liver, spleen, kidneys, adrenals) are checked for swellings. A neuro-local exam checks the brain, special sense organs, and limb strength. In males the prostate is checked with a rectal exam, and in females a pelvic exam with PAP smear is done, and the breasts carefully checked.

Routine Laboratory Tests include Complete Blood Count("CBC") to check for anemia and infection. A Chemistry Panel ("SMA") checks blood sodium, potassium, bicarbonate, chloride, calcium, phosphorus, glucose, cholesterol and liver and kidney function. Routine urinalysis("UA") detects blood, protein, glucose or infection in the urine. If surgery is contemplated, the surgeon will want an assessment of blood clotting ability ("PT/PTT") . Unfortunately, there is no single accurate blood test to pick up lung cancer ("tumor marker") as there is for prostate cancer.

Bone Marrow Biopsy if particularly important for Small Cell Lung Cancer to if the disease has spread there. It goes to bone marrow in about 30% of those tested, which means the disease is incurable by surgery. Bone marrow biopsy is done under local anesthesia by inserting a large-bore needle into the wing of the hip bone above the buttock. If both "iliac wings" are sampled ("bilateral Bone Marrow biopsy) the chance that a positive result will be gotten (i.e. the bone marrow is involved) increases by 10%. In capable hands, the test is not painful but leaves some soreness and bruising.

Radiology Tests include plain Chest X-ray which may show tumors over about 1/2 inch, signs of infection, and signs of lung obstruction or collapse. Failure to see anything on plain X-ray does not rule out cancer, but does suggest that the cancer, if present, is small. A chest X-ray may miss a small tumor hidden by a rib or the silhouette of the heart. More accurate is a CT scan of the chest, which can detect tumors over about 1 cm. in any chest location. CT scan can also pick up enlarged lymph nodes in the mediastinum (middle of the chest). Lymph nodes larger than 1 cm. are suspicious; those over 2 cm. certainly have something wrong with them (infection and/or cancer). If a CT scan is given with "contrast dye" (injected into an arm vein) it helps highlight the blood vessels and is somewhat more accurate. CT scan can also be used for the abdomen and is excellent for showing spread to the liver, or to the adrenal glands. BrainCT will be ordered if the is suspicion of spread there. Magnetic Resonance Imaging ("MRI") is a newer method that used magnetism instead of radiation, it is great for looking at soft tissues in the chest, It is 3 times as expensive as CT (~$1000) and is not routine. Bone Scan involves injecting some radioactive dye into a vein; the dye has a propensity to accumulate in damaged or cancerous bone areas, which are detected by a scan. It is gotten to help rule out spread to bone, especially if new bone pain is noted and surgery is contemplated. Bone Scan is much more accurate than plain X-rays of bone in picking up cancer spread, but also more time consuming, uncomfortable and expensive. Repeat Bone Scans may be needed to help confirm if an area seen is actually cancer, or just an old area of trauma. A"baseline""osteoblastic" meaning they appear as new bone formation, instead of the more common "osteolytic" (a hole) metastasis seen with Non-Small Cell Cancer. Specialized radiology tests such as barium enemas or esophagrams are only gotten if use will be made of the information obtained from them; that is if they may change the treatment for a particular patient.

Sputum Analysis ("Cytology") is useful for making a diagnosis of cancer is a patient who's tumor is shedding off cells that can be coughed up. It is non-invasive and relatively inexpensive, using morning sputum specimens (deeply coughed up specimens, not saliva) collected in plastic containers for analysis. Five consecutive daily specimens may be as much as 90% accurate for detecting Small Cell Cancer, which usually is located in the bronchial tubes or center the chest ("mediastinum").

Biopsy (Sampling) of the tumor is the only way of definitely diagnosing any lung cancer. Either the primary tumor, cells it has sloughed off, or an area of distant spread (a metastasis) may be sampled to confirm or deny cancer. A pathologist is a physician who specializes in making disease diagnoses from tissue samples. There are several standard ways of getting a sample for the pathologist:
a) Endoscopic Brushings and Biopsy means putting a visualization tube down the patients throat into the lungs, where they are under a light anesthesia (usually valium and demerol). If the tumor is"endobronchial" (as Small Cell Cancer generally starts) it may be seen and sampled by brushing it for cells and/or cutting a piece off of it with a special biopsy scissors on the endoscope. This can be therapeutic, too, since a blockage can be relieved to restore air flow.
b) CT Scan Guided Biopsy means the patient is brought down to the CT Scanner, the tumor is visualized, and a fine-needle is placed (under local anesthesia) through the chest wall into the tumor, with pieces of tumor drawn out. It is about 85% accurate at making a diagnosis and quite safe. This is an easier procedure if the tumor is located peripherally. The biggest risk is collapsing the lung (20%) which then will require a chest tube to be put in to re-expand it, and an overnight stay.
c) BronchoAlveolar Lavage (BAL) is like getting a deep sputum specimen, literally by putting washing fluid down into the lungs, re-drawing it out, and looking for cancerous cells. It is most helpful for tumors within the bronchial tree, and can be done at the same time as endoscopy. It is performed by a pulmonologist, a physician specializing in lung disorders.
d) Mediastinoscopy means cutting a small hole above the breastbone (sternum) and inserting a scope into the central part of the chest (the mediastinum). Enlarged lymph nodes can be removed and sent to the pathologist for analysis. Some surgeons base the procedure they will do upon the results of the mediastinoscopy, and order it routinely.
e) Open Biopsy is done if an area looks suspicious, but cancer cannot be confirmed or denied by the above methods. A surgery to remove an unknown type of tumor is an open biopsy. If the entire tumor is removed, it is called an"excisional" biopsy; if it is merely sampled, it is then called an"incisional" biopsy. About 10% of patients have disease that can only be diagnosed with an open procedure, done under general anesthesia. However the biopsy same is obtained, it is sent to the pathologist who examines it to confirm or deny cancer. If cancer is detected, the particular type is specified.
7) Other Standard Tests include lung function studies to determine how much lung may safely be removed, and EKG to check heart function. This is part of a pre-operative evaluation to see if the patient can tolerate surgery. Generally, if there has been a heart attack in the prior 6 months, the risk of major surgery is considered too great. These tests also help tell how well the patient can tolerate the aggressive chemotherapy often used for Small Cell Cancer.

How is the Extent of Small Cell Cancer Guaged?

The extent of any cancer is described by it's "Stage", based upon the evaluation above. There are only two stages given for Small Cell Lung Cancer (as compared to four for most other lung cancers). They are:

Limited Stage Disease means the disease is limited to just one lung and possibly lymph nodes, all on one side of the chest.
Extensive Stage Disease means the disease is more advanced than above, (e.g. spread to bone marrow, other lung, liver, brain).

What is the Conventional Survival from Small Cell Lung Cancer?

This depends upon the stage, the general medical condition of the patient, and the treatment selected. The conventional survivals for lung cancer, from classic textbooks, with surgery or chemotherapy alone, were quite poor:

Fortunately, the Latest Effective treatments have raised these abysmal survivals . Bear in mind that cancer survivals include death from all causes (e.g. heart attack, accidents, a different cancer) and that we cannot predict how long any person will live .

What Factors Help Predict How Well Patients Will Do?

Factors that predict how well patients will do are discerned from studying groups of patients, and are called "prognostic factors" . There a"favorable" prognostic factors, meaning those patients with them tend to do better, and"unfavorable" prognostic factors, which means the opposite. For Small Cell Cancer, favorable factors include:

a) High Performance Status -- means being able to take care of one's self.
b) Limited Stage Disease -- as opposed to extensive disease.
c) Low Blood LDH and Alkaline Phosphatase -- shows more limited cancer.
d) Maintaining normal weight -- as opposed to significant weight loss.
e) Tolerating Aggressive Chemotherapy -- as opposed to not tolerating it.
f) Good Response to Chemotherapy -- as opposed to poor response.
g) Being Female -- they do somewhat better than males.
h) Quitting smoking -- even after the diagnosis has been made.

What is the Conventional Treatment for Small Cell Lung Cancer?

Conventional Treatments include Surgery, Radiation and Chemotherapy. Our understanding of the nature of this cancer has changed over the past few decades; we now realize it is normally spread to other body areas("disseminated") at diagnosis, with explains why"local therapy" alone (e.g. surgery) had such a poor success rate. Thus, we have realized that treatment must travel through the entire body, that is be"systemic therapy" . However, we have also come to realize that just systemic therapy alone is not enough either-- we must give special attention to the local disease for the best hope of cure. The Latest Effective Treatments, as we will see, combine therapies to optimize the advantages of each one. Firstly, we review the individual conventional treatments, and what each involves:

Surgery alone has been very disappointing is Small Cell Lung Cancer. Even small cancers, apparently very localized, develop both"local" and "distant" relapse after apparently successful surgery, with patients dying of widespread disease. Surgery is only a local therapy, but only 4% of patients dying of Small Cell Cancer have exclusively local disease in the chest ("thorax") . Moreover, studies showed no difference in survival for Small Cell Cancer whether patients were operated upon or not! This led"Thoracic Surgeons", who do major lung surgery, to abandon surgery for Small Cell Cancers. It is now used occasionally for making the diagnosis, when an "open procedure" is required (i.e. other tests were inconclusive) but is not considered only "diagnostic", not "therapeutic" . Major lung surgery has an 8% death risk (mortality) in the time period around the operation ("peri-operative" period), 15% infection risk, 10% risk of heart attack or blood clot, and 5% chance of sutures splitting open("dehiscence") . Major surgery takes about 3 weeks to recover from, after which the tissues are back to 75% of their normal strength, and heavy lifting is again possible. The results of surgery show a 5 year survival rate of 2% for "Limited Stage" disease.

Radiation Therapy alone was the next treatment tried for Small Cell Cancer. The results for Radiation Therapy alone were poor, since it is at best a"local" or "regional" therapy, and patients continued to die of distant disease spread. However, unlike surgery, Radiation Therapy remains very important for Small Cell Cancer, when combined with Chemotherapy (see"Latest Effective Treatments" ). Thus, we will describe it in detail. Radiation Therapy has been used for 8 decades for lung cancer, the techniques have been advancing steadily. It is administered by a "radiation oncologist", a cancer physician specializing in radiation therapy. There are 2 standard methods of giving radiation--"External Beam" "Brachytherapy" . External Beam is the more common type and shines a beam of photons or electrons onto a predesignated area of the patient's chest. Thus, it can cover a large area of possible cancer spread. Brachytherapy, also called "intracavitary", means putting an actual radiation source into the lung, either temporarily or permanently, to treat a limited area of tumor. Both techniques may be used in a given patient.

Radiation kills cancer cells by damaging their DNA, they die when they try to divide. Thus, damaged cancer cells die even after the treatment is complete. Radiation will also kill normal cells, which limits the amount that can be given. However, it usually takes more radiation to kill normal cells than cancer cells, and normal cells can often repair the radiation damage, while cancer cell can not. Nevertheless, it is important to be exacting as possible in the administration and dose of radiation, so as to minimize the injury to adjacent normal cells.

To receive therapy, a patient is first seen in"consult" by a radiation oncologist, who reviews the patient's medical record, complaints, and radiology films. After explaining the possible benefits and side-effects of radiation, the patient is scheduled for a "simulation" . This means the area to be treated is marked out on a replica treatment machine, and films are taken. Watercolor marks are painted on the patient to denote the treatment area, and eventually small, permanent tattoos are placed on the skin. Sometimes the patient is sent for a CT scan along with the simulation, the whole process takes less than 2 hours, and is painless. Information from the simulation and relevant scans is placed into a "treatment planning computer", which generates a"plan" . This plan tells how much radiation is going to the tumor area, and how much to adjoining normal tissues. For lung cancer, particular attention is paid for how much radiation is going to the spinal cord and heart. The plan is reviewed by the radiation oncologist and also by a specially licensed Radiation Physicist prior to starting therapy. The patient then comes in for their "treatment start". They are placed on a hard, flat table in a specially shielded room and aligned with laser lights. The actual treatments are given by "Radiation Therapists", or "R.T.T's", who are first certified for diagnostic X-rays and then get additional training to deliver therapy. For the first treatment, "verification films" are taken to ensure proper positioning; they do not tell anything about the cancer. The actual treatment only takes a couple of minutes and is given with a Linear Accelerator (or occasionally older Cobalt-60) which precisely aims a beam of photons at the treatment area. The head of the machine can swivel about the patient, to give the treatment from several angles. The patient needs only to lie still. Areas that are not to be treated can be "blocked" with special lead-type blocks in the head of the treatment machine. Normally, patients area treated 5 days a week, Monday through Friday, taking only several minutes each day.

The usual dose of radiation for lung cancer is 40 - 60 Gray (units of radiation) given at about 2 Gray per day over 4 to 6 weeks. Often, a larger area of the chest is treated initially, and then a "cone down" or "boost" is used to narrow the high dose treatment to the specific tumor area as seen on X-ray (after chemotherapy). Treatment itself is painless, the patient does not become sick, "radioactive" or lose their scalp hair from radiation to the chest. The side effects from chest radiation for lung cancer are divided into two general categories, "acute" and"late" effects."Acute" effects occur during the treatment period, and commonly resolve afterward. "Late" effects may occur months to years after treatment, and may improve very slowly or never resolve. Typical acute effects are skin redness within the treatment area, difficulty or pain on swallowing as the esophagus (food pipe) is treated, and general fatigue. Possible late effects include damage to normal lung ("radiation pneumonitis") which causes cough, fever and shortness of breath. It only occurs in about 10% of patients and is often treatable with steroids. However, it is occasionally fatal. Treating large areas of lung, and/or giving chemotherapy along with lung radiation, increases the chance for radiation pneumonitis. Another feared complication of lung radiation is spinal cord damage, since the spinal cord is very close the the back portion of the lungs. This may manifest as a temporary sensation of "electric shocks" shooting down down the body with neck flexion ("Lhermitte's sign") which is scary but commonly resolves. Worse but very rare with modern techniques is "transverse myelopathy", which means severing the spinal cord from too much radiation-- this will cause permanent paralysis below the injury. The spinal cord tolerates about 45 Gray with less than 1% chance of damage, and this is a reason why careful "simulation" and review by a radiation physicist is crucial to ensure that the cord is not being overdosed. As mentioned, this is very rare with today's technology and training. Radiation can also cause heart damage, such as irritation of the fluid-filled sac around the heart ("pericarditis") which may cause chest pain and fever, and need a surgical procedure to drain excess fluid. This is also very rare. Overall, external beam chest radiation is very well tolerated and of proven benefit for increasing survival in lung cancer, for patients who cannot tolerate surgery.

Brachytherapy is being used more commonly today, since it gives a high dose of radiation to a local tumor area with minimal side effects to surrounding normal tissues. In practice, it is usually given in conjunction with external beam therapy, since we are worried about cancer cells that may have escaped around the periphery of the tumor, and into local lymph nodes, which would not be adequately treated with any brachytherapy alone. Giving brachytherapy, or"intracavitary" therapy, can be done in several ways. One is surgical placement of permanent "Iodine -125" seeds in the area of the tumor, often at surgery. These seeds have an effective life of about 90 days during which they give potent radiation to their immediate area, but nearly none just a couple of centimeters away. Another option, especially for patients not getting surgery, is treatment with high-dose radioactive sources contained in a small tube("catheter")placed with an endoscopy tube through the mouth, down the throat and into the lung. Brachytherapy is particularly useful for tumors in the bronchi, since the endoscopy tubes travel through the bronchi and can place the catheter there. Thus, such tumors are usually more in the center of the chest, as opposed to the periphery. Multiple treatments may be given, 2 to 4 weeks apart, with high dose brachytherapy (HDR) ; the actual time of treatment is only a few minutes. If a segment of lung has recently collapsed owing to tumor, there is a good chance (up to 70%) that it can be re-opened using this "endobronchial brachytherapy", which is available at most Academic University Radiation Oncology departments. CancerAnswers offers an In-Depth transcript available on understanding Radiation Therapy, available through our Web Site. The results of Radiation Therapy alone show a 4% survival rate at 5 years.

Chemotherapy alone was the next treatment for Small Cell Cancer. Unlike Non-Small Cell Cancers, the Small Cell type is often very responsive, at least initially, to our current chemotherapy. Furthermore, given the abysmal survival with the just local methods (surgery and radiation), it was obvious that patients needed therapy that treated their entire bodies ("systemic" treatment). Chemotherapy was the first treatment that showed significantly improved survival over no therapy at all . A major problem with chemotherapy alone is that patients continued to succumb to local disease in the chest, which was insufficiently treated by chemotherapy alone. Another problem is that cancers become resistant to chemotherapy, much as bacteria become resistant to antibiotics, so patients could "relapse". A final problem with chemotherapy alone is that it failed to reach the central nervous system (brain and spinal cord) effectively since the"blood brain barrier" kept it out, so patients would relapse there. We are trying to overcome these problems with "Latest Effective Treatment", as will be seen. Effective chemotherapy agents include Cyclophoshamide, Adriamycin, Vincristine and Etoposide . Combining the agents is more effective (and more toxic) than using them individually . A popular regimen combines the first 3 drugs above ("CAV" regimen) while another combines all four ("CAVE" regimen). Except for the Cyclophosphamide ("Cytoxan") they all given into the veins (intravenously) in monthly "cycles" . Normally the drugs are given just one (or a few) days at the beginning of each cycle, and the rest of the month is left to recover before the next cycle. The idea of combination therapy is to try to kill the cancer cells before they can become resistant.

Chemotherapy Side Effects:

1) Adriamycin can cause heart damage and the dose is limited to 500 mg/ per square meter of patient body surface area. It is common to get a "heart scan" called a "MUGA" test before giving adriamycin. It also causes greater skin redness and irritation if radiation is given. It causes temporary baldness ("alopecia") and sterility.
2) Cyclophosphamide is derived from mustard gas and causes a lowering of blood counts. Drops in red-blood cell count cause anemia, with paleness and tiredness, drops in white-blood cell count lead to "neutropenia" which shows as infections and fevers, while a drop in platelet count leads to prolongued bleeding and easy bruising. It can also cause sloughing of the bladder lining with bleeding into the urine ("hemorrhagic cystitis") which may be prevented by the drug "MESNA".
3) Vincristine is a plant "alkaloid" which can cause nerve damage with numbness and weakness, hearing loss, and kidney damage. These effects may or may not improve when the drug is stopped. It also will lower blood cell counts, so can lead to infections and bruising.
4) Etoposide ("VP-16") is also an plant alkaloid that has similar effects to vincristine, it is particularly damaging on the kidneys.
5) Cisplatin is an "alkylating agent" which causes nerve and kidney damage. A similar drug called "Carboplatin" may give good results and is less damaging to these organs.

Adding the "Etoposide" to"CAV" to make "CAVE" helps response, but not overall survival. Alternating Etoposide and Cisplatinum ("EP") with "CAV" is used as a "salvage" regimen for patient's that have failed chemotherapy, with a 50% response rate (that is at least some shrinkage of tumor). Another salvage regimen is"ICE", where an alkylating agent called Ifosphamide (similar to Cyclophosphamide) is added to Cisplatinum and Etoposide. The "Complete Response"("CR"), which means no detectable tumor left at all, is about 30% for initial multidrug therapy, and 15% for salvage therapy. However, patients may still relapse later. Giving long term chemotherapy ("Maintainance Therapy") has not improved survival. CancerAnswers offers an In-Depth transcript on understanding Chemotherapy available through our Web Site. The results of chemotherapy alone show a 10% survival rate at 5 years.

What is the Latest, Effective Treatment for Small Cell Lung Cancer?

The latest effective therapy involvescombining chemotherapy with thoracic irradation to treat both local and distant spread of disease. Chemotherapy alone had an up to 80% "failure rate" for "bulky" disease in the chest, showing the necessity of adding a "consoladative" local therapy like radiation"boost" to areas of residual disease. We do not definitely know that a residual mass in the chest after chemotherapy and radiation is actually cancer unless it starts to grow again; it may merely be scar tissue. Large studies showed that adding thoracic radiation to"CAVE" improved survival for limited stage disease-- on average 25% survival at 2 years was seen with combined therapy, compared to just 8% with chemotherapy alone . A large analysis looking at 13 studies showed there was an overall 14% reduction of death in patients getting combined therapy compared to chemotherapy alone, and this has become the standard of care. For patients with extensive-stage disease, adding thoracic irradiation is not proven to increase survival, but it does reduce local disease in the chest.

Another issue is whether the brain should be "prophylactically " irradiated. This is called "PCI" (prophylactic cranial irradiation") and it's justification is that 80% or so of patients with Small Cell Cancer will ultimately develop detectable brain metastasis . The drawback of the treatment is"neurological toxicity", that is brain damage, in some patients who get it. Normally the dose is 30 to 36 Gray in 10 to 15 treatments to whole brain. Brain damage may appear months to years later in survivors, but the chance of getting it is reduced if the brain is treated more slowly, with lower dose"fractions" each day. Giving PCI reduces "failure" in the brain to just 10%, but proving it improves survival has been difficult. Nonetheless, in some studies the ONLY patients who were long term survivors were ones that got PCI, so it is still recommended today in patients who have a complete response to their disease in the chest. The actual treatments are painless, patients may get some ear or scalp irritation and have hair thinning (it usually grows back). Patients are often quite tired when getting brain irradiation. The current thinking is that PCI is appropriate for patients with limited stage disease who have a good response in the chest.

The very best results for Small Cell Lung Cancer have been obtained with the most radical treatment, devised by Dr. Turrisi (well known in the field). He gives patients high dose Platinum (60 mg per square meter of body area) on days 1 and 22 of each cycle, and Etoposide (120 mg per square meter of body area) on days 4,6,8,25,27,29) will giving CONCURRENT (at the same time) TWICE PER DAY thoracic irradiation (at 1.5 Gray per fraction to a total dose of 45 Gray). PCI is given to all complete responders, to a dose of 24 Gray. Dr. Turrisi's results showed a complete response in 94% of patients with limited stage disease, and more than half of patients had no detectable disease at ~4 years! This shows how far we have progressed compared to 2% survival at 4 years for these patients 30 years ago.

What About Advanced Small Cell Lung Cancer?

When Small Cell Cancer is extensive, and fails to respond to chemotherapy, it will spread through the body. The objective then is no longer cure, instead "palliation" (meaning relief of pain and other symptoms). The patient would be made as comfortable as possible, and narcotic medicines like morphine (which Osler called "G-d's own medicine) should never be withheld for fear of causing"addiction" . Importantly, Radiation Treatment can help relieve chest pain, bone pain, airway obstruction and coughing up of blood in over 80% of patients. It is also useful for reducing the symptoms, and even extending survival, in patients with spread to the brain. Sometimes radiation therapy is used as an emergency measure when the cancer spreads to the spinal column and threatens to cause paralysis by pressing upon the spinal cord. Any patient with lung cancer who experiences new weakness of the extremities, numbness, or loss of bowel or bladder function must be brought into the Emergency Room immediately to see whether the tumor is compressing the spinal cord causing these symptoms. Up to 60% of new back pain in a cancer patient is caused by spread of cancer there. The patient is given a painless Magnetic Resonance Imaging (MRI) scan to check for "epidural spinal cord compression". If this is caught early, and treatment is given, permanent paralysis may be prevented. It is unfortunately uncommon to reverse symptoms of paralysis once they have set it, however, so quick recognition is essential. Another syndrome that lung cancer patients may get is called"Superior Vena Cava" or "SVC" syndrome; this is from the tumor pressing upon the blood supply to the heart, causing swelling of the face and arms, with shortness of breath. This can be relieved rapidly by local radiation treatments, and does NOT mean that the patient will necessarily do worse than those patients without this syndrome. It is common with Small Cell Lung Cancer, since that is a disease mainly of the center portion of the chest.

As mentioned, radiation treatment can be very helpful for metastatic lung cancer. A relatively new method of radiation for spread to the brain (one of the most common areas of spread) is"Stereotactic Radiosurgery", where multiple beams of convergent radiation are aimed onto the area(s) of spread in brain, in a single painless session of one afternoon. This is usually followed by conventional External Beam Radiation, since we presume there are other involved, but undetected, areas of brain spread. The advantage of Stereotactic Radiosurgery is that it can give a very high dose of radiation to areas of brain metastasis, and possibly enhance survival for these patients, without the risk of an open brain surgery from a neurosurgeon. CancerAnswers has a transcript on In- Depth Symptom Relief available through our Web Site.

Conclusion

The patient with newly diagnosed Small Cell Lung Cancer should not rely on any one therapy, but instead should use a combination approach to maximize the chance for success. Specifically, besides the conventional medical therapies mentioned above, consider the use of a non-toxic, not over-expensive alternative therapy that you believe in, a program of spiritual renewal, "mind over cancer', nutritional therapy and exercise. Keep the most positive attitude possible-- research has shown this to be an important factor in survival. Using a true "multi-modality" approach will give the confidence that you have done everything possible for a happy outcome, and certainly improve the current quality of life.

In conclusion, new techniques utilizing combined radiation therapy and chemotherapy are showing better survival rates than ever before for lung cancer from muscle, cartilage or fat, and Bone Scan, as is done with breast cancer, may be reasonable so that later bone scans can be compared to it. For Small Cell Cancer spread to bone, the metastasis are usually and . The higher the radiation dose to the chest (to a point), the more success was seen in controlling disease there. An optimal dose was found to be about 50 Gray, with 40 Gray to the original area of disease and a 10 Gray . If cure is the objective, consider getting treatments at a University Academic Center and joining ongoing research trials which offer the latest therapies. Know that in joining a trial, you are giving up control of the treatment you will receive, but most new trials offer at least the standard treatment as a baseline. The future has never looked brighter for Small Cell Lung Cancer patients.