Treatment of Advanced Lymphomas with Bleomycin (NSC-125066)
Supported in part by Public Health Service Grant CA-05186 from the National Cancer Institute.National Institutes of Health. Department of Health,Education,and Welfare
The Blcomycin-compounds in this study were supplied by Cancer Therapy Evaluation,Division of Cancer Treatment. National Cancer Institute
W.J.DURKIN,R.P.PUGH,J.SOLOMON,P.ROSEN,TH.F.PAJAK,and J.R.BATEMAN
Oncology Service,School of Medicine,and Medical Center,University of Southern California.Los Angeles,California
City of Hope Medical Center.Duarte,California
Ellis Fischel State Cancer Hospital.Columbia.Mississippi
Abstract. 88 patients with far-advanced lymphomatous malignancy were treated with Bleomycin given by cither intramuscular(i.m.)or intravenous (i. v.)injection according to a randomized treatment assignment.Response occurred most frequently in Hodgkin’s disease (i. m. 7/24; i. v. 4/18),least often in histiocytic lymphomas (i.m. 0/8;i.v. 1/8), and with intermcdiate frequency in lymphocytic lymphomas (i. m. 3/16;i.v.0/14).While toxicity was common (70%),severe toxicity was unusual(8%) with severe pulmonary toxicity occurring in four patients (three i.m.;one i.v.).All three drug associated deaths occurred in i. m. patients.Unexpected life-threatening pericarditis occurred in two i. m.treated patients.Al-though response anddrug related deaths occureed more often in the i.m.patients, the comparison with i.v.patients was not statistically different.
Key Words.Blcomycin(NSC-125066)-Responsc-Toxicity-Lymphomas
Introduction
Preliminary reports of Bleomycin treatment for lymphomatous malignancy suggested a response rate as high as 71%[1]. These reports have been followed by more extensive trials suggesting response rates varying between 10-60%(2,3,4,5, 6,7,91.The Western Cancer Study Group undertook the present study to define further the role of Bleomycin in lymphomatous malignancy by comparing two different routes of administration.
Materials and Methods

count,and platelet count.Serum urca nitrogen,uric acid. clectrolytes,bilirubin alkaline phosphatase and SGPT deter-minations,urinalysis and chest roentgenograms were done before the study and repeated monthly.
To assess the degree of the response,the products of the per-pendicular diamcters of each measurable tumor were added together.A complete response was defined as the complete disappearance of all signs and symptoms of the disease and the appearance of no new lesions for at least one month. Re-staging was not required to document a complete response.A partial response is defined as at least a 50% reduction in the measured pretreatment tumor bulk with symptomaticimprove ment and the appearance of no new lesions for at least one month.The onset of response is dated from the first detectable tumor shrink as generally verified by at least one subsequent measurement. Disease progression was considered to be a 50% increase in measured tumor bulk from the smallest recorded parameters.
Patients admitted to the study were ranomized by the Studies Analysis Center of the Western Cancer Study Group to one of two treatment groups:
(1) Bleomycin given intravenously;
(2) Bleomycin given intramuscularly.
The dose schedule was identical for both treatment routes: 10mg/㎡ twicc a weck (Monday and Thursday) with no other concurrent anti-ncoplastic treatment. An initial test dose of 1 mg was suggested for all patients. Patients were continued on treatment until
(1) definite disease progression;
(2)the devclopment of abnormal respiratory function as detected by physical examination or chest roentgenogram, or
From February 1971 to June 1973,patients with lymphomas wcre eligible for study if they met the following criteria:
(1)Histologic proof of lymphomatous malignancy (referee review optional);
(2) presence of measurable lesions;
(3)refractoriness to all other treatment modalities including conventional chemotherapy;
(4) no radiation or chemotherapy for four weeks prior to study entry;
(5) patients prevously treated with Bleomycin were incligible. Patients were cvaluated wcekly with a complete history and physical examination with measurement of the visible or palpable disease, hemoglobin, leukocyte count,differential

(3) a total dose of 300 mg.
Additional Bleomycin was permitted at the discretion of the investigator for patients who showed a tumor response without any evidence of pulmonary toxicity.
Results
93 patients were entered into the study. Five patients were excluded from analysis: Two patients were found on histologic review not to have lymphomas. Three other patients died before the first dose of Bleomycin was given. 48 patients were randomly assigned to intramuscular Bleomycin and to

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Durkin et al.:Bleomycin in Lymphomas
intravenous Bleomycin. Pretreatment characteristics were comparable for the two groups and are outlined in table I.
Of the 88 cvaluable patients.66 complained of weakness,49 of pain and 47 of fever (table II). 68 patients had evidence of hepato-splenic involvement;69 of nodal disease; and 39 bone marrow invasion (table III). 17 patients died of diseasc during the first two weeks of treatment. An additional nine others

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failed to complete the first two weeks; five because of pro-gressive disease,and four because of toxicity.
Responses
15 of 88 patients (17%) showed a response to Belomycin(13 partial, two complete). There were ten responders in the i.m. group (7/24 in Hodgkin’s disease; 3/16 in lymphocytic
Table I.Lymphomas-pretreatment characteristics by route of administration.
Hodgkin’s Lymphocytic Histiocytic
intra- intra- intra- intra- intra- intra-
muscular venous muscular venous muscular venous
Number of patients 24 18 16 14 8 8
KPS(mean) 54 51 50 54 52 63
Age(mean) 35.2 33.3 51.5 52.5 51.5 54.8
Duration(mean) 4.1 3.5 2.8 4.8 5.4 2.1
Scx
male 14 15 6 6 7 3
female 10 3 10 8 1 5
Patients on concurrent
steroid treatment 8 6 5 7 3 3
Lymphocyte count(mean) 499 559 1181 1846 508 1226
Patients with prior radiotherapy
extensive 10 8 4 3 1 3
moderate 7 5 5 2 4 3
minimal 3 0 2 3 1 1
none 4 5 5 6 2 1
Patients with prior chemotherapy
extensive 12 11 5 5 3 3
moderate 7 4 5 7 1 1
minimal 2 2 6 2 4 4
none 3 1 0 0 0 0
Extensive prior radiotherapy is radiation to areas on both sides of the diaphragm with total doses to each side in excess of 3000 rad.
Moderate prior radiotherapy is radiation to one or both sides of the diaphragm with only one port delivery 3000 rad or greater.
Minimal prior radiotherapy is radiation on one or both sides of the diaphragm with no port receiving 3000 rad or greater.
Extensive prior chemotherapy is defined as 30 or more prior full drug trials.
Moderate prior chemotherapy is defined as two prior full drug trials.
Minimal prior chemotherapyis defined as only one prior drug trial.
Table II.Response at entry by symptoms.
Hodgkin’s Lymphocyt ic Histiocytic
re- non-re- percent re- non-re- percent re- non-re- percent
sponders sponders responders sponders sponders responders sponders sponders responders
of total of total of total
Total patients 11 31 26% 3 27 10% 1 15 %9
Fever 8 23 26% 1 9 10% 0 6 %0
Weakness 10 20 33% 1 24 4% 0 11 %0
Pain 2 14 13% 2 21 8.7% 0 10 0%
Cardio-respiratory 3 10 23% 0 6 0% 1 5 16%
G.I. 1 4 20% 0 12 0% 0 0 0%
Infection 0 4 %0 1 1 50% 0 0 0%
Itching 0 4 0% 0 1 %0 0 0 0%
Bleeding 0 3 0% 0 2 %0 0 0 0%
CNS 0 3 0% 0 3 %0 0 0 0%
Gout 0 0 0% 0 1 %0 0 0 %0

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lymphomas). The duration of response was short with a mean of 2.9 months (one to seven months).There was no statistical difference in the response proportion between the two arms (table IV).
Further analysis revealed somewhat unexpected trends.32 patients were treated with concurrent steroid therapy with only one patient responding. 13 female patients with Hodg-kin’s discase were treated and only one response wasseen.High lymphocyte counts were noted to be favorable indicators of response in Hodgkin’s discase, but were unfavorable in non-Hodgkin’s lymphomas (table V).
Toxic Effects
Patients treated by the i.v.route received an average cumula-tive dose of 161 mg(4-401) with 12 of 40 exceeding 200 mg and eight exceeding 300 mg.Patients treated by the i.m.route received the average cumulative dose of 166 mg(17-495) with 12 of 48 exceeding 200 mg and eight exceeding 300 mg. Definite drug toxicity was common,occurring in 70% of the cases. Minor skin lesions were seen in 44% of the cases while

Durkin et al.:Bleomycin in Lymphomas
24% had mild nausea associated with occasional vomiting.26 or 30% had fever related to drug administration.Pulmonary toxicity occurred in less than 15% of the cases. Myclosup-pression was uncommon occurring in only four cases and was mild in each casc(table VI).
Four cases (3 i.m.; I i.v.) of severe pulmonary fibrosis was ob-served on study, with three patients dying from this complica-tion. The three dying patients had been treated with intra-muscular Bleomycin. One patient died after receiving 86 mg total cumulative dose while the other two received 165 mg and 345 mg respectively (tables VII and VIII).
There were two patients on study who developed life-threatening pericarditis with effusions and tamponade.Both these patients had Hodgkin’s disease and were randomized to intramuscular treatment.They had been treated with mediasti-nal radiation in the past (table VIII). Both patients survived this complication.
One patient with a histiocytic lymphoma,after receiving a test dose of 1 mg of Bleomycin i. v., collapsed with severe hypo-tension,confusion and wheezing. After treatment with fluids.
Table III.Response by site of involvement.
Hodgkin’s Lymphocyt ic Histiocytic
re- non-re- percent re- non-re- percent re- non-re- percent
sponders sponders responders sponders sponders responders sponders sponders responders
of total of total of total
Total patients 11 31 26% 3 27 %01 1 15 %9
Hepato-splenic 9 28 24% 1 21 4.5% 1 8 %61
Nodal 7 22 24% 3 24 11% 1 12 19%
Bone marrow 6 6 50% 1 20 4.7% 1 5 26%
Lung 2 10 17% 0 10 %0 1 6 12%
CNS 0 2 %0 0 3 %0 0 1 %0
Other 1 2 33% 1 15 6% 0 8 8%
Table IV.Lymphomas-post-treatment characteristics by route of administration.
Hodgkin’s Lymphocytic Histiocytic
intra- intra- intra- intra- intra- intra-
muscular venous muscular venous muscular venous
Number of patients 24 18 16 14 8 8
Duration of treatment(mean) 1.5 1.8 1.6 9 8 1.25
Patients completing less than
15 days of treatment 5 3 5 5 5 3
Patients completing greater than
15 days of treatment 19 15 11 9 3 5
Total average drug dosage 179 194 164 131 134 214
Patients who received
intercurrent steroid treatment 8 6 5 7 3 3
Patients with I-Bresponse 7(29%) 3(16%) 2(12.5%) - - 1(12.5%)
Patients with I-C response - 1(5.6%) (%9)1 - - -
Patients with total response 7(29%) 4(22%) 3(19%) (%0)0 (%0)0 1(12.5%)
Duration of response(mean) 2 3.5 3.7 0 0 4.5

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vasopressors and steroids for 24 hours.full recovery occurred. This was considered by the investigator to be a case of anaphy-laxis. In addition to patient recovery at 24 hours, the investi-gator noted the disappcarance of large bulky tumor masses. Further treatment with Bleomycin was not undertaken (table VIII).
Discussion
Blcomycin has been recently reported to be most effectively administered by a slow intravenous infusion. Our data general-ly support the conclusion |10] that duration of drug exposure is

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a critical factor affecting the tumoricidal efficacy of Bleomycin. While the overall response to Bleomycin in this groups was only 17%,responses were seen in 21% of the patients in the i. m. group as opposed to 13% in the i. v. group with all drug deaths occurring in the i.m.group.
Favorable prognostic variates of responsc have been recogniz-ed to be:
(1)histologic type(Hodgkin’s disease)[4]
(2) absence of prior chemotherapy.
Our data generally support these conclusions. In addition. other favorable response prognostic variates were considered to be:
Table V.Lymphomas-responders compared to non-responders.
Hodgkin’s Lymphocytic Histiocytic
responders non- responders non- responders non-
responders responders responders
Number of patients 11 31 3 27 1 15
KPS(mean) 62.3 49.3 66.7 50.2 80 56.3
Duration(mean) 3.3 4.1 3.6 3.8 1.3 3.9
Age 41.6 31.8 60.7 51 64.5 52.4
Sex
male 10 19 1 11 0 10
female 1 12 2 16 1 5
Patients on concurrent
steroid treatment 1 13 0 12 0 6
No patients on concurrent
steroid treatment 10 18 3 15 1 9
Patients with prior chemotherapy
extensive 5 8 2 10 0 6
moderate 2 11 0 10 0 2
minimal 0 4 1 7 1 7
none 4 0 0 0 0 0
Patients with prior radiotherapy
extensive 5 13 0 7 0 4
moderate 2 10 2 5 0 7
minimal 2 1 1 4 1 1
none 2 7 0 1 0 3
Lymphocyte count(mean) 614 475 947 16.11 290 967
Table VI.Toxic effects by route of administration.
Intramuscular 48) Intravenous(4 0) All(88)
number of % of patients number of % of patients number of % of patients
patients with treated patients with treated who patients with treated who
toxic effect developed toxic effect developed toxic effect developed
toxic effect toxic effect toxic effect
Skin 22 46% 17 43% 39 44%
Fever 16 33% 10 25% 26 30%
G.I. 13 27% 8 20% 21 24%
Pulmonary 7 15% 3 7.5% 10 11%
Leukopenia 0 0% 2 5% 2 2.3%
Neurolgic 0 0% 2 5% 2 2.3%
Pericarditis 2 4.2% 0 %0 2 2.3%
Anaphylaxis 0 0% 1 2.5% 1 1.1%
No toxic effect 13 27% 13 33% 26 30%

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Durkin et al.:Bleomycin in Lymphomas
Table VII.Pulmonary toxicity.
Patient Probability of Age Prior Prior Karnofsky Total Route Toxicity
number pulmonary toxicity chemotherapy’ radiotherapy’ performance dose
score(KPS)
4 probable 53 extensive minimal2 80 345 1.M. died
5 probable 30 modcrate 0 20 105 1.V. 3+
15 probable 30 cxtensive moderate2 30 156 I.V. 2+
32 probable 29 extensive 0 70 165 I.M. died
36 unlikely 21 extensive moderate3 30 72 I.V. 1-2+
45 probable 31 minimal moderate2 70 378 I.M. 1+
47 probable 58 extensive moderate3 50 270 I.M. 2+
49 unlikely 45 extensive 0 30 119 1.M. 1-2+
92 probable 72 minimal modcrate3 30 86 I.M. died
93 probable 35 minimal modcrate 100 265 I.V. 2+
See table 1
2 Radiation port to thorax
3No radiation port to thorax
Table VIII.Severe to extreme toxicity by route.
Intramuscular Intravenous All
Number of % of patients Number of % of patients Number of % of patients
patients with treated who patients with treated who patients with treated who
toxic effect developed toxic effect developed toxic effect developed
toxic effect toxic effect toxix effect
Pulmonary 3 %9 1 3% 4 5%
Anaphylaxis 0 %0 1 3% 1 1%
Pericarditis 2 4% 0 0% 2 2%

(1) higher Karnofsky clinical performance score;
(2)shorter disease duration;
(3) high lymphocyte counts in Hodgkin’s discasc with the reverse being true in non-Hodgkin’s lymphomas.
Bleomycin has been reported to potentiate the toxic effects of radiation. Synergistic pulmonary toxicity has been noted when radiation and drug administration werc separated in time [9]. Pulmonary toxic events, however, in our experience occurred with cqual frequency in the prior chest radiotherapy group (4/28;14%) and in the no prior chest radiotherapy group (6/50; 12%). The occurrence of life-threatening pericarditis in two patients who received prior mantle radia-tion strongly suggests this as a new and serious toxic effect.

(1) Drug associated deaths due to pulmonary toxicity and tumor responses may occur more frequently with intra-muscular treatment.
(2)Patients with Hodgkin’s disease respond to treatment more frequently than patients with non-Hodgkin’s lymphomas.
(3)Pericarditis may represent a possible toxic drug effect in a previously irradiated mediastinal field.
(4)Prevailing hormonal conditions (sex and concurrent ster-oid treatment) in the treatment population may influence the tumoricidal efficacy of Bleomycin.
Acknowledgments
Sex and concurrent steroid treatment were noted to have a striking effect on the response analysis. This to our knowledge has not been noted in previous studies. Patient conditions in the treatment population prevent definite conclusion,but some considerations to these findings should be given in future prospective studies.
Conclusion
In the experience of the Western Cancer Study Group,the following conclusions secm warranted:

The following members of the Western Cancer Study Group participated in this study:L.IRWIN,D.STOLINSKY,G.HUM, University of Southern California School of Medicine and John Wesley County Hospital,Los Angeles,Calif.;A.GLASS, Kaiser Permanente,Portland,Oreg.;F.BULL,University of Michigan,Ann Arbor,Mich.; R.DONNELL,Naval Hospital, Oakland,Calif.;L.SADOFF,Kaiser Permanente,Los Angeles, Calif.;J.LINMAN,University of Oregon,Portland,Oreg.; E.JACOBS,Cancer Rescarch Institute,University Medical Center,San Francisco, Calif.; R. BOHANNON,San Francisco General Hospital,San Francisco,Calif.;R.REYNOLDS,David

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Durkin et al.:Bleomycin in Lymphomas
Grant Medical Center,Travis Air Force Base,Calif.;J.LEwIs, University of California,Davis,Calif.; J.McCRACKEN, Madigan General Hospital,Tacoma,Wash.;R. WEISBERG, Beaumont General Hospital,El Paso,Tex.; R.HESTORFF, Kaiser Permanente,Oakland,Calif.;1.SILVERBERG,Mount Zion Hospital,San Francisco,Calif.;W.WIISON,Western Montana Clinic,Missoula,Mont.; R. MAss,Veterans Admini-stration Hospital,Portland,Oreg.
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Request reprints from:J.DURKIN,MD,University of Southern Cali-fornia.Oncology Service,2825 S.Hope Street,Los Angcles,CA 90007(USA)
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