EORTC Group Phase II Study of Oral Etoposide for Pretreated Soft Tissue Sarcoma

Purpose. This study investigates the efficacy and toxicity of daily oral etoposide in chemotherapy for non-heavily pretreated advanced and metastatic soft tissue sarcoma (STS). Subjects. Twenty-seven patients with progressive and measurable disease were treated. Median age was 53 years (range 20–71 years) and performance status WHO 0 or 1. Histologies included mainly leiomyosarcoma (8), malignant fibrous histiocytoma (4), rhabdomyosarcoma (4), liposarcoma (2) and synovial sarcoma (2). Fifteen patients had received prior radiotherapy, of whom three included sites with haematopoiesis. All patients had received prior chemotherapy, including adjuvant therapy (7) and mostly consisted of one two-drug schedule (ifosfamide and doxorubicin) or two single-drug regimens. Methods. Chemotherapy consisted of etoposide (VP16-213), 50 mg m-2 day-1 × 21 q 4 weeks. Blood cell counts were done weekly. Dose reductions and a maximum delay of 2 weeks was allowed depending on cell counts during treatment and at the start of a new 4-week treatment cycle. Results. No objective response was observed. Progressive disease was observed after two treatment cycles in 17/27 patients (68%) and after three cycles in 22/27 patients (81%). The other patients received three to five cycles. Twenty-four patients went off study due to progressive disease. Grade 3 and 4 neutropenia was observed in eight and one patients, respectively. Thrombocytopenia grade 3 was seen in two patients. Non-haematological toxicity grade 3 (nausea, diarrhoea or alopecia) was observed in three patients, and grade 4 (dyspnea, hypotension or haemorrhage) in three patients. Discussion. No objective response was obtained. Oral etoposide at a dose of 50 mg m-2 day-1 × 21 q 4 weeks is inactive in chemotherapy of pretreated STS. Disease progression occurred within three cycles in the majority (81%) of patients. Toxicity of this regimen in non-heavily pretreated patients is low.


Introduction
Etoposide (VP16/213) is a m ajor cytostatic agent w ith a broad antitum our spectrum. 1 In clinical practice, its schedule dependency has been established. 1,2 Frequently used schedules are daily adm inistrations for 3 to 5 days or at days 1, 3 and 5. This schedule dependency prom pted clinicians to exam ine prolonged adm inistration schedules, in particular daily oral dosing, for 14± 21 days in 3-or 4-w eek cycles. This chronic adm inistration proved to be active in several m alignancies including solid tum ours such as breast cancer, gastric cancer, m esotheliom a and Kaposi sarcoma. 1 Interestingly, som e tum ours, resistant to standard treatment schedules, responded again following chronic oral schedules. The E ORT C Soft Tissue and Bone Sarcom a Group and others found no signi® cant activity of VP16 intravenously at dosages of 120± 130 m g m 2 2 , days 1± 3 or days 1± 5, respectively, every 3 weeks. 3,4 However, m ost of these patients were heavily pretreated. T he Scandinavian Sarcom a G roup used a combination of ifosfam ide (450 m g m 2 2 ) and etoposide (600 m g m 2 2 ) as a continuous infusion. The 42% response rate was considered prom ising by the authors, who also claim ed the effectivity of continuous etoposide adm inistration. 5 Chronic adm inistration of oral etoposide, planned dose 150 m g/day for 15 days q 3 weeks, w as studied in 15 heavily pretreated advanced soft tissue sarco- 1357-714 X/97/020099± 03 $9.00 Ó 1997 Carfax Publishing Ltd m as (STS). 6 N o objective responses were observed. H alf of the patients received one cycle only, while the others received two cycles. Frequently, the daily dose or the num ber of treatment days had to be lim ited. Based on data of objective responses after prolonged adm inistration of oral etoposide in nonheavily pretreated patients, reported by som e m embers, the EO RT C-ST S G roup initiated a phase II study in pre-treated patients who had received one two-drug schedule or tw o single drugs only.
All patients had received prior chem otherapy, including adjuvant therapy (7). T his chemotherapy consisted of one tw o-drug schedule (usually ifosfam ide and doxorubicin) or two single-drug regim ens. F urther in-and exclusion criteria were sim ilar to the standard phase II criteria of the EO RTC-ST S G roup.

Treatment
C hemotherapy consisted of etoposide (VP16-213) 50 mg m 2 2 day 2 1 orally for 21 consecutive days, repeated every 4 w eeks. W eekly haem atological param eters w ere determ ined. If at day 1 of a treatm ent cycle, white blood cells (W BC ) or platelets w ere below 3 3 10 9 /l or 100 3 10 9 /l, respectively, treatment w as delayed until recovery for a m axim um of 2 weeks. If no recovery took place, a dose reduction was m ade.

Results
N o objective response w as obtained. After two cycles of treatment, progression was already present in 17/27 patients (68% ) and after three cycles in 22/27 patients (81%). T he ® ve rem aining patients had`no change' as their best response and received three to ® ve cycles of treatm ent. A total of 24 patients went off study due to tum our progression.
Only one patient experienced grade 4 neutropenia (patient went off study), eight patients had grade 3 neutropenia, w ithout any fever. G rade 3 throm bocytopenia w as observed in two patients. O ne patient went off study after 2 weeks with a platelet count of 54 3 10 9 /l. Grade 4 non-m yelotoxicity occurred in three patients (one pulm onary embolism , one acute respiratory failure after the ® rst cycle and one gastrointestinal bleeding, without throm bocytopeniaÐ this patient went off study). T hese latter toxicities were de® nitely considered to be unrelated to the chem otherapy.

D iscussion
T he data presented show that in 27 patients w ho had been previously treated with two single-drugs regim ens or one two-drug combination, a regim en of 3 weeks oral etoposide (50 m g m 2 2 day 2 1 3 21, q 4 weeks) failed to achieve an objective response. M oreover, 22/27 patients (81%) already showed progressive disease after two or three courses of treatment. The toxicity of this regimen is low, which m ay be explained by the relatively low dose and the previously received chem otherapy.
Yet, with a sim ilar regimen, Hainsw orth et al. 7 in refractory or resistant patients, reported 2/3 partial responses. Using higher dosages (3-w eekly intravenous 130 m g m 2 2 ) the EORT C-ST S G roup reported 1/26 patients with a partial response. 3 T he use of higher dosages in a daily oral schedule was reported by K am pe et al. 6 and resulted in severe m ucositis, gastrointestinal side-effects and m yelosuppression. N o response was seen in the 15 heavily pretreated patients (no further speci® cations were given). D iscontinuation of treatm ent and dose reductions were frequently needed in this latter study.
There is hardly any data on etoposide as a single agent, in ® rst-line treatment for STS. T he Scandinavian Sarcom a Group used a com bination of etoposide and ifosfam ide (both as a continuous infusion) and found a 42% objective response rate. In second line studies the m ajority of reports, including our own, indicate that this drug does not have signi® cant ef® cacy. T he effect of etoposide as a ® rst-line single agent (oral or intravenous) in ST S has yet to be determined.