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Every Day is a Good Day  Chapter Six

Berry Pix!!!

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Berry's Diagnosis & Treatment

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After diagnosis, your dog will have regularly scheduled treatment appointments based on his drug protocol. Typically, there is an initial period of several months of intensive therapy during which your dog is tested and treated every week. If this therapy is successful, as determined by more extensive tests, called "restaging" (discussed below), treatments are then spread out, and, if you are lucky, later spread out again. Some dogs reach a point at which the entire treatment cycle is completed, and if they are still in remission, treatment is stopped. These dogs either are cured or may come out of remission, in which case a new series of treatments may be commenced (see "Rescue Protocols," in Chapter 7). Chapters 6 and 7 describe from a lay person’s perspective how a treatment plan is formulated and carried out. This chapter discusses the examinations and tests that are performed as part of the regular treatment appointments, what information is being collected, and how that information is used in evaluating your dog’s condition and progress. Chapter 7 describes some of the drugs that are used in standard canine lymphoma chemotherapy as well as common drug reactions and side effects.

In addition to the chemotherapy itself, which Berry received at his appointments, VHUP performed numerous physical examinations and tests. Physical exams are pretty straightforward and have little or no effect on your dog, but the tests can be complicated, harder on your dog, and expensive. There are basically two different reasons for tests: some tests are done to determine if your dog can have his next chemotherapy treatment; other tests evaluate the status of your dog’s cancer. We had VHUP do all of the treatment related testing, but were a little more sparing on the other tests for the reasons discussed later. Understanding the purpose of each test helps you decide where to "draw the line". We’ll discuss this in the routine stuff first, then "restaging", and then some exotic tests.

The first task for the professionals at each treatment appointment is to assess your dog’s current condition. In the same way that the initial "staging" provided data for your dog’s overall diagnosis and treatment plan, the examination and tests performed at each visit provide a snapshot of data for that point in time and treatment session. The first step in this assessment is the conversation with you in the waiting room. At that time, the professionals learn about your dog’s general health since his last appointment. They may also ask specific questions (such as whether your dog has experienced diarrhea, vomiting, difficulty urinating, etc.). Your answers to these questions may indicate whether particular drug reactions or side effects have occurred. A physical examination is the next step, and blood work is frequently included. From time to time, lymph node and bone marrow aspirates may also be done. All of this information assists determining:

· Your dog’s overall health

· Whether the disease growing, static, or retreating

· Whether your dog can tolerate additional treatment, and if so, what type and how much

· If there are indications of possible reactions or side effects from prior chemotherapy

In the physical exam (sometimes referred to or noted by the doctors as the "PE"), the vets and oncology nurses -- CVTs -- check your dog for basic signs of disease. Your dog’s lymph nodes are palpated (professionally examined by hand) to determine their size and consistency (Are they apparent at all? Small and soft? Large and firm? Bigger or smaller compared to previous visits?). His abdomen is also palpated to determine the size of the spleen and other internal organs. For example, as reported in Chapter 2, Berry’s PE notations in the first three months of his treatment documented the slowly but steadily decreasing size of his lymph nodes and spleen.

The Oncology team will also weigh your dog. This simple step reveals two important things. First, if your dog is maintaining his weight or gaining, this is good news since both the cancer and drug side effects can cause weight loss. Second, your dog’s weight is often critical to calculation of the correct dosage of some chemotherapy drugs: enough must be administered for the drug to be effective, but too much medicine can be toxic to your dog.

In addition to the cancer–specific concerns, the physical exam in theory should identify other new physical problems that are not lymphoma related. Based on our experience, however, the oncologists tend only to see what they were looking for – cancer-related changes. On several occasions over Berry’s years of treatment, a condition that might have been observed during an oncology appointment turned into a significant problem the very next day. These included his puffy bone marrow aspiration wound, a hot spot on Berry’s neck, and a large hot spot under his tail. Near the end of his life, we also found an ominous looking tumor between the toes of Berry’s left front paw – probably another cancer, hidden in a place that none of us had thought to check. The point is: don’t expect the oncologists to find everything, or think you can give up your role as custodian of the "whole dog".

We may think of veterinarians as all-knowing, but, realistically, thorough inspection of your pet is your responsibility. The oncologists and other veterinary specialists attempt to be comprehensive, but each is focused on his or her own specialty or task and is not all-knowing or all-seeing. Especially if you have a thick-coated dog, the professionals will not find certain kinds of problems in relatively brief appointments. So, while your dog is in chemotherapy, literally keep in touch with his body. Brush or comb, but also pet, and firmly feel your dog’s head and neck, torso, and limbs -- as we learned, even be sure to check between his toes. Know the landscape, and tell the professional caregivers about it. For example, Berry had always had a small lump the size of two grains of rice on his torso. We asked VHUP aspirate the lump once early in his treatment to confirm it was benign. When it was aspirated again a month later by a well-intentioned student, we noted it on Berry’s treatment form so that it was not investigated further.

Complete blood count (CBC). The complete blood count is the most basic data gathering test used by the oncologists. The CBC provides critical information about the numbers of red and white blood cells, platelets, and hemoglobin present in the blood. Each of these blood components must be present in sufficient numbers in your dog’s blood to enable transport oxygen throughout the body (red), to fight infection (white), and to promote blood clotting (platelets). Without proper amounts of these vital components, your dog will be weak and anemic, unable to fight infection, and susceptible to internal bleeding.

Each of these blood components is made in the bone marrow where cells called "precursor cells" are produced. As discussed in Chapter 7, chemotherapy can suppress the production of these precursor cells in the bone marrow. As a result, the numbers of red and white blood cells and platelets in the CBC allows the doctors to infer how prior chemotherapy has affected your dog’s bone marrow as well as his ability to generate new blood cells. These numbers also inform the doctors about whether your dog can tolerate additional chemotherapy. If your dog becomes seriously anemic during chemotherapy, treatment must be postponed until the bone marrow has recovered sufficiently to produce needed blood cells; this can become a race against time if your dog’s lymphoma is also asserting itself. Berry was only mildly anemic during his treatment, but not so much so as to delay his treatment. Some dogs develop serious anemia or lose white blood cells, however.

When lymphoma is the cancer being treated, the doctors are also performing the CBC to count the number and kind of lymphocytes contained in a blood. This count can be done by machine or manually. How accurate the count is depends in part on how apparent your dog’s cancer cells are. In Berry’s case, it was sometimes difficult for the pathologists to distinguish between regular cells and cancer cells. A good explanation of the CBC can be read at http://www.perseusfoundation.org/oc.html (page 64).

Chemistry Screen or Blood chemistry. The chemistry screen or blood chemistry is a snapshot of how your dog’s body is functioning at a specific point in time. It aids in determining your dog’s overall health and whether your dog is having problems with his kidneys, liver, pancrease or other vital organs, which may be affected by either the disease or by the chemotherapy. A good explanation of the CBC can be read at http://www.perseusfoundation.org/oc.html (page 68).

The urinalysis shows the chemicals your dog is releasing in his urine. This information is compared against a "normal" profile for a healthy dog. If your dog’s values are abnormal, this may mean there is a problem with your dog’s kidneys or urinary tract. Abnormal levels of chemicals may reflect disease progression, or they may reflect damage to the kidneys resulting from the chemotherapy itself. In particular, Cytoxan may cause damage to your dog’s kidneys or bladder.

A sample for urinalysis is usually collected by gathering from the stream produced when your dog urinates. For some tests, a sterile sample may be desired (for example, if Cytoxan-related cystitis is suspected), in which case urine is aspirated from the bladder or obtained by passing a sterile catheter into the bladder through the urethra.

Material from your dog’s lymph nodes may be examined in one of several ways. "Aspiration" refers to the withdrawal of a very small amount of material, using a hollow needle, from the lymph node. The cells in the sample are then evaluated. A "biopsy" involves the removal of tissue. Both aspirates and biopsies are used in diagnosis and treatment. The limitation of an aspirate is that it provides information only about the precise location at which the needle is located, whereas a biopsy is a larger sample that provides more data. Occasionally, oncologists will remove the entire lymph node, known as a "whole node biopsy"; this procedure provides much more material to analyze. http://www.oncolink.upenn.edu/experts/article.cfm?c=3&s=32&ss=86&id=1236   Berry had many aspirates and they appeared to be accurate indicators of the status of his lymphoma.

One of the staging tests is a bone marrow aspiration, in which a hollow needle is inserted into the bone marrow in order to withdraw a sample to determine if the lymphoma has invaded the bone marrow. If your dog’s lymphoma has spread to the bone marrow, periodic aspiration of the bone marrow is important to determine if the bone marrow is "clear" or continues to shows the presence of lymphoma. In addition, bone marrow aspirates reveal -- in a more direct manner than the CBC -- the actual status of production of blood components – the red and white cells and platelets -- that is occurring in the bone marrow.

Bone marrow aspirates are taken by inserting a needle into your dog’s hip or shoulder. Even though only a small wound is visible, bone marrow aspiration is an invasive test that carries with it a risk of infection. You need to monitor the shaved area closely for any redness or swelling. Berry was the only dog in recent memory at VHUP to develop an abscess at his test site. The surface cut healed over quickly and passed muster on Berry’s next weekly visit to VHUP. Then, overnight, a golf-ball sized abscess mushroomed on Berry’s hip, resulting in a weekend trip to the Emergency Service. Each time Berry was subsequently re-staged, we closely monitored his bone marrow test site for swelling.

After a dog has been in chemotherapy a long time, his bone marrow may become "soft" or "spongy", meaning it is difficult to obtain a good diagnostic sample through aspiration. This happened to Berry after a year and a half of chemotherapy. On the last check-up of his first 18 month protocol, the doctors had to make several attempts before they obtained a "good" sample. We worried that this condition meant Berry was sick but it did not.

Getting your dog’s lymphoma into "remission" is the goal of chemotherapy. There is no guarantee that chemotherapy treatment will result in remission, although according to VHUP, about 80% of dogs with lymphoma will go into remission with treatment. http://www.oncolink.upenn.edu/types/article.cfm?c=22&s=69&ss=545&id=6020, http://www.vetmed.lsu.edu/oncology/lymphoma1.htm,

For dogs with external lymph node enlargement, the most common form of lymphoma, VHUP estimates an average remission time of 8-10 months with overall survival time of about one year.

http://www.oncolink.upenn.edu/types/article.cfm?c=22&s=69&ss=545&id=6020

What does remission mean?

Remission means that there is no detectable evidence of cancer. Remission does not necessarily mean that your dog has been cured – only that the disease has been beaten back. http://www.oncolink.upenn.edu/types/article.cfm?c=22&s=69&ss=545&id=6020

Generally speaking, the goal of chemotherapy in small animals – dogs and cats – is to slow down the disease and prolong life. This is because, unlike humans, dogs can’t tell us precisely how they feel and how treatment is affecting them. As a result, while treatment is aggressive, it is not as aggressive as in humans. Hence, there is less likelihood of a cure. If you are really lucky, your dog has been cured. Only time will tell. But even if not cured, your dog, like ours, may have wonderful, additional time treatment.

Remission is diagnosed using the same tests that are done in staging and during treatment, the physical condition of the lymph nodes, results of the CBC and lymph node aspirates, bone marrow aspirates, and imaging. As discussed below, we stopped short of the full set of tests.

Once remission has been achieved, it can last as little as a few weeks or the rest of your dog’s life. Remission may be sustained for several weeks or months while treatment continues. Remission may also be sustained after treatment ceases, either for some period of weeks or months (as in Berry’s case), or indefinitely, in which case your dog is considered cured. VHUP estimates the average remission time for external lymph node lymphoma at 8-10 months, with overall survival time of about one year. The anticipated duration of the remission may be predicted by the doctors based on the type of lymphosarcoma your dog has. But in fact they simply do not know which dogs will be at the low and high ends. Making up that average are dogs that achieve only brief remissions and dogs like Berry and others with remissions of 18 months or more. In addition, a small percentage of dogs are cured.

Dogs with lymphoma may have multiple remissions. VHUP’s materials, and some of the other literature, state that the first remission is typically the longest one.

For canine lymphoma treatment, as a very general rule of thumb about one half of patients will go into a second remission, and this remission will generally last about one half as long as the first remission. Treatment is usually (but not always) more time intensive and has more side effects than the initial treatment protocol did.

http://www.oncolink.upenn.edu/experts/article.cfm?c=3&s=32&ss=86&id=2086

However, Berry’s case, and at least two other cases found on the internet, involved lengthy second, or even third remissions. One website (www.pyrbred.org/lymphoma/html) reports a Great Pyrenees whose third remission – 16 months – was twice as long as the first and second remissions combined. And another site (www.haileybell.homestead.com/HaileysSotry.html) reports four remissions of increasing duration – 5, 6, 8, and over 18 months.

Berry did substantially better than VHUP’s predictions for both remission, and for overall survival. His first remission, officially diagnosed at his June 8, 2000 restaging, lasted until December 2001, a total of 18 months. He was in chemotherapy for most of that time, until August 2001. After chemotherapy stopped, he remained in remission for 4 more months, until December 2001, when his cancer began to seemed to be reasserting itself. Berry’s second remission lasted from January 2001 until June 2003, another 18 months. His third remission was achieved sometime in the summer of 2003 and lasted about two months -- until two weeks before his death on October 13, 2003.  His death was probably caused by a cancer other than the lymphoma, so we don’t know how long the third remission might have lasted if other disease had not been present.

If your dog was "staged" when he began treatment, in-depth tests were performed at that time to obtain baseline data about his condition. These tests included a CBC, chemistry screen, and urinalysis. Aspirates of the lymph nodes and the bone marrow, chest radiographs (x-rays) and an abdominal ultrasound may also have been performed. Restaging usually occurs when your dog reaches predetermined points in his chemotherapy protocol. The purpose of restaging is to do a similar, detailed evaluation of your dog’s condition before modifying one or more aspects of his treatment protocol. If your dog has been on a protocol similar to Berry’s and the chemotherapy appears to be controlling his lymphoma, the first restaging will typically occur around 16 weeks. At this time, the weekly sequential chemotherapy protocol often begins to affect a dog’s body. As a result, if the data obtained in the restaging indicate your dog’s lymphoma is under control, the time between treatments will be lengthened to 2 weeks.

In Berry’s first 18 months of treatment, he was restaged three times. The first was in June 2000, 4 months after his treatment began. The tests confirmed that his lymphoma was in remission, and his treatments were spread to every other week. He was restaged again in March 2001, at the end of an 8-month treatment cycle. Berry's blood work was in normal limits and his chest x-rays showed no cancer in the lungs or lymph nodes; in addition, his chemistry screen characterized by the VHUP doctors as "beautiful" and his bone marrow was "even more beautiful -- perfectly normal." Berry's treatment cycle was spread out to every 3 weeks. Berry’s third and final restaging came at the end of the 18 month treatment cycle. Berry again came through with flying colors. At each of these restagings, VHUP recommended an abdominal ultrasound. This was the one test we did not do. Our reasoning was that if the other tests were clean, we would take the risk.

The standard treatment protocols diminish the frequency of treatment over time, eventually reaching a point at which chemotherapy is terminated. Berry was one of the lucky dogs who makes it to the point where the doctors consider discontinuing chemotherapy because the entire treatment protocol had been completed without recurrence of lymphoma. After 18 months of therapy, in August 2001, we were counseled that our choice was either to discontinue chemotherapy, or to continue it for another six months. There was little hard data available on which to base a decision. We were told that, of the relatively small percentage of dogs in treatment that make it to this point, 60-80% would not have a recurrence, but 20-40% would.   We were also told that relapse was somewhat more likely in dogs with indolent small to intermediate cell lymphoma such as Berry had. However, VHUP also had had more success in achieving a significant second remission in dogs with Berry's type of lymphoma than with other types. In consultation with Berry's oncologist, we decided to stop chemotherapy. Continuing might have kept him in remission for another six months, but our oncologist also indicated that it could be more difficult to achieve a second remission if Berry was still in chemotherapy at the time the lymphoma returned.

We gave Berry a break and let VHUP monitor him in monthly visits. We hoped that, should Berry come out of remission, effective treatment would be possible. Of course, in our hearts, we hoped that Berry was cured. It was possible he was, since Berry had never come out of remission even as his treatments had been spread out over the last six months of his protocol.

If your dog achieves remission and later "comes out" of remission, what does this mean? What is the likelihood that a second remission will be achieved and how long will it last? The answer in both cases is, "it depends". It may depend in part on the length of the first remission. As discussed above, generally, the first remission is the longest one, and subsequent remissions are shorter. A dog with a lengthy first remission may not have aggressive lymphoma, and, like Berry, such a dog may have a lengthy second remission. But at least some dogs with relatively short first remissions go on to have significantly longer second or even third remissions. No one knows exactly what will happen to your dog.

It also may depend on how far "out" of remission your dog is when the relapse is identified. In January 2002, the first time Berry was officially diagnosed as being out of remission, he appeared to be tettering on the brink – it took several VHUP oncologists and pathologists to make the determination. In late December, his mandibular lymph nodes (under the jaw) felt a bit firm, and his prescapular (in front of the shoulder) and popliteal (behind the knees) nodes felt asymmetrical but were too small to aspirate. A week later, the nodes were mildly enlarged, and although the sample was compromised, preliminary results indicated possible lymphoma in his bone marrow. Even after further diagnostic work, VHUP could only say he was "probably out" of remission, but we decided not to wait for the cancer to creep further. So Berry moved gracefully back into treatment and his second, 18 month long remission without missing a beat. When he came out of remission the second time, in June 2003, he was again borderline. VHUP considered 20% small lymphocites in the bone marrow as indicative of lymphoma, and Berry’s sample read at 17%, so we began a third course of chemotherapy. In each of these cases, had his disease been more advanced, perhaps it would have been more difficult to achieve the second and third remission.

Why is each successive remission harder to achieve? The VHUP doctors theorized to me that it is the the least aggressive cancer cells that are killed off by chemotherapy treatment. The cancer cells that survive treatment, lurking in the background to surge back when chemotherapy is reduced or discontinued, are the strongest, most drug resistant cancer cells. Other factors may also be involved. Certain powerful drugs like Adriamycin can only be used a limited number of times in a dog’s chemotherapy before there is a risk of toxicity. In addition, some drugs may also be inappropriate for your dog because he had reactions or debilitating side effects when they were used. Finally, the cancer may have developed resistance to a drug.

This is illustrated by our dog’s case, where certain drugs were no longer usable, but other options still remained. Cytoxan was no longer an option for Berry after 2001 because of bladder problems it apparently had caused. Then, in 2003, when Berry came out of remission, it was the very last month of his treatment protocol and he was still taking Leukeran, albeit very small amounts. Leukeran had become ineffective, either because the cancer had developed resistance, or the reducing dosage had become too small, so he was moved to Lomustine. If, as in Berry’s case, some drugs cannot be used and the lymphoma has developed resistance to other previously used drugs, the list of effective chemotherapeutic agents for your dog may diminish as treatment progresses. This is where the knowledge and creativity of your oncologist come in.

Finally, chemotherapy itself is hard on your dog. As discussed throughout these materials, in addition to killing cancer cells, chemotherapy adversely affects beneficial cells and essential bodily organs and systems. The heart, liver, kidneys, bladder, GI tract, and the bone marrow -- that produces the essential components of blood that carry oxygen to other organs, fight infection, and promote healing – are all affected by chemotherapy. Your dog’s body must work harder to maintain health – to produce lost blood components, to replace damaged cells, and to handle drug side effects. At some point your dog’s body may simply become too tired to maintain the status quo AND fight its disease.

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