Prolonged Administration of Bleomycin without Clinical Toxicity

circuits arising in pulmonary, mediastinal, or particularly left abial receptors. Finally, some have suggested discharge of a humoral mediator to act at the hypothal.. amoneurohypophyseal level. The characteristics of the pulmonary pathologic findings in this patient do not serve to define an underlying mechanism but broaden the scope of association. A peculiar circumstance was the history of medication with phenytoin, which is known to suppress central secretion of vasopressin. The daily dosage likely was insufficient for complete suppression, although it was not increased to prove this. Other medications prescribed have not been reported to alter the effect of vasopressin on the renal concentratipg mechanism or to induce the syndrome of inappropriate secretion of antidiuretic hormone. Finally, the delayed appearance of maximal hyponatremia is speculative; it is probable that its association with the pneumothorax was coincidental. .While it is known that obtundation may be associated with anaerobic pulmonary infection, an electrolye disturbance should be considered; unexplained alterations of mental status may be secondary to the syndrome of inappropriate secretion of antidiuretic honnone. In addition, since it is common practice to vigorously induce hydration in patients with pulmonary suppuration, the clinici~ should ~ wary that such therapy may exacerbate a preexisting hyponatremic state.

REFERENCES

1 Schwartz WB, Bennett W, Curelop S, et al: A syndrome of renal sodium loss and hyponatremia resulting from inappropriate secretion of antidiuretic hormone. Am J Med 23:529-542, 1957 2 Amabuda TT, Jr, Mulrow PJ, Gallagher JC, et al: Carcinoma of the lung with inappropriate antidiuresis: Demonstration of antidiuretic-hormone-Iike activity in tumor extract. N Engl J Med 269:544-549, 1963 3 Spanos BM, Spry CJ: Inappropriate secretion of antidiuretic hormone with chronic chest infections. Br Med J 3:785-786, 1974 4 Rosenow EC, Segar WE, Zehr IE: Inappropriate antidiuretic hormone secretion in pneumonia. Mayo Coo Proc 47:169-174, 1972 5 Utt1e TM, Dowdle RH: Mycoplasma pneumonia with inappropriate secretion of antidiuretic hormone. Br Med J 4:517,1974 6 Weiss H, Katz S: Hyponatremia resulting from apparently inappropriate secretion of antidiuretic hormone in patients with pulmonary tuberculosis. Am Rev Respir Dis 92:609-616, 1965 7 Utz JP, German JL, Louria DB, et al: Pulmonary aspergillosis with Cavitation: Iodide therapy associated with an unusual electrolyte disturbance. N Engl J Med 260:264268. 1959 8 Sladen A, Laver MB, Pontoppidan H: Pulmonary complications and water retention in prolonged mechanical ventilation. N Eng! J Med 279:448-453, 1968 9 Bartter Fe: The syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Disease-a-Month 19:147,1973 10 Vorherr H, Massry SG, FaUet R, et al: Antidiuretic principle in tuberculous lung tissue of a patient with pulmonary tubercuIosis and hyponatremia. Ann Intern Med 72:383-387, 1970

798 JOHN E. KURNICK

Prolonged Administration of Bleomycin without Clinical Toxicity· Therapy with 2.700 Units over Four Years John E. Kumick, M.D.

A 26-yeu-old white III8D with stBge 4-8 HodPIn'. . . . ease resistant to conventioaal cbemotherapy oIJtaIned complete remission with administration of bleomydn. Maintell8DCe of this remissioD required cOldlDaed therapy with bleomycin. The patient received a total of 2,700 units of bleomycin over a 51-month period wItbo8t ...... or symptoms of p~onary tosidty. Serlld studies of palmonary functiOD have shown a stable forced ~ capacity aDd minimaOy decreased totll1 ..... volume .... pulmonary dUfusIDg capacity. ThIs case demollltndes the ability of a patient to tolerate ......ve c......ulatlve doses of bleomycin over a protrac:ted period without severe 1011 of pubnoQIIIY fuDctioa.

W e have been observing a patient whose continued . complete remission of stage 4-B Hodgkin's dis-

ease has been dependent upon maintenance therapy with bleomycin for the past three years. In this time, he has received a total of 2,700 units of bleomycin without serious impairment of pulmonary function or changes in chest x-ray films.

CASE REPoRT A 26-year-old man had Hodgkin's disease with mixed cellularity diagnosed on uillary node biopsy in February, 1972. His disease was classified as stage 4-B on the basis of fever, a 12 kg (25 Ib) loss of weight, and laparotomyproven involvement of the liver, spleen, and para-aortic lymph nodes. Combined chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone failed to produce a significant response. On Aug 7, 1972, the patient was started on a regimen of five daily injections of 15 units of bleomycin and 240 mg of 1-(2-chloroethyl)-3-cyclohexyl-l-nitrosourea (CCNU),. This was followed by 7.5 units of bleomycin twice weekly and 200 to 240 mg of CCNU every ~o months. Therapy with bleomycin was interrupted in February 1973 alb,r a cumulative dose of 480 units, with a status of complete remission having been achieved. Maintenance therapy with CCNU was discontinued nine months later, when fevers, loss of weight, and recurrent adenopathy signaled a relapse of the Hodgkin's disease. Measurements of ptilmonary function were normal on Nov 7, 1973, and therapy with bleomycin was resumed at a dosage of 7.5 units twice weekly, with excellent response. An attempt to reduce the frequency of administration of bleomycin to once weekly failed because of recurrence of fever. Since the patient was unresponsive to all other agents then available and his chest x-ray films and data on pulmonary function remained unaltered, the twice weekly regimen of bleomycin was resumed, and the fever abated. • From the Hematology Section, Deparbnent of Medicine Veterans Administration H~itaI, Denver. ' Reprint requesta: Dr. KumkIC, VA Hospltal, Deooer 80220

CHEST, 72: 6, DECEMBER, 1977

Table l-Serial Meaauremerw of PulmolUJry Funelion in Pcdierd EsptMed 2,700 Uni,. of Bleomyein*

Measurement

eo

11/7/73

5/2/74

12/12/74

3/21/75

12/9/75

11/29/76

480

855

1,305

1,515

2,085

2,700

FVC,L

5.00 (104.8)

4.75 (99.5)

4.71 (98.7)

4.60 (96.4)

4.87 (102.1)

4.58 (96.0)

TLC,L

6.53 (100.0)

6.22 (95.3)

6.05 (92.6)

6.00 (92.0)

5.50 (84.4)

6.10 (93.6)

FEVl , L**

3.93 (101.3)

3.66 (94.3)

3.62 (93.4)

3.60 (92.9)

3.72 (95.9)

3.63 (93.6)

32.4 (106.9)

24.1 (79.5)

24.1 (79.5)

23.7 (78.4)

26.3 (87.0)

Cumulative dose of bleomycin, units

D, ml/min/mm Hg

*Numbers within parentheses indicate percent predicted value. **FEVl , forced expiratory volume in one second. As of Nov 29, 1976, the patient continues in complete remission, having received a total of 2,700 units of bleomycin in 51 months. No respiratory symptoms or signs of pneumonitis have developed, and no changes in chest x-ray films have been observed. Serial measurements of pulmonary function show minimal depression of the total lung capacity ( TLC) and carbon monoxide diffusing capacity (D), while forced vital capacity (FVC ) is essentially unchanged (Table 1). No sign of toxicity to marrow, liver, kidneys, or skin has developed.

patient demonstrates an ability to tolerate massive doses of bleomycin administered gradually. This experience suggests that for patients dependent on therapy with bleomycin for control of a tumor, cumulative doses greatly exceeding the usual recommendations may be a risk well worth taking, provided that no pulmonary symptoms develop and that chest x-ray 6lms and measurements of pulmonary function remain acceptable.

DISCUSSION

1 Blum RH, Carter SK, Agre K: A clinical review of bleomycin: A new anti-neoplastic agent Cancer 31:903-914,

the

Bleomycin-induced pulmonary toxicity occurs with a frequency of 10 percent l and a mortality of 1 percent. The incidence of such toxicity rises steeply at cumulative doses over 450 units,2 leading to a manufacturer's recommendation that dosage not exceed 400 units unless the potential gain outweighs the risk; however, the llllpredictability of bleomycin-induced pulmonary toxicity is illustrated by the fact that fatal pneumonitis has 0ccurred at total doses as low as 105 units,S while therapy with over. 1,000 units has been administered without toxicity.4,6 Experimental evidence suggests that the development of toxicity is dependent upon the concentra.tion of bleomycin in the tissues, which, in turn, is largely a function of the speed of administration. 6 Our

CHEST, 72: 6, DECEMBER, 1977

REFERENCES 1973

2 Yagoda A, Mukherji B, Young C, et al: Bleomycin, an antitumor antibiotic: Clinical experience in 274 patients. Ann Intern Med 77 :861-870, 1972 3 Rudders RA, Hensley GT: Bleomycin pulmonary toxicity. Chest 63:626-628, 1973 4 Ichikawa T, Nakano I, Hirokawa I: Bleomycin treabnent of the tumors of penis and scrotum. J Urol 102:699-701, 1969

5 Samuels ML, Johnson DE, Holoye PY, et al: Large-dose bleomycin therapy and pulmonary toxicity: A possible role of prior radiotherapy. JAMA 235:1117-1120, 1976 6 Fleischman RW, Baker JR, Thompson GR, et al: Bleomycin-induced interstitial pneumonia in dogs. Thorax 26:675-682, 1971

PROLONGED ADMINISTRATION OF BLEOMYCIN WITHOUT TOXlCI" 798