ADVERTISEMENT

Monitoring pulmonary complications in long-term childhood cancer survivors: Guidelines for the primary care physician

Cleveland Clinic Journal of Medicine. 2008 July;75(7):531-539
July 1, 2008|Cleveland Clinic Journal of Medicine
Allen Liles, MD;Julie Blatt, MD;David Morris, MD;Richard Wardrop III, MD;Anjali Sharma, MD;Aimee Sznewajs, MS, PNP;Robert Goldsby, MD
Author and Disclosure Information

Allen Liles, MD
Program Director of the Combined Internal Medicine and Pediatrics Program, Department of Medicine-Pediatrics, The University of North Carolina, Chapel Hill; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

Julie Blatt, MD
Division of Pediatric Hematology-Oncology, The University of North Carolina, Chapel Hill; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

David Morris, MD
Department of Radiation Oncology, The University of North Carolina, Chapel Hill; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

Richard Wardrop III, MD
Director of Resident Research in Internal Medicine, Assistant Clinical Professor of Internal Medicine and Pediatrics, The Carilion Clinic Department of Internal Medicine and Pediatrics and the University of Virginia School of Medicine; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

Anjali Sharma, MD
Division of Pediatric Bone Marrow Transplantation, University of California, San Francisco; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

Aimee Sznewajs, MS
Division of Pediatric Hematology-Oncology, University of California, San Francisco; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

Robert Goldsby, MD
Division of Pediatric Hematology-Oncology, University of California, San Francisco; Pulmonary Task Force, Late Effects Steering Committee, Children’s Oncology Group

Address: Allen Liles, MD, University of North Carolina at Chapel Hill, Pediatric Education Office CB #7593, Room 30137, Women’s Hospital UNC, Chapel Hill, NC 27599; e-mail liles@med.unc.edu

Dr. Morris has disclosed that he has received consulting fees from the Radiosurgery Centers Corporation and that he owns stock in Amgen, Anesiva, and Synarc corporations.

ABSTRACTCurative therapy for childhood cancers poses the risk of long-term complications, necessitating regular lifelong follow-up for survivors. The Children’s Oncology Group (COG) has issued guidelines on this topic (www.survivorshipguidelines.org). This review summarizes the findings of the COG Guideline Task Force on Pulmonary Complications with respect to pulmonary toxicity.

KEY POINTS

  • Radiation therapy causes pulmonary fibrosis, interstitial pneumonitis, and restrictive or obstructive lung disease. The risk is dose-dependent and increases with concomitant chemotherapy, younger age at treatment, atopic history, and smoking.
  • Alkylating agents cause pulmonary fibrosis. Bleomycin can cause interstitial pneumonitis, pulmonary fibrosis, or, very rarely, acute respiratory distress syndrome.
  • Cancer survivors should have a yearly history and physical examination, plus pulmonary function testing and radiography at baseline and repeated as clinically indicated.
  • All patients who smoke should be encouraged to quit.

CHEMOTHERAPY-RELATED LUNG DAMAGE

A growing list of chemotherapeutic agents appears to cause pulmonary disease in long-term survivors.5

Bleomycin

Bleomycin toxicity is the prototype for chemotherapy-related lung injury: bleomycin was the first chemotherapy drug shown to cause lung injury, this effect is suggested by a large database, and the mechanism is typical.5,18 Preclinical studies have attributed bleomycin’s toxicity to its tendency to promote free radicals.

Although interstitial pneumonitis and pulmonary fibrosis have been reported in children, clinically apparent bleomycin pneumonopathy is most frequent in older adults. Usually, the abnormalities began within 3 months of therapy and persisted or progressed. Like the acute toxicity, it is dose-dependent and more common above a threshold cumulative dose of 400 units/m2. Above this dose, 10% of adult patients without other risk factors develop fibrosis; data are not available for these doses in children. At lower doses, fibrosis occurs sporadically in fewer than 5% of patients, with a 1% to 2% mortality rate. In some series, bleomycin toxicity was anticipated on the basis of DLCO abnormalities.

Bleomycin pulmonary toxicity is variably exacerbated by concurrent or previous radiation therapy.

Increased oxygen concentrations associated with general anesthesia have also been found to exacerbate prior bleomycin-induced pulmonary injury.19,20 In one instance (reviewed by Zaniboni et al20), the patient recovered with corticosteroid treatment.

Alkylating agents

Carmustine (also called BCNU; brand names BiCNU, Gliadel) and lomustine (CCNU; CeeNU) are thought to cause dose-related lung injury. When cumulative carmustine doses are greater than 1,500 mg/m2, more than 50% of patients develop symptoms.21

In a careful clinicopathologic review of 31 children with brain tumors, restrictive changes with lung fibrosis were reported up to 17 years after treatment, most often with carmustine 100 mg/m2 every 6 to 8 weeks for up to 2 years.22 Four of the 8 patients still alive at the time of study experienced shortness of breath and coughing; 6 showed a characteristic pattern of upper zone fibrosis on chest radiography and computed tomography; all 8 survivors had restrictive findings on pulmonary function testing, with vital capacities of about 50% of normal. Toxicity increases with more intensive dose-scheduling.

Cyclophosphamide (Cytoxan) may cause delayed-onset pulmonary fibrosis with severe restrictive lung disease in association with marked reductions in the anteroposterior diameter of the chest, although the evidence is less convincing than with carmustine and lomustine, coming from case reports and small series.23

Melphalan (Alkeran), generally in doses used in stem cell transplant conditioning regimens, is also thought to cause pulmonary fibrosis.24

Busulfan most predictably causes toxicity when it is used in transplantation doses (ie, more than 500 mg), and may be associated with a progressive, potentially fatal restrictive lung disease.25 A current trend is to adjust the dose on the basis of pharmacokinetic analysis, which we hope will reduce toxicity.

Other agents

Methotrexate (MTX; Trexall) also has been associated with chronic pneumonitis and fibrosis.26 This probably occurs with an incidence well below 1% and may be idiosyncratic and not dose-related. Asymptomatic changes in pulmonary function tests that do not predict clinically significant problems have most frequently been associated with low-dose oral administration during more than 3 years.27 This is a treatment approach used in patients with psoriasis or rheumatoid arthritis, but is now obsolete for pediatric cancer. Intravenous and, rarely, intrathecal administration also have been associated with pulmonary toxicity.28 A single report of two patients who developed diffuse interstitial pulmonary infiltrates and chronic pulmonary changes links vinblastine to these sequelae.29

LUNG INJURY AFTER BONE MARROW TRANSPLANTATION

Hematopoietic stem cell transplantation is associated with various late pulmonary complications. The factors that influence these complications are similar to those discussed earlier. However, the intensity of therapy in patients undergoing transplantation and the additive effects of previous therapies magnify the risks.

Patients undergoing total-body irradiation as part of their preparation for transplantation have a high incidence of late pulmonary complications.25,30–32 Busulfan, carmustine, bleomycin, and cyclophosphamide, also commonly used conditioning chemotherapies, are known to cause pneumonitis and fibrosis after transplantation.33

Some acute pulmonary toxicities can have long-standing effects, including serious pulmonary infections, idiopathic pneumonia syndrome, bronchiolitis obliterans, acute respiratory distress syndrome, or other damage related to graft-vs-host disease.

ADVERTISEMENT
ADVERTISEMENT
ADVERTISEMENT