Date: January 12, 2005
by Chaya Venkat
Have you heard the story about the king who lost a crucial battle as well as his life because his horse became lame … because the horse lost its shoe … because a nail fell off? "My kingdom for a horse!" the king is reported to have said, desperately trying to hang on to his life, reflecting on equine footwear security. With a little bit of prudent advance planning, he would have seen to it that he had an extra horse around, or at the very least a few nails in his pocket, for repairing horse-shoes.
When you are battling with cancer and cancer therapy, it may seem silly to worry about the odd "cold sore" or "fever blister", or the slightly inflamed gums that bleed just a little when you brush. It is hard to keep up the discipline of brushing after each meal, make and keep the regular appointments with your dentist, when you have so many other things to worry about. There is also the usual hassle of dentists not knowing too much about the risks associated with cancer therapy, and local oncologists not really bothering about dental issues. These "silos" that insulate our experts from broad and across -the-board awareness of problems faced by cancer patients can be the death of us all. Remember all the stories we hear about dermatologists who do not know CLL patients are more at risk of aggressive skin cancer, and CLL specialists who do not deign to worry about skin related issues? The other day I spent an intense hour in conversation with an oncological dentist. The results of that conversation are this article. Take care of your lips, teeth, gums and mucosal lining of your mouth. Not doing so may mean intense pain, inability to eat, extreme weight loss, longer hospital stays, poorer response to therapy, sepsis, death due to invasive infection. Any and all of the above. Have I got your attention? My kingdom for a healthy mouth!
To tell you the truth, I was a bit skeptical when I first heard of mucosal problems during cancer therapy. How bad can a "fever blister" be, I asked my self, in the grand scheme of things? After all, these are cancer patients undergoing chemotherapy. If all they had to worry about was a cold sore upsetting their social life that is not such a big deal. Right? Wrong!! Here is a link to a long article in eMedicine: click on it and scroll down to the picture gallery almost at the bottom of the article. Calling these mammoth lesions "cold sores" is like calling the recent rains we have had in Arizona mere winter showers.
OK, this article and the pictures got my attention, I did my due diligence digging for solid research on the subject.
Below are a slew of abstracts that address questions #1 and #2, but not too many satisfactory answers to question #3. I have been selective in picking only those from top rated institutions. "Mucosal damage" is not restricted to just the inside of your mouth, it can attack just about all of the lining of your GI tract. The words "considerable pain" are a common theme in all of these abstracts. Since mucosal damage is caused by fungal, bacterial or viral pathogens, immune suppressed patients are particularly at risk. If you are neutropenic, have been through heavy duty chemo for, say, a bone marrow transplant and the like, you are a prime candidate for this particular little pain. I have highlighted the relevant portions in each abstract. Where full texts of the articles are available free of charge, I have included the links. It is not a pretty story, but there is a small light at the end of the tunnel. If you are a CLL spouse watching your loved one loosing weight, becoming skinnier by the day, perhaps it is because mucosal damage has made it so hard to eat a decent meal! You might want to learn about things you can do, things you can discuss with your doctor.
Comment: Dr. Sonis at Harvard seems to be a big name in this area. For patients undergoing bone marrow transplants (who are by definition deeply immune suppressed as part of the conditioning regimen ahead of the transplant), folks with a bad case of mucositis have almost four times higher chance of dying by the time the 100 day mark rolls around. Here is what surprises me in his abstract: hospital charges are more than 42 thousand dollars higher for these patients! Wow. Surely that extra big hospital bill should make some public policy or insurance company folks sit up and take notice! It is time we found some solutions to this pervasive problem.
J Clin Oncol. 2001 Apr 15;19(8):2201-5.
Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation.
Sonis ST, Oster G, Fuchs H, Bellm L, Bradford WZ, Edelsberg J, Hayden V, Eilers J, Epstein JB, LeVeque FG, Miller C, Peterson DE, Schubert MM, Spijkervet FK, Horowitz M.
Brigham and Women's Hospital and Harvard School of Dental Medicine, Boston, MA.
PURPOSE: To explore the relationship between oral mucositis and selected clinical and economic outcomes in blood and marrow transplant patients.
PATIENTS AND METHODS: Subjects consisted of 92 transplant patients from eight centers who participated in a multinational pilot study of a new oral mucositis scoring system (Oral Mucositis Assessment Scale [OMAS]). In the pilot study, patients were evaluated for erythema and ulceration/pseudomembrane formation beginning on the first day of conditioning and continuing for 28 days. We examined the relationship between patients' peak OMAS scores and days with fever (body temperature > 38.0 degrees C), the occurrence of significant infection, days of total parenteral nutrition (TPN), and days of injectable narcotic therapy (all over 28 days), days in hospital (over 60 days), total hospital charges for the index admission, and vital status at 100 days.
RESULTS: Patients' peak OMAS scores spanned the full range of possible values (0 to 5) and were significantly (P <.05) correlated with all of the outcomes of interest except days with fever (P =.21). In analyses controlling for type of graft (autologous v allogeneic) and study center, a 1-point increase in peak OMAS score was associated with (1) 1.0 additional day with fever (P <.01), (2) a 2.1-fold increase in risk of significant infection (P <.01), (3) 2.7 additional days of TPN (P <.0001), (4) 2.6 additional days of injectable narcotic therapy (P <.0001), (5) 2.6 additional days in hospital (P <.01), (6) $25,405 in additional hospital charges (P <.0001), and (7) a 3.9-fold increase in 100-day mortality risk (P <.01). Mean hospital charges were $42,749 higher among patients with evidence of ulceration compared with those without (P =.06).
CONCLUSION: Oral mucositis is associated with significantly worse clinical and economic outcomes in blood and marrow transplantation.
J Support Oncol. 2004 Nov-Dec;2(6 Suppl 3):3-8.
Oral mucositis in cancer therapy.
Department of Oral Medicine Infection and Immunity, Harvard School of Dental Medicine, Boston, MA.
Oral mucositis induced by radiation therapy and chemotherapy is a frequently occurring toxicity in patients with cancer. Severe mucositis has a major impact on patient daily functioning, well-being, and quality of life. It can also compromise a patient's ability to tolerate planned therapy, resulting in missed doses or dose reductions. Mucositis negatively affects other health outcomes as well, increasing the risk of opportunistic infections and mortality due to sepsis. It also imposes a significant economic burden, since extended hospitalization and greater analgesic use can substantially increase treatment costs. A five-phase model of the pathobiology of mucositis has been proposed that facilitates our understanding of mucositis pathogenesis and the complex interactions that occur in response to tissue insult. Application of this evolving model has aided in the development of mechanistically based therapies for the prevention and treatment of mucositis. Continued research is needed to optimize when these treatments should be administered during the course of cancer therapy to maximize therapeutic benefit.
Comment: Did you know roughly 40% of all patients who receive chemotherapy are likely to get some degree of mucositis? Among the drugs that are known to be bad actors in this regard are a couple that you may have heard of by now - cyclophosphamide and Cytarabine (cytosine arabinoside). It is becoming ever more popular to keep increasing the alphabet string of drugs, looking for higher response statistics. Just look at this trend in the last few years: F, FR, FRC, CFAR. (F: fludarbaine. R: Rituxan. C: cyclophosphamide. A: alumtuzumab, aka Campath). One can only hope the pain of mucosal lesions is taken into account when calculating the "cost" of these improving response statistics.
Mucositis: Its Occurrence, Consequences, and Treatment in the Oncology Setting.
Pico JL, Avila-Garavito A, Naccache P.
Bone Marrow Transplantation Unit, Institut Gustave Roussy, 94805 Villejuif, France.
INTRODUCTION: Mucositis induced by antineoplastic drugs is an important, dose-limiting, and costly side effect of cancer therapy. The ulcerative lesions produced by mucotoxic chemoradiotherapy are painful, restrict oral intake and, importantly, act as sites of secondary infection and portals of entry for the endogenous oral flora. The overall frequency of mucositis varies and is influenced by the patient's diagnosis, age, level of oral health, and type, dose, and frequency of drug administration. Some degree of mucositis occurs in approximately 40% of patients who receive cancer chemotherapy. Approximately one-half of those individuals develop lesions of such severity as to require modification of their cancer treatment and/or parenteral analgesia. The condition's incidence is consistently higher among patients undergoing conditioning therapy for bone marrow/peripheral blood progenitor cell transplantation, continuous infusion therapy for breast and colon cancer, and therapy for tumors of the head and neck associating concomitant chemotherapy and radiotherapy. Among patients in the high-risk protocols, severe mucositis occurs with a frequency in excess of 60%. Concomitant with mucositis is often a chemotherapy-induced myelosuppression. The neutropenia that results puts the patient with oral mucositis at significant risk for systemic infection. Patients with mucositis and neutropenia have a relative risk of septicemia that is greater than four times that of individuals without mucositis. The morbidity of all mucositis can be profound. It is estimated that approximately 15% of patients treated with radical radiotherapy to the oral cavity and oral pharynx will require hospitalization for treatment-related complication. In addition, severe oral mucositis may interfere with the ability to deliver the intended course of therapy, leading to significant interruptions in treatment, and possibly impacting on local tumor control and patient survival. It is also not unusual for mucositis to necessitate delays in cancer chemotherapy particularly with those agents that are known to be mucotoxic, including 5-fluorouracil with or without folinic acid, methotrexate, doxorubicin, etoposide, melphalan, cytosine arabinoside and cyclophosphamide. In addition to its impact on a patient's treatment course, on quality of life, and morbidity and mortality, mucositis can also have a significant economic cost. This is particularly true in the autologous and allogeneic bone marrow transplant settings for hematologic malignancies, where the length of hospital stay may be prolonged due to severe mucositis.
Comment: I think we have answered the first and second question in our list. Mucositis is very much an issue for CLL patients, and yes, the drugs commonly used in treating CLL patients are in the list of potential culprits. The third question is the most important one. What can we do about it? 90 patients took part in this study. Roughly half rinsed 3 times a day with a chlorhexidine product, an antiseptic. The other half did not. The antiseptic rinse did its job, there were fewer bacteria in the mouth after rinsing. But to the disappointment of the researchers, not only did this not reduce the number of patients who got severe mucositis, there was an increased risk of mucositis in the experimental group! They concluded, this antiseptic mouthwash seemed to enhance the risk of mucositis, and its nasty side effects. Think about that as you swish away with the latest Listerine type of mouthwash.
Every oncologist and cancer hospital seems to have its own version of a "magic mouthwash". The second abstract below compared three mouthwashes, plain old salt + baking soda, the infamous chlorhexidine discussed above, and a "magic" mouthwash consisting of lidocaine, Benadryl and Maalox. Guess what, in this large group of 200 patients, there was no difference between the three mouthwashes. The researchers concluded the old wives' remedy of gargling with salt and soda water was just as good, and a whole lot cheaper.
J Hosp Infect. 2003 Apr;53(4):283-91.
Do cancer patients with chemotherapy-induced leukopenia benefit from an antiseptic chlorhexidine-based oral rinse? A double-blind, block-randomized, controlled study.
Pitten FA, Kiefer T, Buth C, Doelken G, Kramer A.
Institute of Hygiene and Environmental Medicine, University of Greifswald, Germany.
Patients undergoing cancer chemotherapy frequently suffer from mucositis, particularly if they become leukopenic (leucocytes <1000/microL). To identify a possible benefit from antiseptic rinsing of the oral cavity, 47 patients were randomized to rinse either with a chlorhexidine-based product (chlorhexidine concentration 0.3%; N=24) or with an amine-stannous fluoride combination (control group; N=23). Patients were asked to rinse three times a day for 30s from the beginning of chemotherapy until the end of leukopenia. Before rinsing, as well as during and after leukopenia, aerobic and anaerobic bacteria in the oral cavity were counted. At the same time, the patients were assessed for mucositis. In the chlorhexidine-based group, a significant decrease of the aerobic (P=0.042) and anaerobic (P=0.008) bacterial flora was identified. In the control group, the numbers of aerobic and anaerobic bacteria remained unchanged (P>0.05). Fifteen patients in the chlorhexidine-based group had a C-reactive protein (CRP) increase >50mg/L, compared with only eight patients in the control group [odds ratio: 3.13, confidence interval (CI) 0.82-12.39]. Nine patients in the chlorhexidine-based group but only two patients in the control group developed severe mucositis. This difference was statistically significant with an odds ratio of 6.30 (CI: 1.02-49.67). As not all of the 47 patients developed severe leukopenia, a separate analysis was carried out for patients with <1000 leucocytes/microL for a minimum of three days. The results of the microbial counts were very similar, with a clear reduction in the chlorhexidine group and no major alterations in the control group. Twelve of 15 patients in the chlorhexidine-based group had a CRP >50mg/L whereas only eight of 15 patients did so in the control group, which can be regarded as a slightly elevated risk for a CRP increase in the former group. Seven of 15 patients developed severe mucositis in the chlorhexidine-based group, but only two of 15 patients in the control group. These differences were not significant, but patients treated with chlorhexidine-based product seemed to have more problems with inflammation of the oral mucous membranes, resulting in an elevated mucositis score and a CRP increase. Other parameters such as body temperature or application of antibiotics did not differ between the two groups. We conclude that treatment with the chlorhexidine-based product did not provide a clinical benefit for cancer chemotherapy patients. On the contrary, the risk of mucositis and clinical sequelae seems to be enhanced, although the counts of micro-organisms on the oral mucous membranes are significantly reduced.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2000 Jul;90(1):39-47
Randomized clinical trial of the effectiveness of 3 commonly used mouthwashes to treat chemotherapy-induced mucositis.
Dodd MJ, Dibble SL, Miaskowski C, MacPhail L, Greenspan D, Paul SM, Shiba G, Larson P.
Department of Physiological Nursing, School of Nursing, UCSF, San Francisco, CA
OBJECTIVE: To test the effectiveness of 3 mouthwashes used to treat chemotherapy-induced mucositis. The mouthwashes were as follows: salt and soda, chlorhexidine, and "magic" mouthwash (lidocaine, Benadryl, and Maalox).Study Design: A randomized, double-blind clinical trial was implemented in 23 outpatient and office settings. Participants were monitored from the time they developed mucositis until cessation of the signs and symptoms of mucositis, or until they finished their 12-day supply of mouthwash. All participants followed a prescribed oral hygiene program and were randomly assigned a mouthwash. Nurses used the Oral Assessment Guide for initial assessment and taught patients how to assess their own mouths, then phoned the patients every other day to gather status reports.
RESULTS: In 142 of 200 patients, there was a cessation of the signs and symptoms of mucositis within 12 days. No significant differences in time for the cessation of the signs and symptoms were observed among the 3 groups.
CONCLUSIONS: Given the comparable effectiveness of the mouthwashes, the least costly was salt and soda mouthwash.
Comment: So, where is the silver lining? Is there anything we can do to help matters? I asked my contacts at the Mayo Clinic the same question. What is their "best practice" in this regard? The answer - suck on ice. The fancy name for it is "cryotherapy", means the same thing as sucking on small pieces of ice. Keeping the inside of your mouth cold seems to help with the symptoms, and who knows perhaps it will help with the healing process as well. Talk about low-tech answers!
But, there do seem to be some more high-tech solutions just round the corner. One of the reasons for mucosal problems during therapy is that chemo drugs target and kill rapidly proliferating cells. The cells lining the inside of your mouth and the rest of your GI tract fall into the category of cells that are made to multiply rapidly. This makes sense since there is a lot of wear and tear on these cells and the body is used to replacing them frequently as they wear out. This very feature of the mucosal cells makes them prime targets for chemotherapy and they are killed in vast numbers as therapy proceeds. Now comes the new growth factor, called "fibroblast growth factor-20 (rHuKGF; palifermin), which helps the body repair the damage, heal the wounds.
The second abstract below from the City of Hope describes their double-blinded phase 3 clinical trial, with a large cohort of 212 patients. Half of the patients got palifermin, the growth factor. The other half got a placebo. In the lucky bunch that got the palifermin, a mere 63% got serious oral mucositis. That sounds terrible, but not when you compare it against the control group. A whopping 98% of these poor guys got severe mucositis. Furthermore, the group that got the palifermin recovered sooner, in 6 days, while the control group folks took 9 days to recover. Hey, that is three extra days of pain and potential for things getting out of control. This is the first good news I have seen on this subject in a well conducted and detailed study that shows clear benefit for use of this drug.
Semin Oncol. 2004 Jun;31(3 Suppl 8):35-44.
Mucosal damage: a major risk factor for severe complications after cytotoxic therapy.
Peterson DE, Cariello A.
Department of Oral Diagnosis, School of Dental Medicine, Cancer Center, University of Connecticut Health Center, Farmington, CT 06030-1605
The oral and gastrointestinal mucosa is frequently damaged during chemotherapy and radiotherapy in patients with cancer, leading to a high incidence of mucositis (ie, oral, esophageal, lower gastrointestinal tract mucositis). Patients with mucositis often experience considerable pain and discomfort. Furthermore, neutropenic patients with mucositis have an increased risk of potentially life-threatening infections as well as prolonged hospital stays. Mucositis may also require that subsequent chemotherapy or radiotherapy doses be reduced, thereby potentially compromising the efficacy of cancer therapy. Standard care for oral mucositis is based on effective oral hygiene, appropriate analgesia, infection management, and parenteral nutrition when needed; few other approaches have been shown to be effective. The evaluation of new options to treat and prevent mucositis rather than control the symptoms is therefore an urgent priority. A comprehensive understanding of the complex pathobiology of mucositis will help to identify potential targets for new drugs. Promising investigational approaches have recently emerged. These include fibroblast growth factor-20, which is effective in animal models of chemotherapy/radiation-induced mucosal toxicity, and is being investigated in clinical studies. The candidate that is most advanced in terms of drug development is recombinant human keratinocyte growth factor (rHuKGF; palifermin), which in phase III clinical trials was shown to reduce the severity and duration of oral mucositis and improve clinical sequelae.
N Engl J Med. 2004 Dec 16;351(25):2590-8.
Palifermin for oral mucositis after intensive therapy for hematologic cancers.
Spielberger R, Stiff P, Bensinger W, Gentile T, Weisdorf D, Kewalramani T, Shea T, Yanovich S, Hansen K, Noga S, McCarty J, LeMaistre CF, Sung EC, Blazar BR, Elhardt D, Chen MG, Emmanouilides C.
City of Hope National Medical Center, Department of Hematology and Hematopoietic Cell Transplantation and Kaiser Permanente BMT Program, Duarte, Calif 91010
BACKGROUND: Oral mucositis is a complication of intensive chemotherapy and radiotherapy with no effective treatment. We tested the ability of palifermin (recombinant human keratinocyte growth factor) to decrease oral mucosal injury induced by cytotoxic therapy. METHODS: This double-blind study compared the effect of palifermin with that of a placebo on the development of oral mucositis in 212 patients with hematologic cancers; 106 patients received palifermin (60 microg per kilogram of body weight per day) and 106 received a placebo intravenously for three consecutive days immediately before the initiation of conditioning therapy (fractionated total-body irradiation plus high-dose chemotherapy) and after autologous hematopoietic stem-cell transplantation. Oral mucositis was evaluated daily for 28 days after transplantation.
RESULTS: The incidence of oral mucositis of World Health Organization (WHO) grade 3 or 4 was 63 percent in the palifermin group and 98 percent in the placebo group (P<0.001). Among patients with this degree of mucositis, the median duration of mucositis was 6 days (range, 1 to 22) in the palifermin group and 9 days (range, 1 to 27) in the placebo group. Among all patients, regardless of the occurrence of mucositis, the median duration of oral mucositis of WHO grade 3 or 4 was 3 days (range, 0 to 22) in the palifermin group and 9 days (range, 0 to 27) in the placebo group (P<0.001). As compared with placebo, palifermin was associated with significant reductions in the incidence of grade 4 oral mucositis (20 percent vs. 62 percent, P<0.001), patient-reported soreness of the mouth and throat (area-under-the-curve score, 29.0 [range, 0 to 98] vs. 46.8 [range, 0 to 110]; P<0.001), the use of opioid analgesics (median, 212 mg of morphine equivalents [range, 0 to 9418] vs. 535 mg of morphine equivalents [range, 0 to 9418], P<0.001), and the incidence of use of total parenteral nutrition (31 percent vs. 55 percent, P<0.001). Adverse events, mainly rash, pruritus, erythema, mouth and tongue disorders, and taste alteration, were mild to moderate in severity and were transient.
CONCLUSIONS: Palifermin reduced the duration and severity of oral mucositis after intensive chemotherapy and radiotherapy for hematologic cancers.
Comment: Apparently the FDA had the same take on these results as I did. Upon completion of phase III trials and the positive results reported above, the FDA has approved palifermin as the first drug available for the prevention of mucositis. Below is a press release, hot off the presses, for your reading pleasure. Notice, at this point in time this drug manufactured by Amgen has been approved for leukemia patients undergoing bone marrow transplants, not for the garden variety patient undergoing, say, FRC therapy with all that lovely cyclophosphamide. But then, the FDA has not approved Rituxan as a single agent for treating CLL patients, either. That has not stopped many patients making that their therapy of choice. If you are undergoing therapy, and your mouth is sore as hell to the point where you cannot talk, eat or even smile, do yourself a favor, talk to your doctor about palifermin. Remember that name, trade name Kepivance. I am willing to bet most of CLL patients will have reason to think of this drug at some point in their saga.
New Drug for Mouth Sores after Bone Marrow Transplants – Palifermin Approved for Leukemia, Lymphoma Patients
Article date: 2004/12/29.
From: ACS News Center.
Leukemia and lymphoma patients who need a bone marrow transplant now have a drug to help them cope with one of the treatment's most common side effects: mouth sores (called oral mucositis). Most patients develop these mouth sores, which are often painful enough to need treatment with intravenous narcotics.
The US Food and Drug Administration has approved palifermin (sold as Kepivance), after a study showed it cut the severity of mouth sores and helped them heal faster. The study was published in the New England Journal of Medicine (Vol. 351, No. 25: 2590-2598).
The drug is the first to be approved to treat this painful side effect of the high-dose chemotherapy and radiation needed before a bone marrow transplant.
"Until now. the most we could do for our patients was to give them ice chips and narcotics to try and manage their pain," said Patrick Stiff, MD, in a statement. He was one of the study's lead investigators and is director of the Cardinal Bernardin Cancer Center at Loyola University Health System.
Less Pain with Palifermin
Stiff and his colleagues studied 212 people with leukemia, Hodgkin disease, non-Hodgkin lymphoma, or multiple myeloma who were having a bone marrow or stem cell transplant. Half the patients received palifermin, and half were given a placebo.
Nearly all the patients in the study developed some degree mouth sores. But severe mouth sores were less common and healed more quickly in the people who received palifermin. Just 68% of those patients developed grade 3 sores (where the patient can only swallow liquid) or grade 4 sores (where the patient can't eat at all and must be fed through a vein). By contrast, 98% of the people on placebo reported grade 3 or 4 sores. The sores lasted about 6 days in the patients on palifermin, and 9 days in those on placebo.
The people who took palifermin also had less pain than people on placebo; they used less narcotic pain medication and didn't need to use it for as long a time. And, fewer palifermin patients needed vein feeding. Side effects of the drug included rash, itching, skin tingling and redness, taste changes, and tongue thickness. These side effects were not severe. The research was funded by Amgen, the drug's maker.
Drug Makes Cells Grow
Palifermin is a type of drug known as a keratinocyte growth factor. It is a form of a human protein. The drug helps the cells lining the mouth grow and multiply. This action counteracts the damage to the lining of the mouth caused by the high-dose chemotherapy and radiation given before a bone marrow transplant.
Palifermin is given directly into a vein. Patients get the drug on each of the 3 days just before high-dose chemotherapy and radiation, and for 3 more days right after the bone marrow transplant.
So far, palifermin is only approved for use in patients with leukemia, myeloma or lymphoma who receive high doses of chemotherapy and radiation therapy followed by stem cell rescue. Amgen said about 11,000 US adults with blood cancers receive bone marrow transplants each year.
Palifermin is being tested in patients with other types of cancer.
Copyright 2005 © American Cancer Society, Inc.
Moffitt Center Pharmacotherapy Article;
Best Practice Information Sheet from the Joanna Briggs Institute;
Oncology Nursing Practice;
Article on Mouth Sores;
NCI Supportive Care Guidelines for Professionals.
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Topic: CLL Complications