Hope For Cancer

The utilization of more than one therapy to battle cancer has been the direct cause for the overall increase in survival rates we have seen in the past 2 decades. In the early 1970’s, the overall survival at 5 years for newly diagnosed cancer was 50%; in 1997 it was 70%. This dramatic improvement (which excludes skin cancer since it is the most common type of cancer and so readily curable in its early stages) is mostly attributable to today’s cancer doctors appreciating the benefit of combining our most effective treatments for aggressive disease. This appreciation arose from research oncologists conducting Clinical Trials where they examined the results of using one therapy (”Monotherapy”) as opposed to several therapies (”Combination Therapy”). These results were published in the Oncologic literature over the past 2 decades, and excitedly talked about at Oncologist’s conventions.

The main thrust of this recent research is to try to generalize the principles of Combination Therapy, where they have proven successful, to cancers that remain difficult or seemingly impossible to cure. This transcript will examine the fundamental reasons why cancer often responds to Combination Therapy, how that therapy has been used successfully for particular cancers in the past 2 decades, and what the Latest Effective Combination Therapy is for each major cancer today. We will also examine the side effects (”toxicity”) of aggressive Combination Therapy, showing that it may represent “overkill” for easily curable cancers, and thus is reserved for necessary situations. These situations are those where Monotherapy frequently fails, or has unacceptable side effects (such as mutilating surgery). Happily, today’s patients have more hope for survival than ever for many cancers, since Combination Therapy is becoming more accepted, more refined, more widely available and less toxic. Finally, we will see that some form of “Combination Therapy” is practicable for all cancer patients, both in helping treat a cancer, preventing future cancers, and enhancing overall quality of life.

Combination Treatment will commonly utilize all three modalities of Surgery, Radiation Therapy and Chemotherapy to annihilate tumor cells, as well as Alternative Therapy to boost immune function and overall quality of life for the patient. If the tumor is hormonally responsive, then Hormones can be used to shrink it or help prevent relapse. In the settings of Clinical Trials we are using Immunotherapy, Gene Therapy, and Bone Marrow Transplant as part of new Combination Therapy regimens.

There are basically three causes (”etiologies”) of cancer symptoms. The first is the cancer itself — by definition a malignant tumor can spread to anywhere in the body. This means than any of the body’s numerous systems may be affected. It is unusual to cure cancers when they become widespread(”disseminated”) although there are notable exceptions (e.g. choriocarcinoma, germinoma, thyroid cancer, leukemias). In general, organ cancers (e.g. lung, liver, esophagus, stomach, pancreas, colorectal, kidney, prostate, bladder, breast) have particular ability to spread(”metastasize”) to“distant sites” and cause symptoms there. The cancer causes symptoms by“invasion” both locally (the site of the“primary tumor” ) and distantly (the“metastatic sites” ). This invasion may be into lymph glands, which are normally pea-sized filters for blood serum; they interconnect to “lymph channels” to return the purified serum to the bloodstream. The lymph glands (”nodes”) normally contain white blood cells, when they are invaded by infection or cancer they can swell to large sizes (”lymphadenopathy”) and press on neighboring structures. Cancer can directly “eat” through organ walls(”perforation”), causing spillage of their contents. This may lead to infection such as “peritonitis”(internal abdominal infection from bowel contents leakage),“mediastinitis” (from leakage of food and bacteria into the center of the chest) or “cutaneous emphysema” (air in the lung leaking out through a hole into surrounding tissues). Also, a growing tumor can block off (”obstruct”) hollow organs, such as the esophagus, larynx, lung, intestine, colo-rectum, bladder and cervix. This obstruction may lead to malnutrition, breathing difficulty (”dyspnea”), trouble passing urine(”voiding”) or stool (”defecation”) . Furthermore, cancer can invade nerves, causing local pain, or enlarge organs (i.e. “Hepatomegly” –liver enlargement , “Splenomegaly” –spleen enlargement) and exert pressure on their nerve-rich capsules, causing pain. The bone may be invaded leading to“pathologic fractures” in weight bearing areas, or the brain leading to“neurological symptoms” (e.g. seizures, coordination, motor and sensory problems, judgment and memory lapse). The cancer can invade the bone marrow causing diminution of normal blood cell output (“erythrocytes”[red cells], “ leukocytes” [white cells], and “platelets” [fragments used for clotting]. The tumor itself may produce unusual biochemical substances leading to remarkable effects from so called“Paraneoplastic Syndromes” (”PNS”) . These effects include change of skin color, spontaneous clotting of blood in veins (”thrombophlebitis”), imbalance(”cerebellar ataxia”, and metabolic disturbances including changes in blood electrolytes, increased steroid or hormone production or acute weight loss. They are not all listed here since they are varied and rare (about 2% of patients get a PNS). Moreover, the general effect of advanced cancer can reduce a persons appetite (”anorexia”), cause them to become too thin(”cachexia”), fatigued, debilitated, and depressed. Most of these above symptoms have effective palliative treatments.

The second category is that the symptoms can arise from thetreatment itself. Surgery, Radiation, Chemotherapy and Hormones all have Side-Effects (listed in particular Transcripts for specific cancers). These side effects may include skin irritation, pain, nausea and vomiting, bone brittleness, hair loss, and lowered blood counts leading to fatigue and infections, easy bruising and internal bleeding. Drugs may have unusual effects in any given given patient(”idiosyncratic reactions”) which are unpredictable. Undeniably, there have been many cases where the “treatment was worse than the disease”, and the patient not only failed to benefit from the treatment but acutely suffered from it. On the other hand, cancer is usually an aggressive disease, and requires aggressive therapy to have a chance to cure it. We (often) do not know in advance who will benefit from aggressive treatment and who will not. We tend to give the benefit of the doubt in prescribing aggressive therapy. Even comfort care may have unanticipated side effects which distress the patient, and all care needs to be fine-tuned to maximally benefit each patient .

The third category is problems caused by psychological or emotional reactions to the cancer or it’s treatment, often leading to actual physical symptoms (”somatization”) . This is normal for may patients, and is just as real to them as if the symptom(s) had a physical cause . Examples are intense nausea immediately before chemotherapy, severe depression, pain beyond that explainable by the physical cancer, and perhaps some of the cases of pain within phantom limbs (ones that had been previously amputated). These symptoms demand treatment just as though they had “actual” causes, albeit the treatment may be different. The fact is the symptom may have an unrecognized physical cause, or excellent explanation. No patient should have their symptom(s) arbitrarily dismissed by the doctor. This is because “symptoms” are what the patient feels– which is inarguable . On the other hand “signs” (e.g. fever, weight loss, blood pressure) can be measured and confirmed. With increasing diagnostic technology, previous “symptoms” (i.e. abdominal pain) may now be found to have a “sign” (i.e. tumor spread) causing it. Modern psychiatrists are taught to obviate(”rule-out”) physical disease (e.g. pancreas cancer) in patients with new onset depression, by referring them to appropriate doctors.

Additionally, there is the fact that cancer may make worse(”exacerbate”) other unrelated medical conditions, such as a weak heart, diabetes or arthritis. Also, the social, emotional and financial hardships of cancer and it’s therapy must be individually addressed for each patient, by competent and caring professionals.

As we explained above, the main limitation to giving higher dose chemotherapy or moderate dose Total Body Irradiation to kill cancer is Bone Marrow Suppression. Patients who get chemotherapy often have a significant LOWERING of their blood counts; the lowest counts (called the “nadir” ) are usually about 18 days after each “cycle” is given. Then we (hopefully) expect a brisk recovery over the next 7 days, so that by 30 days after administration of a chemotherapy cycle blood counts should return to [near] normal. This is why conventional chemotherapy is usually given in cycles ONE MONTH apart, to allow for Bone Marrow Recovery. Sometimes, the marrow does not recover well, and this explains why oncologists are so adamant about getting a “Complete Blood Count” (”CBC”) prior to giving more chemotherapy. We are particularly interested in whether the Red Blood Cell count is at least 10.0 grams of hemoglobin per deciliter, the Platelet Count is above 100,000 and the “Absolute Neutrophil Count” or “ANC”– (a type of White Blood Cell) is over 1,000. If not, further chemotherapy will commonly be suspended until the “counts”recover. While the fast majority of patients will have a complete bone marrow recovery with conventional doses of modern chemotherapy, some will have a “delayed recovery” lasting month or even years– a consequence of killing some Stem Cells in the marrow. Very rarely, some patients will apparently have all their Stem Cells killed and go on to total “aplasia” — no new blood cells being formed whatsover. This will obviously be fatal if the bone marrow cannot be replaced (”reconstituted”) using someone else’s(”donor”) bone marrow.

It became apparent, in the 1970’s, that we could give more chemotherapy, and possibly cure the patient, if only we could get around the problem of bone marrow damage. We could also give higher doses of radiation to the whole body– about twice as much (12 Gray versus 5 Gray) if we could replace the bone marrow. It had been known for about 20 years that some patients could survive bone marrow failure from other causes (i.e. a drug side effect or virus) if they got a “Transplant” with another person’s healthy marrow. However, in the early studies, most patients did NOT do well getting someone else’s marrow (unless they were an identical twin) since it did not match the marrow they had lost . As transplant of other organs (i.e. kidneys, livers) developed, new drugs became available to “dampen” the immune response against them, called“rejection” . This re-awoke interest in being able to give a cancer patient very“high dose chemotherapy” — enough to actually kill their cancer, but also enough to kill all their Stem Cells. If the patient’s destroyed (”ablated”) marrow could be replaced by someone else’s after the chemotherapy, it might take(”engraft”) and re-establish new blood cell formation. This was especially appropriate for cancers in which we really wanted to destroy the patient’s native marrow anyway– that is when it was contaminated with cancer cells! Thus the first attempts with “High Dose Chemotherapy Followed by Bone Marrow Transplant for Rescue” were done on patients with leukemias, lymphomas and myelomas which dwelt in the bone marrow. Although some patients were cured (~20%) in the 1970’s and 80’s, the main problem for getting higher cure rates and extending the use of Bone Marrow Transplant to other cancers was two-fold. The first problems was that some cancer cells might persist in the body even after high dose chemotherapy– especially for cancers that had already been exposed to chemotherapy and developed a resistance to it. The second was a problem of“rejecting” the transplant, called “Graft Versus Host” (”GVH”) Disease . This was a unique form of rejection, since the patient’s native immune system had been destroyed by ablating their bone marrow. Instead of their body rejecting the transplanted bone marrow, in Graft Versus Host Disease THE NEW MARROW REJECTS THE BODY IT WAS TRANSPLANTED INTO! Every cell in the body has particular protein markers(”antigens”) on its surface to identify it as a member of that unique body, and not someone else’s body or an animal or vegetable. This is what normally stimulates to immune system to recognize and destroy foreign tissue. With Bone Marrow Transplant from another Donor, the patient’s native immune system is dead– they have lost “immunocompetence” . Instead, the immune capability resides in the Transplanted Marrow, which identifies THE BODY as foreign and seeks to destroy it. As will be discussed, newer drugs to“immunosuppress” the transplanted marrow can usually alleviate Graft Versus Host Disease, and allow patients who would previously have died of it to survive.

Besides giving higher doses of chemotherapy, we could also give higher doses of “systemic” (whole body)radiation if we could get around the“dose limiting toxicity” — that is bone marrow destruction. With particular cancers (i.e. lymphoma, myeloma) some cancer cells often will spread to areas where there is poor blood supply or protective membranes exclude chemotherapy. These areas (i.e. brain, spinal cord, skin, testicles) are called “sanctuary sites” . Putting enough drug into the bloodstream to properly diffuse into these sanctuary sites would cause other serious toxicities (i.e. to lung, liver and heart) which still limit the amount of chemotherapy that can be safely given– even with a Bone Marrow Transplant. Gamma Radiation(”photons”) of high energy (i.e. over 10 Megavolts) travels right through the body, killing cancer cells in all the sanctuary sites. Thus, givingTotal Body Irradiation (”TBI”) complements high dose chemotherapy; both kill cancer cells and destroy the bone marrow (which may itself be infested with cancer). If we successfully replace the Bone Marrow Stem Cells, and they start growing (”engraft”) on the bony spicules inside the marrow cavities of bone, they will produce new blood cells. We will then have been able to give higher doses of cancer cell killing(”cytotoxic”) therapy– and have a better chance at curing the patient . Importantly, to “Transplant” Bone Marrow or the Stem Cells which reconsitute it, we DO NOT NEED TO STICK THE NEW MARROW INTO THE PATIENT’s (recipient’s) BONES. Instead, we need only inject it into an an arm vein and the Stem Cells WILL FIND THEIR OWN WAY BACK INTO THE BONES TO RE-ESTABLISH THEMSELVES . Thus “High Dose Chemotherapy” (and possibly Total Body Irradiation ) followed by a “rescue” with“Bone Marrow Transplant” has become the“Latest Effective Therapy” to cure a variety of cancers.

In the past 2 decades, there have been exciting developments in Radiation Therapy based upon both new technology and a better understanding of radiobiology. These developments offer new hope for previously impossible cases, and are helping extend survival from cancer today. A look at these areas is enlightening:

Brachytherapy is useful to give high doses to local areas, while sparing the surrounding tissue. It is often combined with External Beam to succeed in giving a very high dose to the tumor proper, but a more moderate dose to areas peripheral to the tumor (where cancer cells may have escaped to). The larger a tumor, the greater amount of radiation is required to destroy it. Often, for a few clumps of escaped cells outside of the immediate tumor area, a much smaller dose of radiation may be all that’s needed. Brachytherapy in combination with External Beam is standard for cervical and uterine cancer, and may be used alone with early vaginal cancer. It is useful for shrinking tumors of hollow areas, such as the esophagus and airway tubes (”bronchioles”). It is also used on eye tumors (”choroidal melanoma”) as the therapy– instead on removing the eye (”enucleation”). Brachytherapy always used to take at least a day for it’s “application” time, but new High Dose Brachytherapy (”HDR”)

Hyperfractionation– Recall that the dose of radiation given to an area will be limited by the normal tissue tolerance, which varies. Also, that concerning late effects are less if smaller “dose fractions” are used for each treatment. The idea of Hyperfractionation is to give more treatments with a lesser dose for each one, which not only decreases the risk of late effects, but actually allows more total dose to be given (and so a better chance of tumor control). In practice, cancers that have a rapid growth rate get more benefit from hyperfractionation than those with slow growth rates. The patient must come into the Department twice each day (usually 6 hours apart) for treatment, which is inconvenient. However, the increased rate of control for certain cancers (e.g. head and neck cancer) can increased by up to 15% with hyperfractionation, which may make the inconvenience worthwhile. Giving more than once daily treatments with full doses each time is called “accelerated hyperfractionation” and definitely helps control fast growing tumors, but the acute effects can be too uncomfortable to tolerate. The most aggressive protocols (new studies) using radiation now often have an “arm” (portion) of patients getting hyperfractionation, to see how much it helps. Interestingly, brachytherapy is a form of hyperfractionation, since it essentially breaks the treatment into infinitely close together smaller doses.

Hyperthermia– increasing the temperature to the area to get radiated has been shown to increase the effectiveness of radiation cell killing. This is though due to certain proteins in the cells which help protect against radiation, but are inactivated via heating. The temperature needs to be raised about 7 degrees over normal body temperature, which can be done with a heating pad (for skin) or by using microwaves (for deeper tissues). Early studies showed only definite benefit for tumors involving the skin (as advanced breast cancer often does), the main problem with deeper tumors seemed to be inadequate and uneven heating. It has long been known that some cancer patients who got high fevers experienced a remission from disease; new studies are re-examining heating.

IORT (”Intra-Operative Radiation Therapy”)– surgeons can often see tumors when the patient is opened up at operation, and that might be a perfect time to give a focused radiation treatment! New operative suites at Academic Hospitals have an External Beam Machine delivering electrons right in the operating room, so can shine a high dose radiation beam on the tumor proper during surgery. Of course, high doses at one time can lead to greater late effects, and it is not practical to keep opening patients up to give radiation treatments! However, it has been found that one moderately high dose treatment (i.e. 20 Gray) using IORT seems to help survival in many organ cancers without undue late effects. Particular examples are pancreas, liver, and stomach cancer; we are now looking at many surgical cancer situations that may benefit from IORT. 5) Neutrons– and other heavy particles (i.e. helium or metal ions) can be focused into a high radiant energy treatment beam, and obliterate cancers. These are called “high linear energy transfer”(LET) radiation and do not have a dependence upon oxygen that conventional photons have. Several major Universities in the U.S. built machines to give high let radiation to cancer patients, but enthusiasm has declined. The reason is that that slowly dividing normal cells are obliterated by this treatment, and so the Late Effects are much greater. Nonetheless, neutron therapy has achieved success in slowly growing salivary gland and spinal cord tumors, but is still hard to obtain and very expensive.

Stereotactic Radiosurgery– means aiming multiple photon beams at a patient in a single treatment session to destroy a tumor. The risk of late effects is reduced by using these “multiple convergent beams”, since each area of normal tissue that is around the tumor gets only a very small fraction of the dose the tumor gets. To date, stereotactic radiosurgery has been used for brain tumors, since the head can be kept immobile in a “halo”, and no movement is essential for the accuracy of the treatment. The patient comes into the the hospital, has a “halo” (frame) fitted on their head, and gets a CT or MRI scan. They wait in their room, while the neurosurgeon, radiation oncologist and radiation physicist devise a “treatment plan” by using a computer that keeps track of the beams in 3-dimensions. Several areas may be treated in one afternoon. The patient is called, set up in a modified LINAC (or sometimes a specially designed Cobalt-60 unit called a “Gamma Knife”) and the painless treatment is given. The halo is removed, but patients are often kept overnight for observation, and go home the next day. This is a major improvement over having to go through open brain neurosurgery (”craniotomy”) to remove a metastatic brain tumor, or a brain tumor which has relapsed after regular External Beam Treatment. Some facilities routinely use stereotactic radiosurgery as the “boost” after External Beam; it is easier and safer than surgically implanting radioactive rods into the brain to boost External Beam treatment as used to be done. New efforts are underway to utilize stereotactic radiosurgery for other body areas.

Whole Body or Hemibody Radiation– Normally our ability to give radiation to large areas of the body is limited by the normal tissue tolerance. We can often give a small portion of an organ(s) high dose, but will cause total organ failure if we treat the whole thing. Whole body radiation must either be relatively low dose of superficial to avoid excessive damage. In preparation for bone-marrow transplant, a beam of photons may be used (usually in 5 – 6 treatments) to obliterate the existing bone marrow, blood cells, and (hopefully) cancer cells. This is done with a high-energy LINAC, a plexiglass “scatter” screen is put front of the patient to boost skin dose (recall that high energy beams poorly treat skin). This would be lethal (owing to destroying blood forming capacity) if a transplant were not given afterward to reconstitute blood forming ability. However, it shows extremes we can go to for killing cancer cells, so long as we can still save the patient. For certain very widespread leukemias involving on the skin (”mycosis fungoides”) a beam of electrons can be used to treat the whole skin surface to cure disease.

Hemibody Radiation– For patients with advanced cancer involving many areas of bone, quick relief can be gotten by a low dose (i.e. 8 Gray) of radiation aimed at one-half of the body, so called “Hemi-Body” therapy. This is done is a single session and takes only a few minutes of the machine actually being on. It’s main side effects are nausea (which can be controlled with medicines) and lowering of blood counts, but is is normally effective palliation. Wide areas of radiation may succeed in putting chronic lymphoma or leukemia patients into remission, or even possible cure. This is owing to tendency of certain white blood cells to undergo bursting (”apoptosis”) if treated with relatively low dose radiation.

Combination Therapy– means using radiation as one of several “modalities” (i.e. surgery, chemotherapy) when treating cancer. Many new strategies using combination therapy are in current testing, in clinical trials. It makes sense that radiation is a local, or at best regional, therapy– and something else such as hormones or chemotherapy may kill distant cells which have escaped from the main tumor. These cells are often too small to be detected(”micrometastasis”) but we know the are they in some patients who relapse years later in distant areas (such as a breast cancer though cured which reappears in bone a decade later). Radiation may be given prior to, during (IORT) or after surgery, and also scheduled in many ways with chemotherapy. Combination therapy has dramatically raised cure rates for many childhood cancers, and improved the results for adult organ cancers (i.e. stomach, esophagus, pancreas). Although side-effects tend to be greater with combination therapy, the increased cure rates are worth it to many.

There are basically 2 ways of increasing immune capability– we can either confer“passive immunity” or stimulate“active immunity” . When children nurse breast milk, they receive antibodies from their mother which travel (undigested) into their bloodstream. This confers upon the infant immunity against those germs that the mother is immune to– but only until the child is weaned. This “temporary” immunity is basically being borrowed from someone else, without stimulating the child’s own immune system, and so is called “passive immunity” . If an adult is exposed to Hepatitis-A at an unsanitary restaurant, they go to their doctor for a shot of “gamma globulin” – that is pooled antibody from people who have successfully fought hepatitis- A in the past. This “passive immunity” is enough (if given at the right time) to kill the hepatitis-A germ in our exposed adult. After a few weeks, this temporary immunity will be lost, so if the adult is exposed again they will require another dose of gamma globulin.In contrast, when a child receives vaccinations (e.g. polio, mumps, measles, tetanus) they are being exposed to either a killed germ or a weakened living one. This stimulates their immune system to recognize that germ, and start to produce protective“antibody” against it. The T-helper memory cells can recall for years, or even a decade, what that germ’s protein coat looked like, and what the right antibody was to combat it. Since we are stimulating the child’s own immune system, this defence is called “active immunity”, and will be long-lasting. As adults, if we sustain a deep injury with a soiled object, and we have not had a tetanus shot in ~10 years, we are given “tetanus immune globulin” to confer passive immunity for the current injury, and also “tetanus toxoid” to stimulate active immunity for the future. Thus a person may receive both types of“immune therapy” . Immune therapy may be very “specific”, only meant to combat one type of germ, or it may be “general”, to boost the entire immune system to a higher level of functioning. Adjusting the immune system’s functioning, up or down, is called “immune modulation” . If one removes immune system cells and stimulates them in the laboratory to become more effective against a particular antigen, this is called“Adoptive Immunotherapy” .

Understanding how immune therapy works for germs also helps us understand it’s use for cancer. Passive, Active, and “Adoptive” immunotherapy can be utilized to help cure cancer . An example of using passive immunity would be manufacturing (”cloning”) monoclonal antibodies to a particular cancer’s protein coat, and then injecting them into the patient. These antibodies would (hopefully) gravitate and join exclusively to the tumor cells, and thus be extremely specific. Once coated, the cancer cells would be easily identifiable as foreign to other WBCs, and be quickly destroyed by an “immunocompetent” individual. Eventually the monoclonal antibodies would be all used up, degraded by the liver, or themselves targeted by the immune system as being “foreign”. Since the patient themselves would not produce any more, this would be temporary, passive immunity.

An example of stimulating active immunity is when the BCG vaccine (used as a test for tuberculosis) is injected in the patient– it prompts a strong, non-specific immune response. We are basically flooding the immune system with a foreign antigen, and it gears both to start producing antibody (humoral immunity) and to engulf the foreign antigen by“phagocytosis” (cell eating– cellular immunity). Fluids around the tumor can actually be dranken up by the process of“pinocytosis” (cell drinking). Thus, the immune system cells can literally gobble up the BCG antigen. The patient’s immune system will remember the BCG vaccine, and if it encounters it again will quickly make antibodies to it– thus it is nearly permanent, active immunity (it is “nearly permanent” since eventually the long lived T-memory cells will die off).

The BCG vaccine, used for bladder cancer, is non-specific, but other tumor vaccines are specific for their particular targets. A classic example of this is the “melanoma vaccine”, made up from the TILs of patients who have mounted a successful immune response to melanoma. If this vaccine is then injected into another patient, it can “teach” their immune system how to fight melanoma– this is stimulating active immunity against the melanoma itself. Theoretically, this treatment should have no significant side effects against any normal cell, just boost the immune response (as seen by the TILs around the tumor).

Adoptive Immunotherapy is used when NK cells or TILs are removed from the region of the tumor, and worked with in the laboratoy. They are given “mitogens” which cause them to divide (undergo “clonal expansion”) as well as lymphokines like interleuken-2 to activate them. Once they are plentiful and active, they are injected back into the patients tumor and/or bloodstream, where they will hunt down cancer cells and kill them. This is then using a combination of natural active immunity (the patient’s own response to the tumor) and passive immunity (artificially multiplying and implanting an immune response) to treat cancer.

The main drawback of all of the above therapies is that their effects tend to be temporary and non-curative if used alone.Cancer cells have a nascent genetic “intelligence” which allows them to overcome therapies which should theoretically decimate them . Of course, billions of cancer cells are killed by surgery, radiation, chemotherapy, hormonal therapy, and immunotherapy, but the problem lies with those few that remain, and are the strongest and best able to re-establish the tumor. We previously said that immune therapy is much more successful at killing small numbers of individual cancer cells than attacking large tumors. It is the principle therapy in killing “micrometastasis” of tumors prior to seeding the cancer to distant body areas. The current key to cure cancer is by using MULTI-MODALITY therapy, that is attacking the cancer from many different vantage points simultaneously, not allowing it time to develop resistance. A careful strategy of conventional therapy is required to help ensure that the immune system is not being too supressed to help cure the cancer. No single therapy today cures anything but the earliest cancer . Immunotherapy is crucial in a successful campaign, since it is the ONLY known therapy (within normal tissue tolerance) capable of annihilating the last, stongest, cancer cells.

As is evident from the above discussion, hormones stimulate the origination and propagation of certain cancers by giving a message for cells to reproduce, including cancerous ones. Preventing hormone release by destroying the pertinent gland, or giving counter-acting acting hormones thus turns off the message for these cells to divide. Unfortunately, once a cancer starts, it is rare to be cured by hormonal shutoff alone, but it is often slowed down by removing the stimulating hormone . However, newer studies are showing that appropriate “hormonal therapy” may help cure early cancers in conjunction with other treatments, or extend life in advanced cancers. Since hormones are naturally occurring substances that deliver specific messages, we often expect less side effects (”toxicity”) than other conventional treatments. Although hormones do not have the poisonous side effects of excessive chemotherapy or radiation, they do have side effects when adjusted (”modulated”) to help a cancer patient, as discussed below.

What are the Hormonal Adjustments used in Cancer Therapy?

There are basically 3 ways of modulating hormones– by doingsurgery to remove the hormone producing gland, by givingradiation treatments to the gland to lower hormone production, and/or by givingdrugs which either counteract the cancer-stimulating hormone (work in opposition to it) or damage the glands ability to produce the offending hormone. Drugs are being used more for this as they are discovered.

Surgery is the oldest therapy for modifying hormones, and is still done (though not as frequently as in the past). The surest, simplest way of modifying the amount of testosterone a man in making is by cutting off his testicles(”orchiectomy”) . This is often the least expensive way and least dependent upon the patient following future instructions. Note that the actual operation preserves the scrotal sac, the testicles are cut out and plastic or metal “balls” can be sewn into the sac to preserve the appearance and weight of testicles. The surgery can be done under general or spinal anesthesia. The operation takes only an hour or so, with about 3 days recovery time. There is 1% chance of operative death, and 10% risk of infection or other complications. Obviously, a man will be rendered infertile (”sterile”) and lose libido immediately. The biggest problem with castration alone for reducing testosterone is that some androgens (about 5%) are still made in the adrenal glands and body fat. Thus, a prostate cancer can continue to grow under some androgen stimulation, albeit more slowly. Another problem is the psycho-social issues involved in being castrated. Thus male castration alone is seldom used today for prostate cancer, although it was common in the past.

Female castration can also be done by removing the ovaries (”oophorectomy” ) under general or spinal anesthesia; an incision is made into the lower abdomen and the uterus and fallopian tubes are usually removed also. The complete operation is called “Modified Radical Hysterectomy with Bilateral Salpingo-Oophorectomy” or “TAH-BSO” for short. There is about 2% operative death rate, 10% infection rate, and 10% risk of other serious complications including heart attack, stroke, or blood clots in the lungs (”pulmonary embolism”). Recovery time is about 1 week, with the tissues being 75% back to normal strength at 3 weeks; at this point heavy lifting is again possible. The operation was commonly done for cancers of the breast, uterus and ovaries, with the primary aim of reducing estrogen production. Obviously, it induces an immediate menopause with mood changes, hot flashes, and long term bone weakening and heightened risk of heart attack. The main problem with female castration alone is similar to that of male castration– the adrenal glands and body fat continue to produce estrogens. If additional drugs are not given to block this other estrogen, the cancer will continue to be stimulated, albeit more slowly. Again, female castration is seldom used alone today for estrogen-sensitive cancers.

Another gland destruction which can reduce both male and female hormones, and relieve pain from advanced cancer is“pituitary ablation” . Ablation means destroying the gland, and it can often be done by inserting an instrument up through the nose, breaking through the thin bone at the base of the midbrain, and mashing the pituitary. This procedure is called a “trans-sphenoidal pituitary ablation”, and is relatively safe. Complications include destruction of needed pituitary hormones (i.e. thyroid hormone and adrenocorticotropic hormone) which will require replacement therapy. Problems with this operation include an infection risk of 5%, and a 10% risk of blood clots, bleeding, or drainage of the brain-cushioning cerebral-spinal fluid

(”CSF”) out of the nose (”rhinorrhea”). Besides for the latter problem, the risks of doing an open brain procedure (”craniotomy”) with with neurosurgery are about twice as high. In practice, pituitary ablation today is reserved for tumors of the pituitary unresponsive to radiation, or possibly for severe pain from metastatic cancer.

Another hormone producing gland that is surgically removed for treatment is the thyroid– the operation is called a“thyroidectomy” and is done under general anesthesia. It is important to remove and re-implant the four parathyroid glands, so that parathyroid hormone continues to be produced– these are often placed into the forearm. The operation carries a 2% death risk, and 15% risk of complications including infection, blood clots, heart attack, stroke or pneumonia. Obviously, thyroid hormone (thyroxine) will need to be forever replaced, by fortunately it comes as a simple pill taken daily. If the lower thyroid is also removed (for medullary carcinoma of the thyroid) calcitonin may also require replacement, it comes as an injection (”Calcimar”) which can be given under the skin several times per week.

For “insulinomas” and “glucagonaomas” of the pancreas, “gastinonomas” of the stomach , “vipomas” of the intestines, and “pheochromocytomas” of the adrenal glands, simple surgery to remove the hormone producing tumor is usually curative. Hormone levels should be carefully monitored afterwards by an endocrinologist, with appropriate replacement therapy if they drop too low.

Gene Therapy simply means artificially changing the genetic information in a cell to alter it’s functioning. The cell may be changed temporarily or permanently. The technology relies upon“genetic engineering” ; that is being able to tinker with the genome. A main problem was how to get foreign DNA into a cell, since they are protected from such large molecules getting in by their cell membranes. In the 1950’s it was found that genetic information could sometimes be transfered from one cell to another by soaking them in a solution of calcium chloride, which opened up “pores” within the cell membrane. Another method was “electroporation”, meaning giving a small electrical shock to the receiving cell to increase it’s membrane permeability. The problem with these techniques was the difficulty in transfering large pieces of DNA, and how to get the new DNA into every cell. Other challenges including getting the DNA specifically into the cells we wanted to treat, getting the new gene(s) into the right place in the “transduced” cell, and getting the new gene(s) to turn on (and stay turned on!). Sometimes the unhealthy human cells were removed from the patient and the DNA transfer was done in the laboratory, a technique called “in vitro” (in glass). The cells that has successfully taken up the new DNA could be isolated and then re-injected back into the patient. The other option was to do the gene transfer within the patient themselves, by directly injecting the with the new DNA carried by a “vector” . The most effective vectors were found to be stripped-out viruses, since these naturally bound to human cells and injected their foreign DNA into them. Placing the new genes directly into the patient is called“in vivo” (in life) gene therapy.

What is Gene Therapy Cont.

It was found that viruses were constructed out of a protein coat surrounding a small amount of DNA. The virus had an actual injection system whereby it could land on a host cell (it has little “legs” making it look like a lunar lander) poking a hole with a hollow tube through the cell’s membrane. Once “docked” onto the host cell, the viral DNA is injected into it. The DNA may just float about in the cell fluid (”cytoplasm”) or may insert itself into the host DNA. Empty viral protein “capsules” could be stuffed with custom DNA and let loose to transduce this DNA into the target cell. Furthermore, certain types of viruses had a predilection to latch on to particular body cells. For example, adenovirus tends to go the lung while hepatitis virus attatches to liver cells. Thus, we could get at least some “specificity” to correctly target the modified viral DNA to the diseased cells.

A further way of getting new gene information into cells using viruses is by linking the information to a class of viruses called “retroviruses”, which include the deadly HIV (AIDS causing) virus as well as less harmful mouse (”murine”) viruses which can be used for therapy. Transfering genetic material this way is called “In Vivo Gene Therapy”, meaning instilling the gene via a “living” entity directly into the Human body. The gene we want to transfer can be “spliced” into the retrovirus, which has the ability to enter a Human cell and integrate directly into the Human genome! This exact capability which makes retroviruses so dangerous also makes them extremely useful tools for gene therapy, as we will see later with specific examples.

On recent idea of a way to get a new gene into a cell is by encapsulating them in a “liposomes”, which are basically storage sacs which float about in the cell cytoplasm to store fats, enzymes, proteins, drugs, or whatever. They appear under the light microscope as little “bubbles” within the cell fluid, and have the ability (sometimes) to pass through the normally poorly permeable cell membranes. Cell membranes have to be very selective in what they let through, otherwise they would serve no purpose in protecting the cell from the hostile outside world. Apparently, things which ordinarily would be too large to pass through cell membranes can be packaged in real or artifical liposomes, and then induced to enter cells. Once inside, the liposome coating may be broken down by intracellular enzymes, and the contents (such as a new gene) released. It is possible (but far from certain) that the new gene will successfully integrate into the “host” DNA, and start functioning! The chances for this happening are greater if many “copies” of the gene are introduced into the host cell, instead of just one or a few . Much research is going on using liposomes as the transporter.

An important development was the ability to isolate the particular genes we wanted
from a genome which might contain 3000 genes! It was easier to get a small bit of foreign genetic material to penetrate through a receiving cells membrane using calcium chloride or electroporation, than to try to get a large chromosome through. Also, it was much easier to pack a small piece of genetic material into an empty virus shell than to incorporate a large piece. Furthermore, we didn’t want to transfer unwanted genes into our “host” but only ones coding for the specific attribute of interest. The ability to “map” genes to particular chromosomes, and then to actual physical areas on the chromosomes, was crucial to isolating, cutting out and transfering genes. The actual method of localizing genes was called“hybridization”, whereby we would work backward from the product that the gene made, looking in the cell for the“messenger RNA” coding sequence that was coming out of the nucleus to attatch to the cell’s ribosomes (in the cytoplasm). These ribosomes represented the actual “machinery” which translated the genetic message into protein and enyzmes which in turn build a living organism. By examining the RNA, we could elucidate the corresponding DNA sequence that producing it. By synthesizing a radioactively labelled “complimentary” DNA sequence and putting it into the cell, we could see where it migrated and attatched to within the nucleus, and viola, know where the gene of interest was located.

Once the gene of interest was localized, we had to know how to “cut it out” (excise it) so as to isolate it. Fortunately, we discovered that the cell itself produced special enzymes to slice and dice up DNA, and that we could use these enzymes to cut up the DNA for our own purposes. These particular enzymes were called “Restriction Endonucleases”, and more are still being discovered today. They acted as “scissors” for cutting the DNA only in a specific area. Now the DNA is composed of four “bases”, which are Adenine, Guanine, Cytosine and Thymine. Adenine always pairs to Guanine on the “complementary strand” (the opposing strand of the double helix), while Cytosine always pairs to Thymine. It is the varying arrangement of these these 4 simple bases which gives DNA it’s final complexity, and which accounts for the innumberable possibilities– complexity is from the simple, repeated over and over!

The Restriction Endonucleases “cleave” the DNA at a particular site, such as when a Cytosine follows two consecutive Adenines which themselves follow a Guanine. There may be many such sites in a long DNA molecule, and so several Restriction Endonucleases which cut in different areas may be used to isolate a sequence of interest. Even after cutting the DNA up, we still must somehow tease out the piece of it we want. Since the pieces of DNA will have different lengths, they will also have different weights and we can separate them by using an electrical current to drag them along a “medium”, like filter paper or special “agarose gel”. The heavier pieces will move more slowly than the lighter ones, and so can distinguish them by weight (and thus by length). Once collected, we are now ready to put our piece of DNA, with it’s particular genes(s), into a receiving“host” cell. This is called“Gene Transfer”, and results in a new “combination” of genes of genes in the host. Thus the whole process is called “Recombitant DNA Technology”.

The initial uses for this new “Recombitant DNA Technology” was in putting genes that manufactured specific proteins or enzymes into bacteria, to make useful chemicals in large quantities. For instance, it takes many pig (”porcine”) pancreas’ to extract enough purified insulin for diabetics, but simple bacteria (like the E.Coli found in the human intestines) can be modified by insertion of the insulin-producing gene to become factories manufacturing insulin. These bacteria can be grown in large cultures (glass dishes), and the insulin they produce drained off, packaged, and sold to diabetic patients. It turns out to be a cheaper, safer way to make insulin, since there are no foreign pig proteins contaminating it (which can cause allergic reactions). Human Growth Hormone used to be extracted from thousands of dead people’s brain pituitary glands, and was very expensive. It’s a needed hormone for children who lack it, since they will be midgets without it. Recombitant DNA Technology allowed the gene that “codes” for the production of growth hormone to be isolated, cut out of the neighboring DNA, and transferred into bacteria. These bacteria can then produce great quantities of Growth Hormone at much less cost and logistical problems than collecting it from deceased people’s brains. A further use was developing “Oil Eating” bacteria to combat oil spills from tankers. Thus, the basic technology of “Gene Transfer”, at least into bacteria, is already well established and used every day .

The next logical step was using Recombitant DNA Technology in Human cells instead of just bacteria. The idea was to insert a gene to make a necessary enzyme in human cells that were missing them. The lack of an enzyme, caused by a flaw in or absence of necessary genes, is responsible for many “metabolic” diseases. While these diseases are mostly rare, they are often severe or fatal for those afflicted. Examples include Cystic Fibrosis and Adenine Deaminase Deficiency . If we could insert the proper genes into cells lacking them, the crucial enzymes would be produced, and these diseases cured. This was the first real attempt at primary “Gene Therapy”, but proved to be a lot harder than working with bacteria. For instance, it is more difficult to get the new genes into human cells, and to have them “integrate” into the right place in the human genome. With bacteria, we can bombard them with the new genes, see which bacteria take them up and separate them out of the bunch. Then we can induce them to divide to produce new bacteria with the desired gene, and grow them in vast quantities. Trying to put genes into Human Cells is tougher, since we can’t just “select out” the cells which have uptaken the new gene, or cause them to divide and grow more than they ordinarily would. Also, even after we get the new genes into the Human cells, there is no guarantee that they will migrate to the right place in the genome to function properly; they might just lie dormant and do nothing.

Furthermore, even when they do go to the right place, and start working, their action (called“expression” ) may be temporary. For reasons we are still trying to figure out, they may get turned off and quit working, defeating the whole therapy. Moreover, there are safety issues. it is possible that inserting the new gene into the diseased cells will actually turn on an Oncogene or turn off a Suppressor Gene, starting a cancer! Also, if we use “living” retroviruses to transfer genes, they may mutate into dangerous forms capable of “replication”, and actually start a new disease in the Human population! In general, however, this risk is small and the possible benefits of inserting functioning genes into gene-lacking cells cells are great– curing otherwise deadly diseases. The first success has already been seen with this therapeutic gene transfer, for the Adenine Deaminase Deficiency Syndrome.

When the Adenine Deaminase gene is successfully integrated into a diseased child’s genome, the disease is cured. Cystic Fibrosis cells have been “cured” in Clinical Trials, and future possibities include cure of all sorts of hereditary genetic diseases, from hemophilia and Tay Sachs disease to Muscular Dystrophy and Parkinson’s Disease.

The most complex use of Gene Therapy is going beyond replacing a non-functioning gene with a working one– it is actually turning on or off existing genes within Human Cells, or even fixing damaged ones. We are currently mapping the entire Human Genome, consisting of about 3 billion base pairs, to localize the genes for every physical human trait- – eye color, height, fingerprints, inborn diseases, etc. This enormous undertaking will give us a “road map” of all Human genes, enabling us to quickly identify missing, broken or duplicate ones in patients. When we can go into cells and modify the genes at will, we shall have incredible powers to cure disease– and“genetically engineer” ourselves. For example, we will be able to change a person’s height or eye color, cure Down’s Syndrome and maybe regrow amputated limbs or weak organs. We shall likely be able to increase our lifespan by turning off “aging genes”. We will be able to cure most every illness, including any cancer, by merely shutting off the “grow” message in sick cells, and encouraging the healthy cells to grow instead . The possibilities are limited only by our imagination. The usage of them, for good or evil, will surely test the basic nature of humankind.

Obviously, chemotherapy works by killing cancer cells. In our current theory, it seldom, if ever, kills the last remaining cancer cells. Instead, it dramatically reduces the number of such cells, and the body’s immune system “mops-up” those few that remain. This is a paradox, since many chemotherapy agents weaken the immune system, thus compromising it’s ability to recognize and kill abnormal cells. Various agents kill cancer (and normal) cells in different ways, and it is instructive to get a better understanding of this process.

The study of how chemotherapy effects living cells is called molecular biology and this field has exploded with new information in the last 2 decades, as nuclear physics did in the early twentieth century under Einstein. To understand how chemotherapy effects both normal body tissues and cancers, we look at living organisms at their”cellular” level. All living things have as their basic unit the “cell” ; similar cells combine to form “tissues”, and tissues combine to form “organs” . This is analogous to the way in which atoms are the basic unit of elements, elements of molecules, and molecules of compounds. Simple creatures may have only a single cell (e.g. a bacterium or amoeba), while plants, animals and humans are composed of billions or trillions of cells. A spherical piece of flesh 1/2 inch across contains about a billion cells! In our bodies old or injured cells die, while new ones form – this constant process is crucial to continued life. We know that if we give enough radiation to any cell, it will die. To appreciate how chemotherapy works, however, we must look even deeper (smaller) than the cell, at it’s “subcellular” components.

Individual cells were first observed in the 17th century by Leiwenhook, who had invented the microscope. More powerful magnification showed a world of activity going on within cells, the process of “life” . Electron microscopes now show yet more.

The first thing noted was that every mammalian cell had a “membrane” around it, a darkly staining central spot called the “nucleus”, and between the outer membrane and the inside nucleus was “cytoplasm”fluid. Closer inspection showed the cytoplasm to actually be filled with apparent machinery, called”organelles” for small organs. The nucleus was made up of dark staining strands, called”chromosomes”. These chromosomes became especially visible when the cell divided, a process called”mitosis” . Furthermore, each chromosome was a slightly different shape, but they appeared to arrange into pairs at mitosis. Closer study of the chromosomes showed that there were 48 total in a humans, 23 which paired up as “autosomes” and 2 “sex chromosomes” . In females both “sex chromosomes” were called “X-chromosomes” (for their shape), while males had one “X-chromosome” and a smaller”Y-chromosome” . Staining and studying the chromosomes during mitosis was called a “karyotype”, and it was soon seen that various serious diseases corresponded to abnormal chromosome patterns . For example, in Down’s syndrome where severe mental retardation and abnormal features were present at birth, these children were shown to have three Chromosome #21’s (”trisomy 21″) instead of the normal two. In girls who had short stature, webbed neck, and were infertile, they were found to be missing one of their two sex chromosomes (”Turner’s syndrome”). Many such syndromes were found, but not every obviously inherited disease had clearly abnormal chromosomes.

It became obvious that chromosomes controlled heredity, and that one of each pair of chromosomes was inherited from each parent. Chromosomes themselves were found to be composed of thousands of much smaller elements called”genes”, short for “genetic materials”. Somehow, a”genetic code” existed that told the cell how to live, function, and even when to die. This code was “cracked” (to a point) in the 1950’s by Watson and Crick, who demonstrated the model for “Deoxyribose Nucleic Acids” (”DNA”) . These DNA molecules were shown to be twisted into a “double helix” which formed the genes. DNA itself was shown to be made up of a long “sugar” backbone (the “ribose”) and just four other molecules,(the “nucleic acids”). These four molecules (adenine, cytosine, guanine, and thiamine) were paired up on the two “strands” forming each double helix – adenine always paired to thiamine, while guanine always paired to cytosine. The amazing thing was, that the arrangement of these 4 molecules were different in every different gene, made up the genes, and so would determine every physical characteristic of every plant, animal and human! There were found to be about 3 billion “DNA base-pairs” in the human”genome”, different for everyone except identical twins. It was soon seen that damage to these ultramicroscopic (smaller than an ordinary microscope could see) base pairs were associated with every inherited disease known. For the cell to produce new products (”proteins”) the DNA double-helix “unzipped”, and a strand of “messenger RNA” was formed along one DNA strand. This RNA stand then separated from the parent DNA, and traveled outside the nucleus to the cytoplasm. In the cytoplasm exist protein manufacturing factories, called “ribosomes”, which get their message on what do do from the messenger RNA. Proteins and enzymes are then produced, which may utilized inside the cell, or sent outside of it as a “gene product” such as a hormone or antibody. Now we knew that if this process went awry, and DNA was damaged, cell products would be abnormal and disease could result.

One more important facet before describing chemotherapy effects is a deeper understanding of how cells divide. When the cells divided, the double helix of DNA base pairs “unzipped” and doubled itself by forming two new “complimentary” strands, using the two previous strands as a “template” . As mentioned, this process, called “mitosis” for regular body cells, is essential for life, but also for cancers to grow and spread. We know that we all start out in womb life from the contribution of a sperm from our father and an egg (”ovum”) from our mother. To form these “germinal cells” in our father’s testicles and mother’s ovaries (our parents “gonads”), a unique type of cell division occurred, called”meiosis” . For normal cell division, mitosis, the DNA duplicates (doubles), the divides in half, so we end up with 2 identical “daughter” cells(which can each go on to double their DNA and divide again). Each of these daughter cells still retains the contribution of DNA design from both parents, even if the individual is 100 years old. Thus, there is an identical type, and amount, of DNA in every body cell – each cell has within it the information on how to form a whole new body! Now if each parent gave us this type of cell, with a full amount of DNA, we would have enough information for two bodies – not one. Therefore, the “meiosis” process that occurs to make sperm and eggs cuts the amount of DNA in half, instead of ultimately keeping it the same like mitosis. Fascinatingly, the DNA is sliced in half differently for each sperm or egg produced, which explains why siblings look different. As will be seen, the testicles and ovaries are particularly sensitive to chemotherapy damage, and if they are “overdosed” then infertility (”sterility”) will result.

The sperm and egg combine upon the spongy inner lining of the uterus (”endometrium”), re-forming the normal amount of human DNA in this newly “fertilized egg”. From this point on, until the incipient child begins forming their own eggs or sperm at puberty, all cellular division is mitotic, not meiotic. Thus, the normal human compliment of DNA, one-half being from each parent, is restored in every cell division. The fertilized egg starts dividing, forming an”embryo” . At first, all of the cells are the same (”pleuripotential”), but then the genes within some of the cells activate and cause them to change (”differentiate”) from the other cells. Thus muscle, fat, heart, lung, bone, brain, skin etc. form, from these specialized cells. After 8 weeks, the embryo has a heartbeat and is recognizable as a tiny human, and is called a”fetus” .

From the fetal point onward, all the organs are formed, and the merely develop and grow larger.
In womb life, early childhood, and through puberty all of the body’s cells are “turned on” to divide and grow an adult human. The genes exert very exacting control over cellular division, to ensure that it does not run amok. Gradually, certain systems become fully grown, and cell division completely ceases. Other systems will regenerate new cells to replace those that have died as a result of old age or injury, while still others constantly generate new cells throughout life. For example, the brain cells (”neurons”) cease dividing by puberty, and will never divide again in a normal brain. The cells of the liver or skin are capable of dividing to replace injured ones, while the blood cells and intestinal lining are continuously being renewed. As long as tight control is maintained by the genes, everything grows in it’s proper time.

Each of the body’s cells has a specific “cell cycle” related to reproducing, and this cycle may change over time. The cell cycle, and thus division, is controlled by the genes. A cell may spend a prolonged period (or even the rest of it’s existence) in a quiescent period, where it is not reproducing (the “G1 phase”). If the genes trigger instructions for a cell division, the cell starts duplicating it’s DNA (the “S phase”). Once the DNA is doubled, it prepares to divide (the “G2 phase). Then the actual division takes place (the “M phase”) to produce two identical daughter cells. At certain points in the cell cycle, there are “checkpoints” to ensure that the DNA is intact, that is has doubled normally, and that the cell is indeed ready to divide. Each of these division checkpoints is controlled by genes, which should not let the division take place is something is wrong. Normally, this system works with incredible speed and harmony.

Now we have a background to understand what happens to make a cell turn cancerous . Something damages the genes that control cell division, resulting in a cell which divides out of control. That something may be a chemical (”carcinogen”), virus, radiation, or just a random”mutation” (change; deviation) that occurred during a previous division. Anything that damages the controlling genes in a cell can lead to cancer . The genes damaged may be the ones that “check” the cell at the division checkpoints, and so erroneously allow a damaged cell to divide. Alternatively, they may be the same genes that were normally turned on in the womb and childhood, but in adulthood they should be turned off (”oncogenes”) . Another scenario is the damaged genes are ones that normally suppress excessive division (”suppressor genes”) and now the cell divides without regulation. Whatever genes were damaged to cause cancer, it is ultimately a disease of the DNA, the molecules which form the genes. Chemotherapy can damage DNA or interfere with the protein products it produces, either killing a cell or causing it to become abnormal.

At the cellular level, then, chemotherapy either blocks something needed for the DNA to replicate (preventing cell division), or interferes with protein production by disturbing the RNA, ribosomes or their necessary “metabolites”. Since both division and protein production are essential to a cell’s functioning, derailing either effectively kills that cell. In cancer terms, a cell which can’t divide is as good as dead, for it can no longer add to the “tumor burden”. Interestingly, some cells produce proteins which act as local hormones and stimulate their own, or their neighbors division – these are called “autocrine” proteins. These are well described in brain cancer (”gliomas”). Being able to block these autocrine substances will naturally slow cancer replication. Of course, effectively blocking cancer cell division will also impair normal cell division, leading to side effects. This is less problematic when bacteria are treated with antibiotics, since the bacterial ribosomes are different than human (and animal) ribosomes. Therefore, bacterial reproduction can selectively be blocked by targeting those non-human ribosomes, leaving the human ones untouched. The problem in giving chemotherapy is that the DNA, RNA, Ribosomes and major Proteins within cancer cells are virtually the same as in normal cells! Of course, we said their are differences, for the DNA is damaged and abnormal RNA and proteins may be made. However, the differences are slight, often only at the gene level, and our current agents don’t distinguish normal cells from cancer cells at that level. The crude way we do distinguish normal cells from cancer cells is by the rate of cell division, which tends to be faster in cancer cells. Thus, depriving the cells of what they need to divide, or otherwise poisoning the division process, will tend to selectively weed out cancer cells first . Naturally, quickly dividing normal cells (i.e. blood cells, scalp hair follicles, gastrointestinal lining cells) will also succumb, explaining the classic side effects of chemotherapy. However, they can repair damage and heal better also.

The previous discussion also explains the paradox of why more aggressive cancers may actually be more easily cured than less aggressive (”indolent”) ones. Aggressive cancers (e.g. choriocarcinoma, lymphoblastic lymphoma, small cell lung cancer) tend to be quickly dividing and so rapidly killed off by chemotherapy. In contrast, more indolent cancers (e.g. low grade sarcomas, chronic lymphoma, hormone-responsive breast cancer) that are slower growing won’t be killed off much faster than slowly cycling normal cells (i.e. muscle, nerve, fat, bone) and so the chemotherapy will hit the normal cells just as hard. This causes the side effects of the required doses to kill off most all of the cancer cells too hard for the body to tolerate. Enough of the chemotherapy would decimate the cancer, but the patient would succumb also. Thus we are relegated to giving lower doses, which may (or may not) effectively kill enough cancer cells to make a noticeable(”clinical”) difference.

Interestingly, their is a range of sensitivities in the tumor cells (even a single patient in a single tumor). Some will be readily killed by the chemotherapy, but others will live. Even if 95% of the cancer cells are killed by the drug, the 5% remaining tend to be more resistant and require much more drug to kill them, probably more than the normal cells can tolerate. This is called the “Goldie-Coleman” hypothesis – as we are more successful in killing cancer cells, the remaining ones are the most impervious to our treatment . We need to kill the vastest majority right at the outset, since the resistant population can develop over time (much like insects grow resistant to pesticides). This is a major reason for using multiple drugs, and for using multiple therapies such as radiation and surgery together with chemotherapy, instead of waiting until the cancer grows back to try other therapies.

In medical parlance, Primary Prevention means doing things to prevent ever getting a disease, whileSecondary Prevention means keeping a watchful eye for the first signs and symptoms of disease, to catch it early when chances for cure are greatest. Regarding cancer prevention, a combination of both of these strategies is advocated. The precise degree of how much prevention strategy is appropriate will depend on the the person’s “pre-prevention likelihood” of getting a particular cancer. Thus, if breast cancer runs in the family, it is more important to be vigilant in preventing it than if no cases have occured in the family. It obviously makes no sense for a man to take steps to prevent cervical cancer, or a woman penile cancer or even a male child prostate cancer, since the “pre-prevention likelihood” of these diseases is zero. There is little justification is performing rectal exams on symptomless children to look for rectal cancer, since the disease is vanishingly rare in them. Common sense is key! 

Examples of Primary Prevention include:

1) Avoiding Excess Carcinogens- Cigarette smoking causes the same yearly illness that would occur if one nuclear reactor underwent a complete meltdown in every major city every 4 months! (From Manual of Clinical Oncology 3rd ed.) Again, while a rare puff on a cigar or pipe is unlikely to be harmful to health, the practice of daily smoking (or being in close proximity of heavy smokers) carries danger for cancer, heart disease, emphysema, visual deterioration, ear damage in children, and stunted fetal growth if women smoke while pregnant. Also, since tobacco is high in radioactive Polonium, it can cause cancer by this mechanism. Avoiding frequent marijuana smoking is also important to reduce risk of cancer to the mouth, lungs and and voicebox (”larynx”). While one or two 4 ounce glasses of red wine per day may be beneficial in lowering heart disease risk and alleviating stress, excess hard liquor consump- tion (more than one shot per day) raises digestive cancer risk, especially if one also smokes tobacco. Esophagus, liver and pancreas cancer are particularly raised with heavy liquor consumption; 25% of patients who develop cancer of the mouth area will ultimately develop another cancer (”metachronous”) else- where in the respiratory or digestive tracts. About 10% will have another cancer (”simultaneous”) found at the time of their initial evaluation! Dietary fat has been a controversial area regarding cancer development. The newer studies (1999) have disclaimed the old dogma that high fat (over 30% fat in the diet) itself is a major increasor of breast and colon cancer. This was initially based on the theories that fat consumption raises harmful free radicals, and that it slows the movement of stool through the digestive tract allowing more “contact time” between other possible dietary carcinogens (like soot and nitrites) and the bowel wall. While this has been mostly disproven, people who eat lots of fat also tend to eat less fresh fruits and vegetables, and get less fiber. These help reduce free radicals (see below) and also help keep the bowel walls clean. It makes sense for a prudent person to eat a well balanced diet, but not to be fanatical about avoiding dietary fat. After all, it is fat (not sugar!) that makes our diet taste smooth, soft and palatable. We want to avoid excessive burnt foods, pickled foods high in nitrites, and artificial flavors and dyes. This does not mean such foods should never be eaten; merely that they should not be a staple. It is advisable to well wash plant foods to help remove organophosphate pesticides and herbicides that may be linked to increased lymphoma risk. Flushing out our body and bladder with 6 to 8 glasses of water a day halves bladder cancer risk!

2) Vitamins and “Antioxidants”- These are much in vogue in the prevention and popular health magazines. Scientific research has shown we all need to get enough vitamin A and E. These are thought to “scavenge” free radicals that normally accumulate in cells, especially as they age. Recall that these chemicals are thought to damage DNA and increase mutation and cancer risk. Excess vitamin A is poisonous, leading to liver damage, dizziness and senility. It is very important to get enough vitamin C to help cartilage production; however too much is damaging by making the blood too acidic (”ascorbic acidemia”). Vitamin D is necessary for proper bone growth and calcium metabolism, and the B vitamins are crucial for making the insulation material (”myelin”) which surrounds nerves. The “fat soluble” vitamins are A, D, E and K, which is made by intestinal bacteria and necessary for proper blood clotting. Vitamins B and C are “water soluble” so easily flushed out in the urine; they must be constantly replaced. Excess vitamins B and E are less toxic than excesses of other types. Nonetheless, unless a person has a documented deficiency of any of these and is under medical instruction, vitamins should only be taken in moderation. In general, vitamins act as “co-factors” for chemical reactions in the body, but in themselves are not sufficient. We also need to take in carbohydrates, protein, some fat, water, and trace minerals (like chromium, magnesium, and nickel) for vitamins to be absorbed and effective. Standard vitamin pills like Centrum, One- A-Day and Geritol provide these essential trace minerals. Interestingly, we can help prevent certain squamous cells cancers (e.g. of the mouth or vulva) in those predisposed to them by prescribing topical vitamin A (”Tretinoin”) which is known as the popular anti-wrinkle cream. This is called “chemoprophylaxis” and must be done under strict medical supervision. It cannot be used in pregnancy owing to increased risk for birth defects. In some patients with internal cancers, this vitamin A derivative can be given as pills (”Accutane”); this is more risky for side- effects like body swelling and liver damage. Also, Hairy Cell leukemia often will respond to this drug, and new derivatives are being developed for other cancers. Anti-oxidants are an exciting are of research, they are not yet proven to prevent or cure cancer. However, as mentioned vitamins A and E are thought to work (in part) by an anti-oxidant strategy, accounting for there protective effects against aero-digestive tract and other squamous cancers. Free radicals are thought to be a key factor in cell aging and DNA mutation. Normally, we have a mechanism within cells to help scavenge excess free radicals, called the “glutathione reduc- tase” system. This enzyme is lacking (by heredity) in certain people, who seem to have more rapid cellular aging. Glutathione is a sulfur-based enzyme within the cell that looks for free radicals floating in the cellular fluid (”cytoplasm”) and “reduces” them chemically to a harmless state. Interestingly, sulfur-based drugs have been developed as “radioprotectants” to help protect against the damaging effects of cosmic radiation; astronauts carry these on space missions in case of solar flares. Patients who have Glutathione deficiencies have fragile and easily bursting blood cells; the compounds apparently help strengthen cell membranes. A new type of broccoli has recently been developed at Johns Hopkins that has over 20 times the amount of SGA (sulforaphane glucosinolate), you can seen the prominent sulfur base of this compound which scavenges free radicals. It is to be sold under the name “Brocco Sprouts”; it is the first food ever grown specifically to prevent malignancy. Tablets of “SuperOxide Dismutase” are available in Health Food stores, this dietary supplement putatively helps capture excess Free Radical molecules. Tomatoes are high in “Lycopenes” which are thought to help prevent prostate cancer, and possibly other types. Certainly a salad a day may be helpful in preventing cancer, and Alternative Health writings mention many more foods. 

3) Avoiding Excess Radiation is always advisable given the strong mutagenic capability of ionizing radiation, and the DNA damaging capability of Ultraviolet rays from the sun. We avoid unnecessary medical exposures from X-rays unless they can be justified as their benefits outweighing their risks. Over time, living at high elevations or in areas with high natural background radiation may raise risk, although this has never been proven by any study. It is important to check base- ments for Radon leaks, especially in the Midwest U.S.A. and properly vent the basement if these are detected. It is advisable not to sleep in basements in areas with high Radon levels. Tobacco smoke is high in radioactive Polonium, and is another reason why frequent smoking should be avoided. It is prudent, although not of proven danger, to not live very close by power plants or power distribution junctions, especially if there are young children in the home. Electromagnetic fields from power plants, coal emissions (which can have radioactive isotopes), and slow nuclear power plant emissions are all good reasons to avoid living by these generators. The most common type of clearly damaging radiation is from the sun’s Ultraviolet (UV) rays; exposure is directly related to most skin cancer cases. One should avoid whole body exposure to strong sunlight, and use an SPF (”Solar Protectant Factor”) sunscreen rated at least 20. This is especially important for children or those of fair complexion. Recall that excess tanning is is also associated with decreased general immunity and internal cancers too. 

4) Avoiding Industrial Exposures can mean balancing income prospects with safety considerations. An Occupational Safety and Health Administration (OSHA) in the U.S.A. helps prevent debacles seen in the past, like rampant lung cancer in unprotected talc factory workers and leukemias in power plant workers. Recall that while merely living by power lines or plants remains unproven as a cause for malignancy, cancer rates are definitely higher for actual workers in these plants. Workers in the petroleum and organic chemical industries have higher rates of bladder, lung and skin cancers. Pipefitters and Shipbuilders exposed to asbestos have much higher rates of lung cancer, especially if they also smoke cigarettes. Agricultural workers exposed to herbicides and pesticides have higher leukemia and non-Hodgkin’s lymphoma rates. Many examples were given earlier, and the OSHA has done much to help correct this is America. There is an interesting rule of “diminishing returns” in spending money to improve safety. It has been found that 90% of improved safety can be attributed to the first 10% of money spent, and that spending ten times as much will still not completely eliminate the remaining 10% of risk! It is important to try to work in a fundamentally safe industry, and if one must work in a more dangerous vocation, to minimize collateral risks (like tobacco and excess alcohol) to help ensure overall well-being.

5) Regular Exercise and stress reduction are crucial in preventing heart attacks, strokes, obesity, adult onset diabetes, infections, bone density loss, cancer, and other health problems. Exercising to target levels (heart rate of 200 minus age in years) for at least 20 minutes at least three times per weeks is sufficient to confer great health benefits. Among these is immune system stimulation; it is ultimately the immune system which detects and destroys fledgling or residual cancers.

Again, Secondary Prevention is looking for the first signs of a fledgling cancer, and this can either be accomplished by the patient themselves seeing something concerning, this is called “Self Exam”. They can also undergo standard “Screening Tests” as appropriate. While no particular symptom proves cancer (only analyzing a tissue specimen can) there are “warning signs” that should motivate a person to see their doctor, either for cancer or another possible disease. This is especially true if the person it at increased risk for cancer (as described above). For instance, a heavy smoker develops a chronic cough,
or if someone who’s mother died of breast cancer notices a new breast lump, they shouldn’t delay in seeking treatment. Delay in getting diagnosed and treated is the leading reason for cancer deaths, since the majority of cancers can be cured if caught early enough! The “ten warning signs of cancer” listed below are all more likely to be caused by some non-cancerous medical condition, but they all militate for a medical checkup to confirm or deny a possible cancer.

What is the Vulva?

The vulva is the external female genital organ composed of 3 portions- the “Labia Majora,” “Labia Minora,” and “Clitoris.” The skin between the vagina and anus (”Perineum”) is considered an extension of the vulva. The urethral opening for urination is close to the clitoris, in the upper vulvarregion. Thus, the vulva is the vaginal “lips” and surrounding area. A cancer of the vulva is not considered “vaginal” cancer, since it arises outside of the vagina proper and behaves differently, tending to spread to different areas. There is a system of draining channels (”lymph channels”) to drain blood serum from the vulva. The drained blood serum is purified by glands (”lymph nodes”), which are normally pea-sized but swell (”lymphadenopathy”) when invaded by infection or cancer. Specifically, the vulva usually drains first to lymph nodes in either upper thigh (”inguinal nodes”), it afterward may drain to lymph nodes in the pelvis proper (”pelvic nodes”). These pelvic nodes then interconnect (via lymph channels) to those in the abdomen (”paraaortic nodes”); the filtered blood serum is finally rejoins the bloodstream above the level of the heart (via the “left thoracic duct”). The lymph glands, which are normally filled with White Blood Cells, are important as they can act as a conduit for the spread of infections or cancer . Initially, at least, disease of the right half or the vulva spreads to the right inguinal nodes, and that of the left vulva to left inguinal nodes. A cancer is the midportion of the vulva spreads equally to both right and left inguinal nodes. There is some “interconnection” between the right and left lymph nodes, so this rule is not steadfast, but it is useful “clinically” to doctors. Furthermore, the vulva has a rich blood supply and venous drainage, which can also promote spread of disease to anywhere in the body. However, this distant spread tends to occur only long after the areas(”regional”) lymph nodes are involved. The vulva can be removed (”vulvectomy”) which interferes with sexual function, but it is not considered a “vital organ” (necessary to live).

What is Vulvar Cancer?

The vulva is composed of various “cells,” which are intricately combined together into “tissues” which form the “organ” . The vulva contains fat, muscle and skin cells. These cells divide to produce new ones, and grow very rapidly during womb life, early childhood and puberty. In adulthood, new cells are produced only to replace those that die of old age, injury or disease. Normally, division of 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 ofDNA, 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. Vulvar cancer starts in a single 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, vulvar cancer ultimately kills by urinary blockage, debility, anemia, infection, and damage to distant organs like the liver and brain.

How Does Vulvar Cancer Spread?

The most common area for vulvar cancer to start is on the Labia Majora, it is three times more common here than on the Labia Minora. Only about 10% of cases initially involve the Clitoris. When a cell turns pre-cancerous, it may start dividing but stay localized for many years, or even many decades. This is called“Vulvar Intraepithelial Neoplasia (”VIN”) . A portion of “VIN” cases progress to“Carcinoma in Situ” (”CIS”), which is technically the first stage of actual cancer. Only about 5% of VIN cases progress all the way to“Invasive Cancer,” but we don’t know in advance which ones will or won’t. Once Invasive Cancer manifests, it tends to grow for month to years in it’s local area. It then spreads to the Inguinal lymph nodes(”lymphogenously”), usually to one side first. Then it spreads to deep pelvic lymph nodes. Only 4% of patients have pelvic lymph nodes involved(”positive”) in the absence of Inguinal lymph node involvement. The cancer may then track up through the lymph channels to invade Paraaortic lymph nodes in the abdomen. It continue to grow locally to invade the skin, urethra, bladder, perineum, rectum, and pelvic bone . It tends to spread through the bloodstream (”hematogenously”) only late in the disease, mostly to the liver, lung, bone and brain.

How Common is Vulvar Cancer?

There are about 3200 new cases of invasive vulvar cancer each year in the U.S.A., it accounts for1200 deaths annually. Vulvar cancer represents 4% of the total cancers involving the female genital tract (”gynecologic malignancies”). Overall, gynecologic malignancies account for 13% of new cancer cases in American women. Patients with the precancerous VIN condition have are an average of 44 years old. Frank cancer (but not VIN) is rare before age 50, and the average patient is 61 years old. The overall incidence (number of new cases annually) of vulvar cancer is steady. Over 90% of cases are “Squamous Cell Carcinoma,” which originates from the “epithelial” (skin and lining cells) of the vulva (the ones overlying the fat and muscle). About 7% of cases are“Melanoma,” arising from“melanocyte” pigment cells; this has more predilection for spread in the bloodstream.“Paget’s Disease of the Vulva” is a pre-cancerous condition showing on the vulvar skin a red and velvety area, it has an underlying “invasive cancer” in about 2% of cases. Paget’s is a “marker” for the development of another gynecological malignancy (e.g. cervix or uterine cancer) which eventually occurs in 25% of patients with it. “Bartholin’s Gland Cancer” is an “adenocarcinoma” (arises from gland cells) seen exclusively in post-menopausal women (over about age 50) it makes up less than 1% of vulvar cancer cases. Other rare possibilities are“Sarcoma” (from the underlying muscle or fat), “Lymphoma” (from the immune cells in the vulva) or“Basal Carcinoma” (a skin cancer) The treatment for these follows that in other body areas where they are more common.

What Causes, or Increases the Risk for Vulvar Cancer?

As for any cancer, the exact reason why one woman gets vulvar cancer and another does not remains unknown. However, these “risk factors” are often present:

1) Vulvar Intraepithelial Neoplasia (VIN) or Carcinoma in Situ (CIS) may exist for several decades before manifesting as Invasive Cancer, which they only go on to less in less than 5% of patients.
2) Viruses of the Genital Tract — Specifically Human Papillomavirus (”HPV”) which causes genital warts (”condyloma acuminatum”). Around 5% of patients with vulvar cancer have genital warts. Also Herpes Simplex II is also associated with VIN and later Invasive Cancer. These viruses are sexually transmitted(”STD’s”) .
3) Nulliparity means never having had children, about 25% of American women are “nulliparous.” This is a risk factor for breast, uterus, and ovarian cancer too. Menopause at an early age (i.e. the mid 40’s) has a higher risk also.
4) Lower Socioeconomic Status means being poor, especially as a member of a generally poorer group (Blacks, Hispanics, Native Americans). Some feel that the higher incidence is explained by more promiscuity in these groups (more chance of getting a Sexually Transmitted Disease from multiple male partners). It is probable that the poor don’t get medical attention until the disease is further advanced, and have other medical problems associated with this cancer.
5) Other Medical Problems associated with vulvar cancer include being obese, having high blood pressure, heart disease, diabetes, and kidney problems. All of these conditions are related to each other. 
6) Occupation and Environmental Exposure — Women who worked in the Laundry or Custodian (cleaning) Industries have a greater risk, reason unknown.

What are the Symptoms of Vulvar Cancer?

Very early vulvar cancer has no symptoms, as it is too small to cause problems.
1) A Lump or Bump (”Mass”) on the vulva is the most common first sign, it can become a sore(”lesion”) which will not heal and grows slowly over months.
2) Itching (”Pruritis”) and Pain will occur as the cancer grows in it’s local area.
3) Bleeding will occur as the cancer breaks through the skin. It may be scant.
4) Lymph Gland Swelling (”lymphadenopathy”) in the pelvis; this does not prove that the glands are involved since infection will also swell them. On the other hand, non-swollen glands may still be microscopically involved with cancer.
5) Urinary and Bowel Problems can occur as the cancer invades the urethra, bladder and rectum respectively.
6) Signs of Distant Spread include back pain (from spread to para-aortic lymph nodes), bone pain from spread there, or nervous system problems from brain spread. Vulvar cancer tends to grow large in it’s local area prior to spreading.
***20% of patients have no previous symptoms when their disease is detected.

Is Vulvar Cancer Preventable?

There is no sure way of preventing vulvar cancer . Being careful to avoid getting a Sexually Transmitted Disease will lower the risk, as will good vulvar hygiene. If a woman has the risk factors for this disease, she should be especially vigilant about doing vulvar“self-exam” on a monthly basis to look for any new suspicious areas, and bring them to a doctor’s attention without delay.

The vulva is the genital organ area between the vagina and upper thighs in a women. The vulva includes the mound of tissue on pelvic surface (mons), the vaginal lips (labia), and clitoris. Infections of the vulva, including sexually transmitted diseases, are the main problems women have with this area.Rarely, the vulva gets cancer. It is critical to get prompt diagnosis and proper treatment of a vulvar cancer problem; this can literally make the difference between life and death. In the past, radical and mutilating surgery was all that could be done, and it was often unsuccessful. Fortunately, improved treatments are now available which often maintain sexual function and give better survival than ever before. Understanding your options will give you the peace-of-mind of knowing you have done everything possible to ensure a successful outcome for yourself or a loved one.

CancerAnswersÕs material explains, in plain English, the definition, types, risk factors, frequency, evaluation, historical and latest effective treatments for vulvar cancer. We describe surgery, radiation, and chemotherapy along with their side-effects and results. While we don’t promise a cure, we tell you everything you need to know to help you make the right choices today in dealing with a vulvar cancer problem.

This is just an excerpt of CancerAnswers’s report on Vulvar Cancer. Much more, including latest treatment, can be sent to you by mail when you order the complete Vulvar Cancer transcript at a nominal cost. Thank you for using CancerAnswers as your information resource.