for Treatment of Malignant Pleural Effusion

Intrapleural Pirarubicin (4'-O-Tetrahydropyranyladriamycin) for Treatment of Malignant Pleural Effusion Takechika Gotoh 1 ' 2 , Yoshitsugu Tanaka3, Yukihisa Fujita1, Norihiro Hiramori1, Tsuneo Fujii3, Taichiro Arimoto1, Yoshinobu Iwasaki1, Takashi Fukabori1, Taizo Nakamura12, Norihiro Ono4 and Masao Nakagawa1 Second Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, department of Respiratory Diseases, Kyoto Prefectural Rakuto Hospital, Kyoto, department of Respiratory Diseases, Otsu Municipal Hospital, Otsu and 4Department of Internal Medicine, Saiseikai Shiga Hospital, Kurita-gun, Shiga

(Jpn J Clin Oncol 26: 328-334, 1996) Key Words: Pirarubicin—Malignant Pharmacokinetics

Introduction Malignant pleural effusion is one of the common complications of advanced cancer. If simple needle thoracentesis is repeated in order to decrease the Received: December 7, 1995 Accepted: April 22, 1996 For reprints and all correspondence: Takechika Gotoh, Department of Respiratory Diseases, Kyoto Prefectural Rakuto Hospital, 563, Umebayashi-cho, Higashiojigojoagaru, Higashiyama-ku, Kyoto 605 328

pleural

effusion—Intrapleural

administration—

dyspnea of patients, their quality of life (QOL) deteriorates and finally their survival is shortened. Therefore, after drainage, a variety of anti-cancer agents have generally been instilled into the pleural cavity to prevent reaccumulation of effusion. Such agents are required to kill cancer cells spread throughout the pleural cavity, and evoke tight pleural adhesion for successful treatment. Recently, for pleurodesic treatment of malignant effusion in Japan, adriamycin (doxorubicin), an anthracycline derivative, has played an important role as a single agent1""4' or in combination with other agents1'4>5) Jpn J Clin Oncol 26(5) 1996

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Pirarubicin (4'-0-tetrahydropyranyladriamycin), a new anthracyline derivative, was administered as a single agent into the pleural cavity of 42 patients (total 46 courses) with malignant pleural effusion at a dose of 20, 40, 60 or 80 mg/body. All 46 courses were evaluable for nonhematological toxicities. Fever and chest pain (gWHO grade 2) were seen in 67.4% and 13.0% of courses, respectively. Patients receiving a dose of 80 mg/body developed fever of g39°C in 45.5%, and chest pain lasting more than three days and requiring pentazocine more than three times in 36.4%. In contrast, patients receiving a dose of £60 mg/body presented these toxicities in only 8.6% and 2.9%, respectively. Nausea-vomiting (gWHO grade 2) was observed in only 4.3% of the total 46 courses and alopecia was not observed. Thirty-eight courses (36 patients) were evaluable for hematological toxicities. Myelosuppression (leukocyte nadir count ^1900, WHO grade 3 or 4) was seen in four courses (10.5%), and thrombocytopenia (£49,000, WHO grade 3 or 4) in only two (5.3%). Although the mean AUC (0-24) for pirarubicin in plasma during the four courses that produced myelosuppression was significantly higher than that during the 11 courses without myelosuppression, the difference in the mean dose was not significant. Furthermore, no significant correlation was shown between dose (mg/m2) and AUC in plasma. It is considered that myelosuppression is not a dose-related toxicity at a dose of 20-80 mg/body. The dose-limiting toxicity was fever or chest pain, although unexpected myelosuppression was also encountered. The maximum tolerated dose was 80 mg/body. With regard to clinical efficacy, the overall response rate was 73.7% in 38 evaluable courses (38 patients). The mean T1/2 of pirarubicin concentration in pleural effusion and plasma was 22.1 h and 8.8 h, respectively. We recommend a dose of 40 or 60 mg/body pirarubicin for this pleurodesic treatment.

INTRAPLEURAL PIRARUBICIN THERAPY

because of its strong antineoplastic and pleural irritating activities.^ The response rate for treatment using intrapleural adriamycin, when instilled as a single agent, is reported to be 39.5-87.5%.'"" Pirarubicin (4>-O-tetrahydropyranyladriamycin) is a new anthracycline derivative synthesized by Umezawa et al. in 1979.7"9) It has been found to be less toxic10-n) and superior to adriamycin in its antineoplastic activity.7-8) Therefore, we administered pirarubicin as a single agent into the pleural cavity of patients with malignant effusion in order to investigate its toxicity, efficacy and pharmacokinetics.

Table I. Number of Entered and Evaluable Patients and Courses

Materials and Methods

Table II. Characteristics of 42 Entered Patients

No. of No. of patients courses 42 46 Entered Evaluable for non-hematological toxicity 42 46 Evaluable for hematological toxicity 36 38 Evaluable for efficacy 38 38 Studied for pharmacokinetics in plasma 18 21 Studied for pharmacokinetics in pleural 18 17 effusion

Median age (range)

Forty-two patients with cytologically proven malignant pleural effusion were entered into the study (Table I). Since four of the 42 patients received a second course of intrapleural pirarubicin treatment with an interval of at least 8 weeks because of reaccumulated effusion, a total of 46 courses were entered into the study. Eligibility criteria included: (1) patient age >18 years; (2) leukocyte count >3OOO/mm3 and thrombocyte count > 100,000/mm3; (3) normal GOT, GPT and total bilirubin levels; (4) normal serum creatinine level; (5) a life expectancy of at least 8 weeks; (6) no prior systemic chemotherapy in the preceding 4 weeks or prior intrapleural chemotherapy; (7) informed consent granted by the patient or his/her family before entry. Characteristics of 42 entered patients are shown in Table II.

Males/females

Administered Dose, Maximum Tolerated Dose, and Dose-limiting Toxicity The starting dose was 40 mg/body, and then the dose was escalated to 60 and 80 mg/body. This was based on the the results of phase I trials of systemic pirarubicin12"14' in which the maximum tolerated dose was reported to be 54-66.6 mg/m2, and studies of intrapleural treatment with adriamycin1"5' in which a dose of 20-100 mg/body was administered. Next, because even a dose of 40 mg/body pirarubicin showed favorable efficacy, a dose of 20 mg/body pirarubicin was administered in order to investigate whether a lower dose would provide favorable efficacy with less toxicity. At least six courses were administered at each dose level. The maximum tolerated dose was defined as the dose at which one third of patients experienced dose-limiting toxicities. Since we had found that an intrapleural overdose of pirarubicin caused total pulmonary collapse due to chemical pleuritis in an experimental study of rats'5' and previous studies

Primary tumor lung adenocarcinoma squamous cell carcinoma small cell carcinoma large cell carcinoma stomach breast kidney osteosarcoma tongue Stage, HIB/IV

67 years (26-88) 26/16 37 33 2

20/22

of intrapleural adriamycin had predicted that the major toxicities in this clinical study would probably be local ones such as fever and/or chest pain rather than myelosuppression,1"5' we defined the dose-limiting toxicity as fever if it exceeded 39°C, chest pain if it lasted more than three days and required pentazocine more than three times, other non-hematological toxicities if they exceeded WHO grade 3, or hematological toxicities if they exceeded WHO grade 4. Treatment All patients were hospitalized for each treatment. The effusions were almost completely drained through a double lumen tube inserted into the pleural cavity. After confirming reexpansion of the lung using chest x-ray examination, 20, 40, 60 or 80 mg/body pirarubicin in 10 ml of sterile water diluted to 40 ml in normal saline was instilled into the pleural cavity through the chest tube. The tube was clamped for 5 to 24 h, and the position of the patient was changed as frequently as possible in the 329


Patient Eligibility and Characteristics

GOTOH ET AL.

Table III . Non-hematological Toxicities Dose

No. of

20 mg 11 40 mg 15 60 mg 9 80 mg 11 Total 46 Incidence ( g grade 2)

Fever Grade 1 2(2*) 3 2 7(0) 0 3 8(2) 0 3 5(1) 0 0 11(5) 0 8 31(8) 0 67.4%

Chest pain 4 0 0 0 0 0

1 2 4 2 2 10

2(2*) 3 4 0(0) 0 0 KD 0 0 0(0) 0 0 5(4) 0 0 6(5) 0 0 13.0%

Nauseavomiting 1 2 3 4 0 0 0 0 3 0 0 0 1 1 0 0 2 0 1 0 6 1 1 0 4.;3%

2*; fever a 39°C or chest pain lasting more than three days and requiring pentazocine more than three times.

following 24 h to obtain adequate dispersal of agent. The effusion was then reaspirated, and tube was removed when the volume of drained fusion decreased to less than 30 ml/day. premedications such as analgesics were used.

the the efNo

Follow-up Examination and Evaluation

330

Pharmacokinetic Studies To measure the pirarubicin concentration, plasma and pleural effusion were collected at regular intervals. Two-milliliter blood samples were obtained at 5 min, 30 min, 1 h, 2 h, 4 h, 6 h, 12 h and 24 h, and 1-ml pleural effusion samples were obtained at 0 min (immediately after), 30 min, 1 h, 2 h, 4 h, 6 h, 12 h and 24 h after the intrapleural instillation of pirarubicin. Courses in which pleural effusion samples had not been obtained smoothly through the chest tube were excluded from the pharmacokinetic study. Samples were taken using heparinized syringes, centrifuged immediately if possible, and the supernatants were stored frozen at -30°C before assay. Pirarubicin concentration was measured using high-performance liquid chromatography (HPLC). The limit of detection of pirarubicin was 0.001 /tg/ml. Pharmacokinetics of pirarubicin in plasma were studied in 21 courses (18 patients) and, in pleural effusion, in 18 courses (17 patients) (Table I). The major pharmacokinetic parameters were calculated using moment analysis. The Wilcoxon rank-sum test was used to compare the mean values of each parameter between the two groups. In addition, although we measured the concentrations of active metabolites of pirarubicin (such as adriamycin), we neglected them in this study, considering that the toxicity and efficacy of this treatment were mostly provided by the activity of pirarubicin itself. Results Toxicity The major non-hematological toxicities encountered are shown in Table III. Fever of s38°C ( ^ grade 2) was observed during 67.4% of the total 46 courses and in all of the courses with a dose of 80mg/body pirarubicin. Fever of ^39°C was Jpn J Clin Oncol 26(5) 1996


After the intrapleural administration of pirarubicin, complete blood count, hepatic function (GOT, GPT and total bilirubin) and renal function (serum creatinine) were determined at least once weekly in the following 4 weeks. Toxicities were graded according to the WHO. 1 " Non-hematological toxicities were eligible for evaluation in all 46 courses (42 patients), but hematological toxicities were eligible for evaluation in only 38 courses (36 patients) (Table I), since in eight courses, some blood examinations could not be performed, or intrapleural readministration of pirarubicin or one of several other sclerosing agents was performed within 4 weeks because of residual effusion. To evaluate the efficacy of treatment, pleural effusions were assessed using chest x-ray, computed tomography, and/or ultrasonography, and pleural effusion cytology was reexamined 4 weeks after instillation of pirarubicin in patients with residual effusion. The clinical efficacy of this therapy was evaluated according to the criteria of the "General Rules for Clinical and Pathological Recording of Lung Cancer" by the Japan Lung Cancer Society. A complete response (CR) was defined as disappearance of effusion for at least 4 weeks, a partial response (PR) as markedly decreased effusion with negative cytologic findings for at least 4 weeks, and no response (NR) as no decrease of effusion or positive cytologic findings. We evaluated efficacy in 38 courses (38 patients) of the first intrapleural administration of pirarubicin (Table I). Four courses (four patients), during which additional intrapleural administration of OK-432 was performed on the recommendation of the doctor in charge within 4 weeks because of residual effusion, were ex-

cluded. All 38 evaluable courses were followed up until the patients died.

INTRAPLEURAL PIRARUBICIN THERAPY Table IV.

No. of courses

Hematological Toxicities

Leukocyte Grade 1 2 3 4

20 mg 8 11 40 mg 8 60 mg 11 80 mg 38 Total Incidence (grade 3 or 4)

Thrombocyte 1 2

0 0 0 0 0 0 0 1 1 1 2 0 0 1 0 1

0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0

1 2 2 2 10.:5%

0

Efficacy Efficacy was evaluable in 38 courses (38 patients) (Table V)- The overall response rate was 73.7% with 19 CR cases and nine PR cases. For 28 courses where pirarubicin was administered at ^40 mg/body, the response rate was 78.6% with

1 2 3 4 3 3 1 1

1 4 1 6

0 0 2 0 2 0 3 0

8 12 7 18

0 2 0 5.. 3 %

Table V. Dose (/body) 20 40 60 80

mg mg mg mg

Total

0 0

Efficacy

No. of patients (courses)

CR

10 11 8 9

5 (5) 5 (2) 5 (5) 4 (3)

38

19 (15)

PR 1 3 1 4

NR

60.0% 72.7% 75.0% 88.9%

(1) (2) (1) (3)

9 (7)

Response rate (CR + PR)

10

73.7%

Numbers in parentheses indicate those of patients without reaccumulation of pleural effusion.

14 CR cases and eight PR cases. Of the 28 patients who responded, 78.6% showed no reaccumulation of effusion until their death. The mean period from intrapleural instillation of pirarubicin to removal of the drainage tube in patients with CR or PR was 6.8 days. The median survival time for the total of 34 patients with primary lung cancer was 100.5 days, and that of 24 patients with primary lung cancer who achieved CR or PR was 174 days. Pharmacokinetics The major pharmacokinetic parameters of pirarubicin after intrapleural administration are shown in Table VI. The mean area under the curve (AUC) and maximum concentration (Cmax) of pirarubicin in plasma were markedly lower than those in pleural effusion. In three patients, pirubicin concentrations in plasma were below the measurable level in all instances. The mean half-life (Ti/2) of pirarubicin in pleural effusion and in plasma was 22.1 h and 8.8 h, respectively, and the mean mean residence time (MRT) was 18.7 h and 12.5 h, respectively. The mean T1/2 in pleural effusion was significantly (i*