A Family GuideTORetinoblastoma
by Víctor Peña-Araujo Fall, 1997
Víctor Peña wrote this paper on RB and was gracious enough to allow me to post it here for everyone to see. I think it's a very good, comprehensive writing, if you have the time, everyone should read through it.
On this page:
Table of Contents
*Prologue
*What is Retinoblastoma?
-Incidence of retinoblastoma
-Two different ways by which retinoblastoma can come about
-The hereditary type of retinoblastoma and its consequences
-The sporadic form of retinoblastoma
*How retinoblastoma is treated 4
-The variety of treatments
Radiotherapy
Chemotherapy
Photocoagulation
Surgery
-Description of individual treatments
Radiotherapy
Chemotherapy
Surgery
Newer methods
-Vitamin C as part of treatment?
-A sample follow-up schedule
-Possible side-effects to treatment
-Future alternatives in treatment
*Later risks (secondary cancers) 7
-Reasons why secondary cancers develop
- A genetic predisposition
-Exposure to high levels of radiation
*What is sarcoma? 8
-Incidence of sarcoma
-Treatments for sarcoma
Skeletal scintigraphy
(ABMT) Autologous Bone Marrow Transplantation
A Patient's Story
The Clinical Management of Secondary Sarcomas
-Additional things to consider... 11
...in retinoblastoma
...the risk of developing melanoma as a secondary neoplasm
...in the treatment of osteosarcoma
...in the possible risks to family members
...in the increased odds of children of RB patients
*Final Remarks 13
*Glossary
*Bibliography
*Prologue
Eleven years ago my niece was diagnosed with retinoblastoma and was often brought to New York where she stayed with my family for months at a time while she received treatment at New York Hospital. Sadly, she eventually lost her left eye to the disease. Four months ago, her father called us very concerned after hearing that some retinoblastoma survivors ran a risk of developing forms of bone cancer in their lifetimes. This prompted me to write this 'family guide to retinoblastoma'. It is by no means a comprehensive nor authoritative work. However, it is still meant for general reference to the basic questions you might have if you or a family member is undergoing treatment for retinoblastoma. Consider this a friend's honest attempt to provide you with something to start you up with on your way to understanding the nature of retinoblastoma (RB), as well as its treatment and its eventual influence on your loved one's life.
In order to find the most reliable information and statistics I thoroughly searched all internationally published medical journals printed in the past ten years. I then selected the most revelant publications and read them all. This guide contains what I think you would want to know from the dozens of people across the world who dedicate their lives to learning more about retinoblastoma alone. I included some issues which I believe you ought to be aware of simply so you can discuss them with your specialist and see if and how they may relate to your case in particular. I hope using this guide will save you the burden and valuable time you might have spent researching the latest literature by yourself. I have included a short glossary of some medical terms used in the text for your convenience.
I recognize you might have had to deal with considerable vagueness and confusion in your attempt to understand the nature of this condition which I imagine may seem overwhelming at times. Therefore, I have tried to provide you with the latest published information on RB in a straight-forward and concise way. I hope you will find this guide easy to read and informative. Keep in mind that in some ways, this guide is more like an encyclopedia and less like a night-table book.
Lastly, I ask each and every individual who is living with this condition to receive my utmost admiration and respect for your courage, strength and determination to live on and live well. We have a lot to learn from you.
Sincerely,
Víctor Peña
*What is Retinoblastoma?
Retinoblastoma ('retina' - the inner cell layer of the eye, 'blastoma' - a growth). This is the term used to describe a 'tumor' (which is an abnormal growth). It is made up the cells which normally line the inside surface of the eye. The normal function of this layer is to capture light coming into the eye and convert it into an electrical impulse which is then interpreted by the brain as an image we call 'vision'.
Retinoblastoma is one of the two most common types of eye cancer seen today, the other of which occurs mainly in much older adults and for very different reasons (malignant melanoma) (15, 23). Any uncontrolled cellular growth in the body may be called 'cancer' although it is imperative that we do not fall victims to any preconceptions we may have about this term. In medicine there is a very wide gamma of cancers and each type has its inherent origin, symptoms, and weaknesses which can be manipulated to offer the best treatment. Therefore, doctors have devised specific treatments and have figured different prognoses (expected outcomes) for each type. As stated before, we will only be concerning ourselves with these aspects in regard to retinoblastoma (or 'RB').
This specific abnormal retinal cell growth occurs almost exclusively in young children. In the United States today, the overall survival rate using all of the most effective treatments surpasses 95% (2). Most often times this condition appears in only one of the two eyes. This is referred to as 'unilateral.' Other times, however, it presents itself in both eyes. This is then referred to as 'bilateral' (2).
TOP
-Incidence of retinoblastoma
Retinoblastoma is estimated to affect one out of every 20,000 children (5, 15, 24). Last year a study of the Greater Delaware Valley Pediatric Tumor Registry in the U.S. showed that although the overall incidence of childhood cancers is increasing by 1% every year, there is no increase in RB cases. As a matter of fact, slight decreases were noted in some age and race subgroups (3). For example, a 6.3% decreased incidence was noted in the 1 to 2 years-of-age group between 1970 and 1989 (3).
Previous family history is an important factor which also helps determine the incidence of RB (11, 24). A long-term (31 years) study in Turkey consisting of 636 RB patients noted that 5.3% of them had family with some history of ocular tumors (4).
Retinoblastoma can affect one (unilateral) or both (bilateral) of the eyes of the patient. In the Turkish study mentioned earlier, of the 636 patients treated, over 69% were unilateral while the other 30% were bilateral (4).
-Two different mechanisms by which retinoblastoma can come about
There are two different ways by which retinoblastoma can originate. One way is hereditary (genetic), while the other is sporadic (spontaneous). According to Dr. Knudson, who devised explanations for the two mechanisms, for either type to occur, two separate mutations need to take place in an individual prior to birth.
The first mutation (referred to as M1) causes a predisposition towards malignancy. If this event occurs in the fertilized egg within the mother before its cells differentiate, then the mutation will affect all parts of the body which have cells derived from the mutated cells. This is the hereditary form. If, on the other hand, the M1 mutation occurs at a later stage of development when cellular specialization has occurred, then only retinal cells will be mutated. This, in turn, is known as the sporadic form, which is most often unilateral (13).
If and when a second mutation occurs (referred to as M2), it will trigger the transformation of the predisposed (mutated) cells into malignant cancer cells, thus causing retinoblastoma (13).
-The hereditary type of retinoblastoma and its consequences
All of our inborn characteristics are defined by the genetic information in the nuclei of our cells. Each one of us has hundreds of thousands of genes within each cell which dictatehow it will function. Therefore the nature of our bodies is dependent on our genes. All of our genes are organized into 46 very long, separate braids of genetic material. These braids are called 'chromosomes' and they have all been numbered by geneticists in order to keep track of where individual genes can be found.
Retinoblastoma may aggregate in families because the condition is associated with one of our chromosomes which is passed on from generation to generation (19). The gene for retinoblastoma is found at chromosome number 13. The RB gene (depicted by 'Rb' in medical literature) belongs to a class of genes called tumor-suppressing genes or anti-oncogenes, the normal function of which is to regulate cell growth (12). The chromosomes of tumor cells have been shown to have the segment of the RB gene frequently damaged or even missing (1, 2, 6). This suggests the existence of a cancer-suppressing gene located in chromosome band 13q14 that normally functions to prevent RB formation in the developing retina (6, 15).
40% of all RB cases are hereditary. These are almost always present as bilateral cases (5, 15, 19). As always there must be exceptions, and in a study by Dr. Lee et al. 15% of patients with the unilateral form of RB were found to have the hereditary form (15). All hereditary cases are more frequently associated with secondary malignant neoplasms (5, 15, 19). This is so because any genetic defect at chromosome 13 increases an individual's susceptibility to second neoplasms (new cancerous growths) (5, 22). This was shown by a recent clinical study where all secondary tumors occurred in patients with the hereditary form of RB (12). As explained above, in the hereditary cases, the retina is not the only target for malignancy because many other types of the patient's cells have already undergone the first mutation (M1). Other highly prone targets for the second mutation (M2) are bone tissues, some soft tissues, and the pineal gland, resulting in conditions such as osteosarcoma and pineoblastoma (a form of brain cancer) (13). Secondary cancers (also known as a secondary malignant neoplasm or SMN) are thoroughly discussed in the section about 'Later Risks.'
-The sporadic type of retinoblastoma
In the sporadic development of retinoblastoma, the genetic damage caused by the mutations is confined to retinal cells. This is so because the two mutations required for retinoblastoma to take place occurred within cells already specialized as retinal cells (15). Consequently the risk of developing a secondary tumor elsewhere is significantly diminished but not eliminated by any means. Unfortunately, most children suffering from this form of retinoblastoma are at considerable risk of developing secondary tumors too. This is due to the fact that radiation therapy, one of the most effective treatments against tumors, may also damage the healthy tissue surrounding the tumor (1). This overexposure to radiation rids healthy tissue of its normal tumor-suppressing capabilities, thus making it prone to cancerous growths (1).
*How retinoblastoma is treated
TOP
-The variety of treatments
Today's approaches to battling cancers range widely in their effectiveness. One thing is for sure, their success in saving lives has, and will, increase immensely. Different cancers respond to different treatments. Today's technology is allowing us to customize treatments to each specific form of cancer. Usually the most effective treatments consist of a combination of the following methods:
*Radiotherapy - High levels of radiation are known to damage living tissue. Using this principle doctors use controlled radiation aimed exclusively at the tumor cells, which after all, are also living cells. Radiation damages the genetic material within the tumor cells and halts their reproduction.
*Chemotherapy - Doctors give the patient medications which are toxic to cancer cells. The medication damages the tumors and slows their growth.
*Photocoagulation - by using laser and other sources of light, doctors can directly destroy tumors.
*Surgery - Although it is avoided when possible, surgery provides a life-saving alternative by removing the tumor and any other tissue directly involved. This most often involves 'enucleation' or removal of the eye to ensure that no spreading will occur to other parts of the body, mainly the brain.
Cancer treatment is an extremely delicate balancing act. If too little radiation or medication is given to the patient, then the tumor is not destroyed and continues to grow. On the other hand, if too much radiation and medication is given to the patient then it may damage the healthy tissue surrounding the tumor. Unfortunately, due to the nature of the treatment, it is likely to encounter some of the effects of both extremes. Cancer in children is caused largely by mutations in specialized cells. The immediate consequence of this during treatment is that the tumor cells will bear at least some resemblance to normal cells and place limitations on the use of cytotoxic agents (the substances used to damage cancer cells) (24).
Improvements in early diagnosis has increased retinoblastoma survival from 10% to well over 90% in some instances in the past 90 years (4). The Turkish study of 636 patients (4) showed that 5 years after diagnosis, RB patients had the following survival rates:
81.1% for children with bilateral retinoblastoma
82.2% for children with unilateral retinoblastoma
Improved traditional techniques and the introduction of new treatment modalities undoubtedly explain some of the overall increase in survival (23).
TOP
-Description of individual treatments
*Radiotherapy - RB is a radiosensitive tumor and irradiation can be very effective in destroying it. However, external beam radiation therapy may enhance the risk of second malignancies in patients (1). Therefore it has been replaced in some places by Cobalt plaque radiotherapy for the treatment of small, solitary tumors. This newer treatment consists of small radioactive cobalt plaques which are placed in close proximity to the tumor and left for a specific amount of time to irradiate it at a preset intensity. This method is a good alternative to beam therapy because it is more localized and reduces the amount of irradiation to the bones in the eye's orbit and surrounding soft tissue, thus minimizing the chances of secondary orbital malignancies (4).
*Chemotherapy - Chemotherapy is recommended in cases of overt metastasis (spreading) to the brain and spinal cord, as well as to other remote sites of the body (4). It involves the use of substances which have been proven to obstruct tumor cell activity and/or growth. However, due to intrinsic similarities between the tumor cells and the child's normal cells, side-effects are common although not necessarily serious.
*Surgery - When used, surgery offers patients very good chances of long-term survival. Enucleation (removal) of the eye was used as the treatment of choice in 93.4% of the unilateral cases in the Turkish study (4). Five years later, the advantage of resorting to surgery was more apparent by the survival rates of the patients followed-up:
surgical patients: ~86% survival rate
non-surgical patients: ~79% survival rate
*Newer methods (non-invasive) - These non-invasive variations have been reported to be effective, conservative alternatives in selected RB cases. Examples of these methods include: photocoagulation, cryotherapy and as already mentioned, plaque radiotherapy. The choice and combinations of these depend on the size and number of tumor(s). Another factor that influences which method is used is whether the retinoblastoma is unilateral or bilateral (4).
TOP
-Vitamin C as part of treatment?
Laboratory studies carried out by a team of Spanish and German scientists have shown the possibility that including high doses of vitamin C (ascorbic acid) could be beneficial in the treatment of different pediatric tumors (10). This is possible because tumor cells are scarcely protected against free radicals and oxygen reactive species. This pro-oxidant behavior of ascorbic acid explains its toxicity on cancer cells, including those tested in these studies (10). This study however, did not involve clinical trials and thus is not conclusive nor specific as to the dose required or the results that can be expected during actual administration of ascorbic acid to patients. Future studies and their results promise to be interesting and hopefully even life-saving.
TOP
-A sample follow-up schedule
In the Turkish study already mentioned a model follow-up schedule was used in their 636 patients with successful results (4). Follow-ups were carried out under full anesthesia:
- Visits every 2 months during the first year.
- Visits every 3-4 months during the second year.
- Visits every 6 months during the third year.
- A visit once a year until age of 12.
TOP
-Possible side-effects to treatment
As mentioned earlier, we should remember that all medical treatment is in one way or another obtrusive to the body and so we should be ready to deal with whichever way it reacts. The possibility of side-effects and complications is always imminent. However, the key to good treatment is to try to keep our invasion to a minimum.
The role radiotherapy plays in the development of secondary tumors is discussed at length in the section called 'Later Risks.' Two somewhat less pressing side-effects to external ray therapy are radiation burns and cataracts. It is common for children who undergo this procedure, to develop mildly burned regions on the skin near the eye, mostly near the edge of the orbit. This is due to the burning effects of the radiation beam going through the tissue. Pure aloe applied on the burned area can diminish the redness and dryness. As for cataracts, a study followed-up 25 patients who had undergone radiotherapy without having to resort to surgery (4). Five years later, 18 of them were found to have radiation cataracts to varying degrees (4). However, this specific side-effect may well have been minimized at institutions where the use of Cobalt plaques have substituted external ray therapy.
TOP
- Future alternatives in treatment
Scientists are working on the idea that cancer cells can be attacked with genetically- engineered viruses that will infiltrate individual target cancer cells and halt their abnormal activity rendering harmless, leading to ridding the patient of the cancer (24). This could be done by having the doctors' virus insert the healthy form of the RB gene into the cancerous cells. Certain cancer cells have already been "corrected" in test tube trials. This certainly is a fanciful idea, although not necessarily impossible. These approaches towards stopping cancer cells entail a "rehab" approach rather than the "execution" approach in use today. This is considered a type of 'biotherapy' and is presumed to be very effective and less shocking to the body (24). Close attention to these developments may prove fruitful to future patients.
TOP
*Later risks (secondary cancers)
As the cure for primary childhood malignancies increases, the number of patients at risk for the development of second malignancies also increases (5, 22). Furthermore, it has been shown that retinoblastoma patients have 10 to 20 times greater chances of developing a second malignant neoplasm than members of the general population (11, 21). This is specially true for patients who have the hereditary form. They make up 25% of all RB patients (2). This group most often (98% of times) suffers of the bilateral form of the condition (11, 12).
According to a 40-year study by Dr. Smith and his colleagues, the average interval between the diagnosis of retinoblastoma and a second malignancy is 10.8 years (11, 22). And by far, the most common type of secondary malignancy encountered was bone cancer (osteosarcoma) (2, 9, 12, 18, 22). In other words, the risk of developing osteosarcoma (or one of the few other kinds of cancer) in retinoblastoma patients increases as the following criteria are met (11):
- There is a genetic predisposition in the patient (a family history)
- Retinoblastoma is in the bilateral presentation (in both eyes)
- Time has gone by since the original retinoblastoma diagnosis (as time goes by, the odds of developing a second cancer increase)
TOP
-Reasons why secondary cancers develop
-A genetic predisposition
As mentioned earlier, children who suffered a first mutation (M1) during their very early embryonic development, will have an inborn weakness to resisting the development of any form of cancer. Well after surviving retinoblastoma, these individuals remain at high risk of forming secondary malignant neoplasms, which may or may not be related to retinoblastoma. It was noted above that the most common form of such secondary tumors seen is bone cancer (osteosarcoma) (2, 9, 12, 18, 22). Patients with the genetic predisposition have a risk for bone cancer approximately 300 times greater than the risk in the general population (2, 5). In more general terms, if a child has the genetic predisposition, then he or she has roughly 35% chances of developing some form of a secondary cancer during his or her lifetime (2, 22). These odds vary widely from person to person and also depend on other factors such as the preceding forms of treatments used to battle RB.
-Exposure to high levels of radiation
Most children suffering of cancer can gain a great deal from radiation therapy. However, this treatment does take a toll on all patients, some more than others. Patients who have the hereditary form of RB and were treated with external radiotherapy run a very high risk of developing secondary cancers later in life as shown by Dr. Abramson, one of the leading authorities in the treatment of retinoblastoma (12, 19). According to his estimates, these patients have the following percent chances of developing a secondary cancer (shown at selected age intervals):
- 20% chances at 10 years of age.
- 50% chances at 20 years...
- 90% chances at 30 years...
These results are supported by various other studies, thus establishing this risk among the selected patients (5, 12). While Abramson suggests that the use of radiation, regardless of the size of dose, may increase the incidence of secondary tumors, he states that he has found no relationship between the amount of radiation and the level of incidence of tumors (22). Other doctors however, believe that the impact of increasing the radiation dose in treatments most likely further increases the risk of developing osteosarcoma above the already high level of incidence among RB patients (5, 11, 12, 22).
In 1975 Abramson et al reviewed 2,300 patients with RB and discovered that among the patients who subsequently developed a second cancer, one third of the second cancers occurred outside the radiation field (the area of the head the ray has to go through to reach the retina (12, 18). However, one patient who never received radiation, developed a sarcoma in what would have been considered to be within his radiation field. This suggested that another factor was responsible for the induction of these second tumors(12). This, plus other findings by Dr. Robert Kay (who also discovered malignant growths in children who had not received radiation), supports the belief that radiation treatment is not the only factor increasing the incidence of these secondary cancers. Chemotherapy is also now under scrutiny as another possible cause (5, 22). All this roots back to the genetic predisposition of the specific patient. In a predisposed child the odds may be expected to increase.
Dr. M.J. Brown studied osteosarcomas as a secondary tumor after bilateral RB (2). He found the distribution of such tumors to be the following in regard to the radiation field:
- 70% of the second cancers can be expected to appear within the field
- 30% of the second cancers can be expected to appear outside the field
These results are supported by a Chilean study back in 1990 (17). Of the patients treated with radiation therapy who later developed secondary cancers, six out of eight developed it with in the irradiated area.
TOP
-What is osteosarcoma?
Osteosarcoma involves the abnormal, uncontrolled production of certain types of connective tissues, most often bone. This form of cancer is serious due to the extent of the damage it causes as well as the sites in which it appears. Osteosarcoma creates growths in the tissue which may cause structural weakening such as in the case of a leg bone which may eventually lead to a fracture. Yet more concerning is the fact that this cancer may appear in areas difficult to treat. These areas include the bones of the head which make up the face, house the eye, as well as the throat and brain.
By far, the most common secondary malignant neoplasm in retinoblastoma survivors is sarcoma, more specifically, osteosarcoma (2, 9, 12, 18, 22). There are four subtypes of osteosarcoma, some more frequent than others according to Dr. W.A. Newton who studied bone sarcomas that followed childhood cancers. Based on Dr. Newton's findings, the four types are listed here from the most frequent to the least, each followed by examples of the type of site where it might be found (14):
- osteoblastic - most common, appearing in bone tissue.
example: in a long bone of the arm or leg
- chondroblastic - appearing in cartilage tissue.
example: in the orbit (socket) of the eye or in the cheek bone
- fibroblastic -appearing in other fibrous tissue.
example: in the bridge of the nose
- telangiectactic - least common, appearing in odd places but also the arm or leg long bones.
example: in the throat
In Dr. Newton's study all except 2 of his 17 patients had the bilateral form of retinoblastoma. The first of these two unilateral cases involved an osteoblastic sarcoma while the second involved telangiectatic sarcoma.
A similar study was carried out in Argentina in 1990. Here the doctor followed four unilateral RB patients who eventually developed secondary tumors (18):
- RB diagnosed at 2 years of age. Osteosarcoma of the femur after 12 years.
- RB diagnosed at 3 years of age. Osteosarcoma of the humerus after 8 years.
- RB diagnosed at 6 years of age. Myoblastic leukemia after 2 years.
- RB diagnosed at 4 years of age. Cerebral glioblastoma after 6 years.
Although these cases certainly paint a very grim picture, we must not
forget that these patients were actively sought out in the hopes of finding
patterns and cures. That is, these four cases are very rare and when
presented together they may give the impression that secondary neoplasms in
unilateral cases are much more frequent and deadly than in actuality.
-Incidence of osteosarcoma
As mentioned already, osteosarcoma may appear in retinoblastoma survivors at any time after the first decade of life (5). The percent chances of developing such a condition as time goes by was estimated by Dr. Astigarraga after studying three cases (11):
- 4.4% chances in the first 10 years of life
- 18.3% after 20 years...
- 26.1% after 30 years...
In previously publications however, irradiated patients have shown an up to a 90% chance of developing a secondary cancer at the beginning of the fourth decade of life. In these instances the age at which radiation therapy took place also played a pivotal role when estimating odds of secondary cancers. The administration of radiation during infancy further increases the risk to two or three times that of the risk in an adult. Nevertheless, approximately 1% of the survivors of bilateral RB are expected to develop non-radiation-associated bone cancer. This risk more specifically involves the possible development of one of the following: lymphoma, cancer of the thyroid or the mammary glands, or even cerebral tumors although these are extremely rare (8). Again, this may be due to the fact that these patients have an inborn weakness against fighting cancer in general.
-Treatment for sarcomas
Effective treatment starts with good preventative measures. In the case of a retinoblastoma survivor, knowledge of the association between bilateral RB, the genetic form of RB, and later second bone and soft-tissue malignancies should heighten the clinician's and radiologist's suspicion of malignancy when assessing any bone or soft-tissue mass in these patients(2).
There may come a time when for seemingly accidental circumstances a person may fracture a long bone such as those in the arms or legs. In RB survivors it is extremely important to carefully scrutinize these fractures in order to rule out the possibility that a bone tumor might have caused the fracture by weakening the bone in the first place (5).
Upon confirmation of the presence of a secondary tumor, a therapeutic regiment is quickly designed to hopefully destroy the cancer while retaining as much of the surrounding tissue as possible. Radical resection, post-operative radiation and adjuvant chemotherapy may all be combined to provide the patient the best possible survival (12).
According to Paul Dickman and his colleagues, who studied the nature of secondary cancers, detailed pathological studies are strongly suggested in RB patients. Their belief is that such practice will better define second tumors as recurrent or as new and that way help us to better understand why secondary cancers occur. The results might prove helpful in finding a way to avoid their development in the first place (1). His team has strongly suggested the analysis of second tumors with all diagnostic tools available: microscopy, immunohistochemistry, cytogenetics and molecular techniques. This is especially so when treating hereditary RB patients (1).
SKELETAL SCINTIGRAPHY
There is a technique called skeletal scintigraphy. This is a type of imaging which allows doctors to locate and characterize the spread of bone cancer by using very low levels of radiation. It has been of particular value in the determination of the extent of bony involvement in osteosarcoma. However, it was assumed that using this technique on bilateral RB patients could be used as a preventative measure against osteosarcomas by actively searching them out with it. However, a study of 46 patients concluded that these tests should not remain as part of the initial staging of patients unless there is already clinical or pathologic evidence of extraocular (other place than the eye) disease diagnosing osteosarcoma (21). The researchers concluded that asymptomatic (seemingly healthy) and/or unilateral patients should not have this test done repeatedly with the expectation of an early diagnosis of a second cancer. In other words, their suggestion is that such studies may be safely omitted from routine follow-up procedures. Finally, the radiation exposure associated with bone scans, although low, also argues against repeated studies with such a low yield of success.
ABMT (AUTOLOGOUS BONE MARROW TRANSPLANTATION)
During the past 5 years massive chemotherapy in conjunction with ABMT (autologous bone marrow transplantation) have been increasingly explored in the treatment of pediatric solid tumors, including osteosarcoma and retinoblastoma. This has been used as a means for increasing doses of chemotherapy and radiotherapy to achieve higher cure rates.
This approach is based on the premise that the transplantation of healthy bone marrow into cancer patients allows them to resist much higher doses of radiation and chemotherapy. ABMT has already permitted a 3- to 10- fold increase in drug doses. This means that due to the higher radiation and medication levels given, there are greater chances of destroying the cancerous cells.
As a result of the limited availability of matching donors for bone marrow transplantation, autologous ('from/to oneself') transplantation represents an attractive alternative. In autologous transplantation, bone marrow is taken from a presumably healthy region of the body and is transplanted into the area of need. However, the risk of reinfusing malignant cells represents a significant limitation, particularly when ABMT is used mainly as salvage treatment, where the probability of harvesting marrow contaminated with tumor cells is high.
ABMT itself is not curative. It only enables to overcome marrow toxicity resulting from dose escalation aimed at increasing the tumor kill. Currently, its use is able to change the disease course although long-term survival has not yet been improved much over the other, more conventional treatments. Nevertheless, this method may prove to be the only cure for patients who do respond to it favorably (16).
TOP
A PATIENT'S STORY
As an 18 month-old infant, a baby girl had received radiation therapy for bilateral retinoblastoma. Since she was adopted, it was not known if there was a history of RB in her biological family. Eventually she had to undergo bilateral enucleation. She then spent the next 24 years without any symptoms.
At the age of 25 she noticed pain in her knee, which soon radiated to her groin. X-ray tests showed a growing lesion at the mid-shaft of her thigh bone. CAT and MRI scans supported the results of an abnormal growth. A tissue biopsy (sample) confirmed the diagnosis of telangiectatic osteosarcoma and thus was quickly followed by a limb-salvaging operation.
Fortunately the patient survived this sad episode and the doctors managed to save her leg (2). As of today she is presumed to be leading a healthy and productive life.
-THE CLINICAL MANAGEMENT OF SECONDARY SARCOMAS
The two most common approaches to controlling osteosarcoma are: to undergo a wide local resection of the affected part of the bone, or to undergo amputation of the affected limb along with adjuvant chemotherapy. Fortunately, pre-operative chemotherapy has been used successfully in converting an limb that would require an amputation for local control, into a case requiring only local resection (12).
A tumor that arises within a radiation portal of a previously treated RB patient often is invasive and may involve multiple sinuses in the head, making determination of the primary site difficult. The usual symptoms include: very common nose bleeds, nasal congestion, a persistent runny nose, and swelling of the soft tissue surrounding the eye, nose and cheek bones (12).
In regard to osteosarcomas however, absence of symptoms does not guarantee the absence of osteosarcoma. This is a very important fact to keep in mind when monitoring a retinoblastoma survivor. Since this is so, regular clinical check-ups must be performed for the rest of the person's life and should be accepted as part of his or her normal life.
TOP
-Additional Things to Consider...
... IN RETINOBLASTOMA
As mentioned earlier, deaths attributed directly to retinoblastoma are extremely rare nowadays. This is due to several factors which include better informed and more observant parents, and much improved medical treatments. Unfortunately there are still RB cases which for various reasons are allowed to progress or, less likely, simply do not respond to the treatment. If retinoblastoma is not treated then a far more serious, yet much more remote possibility, may develop. The eye cancer may spread to the brain and spinal cord by way of the optic nerve. This is a serious complication which may eventually lead to death (4). Among the very few RB-related deaths world-wide, the most frequent cause of death was brain and spinal cord extensions of the cancer, accounting for over 90% of the deaths. The other 10% was due to distant metastasis, ectopic intracranial RB and secondary malignancies.
Chances are, if you, your child, sibling, or friend has already been diagnosed with RB, treatment has already been started. This risk being referred to here is most relevant to those who haven't begun treatment either because they haven't been diagnosed yet or don't have the resources to receive treatment. Moreover, if your loved one is suffering from the hereditary form of RB, then it is important for him or her to keep this in mind in the future for the well-being of his or her children.
...THE RISK OF DEVELOPING MELANOMA AS A SECONDARY NEOPLASM
According to a study in the Journal of the American Academy of Dermatology (1990), there is a strong association between the hereditary form of RB (i.e. bilateral RB) and a hereditary form of melanoma (a skin tumor occurring as a secondary malignant growth) which is particularly striking (19).
A second study noted melanomas in 3 of 37 RB patients (Kingston et al). None of these patients had had alkylating agents (chemotherapy) or radiation treatment so this suggests a genetic abnormality which may predispose patients with RB to develop melanoma as a second cancer (22). Consequently, the possibility of melanoma as a secondary cancer should be kept in the mind of the clinician in charge of monitoring any secondary developments.
... IN THE TREATMENT OF OSTEOSARCOMA
IV methotreaxate is a substance that has been shown to be very useful in the treatment of osteosarcomas due to its ability to destroy tumors (20). However, there was an apparently isolated incident in which a patient was treated with a single dose of such substance and tragically and unexpectedly succumbed to its effects within several hours. The exact cause for this dreadful occurrence was not known at the time the report was printed.
Therefore, in the event that the doctor suggests the use of this drug, it would be prudent to ask for the latest findings on the case mentioned above prior to beginning treatment with IV methotreaxate.
... IN THE POSSIBLE RISKS TO FAMILY MEMBERS
Studies have shown an increase of breast cancer among the mothers of RB and osteosarcoma patients (6). Originally, breast cancer was not thought of as associated with retinoblastoma but the mothers' high incidence is starting to change opinions among experts. Breast cancer has not been clinically associated with hereditary RB however, several hypotheses are being considered to explain this (15).
In contrast, , most lung cancers are not known to have a heritable component, and are instead tightly associated to cigarette smoking and environmental exposure. Therefore, in the case of a RB patient with the inherited form, his family could be increasing his odds of survival if they provide him with a smoke-free environment. Recall that these patients have a high risk of developing several forms of cancers.
... IN THE INCREASED ODDS OF CHILDREN OF RB PATIENTS
One study has suggested that children of affected parents have a 50% chance of having retinoblastoma themselves (5). Today's retinoblastoma patients will be having children in the next century. Gene therapy is a revolutionary way of treating and preventing disease at the molecular level. This new approach promises to have excellent preventative capabilities in 15 to 20 years time. Therefore we can be sure that in the case today's patients have children with the same condition, their treatment will be far more effective than anything available today. Their quality of life may prove to be as wonderful as that of an average, healthy individual.
TOP
*Final Remarks
Most reports suggest that these patients must be monitored throughout their adult lives in order to maximize the odds of identifying any potentially dangerous secondary growths (12). It has been estimated that as many as 80% of all cancers may be induced and therefore should also be preventable to a large extent. For example, cigarette smoking alone is the cause of one third of all cancer deaths in the U.S. and Europe. Patients with the propensity of developing cancer should make an extra effort to distance themselves from carcinogens. However, this form of prevention is different when talking about young children since they very rarely engage in such self-destructive habits as smoking. Therefore, the child's family ought to make reasonable efforts to minimize such unnecessary exposures (24).
In our attempt to sort out all the information and feelings we have about retinoblastoma and its possible consequences, we must keep in mind that the ultimate goal is to better the quality of life of our loved one. To do this it is imperative for him or her to be under the care of a doctor who has our trust in his intentions and ability. Once this relationship is well established, we can rest assured that we, our doctor, and the patient, are doing all that is humanly possible in fighting this disease we call cancer. And if things ever look grim, the least we owe to our loved on is our faith and support to help them get better. Let us not forget that they may be fighting for their lives.
I sincerely thank those who have helped me in putting this guide together, particularly George Rodriguez of Schneider Children's Hospital in New York for his help in researching journals, and my father and Lucey-Ann Behar for their revisions and input. And of course, a very special thank you to Mr. Mike Rodriguez for single-handedly making this guide available to those whom I hope it will benefit.
TOP
*Glossary
A
ABMT (Autologous Bone Marrow Transplantation) - a technique that has been used extensively in the last few years in pediatric oncology as a means for increasing doses of chemotherapy and radiotherapy to achieve higher cure rates.
C
contralateral - situated on or pertaining to the opposite side
cutaneous melanoma - a skin tumor originating from the melanin-pigmented cells.
E
enucleation - removal of the eyeball after the eye muscles and optic nerve have been severed.
Ewing's Sarcoma - or tumor - a malignant tumor of the bone which always arises in the medullary tissue, occurring more often in the cylindrical bones, with pain, fever, and leukocytosis as prominent symptoms.
exenteration - surgical removal of the entire contents of the orbit of the eye.
G
glaucoma - condition of the eye characterized by increased intraocular pressure.
H
Hodgkin's Disease - a painless, progressive, and fatal enlargement of the lyph nodes, spleen, and general lymphoid tissues, which often begins in the neck and spreads over the body. Granuloma.
I
ipsilateral - situated on or pertaining to the same side.
N
neoplasm - any new and abnormal growth such as a tumor.
O
osteosarcoma - sarcoma of the bone.
R
Rb - notation used in genetics to represent the retinoblastoma gene.
Reese-Ellsworth Classification Table - a method by which the different stages of tumors are classified.
rhabdomyoma - a benign tumor derived from straited muscle (a.k.a. rhabdomyocellulare).
rhabdomyosarcoma - a combined sarcoma and rhabdomyoma.
retinoblastoma - a tumor arising from retinal germ cells; glioma of the retina. Sometimes written as 'RB.'
retinoma - term used to describe two types of benign retinal tumours previously thought to have been regressions of RB. Retinoma and RB are induced by similar genetic changes. Retinomas can undergo malignant transformation and therefore require the same investigation and follow-up as RB. Clinically, it represents a situation equivalent to that of a successfully-treated RB, with the same clinical and genetic features and possibly the same prognosis.
S
sarcoma - a tumor made up of a substance like the embryonic connective tissue. Often highly malignant. secondary malignant neoplasms - cancerous growths which develop following an initial cancerous growth such as retinobalstoma. The secondaries may or may not appear near the original cancer and are usually of a different type. Sometimes abbreviated as SMN.
SMN - see secondary malignant neoplasms.
T
telangiectatic - a rare, aggressive subtype of osteosarcoma mostly found in the femur, tibia and humerus. Frequently purely osteolytic.
Z
zygote - the cell resulting from the fusion of two sex cells; the fertilized female egg which has undifferentiated cells.
TOP
BIBLIOGRAPHY
1. Malignancy after retinoblastoma: secondary cancer or recurrence? Dickman, P.S.; Barmada, M.; Gollin, S.M.; Blatt, J. Human Pathology. 1997 Feb; 28(2): 200-5.
2. Diaphyseal telangiectatic osteosarcoma as a second tumor after bilateral retinoblastomas. Brown, M.J.; Logan, P.M.; O'Connell, J,X; Janzen, D.L.; Connell, D.G. Skeletal Radiology. 1996 Oct; 25(7): 685-8.
3. Increasing incidence of childhod cancer: report of 20 years experience from the Greater Delaware Valley Pediatric Tumor Registry. Bunin, G.R.; Feuer, E.J.; Witman, P.A.; Meadows, A.T. Paediatrics, Perinatology and Epidemiology. 1996 Jul; 10 (3): 319-38.
4. Retinoblastoma in Turkey - treatment and prognosis. Gunalp, I.; Gunduz, K.; Arslan, Y. Japanese Journal of Ophthalmology. 1996; 40 1: 95-102.
5. Osteosarcoma and Ewing's Sarcoma in a Retinoblastoma Patient. Kay, Robert M.; Eckhardt, Jeffrey J.; Mirra, Joseph M. Clinical Orthopaedics. 1996 Feb (323): 284-7.
6. Regulation of Retinoblastoma Gene Expression in Hormone-Dependent Breast Cancer. Gottardis, M.M.; Saceda, M.; Garcia Morales, P. Fung, Y.K.; Solomon, H.; Sholler, P.F.; Lippman, M.E.; Marin, M.B. Endocrinology. 1995 Dec. 136 (12): 5659-65.
7. Dorland's Illustrated Medical Dictionary, 24th edition.
8. Sarcome de la face survenant 13 ans apres l'irradiation d'un retinoblastomeMachet, M.C.; Despert, F.; Maheut, J.; Grangeponte, C.; Goga, D. Rev. Stomatol. Chir. maxillofac. 1995, 96, no. 3, pp148-50.
9. Chromosome Analysis of Nine Osteosarcomas. Hoogerwerf, W.A.; Hawkins, A.L.; Perlman, E.J.; Griffin, C.A. Genes Chromosomes Cancer. 1994 Feb; 9(2): 88-92.
10. Ascorbic Acid is Cytotoxic For Pediatric Tumor Cells Cultured in Vitro. Medina, M.A.; Garcia de Veas, R.; Schweigerer, L. Biochemistry, Molecular Biology International. 1994 Nov; 34(5): 871-4.
11. Segundos tumores sólidos en la infancia. Revisión a propósito de tres casos. Astigarraga Aguirre, I.; Navajas Gutierrez, A.; Rivera Arnda, A.; Moya Canderon, E.; Benzanilla Regato, J.L.; An Esp Pediatr. 1991 Jul; 35(1): 45-9.
12. Incidence and Management of Secondary Malignancies in Patients with Retinoblastoma and Ewing's Sarcoma. Smith, L.M.; Donaldson, S.S. Oncology-Huntingt. 1991 May; 5(5): 135-41; discussion 142, 147-8.
13. Retinoma. Balmer, A.; Munier, F.; Gailloud, C. Ophthalmic Paediatric Genet. 1991 Sep; 12 (3): 131-7.
14. Bone Sarcomas as second malignant neoplasms following childhood cancer. Newton, W.A. Jr.; Meadows, A.T.; Shimada, H.; Bunin, G.R.; Vawter, G.F. Cancer. 1991 Jan. 1; 67(1): 193-201.
15. Molecular Biology of the Human Retinoblastoma Gene. Lee, W.H.; Bookstein, R.E.; Lee, E.Y. Immunol Ser. 1990; 51; 169-200
16. Autologous Bone Marrow Transplantation in Pediatric Solid TumorsYaniv, I.; Bouffet, E.; Irle, C.; Negrier, S.; Biron, P.; Favrot, M. Philip, I. Brunat-Mentigny, M.; Philip, T. Pediatric Hematology and Oncology. 1990; 7(1): 35-46.
17. Segundo cáncer en pacientes pediátricos Sepulveda, L.E.; Beresi, V.; Quintana, J.; del Pozo, H. Rev Child Pediatr. 1990 Mar-Apr; 61(2): 82-6.
18. Segundo Tumor Maligno en Pediatria Schwartz, L.; Kupferman, J.; Picco, P. Medicina B Aires. 1990; 50 (2): 97-101.
19. Cutaneous Melanoma and Bilateral Retinoblastoma. Albert, L.S.; Sober, A.J.; Rhodes, A.R. Journal of the American Academy of Dermatology. 1990 Nov; 23 (5 Pt 2): 1001-4.
20. Transtentorial Herniation Caused by an Intracranial Mass Lesion Following High-Dose Methotrexate. Villareal, B.; Baum, L.G.; Vinters, H.V.; Feig, S.A. American Journal of Pediatric Hematology and Oncology. 1990 Summer; 12(2): 215-9.
21. Skeletal Scintigraphy in Patients With Bilateral Retinoblastoma. Pratt, C.B.; Crom, D.B.; Magill, L.; Chenaille, P.; Meyer, D. Cancer. 1990 Jan 1; 65(1): 26-8.
22. Forty-Year Experience With Second Malignancies After Treatment of Childhood Cancer: Analysis of Outcome Following the Development of Second Malignancy. Smith, M.B.; Xue, H.; Strong, L; Takahashi, H.; Jaffe, N.; Ried, H.; Zietz, H.; Andrassy, R.J. Journal of Pediatric Surgery. 1993 Oct; 28(10): 1342-8; discussion 1348-9.
23. Eye, brain and nervous system, thyroid, bone and connective tissue. Frisch, M.; Olsen, J.H. APMIS Suppl. 1993; 33: 156-82.
24. Pediatric Molecular Oncology. Kudson, A.G. Jr. Cancer. 1993 May 15; 71 (10 Suppl): 3320-4.
|
 Sends Victor some Email.
Sends Mike some Email.
|