Mucositis: new hopes for chemotherapy patients

teaser

Alois Gratwohl
MD
Haematologist
Department of Haematology
University Hospital
Basel
Switzerland
E:[email protected]

Chemotherapy has achieved a remarkable success in the treatment of chemosensitive malignancies over the past decades, and leukaemias, lymphomas and germ cell tumours, among others, have come within reach of a cure under defined conditions. Multiple studies confirmed the concept of dose–response and have promoted the use of high-dose chemotherapy. Haematopoietic stem cell transplantation (HSCT) permits even further increase of conditioning. Prospective randomised controlled studies have confirmed the advantage of autologous HSCT in the treatment of non-Hodgkin’s lymphoma, multiple myeloma or neuroblastoma. Today HSCT is an accepted treatment modality, and it is estimated that over 60,000 patients per year are treated worldwide with this therapy.(1–4) This dose increase in chemotherapy has its price and is limited by nonhaematopoietic organ toxicity. Veno-occlusive disease, interstitial pneumonitis, cardiac toxicity and multiorgan failure limit dose-escalation above a well-defined threshold. In contrast, “damage” to the mucosa – ­mucositis – has been accepted as inevitable toxicity. Efforts concerning the latter aspect have concentrated on palliation.

Current therapies
Numerous studies have addressed the issue of oral mucositis in chemotherapy-treated patients. They have focused on symptom management and pain relief.(5–8) It is currently accepted that opioid analgesics must not be withheld from patients with severe mucositis. Beyond symptomatic treatment, little progress has been made with regard to prevention or causal treatment, despite the fact that complications with mucositis and its severity have a major impact on outcome and hospital burden. Every point increase in the oral mucosa scale is directly associated with an increased need for opioid analgesics, increased duration of hospitalisation, increased need for total parenteral nutrition, increased incidence of infections and increased mortality. Moreover, oral mucositis inflicts severe pain on patients and promotes a negative attitude towards further treatment. In a survey of HSCT patients, oral mucositis was reported by 45% of them as the most debilitating side-effect, followed by nausea and vomiting (15%), weakness and lethargy (10%), and diarrhoea (10%). Despite the rising awareness of mucositis as an important side-effect of chemotherapy, progress was slow concerning treatment. A Cochrane library analysis showed a long list of approaches with no evidence of efficacy, including chamomile, chlor­hexidine mouth rinse, folinic acid, glutamine supplementation and sucralfate lining. Similarly, the latest Multinational Association of Supportive Care in Cancer (MASCC) clinical guidelines include patient-controlled analgesia with intravenous morphine as the only standard treatment approach for severe mucositis, and acyclovir and its analogues as the only ­pharmacological prevention approach. In addition, use of an oral care protocol including patient education improves patient outcome. No other drug or procedure has a proven efficacy drug record.(9–11)

Despite the lack of progress in prevention and treatment, major progress has been made with regard to insight into the pathogenetic mechanisms. Mucositis in patients with oral mucositis is not restricted to the oral cavity. It affects the mucosa of the gastrointestinal tract in its entire length and is frequently associated with ulcerations and bleedings within the small or large intestine. It concerns the mucosa of the sinuses and increases the risk of sinusi­­tis and upper airway bleeding. It also affects the urogenital mucosa, and severe vaginitis is frequent. Consequently, sexual intercourse is often difficult for a prolonged period of time after therapy. In ­parallel, the complexity of the pathogenetic mechanisms involved are better understood today. Cytotoxic chemotherapy or radiation does not simply destroy ­mucosal cells; a cascade of events is also triggered by tissue injury. Generation of radical oxygen species creates a vicious cycle and induces apoptosis and clonogenic cell death within the mucosa. Furthermore, tissue damage promotes aberrant angiogenesis. These damaging events target the basal membrane, the submucosal tissue and the mucosal stem cells. They occur early in the process at a time when the tissue still appears normal (hence the need for early intervention if the process has to be stopped). Damage only becomes manifest at a later stage. The cytotoxic amplification of tissue destruction induces pain, inflammation and mucosal breakdown. The risk of bacteraemia and sepsis becomes evident. Repair remains incomplete, and the ­underlying residual angiogenesis increases the risk of further episodes of mucositis during subsequent cycles of cytotoxic therapy.(12)

New hopes for chemotherapy patients
Recent developments have changed this somewhat negative approach. A concentrated oral gel containing polyvinylpyrrolidine and sodium hyaluronate forms an adherent barrier over the oral mucosa, shields the mucosa from external stimulation and interrupts the vicious cycle. It reduces oral pain, reduces the need for opioids and improves oral intake. Impact on duration and severity of oral mucositis needs to be evaluated. Prospective randomised controlled studies are still warranted to determine their precise efficacy and impact.(13) More importantly, recombinant human keratinocyte growth factor has become available. In animal models it has been shown to have a beneficial effect on mucositis after chemotherapy.(14,15) It acts as an antiapoptotic survival agent for mucositis stem cells and promotes repair of mucosa. Palifermin decreases ulceration, increases mucosal regeneration and reduces mucosal atrophy and weight loss. A prospective randomised placebo-controlled study in 212 patients with autologous HSCT for a variety of haematological malignancies confirmed these findings.(16) Patients in the treatment group were given three doses of 60µg/kg per day for three consecutive days immediately before, and three doses after, HSCT. Palifermin was well tolerated and side-effects were mild. Rash, pruritus, oedema, sensation of thickening of the tongue and taste alterations were observed, but no severe side-effects were noted. The effects of palifermin were remarkable, as the drug reduced the incidence and severity of oral mucositis by more than 30%. In addition, it reduced the duration of severe mucositis from nine days (0–27 range) to three days (0–22 range); it also reduced the use of opioid analgesics by half and the use of parenteral nutrition from 55% to 31%. Most remarkably, incidence of grade IV oral mucositis, the most debilitating form of mucositis, was reduced from 62% to 20%. The effects of palifermin are not restricted to oral mucositis. Preclinical data suggested an effect on thymic reconstitution after high-dose chemotherapy or total body irradiation and a protective effect on graft-versus-host disease (aGvHD). These animal models were supported by the findings of this phase II study, which were compatible with a reduced incidence of severe aGvHD and improved survival.(17,18)

Conclusion
Convincing data exist that duration and severity of oral mucositis can now be reduced after intensive chemotherapy in patients with haematological malignancies. Prophylactic palifermin can reduce the need for opioid analgesics and parenteral nutrition, and can facilitate oral intake and improve quality of life for individual patients. The reduction of grade IV mucositis by a few days is a substantial relief. The challenge now is to confirm these data and improve the results even further.

It remains to be shown whether the reduction in mucositis translates into improved survival. There are enough known pathogenetic mechanisms to support this assumption, but, if this proves not to be the case, the cost of ­palifermin or oral gel will have to be balanced against quality of life and traditional palliation with opioids.(19)

References

1. Urbano-Ispizua A, et al. Bone Marrow Transplant 2002;29:639-46.
2. Craddock C. Lancet Oncol 2000;1:227-34.
3. Attal M, et al. N Engl J Med 2003;49:2495-502. Erratum in: Engl J Med 2004;350:2628.
4. Gratwohl A, et al. Bone Marrow Transplant 2004;34:855-75.
5. Rapoport AP, et al. J Clin Oncol 1999;17:2446-53.
6. Stiff P. Bone Marrow Transplant 2001;27 Suppl:S3-11.
7. Sonis ST, et al. Cancer 2004;100 Suppl:1995-2025.
8. Woo SB, et al. Cancer 1993;72:1612-7.
9. Rubenstein EB, et al. Cancer 2004;100: Suppl:2026-46
10. Worthington HV, et al. Cochrane Database Syst Rev 2004;CD00197.
11. Ringden O, et al. Lancet 1984;1:744.
12. Sonis ST. Nat Rev Cancer 2004;4:277-84.
13. Innocenti M, et al. J Pain Sympt Manage 2002;24:456-7.
14. Farrell CL, et al. Cancer Res 1998;58:933-9.
15. Farrell CL, et al. Int J Radiat Biol 1999;75:609-20.
16. Spielberger R, et al. N Engl J Med 2004;351:2590-8.
17. Meropol NJ, et al. J Clin Oncol 2003;21:1452-8.
18. Rossi S, et al. Blood 2002;100:682-91.
19. Garfunkel AA. N Engl J Med 2004;351;2649-61.
20. WHO. WHO handbook for reporting results of cancer treatment. Geneva, Switzerland. 1979. p. 15-22.