The largest study of topotecan for recurrent disease is the 'Gordon Study'.r This study is limited by unacceptable levels of toxicities in both arms. The major toxicity of topotecan is haematological. 78% of patients required a dose reduction hence we have recommended a starting dose lower than in this study with the expectation of lower toxicity.
Gordon et al, 2001r compared pegylated liposomal doxorubicin (PLD) with topotecan in a phase lll randomised trial in patients who recurred after, or did not respond to, first line platinum based treatment. A total of 474 patients with measurable and assessable disease were randomised to receive either PLD 50 mg/m2 as a one hour infusion every 4 weeks or topotecan 1.5 mg/m2/day for 5 consecutive days every 3 weeks.
The overall progression free survival rates were similar between the two arms (p = 0.095). The overall response rates for liposomal doxorubicin and topotecan were 19.7 % and 17 % respectively (p = 0.390). The topotecan arm however had more grade 3 and 4 adverse events. Given the similarities in efficacy of both of these treatments, the toxicity profile and resulting tolerability are important when selecting therapy for recurrence.
An updated analysis of the long-term follow-up data confirmed the results that were previously reported showing that liposomal doxorubicin significantly prolongs survival compared with topotecan in patients with recurrent or refractory epithelial ovarian cancer. The survival benefit is pronounced in the subgroup of patients with platinum-sensitive disease but not significant in those with platinum-refractory disease.r
Efficacy
Responser
Efficacy |
Liposomal doxorubicin |
Topotecan |
Overall response |
20 % |
17 % |
Complete response |
4 % |
5 % |
Partial response |
16 % |
12 % |
Stable disease |
32 % |
40 % |
Median progression-free survival |
16 weeks |
17 weeks |
Median survival |
60 weeks |
57 weeks |
Platinum-sensitive tumour subgroupr
Efficacy |
Liposomal doxorubicin |
Topotecan |
Overall response |
28 % |
29 % |
Complete response |
7 % |
9 % |
Partial response |
21 % |
20 % |
Stable disease |
38 % |
38 % |
Median progression-free survival |
29 weeks |
23 weeks |
Median survival |
108 weeks |
71 weeks |
Platinum-resistant tumour subgroupr
Efficacy |
Liposomal doxorubicin |
Topotecan |
Overall response |
12 % |
6 % |
Complete response |
1 % |
1 % |
Partial response |
11 % |
6 % |
Stable disease |
28 % |
43 % |
Median progression-free survival |
9 weeks |
14 weeks |
Median survival |
36 weeks |
41 weeks |
© Journal of Clinical Oncology 2001
Toxicity
Almost all patients reported adverse events. The proportion of grade 1, 2 and 3 events was similar between the two groups, however a greater percentage of grade 4 adverse events were reported in the topotecan group (71% versus 17%).r
Haematological toxicity was more frequent and usually grade 3 or 4 in the topotecan treated patients. 90% of patients in the topotecan group experienced haematological adverse events and two thirds of these were grade 3 or 4 which resulted in the use of haemotopoietic growth factors, blood transfusions and dosing modifications. Nine (3.8 %) patients developed treatment related sepsis (3 of whom died).r
The most common adverse events in the liposomal doxorubicin arm were Palmar-plantar erythrodysesthesia (PPE) and stomatitis. These were treated with dose reduction or delay.r
Toxicity r |
Liposomal doxorubicin (%)
(all grades) |
Liposomal doxorubicin (%)
(grades 3 to 4) |
Topotecan (%)
(all grades) |
Topotecan (%)
(grades 3 to 4) |
Neutropenia |
35 |
12 |
81 |
77 |
Anaemia |
36 |
5 |
72 |
28 |
Thrombocytopenia |
13 |
1 |
65 |
34 |
Leukopenia |
36 |
10 |
63 |
50 |
Alopecia |
16 |
1 |
49 |
6 |
PPE* |
49 |
23 |
1 |
0 |
Stomatitis |
40 |
8 |
15 |
0.4 |
* Palmar-plantar erythrodysesthesia (hand-foot syndrome)
© Journal of Clinical Oncology 2001