CLINICIAN INTERVIEW THE CHALLENGE OF MUCOSITIS IN PATIENTS UNDERGOING HSCT. Interview with Ricardo T. Spielberger, MD

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1 THE CHALLENGE OF MUCOSITIS IN PATIENTS UNDERGOING HSCT Interview with Ricardo T. Spielberger, MD Dr Spielberger is a staff physician and researcher in the Division of Hematology and Hematopoietic Cell Transplantation and the Kaiser Permanente Bone Marrow Transplantation (BMT) Program, Duarte, California. He received his medical degree from the Universidad Central de Venezuela in Caracas, Venezuela, in Since joining the City of Hope National Medical Center in 1993, Dr Spielberger has participated in several clinical trials related to hematopoietic stem cell transplantation (HSCT). This research has included roles as investigator in a phase III multicenter study of valganciclovir for the prevention of late cytomegalovirus (CMV) infection after allogeneic HSCT and as the City of Hope s investigator in the phase III multicenter trial of recombinant human keratinocyte growth factor (KGF) in the reduction of oral mucositis associated with HSCT. A senior clinical editor for Advanced Studies in Medicine (ASiM) interviewed Dr Spielberger to discuss the challenges of mucositis in patients undergoing HSCT. ASiM: Where does mucositis fit in the larger picture of BMT/HSCT therapy? Dr Spielberger: It can be a serious and frequent complication. All the measures used to prevent mucositis have not worked well, so mucositis is going to happen, especially with certain conditioning regimens. We expect the occurrence of mucositis, and we are prepared to manage it. The amount of time spent dealing with mucositis is directly proportional to the severity of mucositis in the patient. Many patients have mucositis that is quite manageable, but if mucositis is severe, as it tends to be with certain conditioning regimens, then closer attention must be paid to prevent serious complications. ASiM: It s been said that 100% of the patients having high-dose chemotherapy for HSCT develop some degree of oral or gastrointestinal (GI) mucositis. Is this true in your experience? Dr Spielberger: I would agree that almost all patients develop some degree of mucositis, but not all patients have severe mucositis. Again, it depends very much on the conditioning. Some conditioning regimens for autologous transplantation will produce severe mucositis almost 100% of the time as in our recent palifermin (recombinant KGF) study in which 98% of the group receiving a placebo with total body irradiation and high-dose etoposide and cyclophosphamide developed severe mucositis. With other regimens, such as some new ablative regimens used in allogeneic transplantation, immunotherapy rather than high-intensity conditioning is the key to success, and the incidence of mucositis often is rare or minimal. ASiM: Is mucositis really a dose-limiting adverse effect in BMT/HSCT? Dr Spielberger: In autologous transplantation the dose of a conditioning regimen usually cannot be reduced, if you are concerned about mucositis. They are established doses. In this setting, the premise is that more is better, thus the intensity of the conditioning is not reduced even if there is concern about the risk of Advanced Studies in Medicine S311

2 mucositis in a particular patient. What can be done in advance is the selection of a regimen that may be less toxic for a particular patient, which is one of the reasons some centers don t use radiation or choose a particular alternative regimen for older patients. With allogeneic transplantation, the intensity of the conditioning is less critical to outcome and reduced intensity conditioning is becoming more common, thus it s easier to consider limiting the dose in a patient at high risk for mucositis or to decrease the risk of other toxic adverse effects. ASiM: What are the potential benefits, beyond patient quality of life, in preventing mucositis in patients undergoing BMT and HSCT? Dr Spielberger: First, if the incidence or severity of this toxicity can be reduced, then the resulting morbidity also may be reduced. A reduction can be made in the need for antibiotics and parenteral feeding and length of hospitalization. Plus overall mortality may improve because, for example, there are fewer infections and complications related to mucositis. The other theoretical benefit of limiting mucositis relates to the dose-limiting effects we were just discussing. If mucositis can be prevented, then the intensity of the conditioning regimen may also be increased. ASiM: Within the City of Hope, who is the handson expert in managing oral mucositis? Dr Spielberger: In our center, the physicians and nurses usually recognize and diagnose the mucositis. We also have a team of respiratory therapists and pulmonary intensivists who can, when requested, come in to evaluate the patients. The nurses are involved in the day-to-day care. ASiM: We tend to focus on oral mucositis, but what are the potential impacts and complications of GI mucositis? Dr Spielberger: It can be hard to distinguish oral from GI mucositis. In this setting, GI mucositis rarely occurs without any oral problems. Some drugs can be administered that cause diarrhea but have less impact on the mouth. However, I can t be certain this is caused by GI mucositis some of these drugs are acting through a secretory mechanism to cause the diarrhea. In general, the oral and GI l problems go hand-in-hand. In some cases, the patient will have symptoms predominantly of upper GI mucositis that often presents within the context of oral and esophageal mucositis, including mouth pain, sore throat, and pain when the patient swallows. Mucositis in the lower GI tract will present more often as diarrhea, sometimes with abdominal cramps. ASiM: Is the mucositis seen in patients undergoing BMT/HSCT different from that seen in patients who are receiving chemotherapy or radiotherapy for cancer but not scheduled for BMT or HSCT? Dr Spielberger: Differences in treatment dose intensity, repetitiveness, and long-term duration do produce some differences in how mucositis develops. With certain radiotherapy regimens, the impact can be more localized and may be more permanent. For example, with radiation to the head and neck, irreversible damage can be done to the salivary glands with resulting chronic complications because of dry mouth and increased dental complications. In some regimens for transplantation, physicians prescribe total body radiation, which produces severe mucositis and, in some cases, permanent damage to the salivary glands. Also, in the non-bmt settings, there are repeated cycles of chemotherapy. The oral damage from the first cycle may not be as acute as that seen in the high-intensity HSCT regimen, but over the long term these repeated cycles actually can produce a worse case of mucositis because the may not have time to heal in between the cycles. ASiM: In the patients undergoing allogeneic transplantation, can you distinguish between lower GI mucositis related to the conditioning and a case of diarrhea caused by graft-versus-host disease (GVHD)? Dr Spielberger: One way to identify these adverse effects is by the time of occurrence. GI mucositis occurs earlier, soon after the conditioning; diarrhea caused by GVHD usually occurs several weeks after the transplant itself, usually after the stem cell engraftment. Clinically, these adverse effects can be similar, although GVHD may cause a bloodier diarrhea with more cramping. A tissue biopsy and culture positively can make the distinction and also can rule out other causes, such as CMV. However, the timing of the occurrence is the main difference. ASiM: Is there any way of predicting which patients are at higher risk for developing mucositis? Dr Spielberger: The conditioning regimen is one of the main factors determining risk. In terms of patient- S312 Vol. 5 (4B) April 2005

3 related risk factors, the scientific literature suggests that poor oral hygiene or poor oral health or dentition before the procedure all increase the patient s risk for developing mucositis. Also, patients who have had prior episodes of mucositis associated with chemotherapy are at higher risk, as are those patients who received radiation to the head or neck. The patient s age and history of smoking and alcohol abuse are other risk factors. ASiM: Do you and your nursing team routinely measure the severity of mucositis? Dr Spielberger: We would like to rate the mucositis in all of our patients but, as is likely the case at most busy centers, we don t do this consistently. Unless you are involved in a prospective study or there is a dedicated team for treating mucositis, it is difficult to provide a rating for all patients. After all, mucositis is not the only health-related problem these patients may have. Some centers are more methodical and rigorous in their routines, but grading the severity of mucositis usually occurs when the patient begins to develop mucositis. ASiM: What mucositis scoring system do you use? Dr Spielberger: We use the WHO (World Health Organization) and the NCI (National Cancer Institute) scales. Radiation oncologists use their own special Radiation Therapy Oncology Group scale. We prefer a scale that includes anatomical descriptors and a physiological score reflecting patient function, which is important because you can t see everything during an examination of the patient. Sometimes there may be mildly impressive sores in a patient s mouth, but the patient complains of throat pain that prevents even the swallowing of pills, which is undesirable functionally but not anatomically. The flip side is when patients have impressive sores in the mouth, but they are able to swallow, eat, and drink. Any scale that is used must reflect function and visible anatomy (Figure). ASiM: What are your overall goals in preventing or managing mucositis in your patients undergoing BMT/HSCT? Dr Spielberger: Until recently, there were no approved agents that could prevent mucositis, thus the overall goal was to prevent the complications of mucositis. For us, this means aggressive oral hygiene measures, pain management, adequate nutritional support, and the early detection of patients at risk for developing respiratory compromise. We also want to decrease the risk of the mouth as a source of infection. We expect mucositis to happen; we just hope it won t be a severe case, and we do everything we can to keep the patient comfortable and have a good quality of life. ASiM: What specific steps do you take to limit the impact of mucositis? Dr Spielberger: Before a patient is being admitted to the hospital, we strongly recommend that they see a dentist for dental cleaning and evaluation to address any urgent problems, such as bad-fitting dentures, gum disease, or tooth extractions or replacements. Ideally, the dentist would be part of our team in the preadmission workup and follow-up oral care. The nurses in the BMT unit are well trained in showing patients what they can and cannot use for mouth or dental care. ASiM: What about prophylactic rinses or drugs? Dr Spielberger: During the conditioning period, we recommend an antiseptic rinse called Biotene. We also recommend nistatin as an antifungal mouth rinse. Systemically, we prescribe a quinolone as a prophylactic antibiotic during the conditioning; this is not meant to prevent mucositis but instead to alter the l flora and perhaps prevent certain types of more serious infections. The antibiotics potentially can protect against certain infections from the central line catheter. We also use acyclovir to prevent herpes-related mucositis in those patients who are serologically positive for herpes simplex type 1. ASiM: What about cryotherapy? Dr Spielberger: Years ago, we used cryotherapy during conditioning, but we no longer use it. I m aware of the reports of efficacy with 5-fluorouracil, but we do not use that drug in our conditioning regimens and have not been impressed with its ability to prevent mucositis. Again, we expect mucositis to occur with certain conditioning regimens. Therefore, our plan is to use all of our supportive measures to treat mucositis when it develops. ASiM: And what are those supportive measures? Dr Spielberger: Once the mucositis has developed, we will try local measures for pain control, such as radio mix (also called magic wash in other centers) that is a combination rinse of lidocaine with Benadryl and Mylanta and temporarily numbs the mouth. If the Advanced Studies in Medicine S313

4 Figure. Mucositis Treatment Assessment Assessment Date: / / Time: Date of Transplant/Chemo: Diagnosis: Male Female RR HR BS SPO2 WBC at start of treatment Platelets Check all that apply: Hoarseness Dysphagia Insomnia Stridor Retractions Unable to swallow secretions Bloody secretions Mouth opening in cm Sleeping position Other: Vermillion border, intermediate, poorly keratinized Gingiva, keratinized Buccal lining, nonkeratinized Upperside of tongue, specialized keratinized Hard palate, keratinized masticatory Soft palate, nonkeratinized lining Underside of tongue, nonkeratinized lining Description of Mouth S = Swollen C = Cracked B = Bleeding N = Necrotic NO = Normal UN = Unable to visualize W = White patches Buccal Mucosa = Hard Palate = Soft Palate = Lips = Tongue = Underside of Tongue = Faucial Pillars = Uvula = NCI-CTC Mucositis Scale: (0 to 4) = Pain Scale (Mucositis): (0 to 10) = PRINT NAME OF RT Signature/Title: Date: Time : Mucositis Scale Grade 0 - None Grade 1 - Painless ulcers, erythema, or mild soreness in the absence of lesions. Grade 2 - Painful erythema, edema, or ulcers, but can eat or swallow. Grade 3 - Painful erythema, edema, or ulcers requiring IV hydration. Grade 4 - Severe ulceration or requires parenteral or enteral support or prophylactic intubation. Example of form used by respiratory therapists at the City of Hope National Medical Center during their initial assessment of patients having transplantation and/or chemotherapy. This assessment form is part of a comprehensive mouth care policy, which includes a checklist of preprinted standing physician orders to facilitate rapid and consistent oral care. IV = intravenous. Reprinted with permission from David Horak, MD, and the Respiratory Care COH TEAM (Critical Oral Hygiene for Treatment of Edematous Aggressive Mucositis) at City of Hope National Medical Center, Duarte, Calif. S314 Vol. 5 (4B) April 2005

5 patient s pain persists or becomes worse, we may start the patient on an intravenous narcotic on an as-needed basis; if the pain is constant, we ll start the patient on a pump device. Patients may self-administer and/or it may be continuous infusion. Our patients remain in the hospital, thus we tend to use intravenous opioids. However, other centers prescribe oral medications or fentanyl patches for outpatients. A patient s worst pain usually occurs 7 to 9 days after the stem cell transplantation. By days 11 and 12, the pain usually begins to subside. If the mucositis becomes severe, the respiratory therapy team may be consulted. This team supervises the rinsing process and can start nebulizers with bronchodilators if there is secretion accumulation. Sometimes a nebulizer with a steroid for a local anti-inflammatory effect will be used. I m not convinced this helps the patient. However, as with many treatments, we have anecdotal experience, thus using the nebulizer has become part of the tradition. ASiM: Do you use any GI-coating agents? Dr Spielberger: We do use oral sucralfate occasionally, but not routinely, to treat esophagitis or to coat the stomach. Sometimes we use an H 2 blocker or a proton pump inhibitor if the patient has reflux symptoms. Our radio mix has an antacid (Mylanta), but it is a thick solution and patients sometimes have trouble swallowing it. Many people use it only to rinse their mouth. ASiM: Do you use anything special to treat diarrhea? Dr Spielberger: For diarrhea associated with mucositis of the GI tract, we prescribe loperamide and, sometimes, octreotide, especially for those patients who can t swallow pills. Also, as many patients are on intravenous narcotics for pain, their diarrhea may improve on that basis. ASiM: Describe your approach to maintaining a patient s nutrition. Dr Spielberger: Our dietary team performs an initial assessment when the patient is admitted to the hospital. As a patient s oral intake diminishes, this team, together with the physician, may decide to intervene with parenteral nutrition. In our center, we tend to initiate parenteral nutrition sooner in the treatment process rather than later. The guidelines are not definitive, but we tend to start total parenteral nutrition (TPN) whenever we see that oral intake is not improving after the conditioning. Many times, no improvement is because of nausea, thus administering TPN may occur until the nausea subsides and the patient resumes eating. In other cases of less severe mucositis, TPN may be delayed because you think the patient will catch up when their counts recover. I also may encourage these patients to use oral supplements, such as Boost or Ensure. However, we don t hesitate to start the TPN in patients with inadequate calorie intake because of severe mucositis. TPN often is administered 24 hours daily, but in some cases when patients are able to eat or drink a little, I may use TPN just overnight. ASiM: Have national guidelines played a role in your own treatment decisions for mucositis? Dr Spielberger: The management of mucositis in our center has been developed based on our own center s experience with patients undergoing BMT and from the published literature. Therefore, the management of mucositis at our center has changed over the years. For instance we have stopped using hydrogen peroxide, glutamine, and some other therapies in an attempt to prevent mucositis; however, these decisions were based on results of individual studies rather than on national guidelines. The new MASCC/ISOO (Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology) guidelines are an impressive effort to provide the oncology community with a more uniform and evidence-based method to assess and manage this problem. These guidelines will be helpful in summarizing the studies and showing us if we need to revise routines. I think we re already following most of their recommendations. ASiM: What about some of the other treatments mentioned in those guidelines? Do you use aids such as amifostine, triclosan, or laser therapy? Dr Spielberger: No, in general, our standard approach is the one we just discussed. Unless it s in the setting of a clinical trial, we currently do not use amifostine routinely to prevent mucositis, nor do we use triclosan, biological l agents, or laser therapy. I m aware of studies showing that amifostine may be effectively used for patients with myeloma, but I don t think the drug is approved for this purpose. I also know that some studies suggest that topical colonystimulating factors may help, but we use these stimulating factors only in a study setting. Advanced Studies in Medicine S315

6 ASiM: What did you learn as an investigator in the phase III trial of the recombinant KGF known as palifermin? Dr Spielberger: The phase III trial was a placebocontrolled and double-blind study that enrolled patients with hematologic malignancies and who underwent an autologous transplant. Thirteen centers across the United States enrolled more than 200 patients. The conditioning for all patients included total body irradiation and chemotherapy, specifically cyclophosphamide and VP-16 (etoposide). The primary endpoint was the duration of severe mucositis. Secondary endpoints were the incidence of mucositis, use of analgesics and TPN, and the patient s quality of life as documented in special questionnaires. We saw statistically significant improvements in all of these endpoints in the groups randomly assigned to receive palifermin. The study results have been reported at several meetings and the full article has now been published. Based on these results, palifermin appears to be a promising agent in this particular setting of a conditioning regimen that causes a high incidence of severe mucositis. In fact, it has now received approval for this indication from the US Food and Drug Administration. ASiM: Are there other agents in clinical testing that have demonstrated promise in preventing or treating mucositis? Dr Spielberger: Yes, but so far the results have not been convincing in phase III trials. For example, there is another type of KGF and I think that agents, such as glutamine, iseganan, interleukin-11, and topical GM- CSF (granulocyte macrophage colony-stimulating factor), still are being tested. Many of these agents appeared potentially useful in phase II trials but then failed to show significant benefit when tested in the randomized and placebo-controlled setting. It s important to realize that this failure to prove the hypothesis may be because of study design (eg, the way the drug was administered, the dose, or perhaps the use of a certain conditioning regimen). Clinicians must examine the study design carefully to weigh the clinical applicability of any positive or negative study results. We also must be aware of the potential for adverse effects with these agents. For example, with interleukin-11, toxicity occurred in the randomized setting. This is a supportive care issue, thus we must be especially wary of using a drug that prevents mucositis but introduces its own adverse effects. ASiM: What were the adverse effects of KGF in your trial? Dr Spielberger: We did not see much toxicity beyond what we expected, based on our experience in previous studies. Because this is a keratinocyte-derived growth factor, KGF can cause transient skin reactions when administered intravenously. It can cause some redness in the skin 2 or 3 days after administration. Because this drug leads to proliferation of the, some patients also complain about thickening of the tongue or unusual tastes. All adverse effects were transient and not severe. ASiM: Looking ahead, what are the challenges for researchers investigating ways to avoid or minimize mucositis in the transplant setting? Dr Spielberger: One challenge is to ensure that we all agree to use standardized methods of grading mucositis. Our observers must be trained to rate mucositis in a standardized fashion, thus our results will be reliable and comparable between trials and publications. Randomized and, if possible, placebocontrolled trials should be encouraged. To date, there is no agreed-upon baseline of supportive care, thus we should begin using the recently published evidencebased guidelines as a possible standard we can all agree to use. Finally, we shouldn t forget that our goal of reducing mucositis is not just a quest for another drug. We also are actively designing new conditioning regimens that will cause less mucositis. Even in the autologous setting there is research on the design of less-toxic regimens that are more tumor specific, thus potentially more beneficial. S316 Vol. 5 (4B) April 2005