lnvestigational New Drugs 8: 305-306, 1990. 9 1990KluwerAcademic Publishers. Printed in the Netherlands. Brief report
A phase II study of mitoxantrone in advanced gastric cancer J.A. Levi 1, P.G. Gill 2 and P. Presgrave 1
IDepartment of Clinical Oncology, Royal North Shore Hospital o f Sydney, Sydney, Australia; 2Department o f Surgery, Royal Adelaide Hospital, Adelaide, Australia
Key words: mitoxantrone, gastric cancer, phase II Summary Sixteen patients with advanced adenocarcinoma of the stomach were entered into a phase II study of mitoxantrone at a dosage of either 12 m g / m ~ or 14 m g / m 2 given at 3 weekly intervals. Nine patients had received prior chemotherapy including doxorubicin. No patients achieved either a complete or partial response, five patients had stable disease and the remainder disease progression. Moderate to severe leukopenia occurred in 10 patients with one septic death. Median survival for all patients was eight weeks (range 1 - 4 9 weeks). It is concluded that mitoxantrone has no worthwhile activity in gastric cancer at the described doses. The anthraquinone, mitoxantrone has been shown to have a similar mechanism of action, spectrum of animal and human antitumour activity and have a relative lack of cross resistance to the anthracyclines [1,2]. Considering this and the demonstrated activity of doxorubicin in advanced gastric cancer [3], a phase II trial of mitoxantrone in patients with advanced gastric cancer was undertaken.
Patients and methods All patients had primary adenocarcinoma of the stomach with histological proof of surgically unresectable, recurrent and metastatic disease beyond the regional lymph nodes. All patients had at least one site of measurable disease, a life expectancy of at least 8 weeks and an E C O G performance rating between 0 - 2 . None of the patients had received any radiotherapy or chemotherapy in four weeks prior to entering the trial. Informed consent was obtained from each patient prior to entry into the trial. This trial was approved by the respective Institutional Review Boards for Clinical Trials. On the basis of phase I data, patients were divided into two categories for dosage determination.
Group I patients were defined as less than 65 years old, with a pretreatment neutrophil count > 2000//A and platelet count > 150,000/IA and with less than 33~ of their bone marrow bearing areas exposed to prior radiotherapy. Group 2 patients were either greater than 65 years old, had a neutrophil count between 1500-2000/~1 and platelet count between 100-150,000/IA prior to therapy or had received extensive irradiation. Group I patients received 14 m g / m 2 and group 2 patients were treated with 12 m g / m 2, both given at 21 day intervals and administered as an infusion over 15 minutes in 100 mls of 5~ dextrose. Pretreatment assessment consisted of clinical examination, full blood count, serum biochemistries, CXR and ECG. Xrays and scans were performed, as required to assess tumour dimensions. Patients were re-examined every three weeks with a repeat blood count at least weekly. Regular assessment of tumour measurements were made with appropriate imaging modalities. Criteria for response and toxicity were reported according to WHO criteria [4]. Therapy was discontinued if disease progression occurred, there was no evidence of response after two courses or if unacceptable toxicity occurred.
306
Results
Table 1. Patient characteristics
A total of 16 patients were entered on trial and all were evaluable for response and toxicity. Pretreatment characteristics are presented in Table 1. Prior chemotherapy included doxorubicin in 9 patients together with 5 fluorouracil and either mitomycin C or BCNU. Patients received a median of 2 courses of therapy (range 1-8). By standard response criteria, no complete or partial responses were observed, 5 patients had stable disease, two of whom had no prior chemotherapy and 11 patients had disease progression. Leukopenia was the predominant toxicity observed with 6 patients experiencing grade 2 (WBC nadir 1000-2000/tA) and one patient grade 4 (WBC < 1000/~1) leukopenia. Three patients developed sepsis during the leukopenia and this was fatal in the one patient with grade 4 leukopenia. Only one patient had significant thrombocytopenia (nadir platelet count < 50,000/~1) without clinical sequaelae. Nausea and vomiting was absent or mild in 14 patients although mild to moderate mucositis was observed in 4 patients. There was no evidence of cardiac, renal or hepatic dysfunction. There was no difference in the spectrum or severity of toxicities observed in these patients according to the dose stratification of mitoxantrone used. The median survival for all patients was 8 weeks (range 1-49 weeks), whereas for those 5 patients with stable disease median survival was 17 weeks (range 9 - 4 9 weeks).
Characteristic
Patient numbers
Total Patients Median age (range) Performance status ECOG 0-1 ECOG 2 Stratification Group 1 Group 2 Predominant disease Abdominal mass Liver Nodal Prior therapy Surgery only Chemotherapy Radiotherapy Radiotherapy/chemotherapy
16 63 (28-83)
Discussion This phase II study of mitoxantrone has failed to demonstrate any useful activity in advanced gastric cancer. Although nine of the patients had received prior chemotherapy including doxorubicin, if these two agents are incompletely cross resistant as suggested by other studies, then the lack of activity observed was real. The only other study of mitoxantrone in gastric cancer by De Simone et al. also failed to demonstrate any benefit [5]. Subjective toxicity in this study was not severe but the considerable leukopenia observed and the lack of correlation between this toxicity, prior ther-
11 5 3 13 9 5 2 6 8 1 1
apy and risk group stratification suggests dose escalation would be neither feasible or beneficial.
Acknowledgements We are grateful for the supply of mitoxantrone and financial support from Lederle Laboratories Pty. Ltd.
References 1. Durr FE, Wallace RE, Citarella RV: Molecular and biochemical pharmacology of mitoxantrone. Cancer Treat Rev 10: 3-11, 1983 2. Neidhart JA, Gochnour D, Roach R, Hoth D, Yound D: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4: 672-677, 1986 3. Levi JA, Fox RM, Tattersall MH, Woods RL, Thomson D, Gill G, for the Sydney Cooperative Oncology Group: Analysis of a prospectively randomised comparison of doxorubicin versus 5-fluorouracil, doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: Implications for future studies. J Clin Oncol 4: 1348-1355, 1986 4. Miller AB, Hoogstraten B, Stacquet M, Winkler A: Reporting Results of Cancer Treatment. Cancer 47: 207-214, 1981 5. De Simone PA, Gams R, Birch R: Phase II evaluation of mitoxantrone in advanced carcinoma of the stomach: A Southeastern Cancer Study Group Trial. Cancer Treat Rep 70: 1043-1044, 1986
Address f o r offprints: J.A. Levi, Department of Clinical Oncology, Royal North Shore Hospital of Sydney, St. Leonards, NSW 2065, Australia
A phase II study of mitoxantrone in advanced gastric cancer J.A. Levi 1, P.G. Gill 2 and P. Presgrave 1
IDepartment of Clinical Oncology, Royal North Shore Hospital o f Sydney, Sydney, Australia; 2Department o f Surgery, Royal Adelaide Hospital, Adelaide, Australia
Key words: mitoxantrone, gastric cancer, phase II Summary Sixteen patients with advanced adenocarcinoma of the stomach were entered into a phase II study of mitoxantrone at a dosage of either 12 m g / m ~ or 14 m g / m 2 given at 3 weekly intervals. Nine patients had received prior chemotherapy including doxorubicin. No patients achieved either a complete or partial response, five patients had stable disease and the remainder disease progression. Moderate to severe leukopenia occurred in 10 patients with one septic death. Median survival for all patients was eight weeks (range 1 - 4 9 weeks). It is concluded that mitoxantrone has no worthwhile activity in gastric cancer at the described doses. The anthraquinone, mitoxantrone has been shown to have a similar mechanism of action, spectrum of animal and human antitumour activity and have a relative lack of cross resistance to the anthracyclines [1,2]. Considering this and the demonstrated activity of doxorubicin in advanced gastric cancer [3], a phase II trial of mitoxantrone in patients with advanced gastric cancer was undertaken.
Patients and methods All patients had primary adenocarcinoma of the stomach with histological proof of surgically unresectable, recurrent and metastatic disease beyond the regional lymph nodes. All patients had at least one site of measurable disease, a life expectancy of at least 8 weeks and an E C O G performance rating between 0 - 2 . None of the patients had received any radiotherapy or chemotherapy in four weeks prior to entering the trial. Informed consent was obtained from each patient prior to entry into the trial. This trial was approved by the respective Institutional Review Boards for Clinical Trials. On the basis of phase I data, patients were divided into two categories for dosage determination.
Group I patients were defined as less than 65 years old, with a pretreatment neutrophil count > 2000//A and platelet count > 150,000/IA and with less than 33~ of their bone marrow bearing areas exposed to prior radiotherapy. Group 2 patients were either greater than 65 years old, had a neutrophil count between 1500-2000/~1 and platelet count between 100-150,000/IA prior to therapy or had received extensive irradiation. Group I patients received 14 m g / m 2 and group 2 patients were treated with 12 m g / m 2, both given at 21 day intervals and administered as an infusion over 15 minutes in 100 mls of 5~ dextrose. Pretreatment assessment consisted of clinical examination, full blood count, serum biochemistries, CXR and ECG. Xrays and scans were performed, as required to assess tumour dimensions. Patients were re-examined every three weeks with a repeat blood count at least weekly. Regular assessment of tumour measurements were made with appropriate imaging modalities. Criteria for response and toxicity were reported according to WHO criteria [4]. Therapy was discontinued if disease progression occurred, there was no evidence of response after two courses or if unacceptable toxicity occurred.
306
Results
Table 1. Patient characteristics
A total of 16 patients were entered on trial and all were evaluable for response and toxicity. Pretreatment characteristics are presented in Table 1. Prior chemotherapy included doxorubicin in 9 patients together with 5 fluorouracil and either mitomycin C or BCNU. Patients received a median of 2 courses of therapy (range 1-8). By standard response criteria, no complete or partial responses were observed, 5 patients had stable disease, two of whom had no prior chemotherapy and 11 patients had disease progression. Leukopenia was the predominant toxicity observed with 6 patients experiencing grade 2 (WBC nadir 1000-2000/tA) and one patient grade 4 (WBC < 1000/~1) leukopenia. Three patients developed sepsis during the leukopenia and this was fatal in the one patient with grade 4 leukopenia. Only one patient had significant thrombocytopenia (nadir platelet count < 50,000/~1) without clinical sequaelae. Nausea and vomiting was absent or mild in 14 patients although mild to moderate mucositis was observed in 4 patients. There was no evidence of cardiac, renal or hepatic dysfunction. There was no difference in the spectrum or severity of toxicities observed in these patients according to the dose stratification of mitoxantrone used. The median survival for all patients was 8 weeks (range 1-49 weeks), whereas for those 5 patients with stable disease median survival was 17 weeks (range 9 - 4 9 weeks).
Characteristic
Patient numbers
Total Patients Median age (range) Performance status ECOG 0-1 ECOG 2 Stratification Group 1 Group 2 Predominant disease Abdominal mass Liver Nodal Prior therapy Surgery only Chemotherapy Radiotherapy Radiotherapy/chemotherapy
16 63 (28-83)
Discussion This phase II study of mitoxantrone has failed to demonstrate any useful activity in advanced gastric cancer. Although nine of the patients had received prior chemotherapy including doxorubicin, if these two agents are incompletely cross resistant as suggested by other studies, then the lack of activity observed was real. The only other study of mitoxantrone in gastric cancer by De Simone et al. also failed to demonstrate any benefit [5]. Subjective toxicity in this study was not severe but the considerable leukopenia observed and the lack of correlation between this toxicity, prior ther-
11 5 3 13 9 5 2 6 8 1 1
apy and risk group stratification suggests dose escalation would be neither feasible or beneficial.
Acknowledgements We are grateful for the supply of mitoxantrone and financial support from Lederle Laboratories Pty. Ltd.
References 1. Durr FE, Wallace RE, Citarella RV: Molecular and biochemical pharmacology of mitoxantrone. Cancer Treat Rev 10: 3-11, 1983 2. Neidhart JA, Gochnour D, Roach R, Hoth D, Yound D: A comparison of mitoxantrone and doxorubicin in breast cancer. J Clin Oncol 4: 672-677, 1986 3. Levi JA, Fox RM, Tattersall MH, Woods RL, Thomson D, Gill G, for the Sydney Cooperative Oncology Group: Analysis of a prospectively randomised comparison of doxorubicin versus 5-fluorouracil, doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: Implications for future studies. J Clin Oncol 4: 1348-1355, 1986 4. Miller AB, Hoogstraten B, Stacquet M, Winkler A: Reporting Results of Cancer Treatment. Cancer 47: 207-214, 1981 5. De Simone PA, Gams R, Birch R: Phase II evaluation of mitoxantrone in advanced carcinoma of the stomach: A Southeastern Cancer Study Group Trial. Cancer Treat Rep 70: 1043-1044, 1986
Address f o r offprints: J.A. Levi, Department of Clinical Oncology, Royal North Shore Hospital of Sydney, St. Leonards, NSW 2065, Australia
