- Email: [email protected]
Gemcitabine and anthracyclines in platinum-resistant ovarian cancer
symposium article
Annals of Oncology 17 (Supplement 5): v195–v198, 2006 doi:10.1093/annonc/mdj980
Gemcitabine and anthracyclines in platinum-resistant ovarian cancer E. Galligioni1*, C. Arcuri1, R. Sorio2 & C. Griso3 Medical Oncology, 1Trento, 2CRO Aviano, 3Verona, Italy
Background: Most of the patients with advanced ovarian cancer will recur after first-line platinum-based
Platinum-based combination chemotherapy is the gold standard for the first-line treatment of advanced epithelial ovarian cancer (OC) following cytoreductive surgery but, in spite of high (up to 70%) response rates (RR), the majority of patients will relapse and need additional treatment. Many active drugs are available for the palliative treatment of recurrent OC, although patients with >6 months treatment-free intervals may benefit from a Platinum rechallenge [1] preferably in combination as shown by the ICON /AGO-OVAR-2.2 trial [2]. In second-line treatment, Topotecan, Gemcitabine, Etoposide and Anthracyclines, obtain 20% to 30% RR, but the time to progression is usually short with no impact on survival, particularly in Platinum resistant or refractory cases [3–5]. Gemcitabine (G) is active in OC (15% to 28% RR) and has a good toxicity profile, which suggest possible combinations with other active agents [6, 7]. Anthracyclines too are active in OC. A meta-analysis of randomized trials has shown increased RR and improved survival in patients receiving Doxorubicin (D) [8, 9]. In many single studies however the addition of Antracyclines, as in the Du Bois study [10], did not improve survival while significantly increased myelotoxicity [10].
*Correspondence to: Dr E. Galligioni, Medical Oncology, St. Chiara Hospital, 38100 Trento, Italy. Tel: +39 0461 902478; Fax: +39 0461 903364; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
Epirubicin (E), a D analogue, is less cardiotoxic than the parent compound and is active in first and second-line treatment of OC [11, 12]. Different G/antracyclines combinations have been investigated in the salvage treatment of OC patients, based on activity of both drugs in this tumor [13–15], their different mechanism of action, the synergistic antiproliferative activity in vitro [16, 17] and their non-overlapping toxicities. In a phase I trial of G/E combination on a 3-week schedule, the MTD of G and E was established at 1000 and 60 mg/m2 respectively, with a 23% RR in 13 recurrent, Platinum-resistant OC patients [18]. In a different phase I–II trial on Platinum-resistant/refractory OC patients, the G/D combination plus G-CSF support obtained 11/49 objective responses (24%), 14/49 stabilizations (31%), with a median survival of 12 months. [19] Toxicity was primarily haematological, and QoL evaluation indicated a good tolerance of this regimen. Pegylated liposomal doxorubicin (PLD) is a formulation of D in liposomes, whose surface contains the hydrophilic polymer methoxypolyethylene glycol. PLD is active in OC and less toxic than the parent compound, with the dose-limiting toxicities consisting of stomatitis and palmo-plantar erythrodysesthesia (PPE) [17]. In a phase I–II study of G/PLD combination on 17 patients (14 evaluable), with a mean of 2.5 prior chemotherapy regimens, the initial dose of G was 800 mg/m2 on days 1 and 8,
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chemotherapy and need additional treatment. Gemcitabine (G) and Anthracyclines are active in this setting and their combination has shown synergistic antiproliferative activity in vitro, due to different mechanisms of action and non-overlapping toxicities. Patients and methods: In 2002 we began a phase II study with G 1000 mg/m2 (day 1,8) combined to Epirubicin (E) 60 mg/m2 (day 1), every 3 weeks for 6 cycles, in Platinum resistant/refractory ovarian carcinoma patients. Results: Among 30 patients enrolled so far (27 evaluable), receiving 149 cycles (median 6), 1 complete and 12 partial responses (48%), 9 stabilizations (33%) and 5 progressions (18%) were observed, with a good correlation with serological responses. Median time to progression was 8 months, while median time to response was 10 weeks and median duration 8 months. Grade 3–4 toxicities consisted of neutropenia (58%), thrombocytopenia (3%), anemia (10%), liver toxicity (13%), and mucositis (7%). Eight patients (27%) received G-CSF and 3 (10%) blood transfusions. No febrile neutropenia nor cardiotoxicity were observed. Conclusions: Although our results are preliminary, G/E combination appears particularly effective and safe in these platinum resistant/refractory patients. Key words: recurrent ovarian cancer, platinum-resistant patients, gemcytabine-antracyclines combination
symposium article
study design On these bases, we have decided to further explore the G/ Antracyclines combination in patients with recurrent histologically confirmed epithelial OC, or cancer of the fallopian tube or the peritoneum, Platinum-resistant or refractory disease, WHO performance status 0–2, adequate haematological, renal and liver functions, age ‡ 18 and £ 75, measurable tumor, no previous anthracycline treatment, FEV > 60% and signed informed consent. The protocol was approved by the institutional ethic committee. Staging procedures included: blood chemistries, physical examination, chest X-ray, abdomen-pelvic CT scan. Patients received G 1000 mg/m2 (day 1,8) and E 60 mg/m2 (day 1) every 3 weeks for 6 cycles, or disease progression, unacceptable toxicity or withdrawal due to other reasons. Patients showing objective response after 6 cycles continued to a maximum of 9 cycles. All pts received anti-emetic medication and steroids. Treatment was delayed and/or doses reduced in case of grade 4 neutropenia or ‡ grade 3 thrombocytopenia or grade 1–2 renal toxicity. G-CSF support was allowed in the case of prolonged leucopenia (> 7 days) or febrile neutropenia in the prior cycle. Objective responses and toxicity were the primary end points. Time to progression, time to response, and overall survival were the secondary end points.
v196 | Galligioni et al.
Tumor assessment was performed, according to RECIST Criteria, £ 28 days before treatment, after 3 and 6 cycles, and subsequently until disease progression. Serological Response was assessed according to Rustin criteria and toxicity according the NCI criteria. Haematological and biochemical parameters were measured on day 1 of each treatment cycle. Time to progression was defined as the time from the first day of treatment until objective progression, or the last date of patient contact. Time to response was defined as the time from the first day of treatment until objective response was documented and response duration from that time to progression. Overall survival as defined as the time from the first day of treatment until death from any cause or the last date of patient contact.
data analysis The Simon two-stage design was planned: if fewer than 16 responses are obtained among the first 46 patients, then the accrual will terminate and the association of G and E is will rejected. Otherwise, accrual will continue to a total of 65 pts. At the end of the second stage, the drug combination will be rejected if the observed responses will be less than 26.
results The study is still open and preliminary results have been recently presented [28]. From June 2002 to February 2005, we have enrolled 30 patients with 1–4 previous chemotherapy regimens (median 1) and a median platinum free interval of 6 months (range 0–12), a median age of 59 years [43–74), and 0–2 (median 1) ECOG performance status. The FIGO stage and number of patients were III/13 and IV/17 respectively. Histology was serous in 21 patients, endometrioid in 2, unclassified adenocarcinoma in 5, tuba in 1 and peritoneal in 1 (Table 1). Cumulatively, 149 cycles were administered (median 6). Among the 27 patients evaluable for response (2 too early, 1 with early worsening of general conditions and progression after 1 dose), 1 complete and 12 partial responses were observed, for an overall response rate of 48%. Nine pts (33%) had stable disease and 5 (18%) progressed (Table 2). The serological responses were substantially in accord to the objective responses and are reported in table 3. Median time to progression was 8 months (range 1.5–23). Among responding patients, the median time to response was 10 weeks (range 8–20) with a median duration of 8 months (range 4.5–12). Major (grade 3–4) toxicities on 29 evaluable patients included: leucopenia 27%, neutropenia 58%, thrombocytopenia 3%, anemia 10%, liver 13%, and mucositis 7%. Eight patients (27%) received G-CSF support, and 3 (10%) blood transfusions (Table 4).
discussion Based on our preliminary results, this G/E combination with a 48% RR and 33% of stabilizations appears effective and safe in these platinum-resistant/refractory patients.
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with a fixed dose 30 mg/m2 of PLD on day 1 of a 28-day cycle. Overall 5 complete responses (36%), 1 partial (7%) and 5 stable disease (36%), were observed [20]. In a different phase I study, on 23 heavily pretreated women, 5 of whom platinum-sensitive, the MTD was reached at 1000 mg/m2 for G on days 1 and 8 and at 30 mg/m2 for PLD. Five partial responses (21%) and 5 stable disease (21%) were observed [21]. G at 2000 mg/m2 combined with PLD 20 mg/m2 every other week, was administered to 16 pts, with at least 4 previous chemotherapy regimens, obtaining 3 complete (19%) and 4 partial responses (25%). Toxicity was high, mainly for stomatitis or palmo-plantar erythrodysesthesia, and 53% of patients had to discontinue therapy. A prospective phase II trial is now underway with these doses in less pretreated patients [22]. Furthermore, 25 heavily pretreated patients, 8 platinumrefractory/resistant and 17 platinum-sensitive, had received PLD 25 mg/m2 on day 1 and G 650 mg/m2 on days 1 and 8, every 21 days. The overall RR was 64%; six patients had stable disease and the median overall survival was 13 months. Toxicity grade 3/4 included neutropenia in 60% of patients, thrombocytopenia in 32%, anemia in 24% and PPE in 12% [23]. Finally, in a phase II study with G/PLD combination on 67 evaluable patients, a 34% RR, with a 10% of complete responses, was reported with manageable toxicity. Among resistant patients, the observed 25% RR favourably compares to the 18– 12% achievable in phase II and III trials with PLD [5, 25] or with G alone [26], as does the 38% disease stabilisation [24]. Recent studies in fact have demonstrated that patients with partial responses and with stable disease after second line chemotherapy, have a similar survival benefit [27].
Annals of Oncology
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Table 1. Patient demographics Patients
Table 3. Serological response 30 (n)
Table 2. Responses on 27 evaluable patients n Objective response Complete response Partial response Stable disease Progressive disease Median duration of response (range), months Sites of response Peritoneum Liver Pelvic and/or aortic lymph nodes Pelvic node Axillary lymph nodes Ascites
13 1 12 9 5 8
(48%) (2.7%) (44.4%) (33.3%) (18.5%) (4.5–12)
8 3 2 2 1 1
This study is still open, so it is too early for any survival evaluation. However, the response duration and the time to progression observed so far are comparable to those of the
Volume 17 | Supplement 5 | May 2006
Serological response
1 RC 12 RP
1 7 1 2 2 7 2 5
9 SD 5 PRO
RC RC RP 50% RP 75% NA SD RP 50% PRO
Table 4. Drug-related grade 3/4 toxicities Adverse event
n (%)
Cycles
Leucopenia Neutropenia Thrombocytopenia Anemia Liver Mucositis Nausea/vomiting
8 15 1 3 4 2 1
6% 20% 1.3% 2% 3.3% 1.3% 1.3%
(27.5) (51.7) (3.4) (10.3) (13.7) (6.8) (3.4)
literature and indicate that patients did benefit from this treatment at the cost of reasonable toxicity. Despite the 54% incidence of Gr 3–4 neutropenia in fact, no febrile neutropenia was observed. Similarly, no cardiotoxicity was reported and others non-haematological toxicities, apart alopecia, were minor. Finally, as the approach to recurrent ovarian cancer is evolving in to a treatment of a chronic disease, not only effective and well-tolerated regimens but also affordable costs are important components of medical decision. [29] The cost of PLD however is substantial. In contrast, the average cost per cycle of E is approximately 2.5 times lower than PLD and may represent a more convenient choice in this context of non curative cancer treatments. In conclusion, our results are still preliminary but the G/E combination that we have studied appears a valid approach in recurrent OC patients and may deserve future studies.
disclosures Dr Galligioni has indicated no financial relationships with companies whose products are mentioned in this article.
references 1. Ozols RF. Recurrent ovarian cancer: evidence-based treatment. J Clin Oncol 2002; 20(5): 1161–1163. 2. Kaye SB. Lancet 2003; 361: 2094–5. 3. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide an second line therapy for platinum-therapy resistant and platinum sensitive ovarian carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1998; 16: 405–410. 4. Markman M. Second-line treatment of ovarian cancer with single-agent gemcitabine. Semin Oncol 2002; 29(S1): 9–10.
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Median age (range), years 59 (43–74) Eastern Cooperative Oncology Group performance status 0 15 1 13 2 2 No. prior chemotherapy regimen 1 17 2 10 3 2 4 1 Sites of recurrence Peritoneum 21 Liver 12 Pelvic and/or aortic lymph nodes 10 Pelvic nodes 2 Ascites 2 Axillary lymph nodes 1 Inguinal lymph nodes 1 Sovraclavear lymph nodes 1 Lung 1 Spleen 1 Histological type Serous 21 Endometrioid 2 Unclassified adenocarcinoma 5 Carcinoma of tuba 1 Peritoneal carcinoma 1 Histological grade 1 0 2 6 3 21 Unknown 3 Platinum-free interval <6 months 21 ‡6 < 12 months 6
Objective response
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18.
19.
20. 21. 22. 23.
24.
25.
26.
27.
28.
29.
antracyclines on malignant lymphatic and myeloid cells. Antagonism or symergism depends on incubation schedule and origin of neoplastic cells. Ann Hematol 2000; 79: 485–492. Pignata S, Varriale E, Casella G et al. A phase I study of gemcitabine and epirubicin for the treatment of platinum-resistant or refractory advanced ovarian cancer. Ann Oncol 2000; 11: 613–6. Goff BA, Thompson T, Greer BE, Jacobs A, Storere B. Treatment of recurrent platinum resistant ovarian or peritoneal cancer with gemcitabine and doxorubicin: a Phase I/II trial of the Puget Sound Oncology Consortium (PSOC 1602). Am J Obstet Gynecol 2003; 188: 1556–64. Tobias D, Runowicz C. A phase I trial of gemcitabine and doxil for recurrent epithelial ovarian cancer. Proc Am Soc Clin Oncol 2000; 19: 1551A. D’Agostino G et al. Phase I study of gemcitabine and liposomal doxorubicin in relapsed ovarian cancer. Oncology 2002; 62: 110–114. Mutch DG. Gemcitabine combination chemotherapy of ovarian cancer. Gynec Oncol 2003; 90: S16–S20. Pujade-Lauraine E. Balancing efficacy, safety, and quality of life: novel approaches to recurrent ovarian cancer. Viewpoint from 40th Annual Meeting of the American Society of Clinical Oncology. D’Agostino G, Ferrandina G, Ludovisi M et al. Phase II study of liposomal doxorubicin and gemcitabine in the salvage treatment of ovarian cancer. Br J of Cancer 2003; 89: 1180–84. Gordon AN, Granai CO, Rose PG et al. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000; 18: 3093–100. Shapiro JD, Millward MJ et al. Activity of gemcitabine in patients with advanced ovarian cancer: responses seen following platinum and paclitaxel. Gynecol Oncol 1996; 63: 89–93. Cesano A. Stabilization of disease as a useful predictor of survival following second-line chemotherapy in small cell lung cancer and ovarian cancer patients. Int J Oncol 1999; 15: 1233–38. Arcuri C, Sorio R et al. Preliminary results of a phase II study of gemcytabine and epirubicin in platinum-resistant or refractory advanced ovarian cancer. Proc Am Soc Clin Oncol 2005; 23: 16S (abstr. 5071). Dizon D. Carboplatin and paclitaxel as initial second-line therapy in recurrent epithelial ovarian carcinoma. Proc Am Soc Clin Onc 2001; 20: (Abstr 809).
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5. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomised phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19: 3312–22. 6. Lund B, Hansen OP, Theilade K et al. Phase II study of gemcitabine in previously treated ovarian cancer patients. J Natl Cancer Inst 1994; 86: 1530–3. 7. Shapiro JD, Millward MJ, Rishin D et al. Activity of gemcitabine in patients with advanced ovarian cancer: Responses seen following platinum and paclitaxel. Gynecol Oncol 1996; 63: 89–93. 8. Fanning J, Bennet TZ, Hilgers RD. Meta-analysis of cisplatin, doxorubicin, and cyclophosphamide versus cisplatin and cyclophosphamide chemotherapy of ovarian carcinoma. Obstet Gynecol 1992; 80: 954–60. 9. Ovarian Cancer Meta-Analysis Project. Cyclophosphamide plus cisplatin versus cyclophosphamide, doxorubicin and cisplatin chemotherapy of ovarian carcinoma: A meta-analysis. J Clin Oncol 1991; 9: 1668–74. 10. Du Bois A, Weber B. Epirubicin/paclitaxel/carboplatin (TEC) vs paclitaxel/ carboplatin (TC) in first-line treatment of ovarian cancer FIGO stages IIb-IV. Interim results of an AGO-GINECO Intergroup phase III trial. Proc Am Soc Clin Oncol 2001, 20: 805A. 11. Trope` C. A phase II study of epirubicin in advanced ovarian carcinoma. In: Bonadonna G (ed.): Advances in Anthracycline chemotherapy. Epirubicin, Milano: Masson Italia Editori 1984; 91–3. 12. Vermoken JB et al. High-dose epirubicin in platinum-pretreated patients with ovarian carcinoma: the EORTC-GCCG experience. Eur J Gynecol Oncol 1995; 14: 433–8. 13. Markman M, Webster K, Zanotti K, Kulp B, Peterson G, Belinson J. Phase II trial of single agent gemcitabine in platinum-paclitaxel resistant ovarian cancer. Gynecol Oncol 2003; 90: 593–6. 14. Gordon AN, Granai CO, Rose PG et al. Phase II study of liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial ovarian cancer. J Clin Oncol 2000; 18: 3093–100. 15. Gordon AN, Fleagle JT, Guthrie D, Parkin DE, Gore ME, Lacave AJ. Recurrent epithelial ovarian carcinoma: a randomized phase III study of pegylated liposomal doxorubicin versus topotecan. J Clin Oncol 2001; 19: 3312–22. 16. Zoli W, Ricotti L, Barzanti F et al. Schedule-dependent interaction of doxorubicin, paclitaxel and gemcitabine in human breast cancer cell lines. Int J Cancer 1999; 80: 413–6. 17. Chow KU, Ries J, Weidmann E et al. Induction of apoptosis using 2‘,2’difluorodeoxycytidine (gemcitabine) in combination with antimetabolites or
Annals of Oncology
Annals of Oncology 17 (Supplement 5): v195–v198, 2006 doi:10.1093/annonc/mdj980
Gemcitabine and anthracyclines in platinum-resistant ovarian cancer E. Galligioni1*, C. Arcuri1, R. Sorio2 & C. Griso3 Medical Oncology, 1Trento, 2CRO Aviano, 3Verona, Italy
Background: Most of the patients with advanced ovarian cancer will recur after first-line platinum-based
Platinum-based combination chemotherapy is the gold standard for the first-line treatment of advanced epithelial ovarian cancer (OC) following cytoreductive surgery but, in spite of high (up to 70%) response rates (RR), the majority of patients will relapse and need additional treatment. Many active drugs are available for the palliative treatment of recurrent OC, although patients with >6 months treatment-free intervals may benefit from a Platinum rechallenge [1] preferably in combination as shown by the ICON /AGO-OVAR-2.2 trial [2]. In second-line treatment, Topotecan, Gemcitabine, Etoposide and Anthracyclines, obtain 20% to 30% RR, but the time to progression is usually short with no impact on survival, particularly in Platinum resistant or refractory cases [3–5]. Gemcitabine (G) is active in OC (15% to 28% RR) and has a good toxicity profile, which suggest possible combinations with other active agents [6, 7]. Anthracyclines too are active in OC. A meta-analysis of randomized trials has shown increased RR and improved survival in patients receiving Doxorubicin (D) [8, 9]. In many single studies however the addition of Antracyclines, as in the Du Bois study [10], did not improve survival while significantly increased myelotoxicity [10].
*Correspondence to: Dr E. Galligioni, Medical Oncology, St. Chiara Hospital, 38100 Trento, Italy. Tel: +39 0461 902478; Fax: +39 0461 903364; E-mail: [email protected]
ª 2006 European Society for Medical Oncology
Epirubicin (E), a D analogue, is less cardiotoxic than the parent compound and is active in first and second-line treatment of OC [11, 12]. Different G/antracyclines combinations have been investigated in the salvage treatment of OC patients, based on activity of both drugs in this tumor [13–15], their different mechanism of action, the synergistic antiproliferative activity in vitro [16, 17] and their non-overlapping toxicities. In a phase I trial of G/E combination on a 3-week schedule, the MTD of G and E was established at 1000 and 60 mg/m2 respectively, with a 23% RR in 13 recurrent, Platinum-resistant OC patients [18]. In a different phase I–II trial on Platinum-resistant/refractory OC patients, the G/D combination plus G-CSF support obtained 11/49 objective responses (24%), 14/49 stabilizations (31%), with a median survival of 12 months. [19] Toxicity was primarily haematological, and QoL evaluation indicated a good tolerance of this regimen. Pegylated liposomal doxorubicin (PLD) is a formulation of D in liposomes, whose surface contains the hydrophilic polymer methoxypolyethylene glycol. PLD is active in OC and less toxic than the parent compound, with the dose-limiting toxicities consisting of stomatitis and palmo-plantar erythrodysesthesia (PPE) [17]. In a phase I–II study of G/PLD combination on 17 patients (14 evaluable), with a mean of 2.5 prior chemotherapy regimens, the initial dose of G was 800 mg/m2 on days 1 and 8,
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chemotherapy and need additional treatment. Gemcitabine (G) and Anthracyclines are active in this setting and their combination has shown synergistic antiproliferative activity in vitro, due to different mechanisms of action and non-overlapping toxicities. Patients and methods: In 2002 we began a phase II study with G 1000 mg/m2 (day 1,8) combined to Epirubicin (E) 60 mg/m2 (day 1), every 3 weeks for 6 cycles, in Platinum resistant/refractory ovarian carcinoma patients. Results: Among 30 patients enrolled so far (27 evaluable), receiving 149 cycles (median 6), 1 complete and 12 partial responses (48%), 9 stabilizations (33%) and 5 progressions (18%) were observed, with a good correlation with serological responses. Median time to progression was 8 months, while median time to response was 10 weeks and median duration 8 months. Grade 3–4 toxicities consisted of neutropenia (58%), thrombocytopenia (3%), anemia (10%), liver toxicity (13%), and mucositis (7%). Eight patients (27%) received G-CSF and 3 (10%) blood transfusions. No febrile neutropenia nor cardiotoxicity were observed. Conclusions: Although our results are preliminary, G/E combination appears particularly effective and safe in these platinum resistant/refractory patients. Key words: recurrent ovarian cancer, platinum-resistant patients, gemcytabine-antracyclines combination
symposium article
study design On these bases, we have decided to further explore the G/ Antracyclines combination in patients with recurrent histologically confirmed epithelial OC, or cancer of the fallopian tube or the peritoneum, Platinum-resistant or refractory disease, WHO performance status 0–2, adequate haematological, renal and liver functions, age ‡ 18 and £ 75, measurable tumor, no previous anthracycline treatment, FEV > 60% and signed informed consent. The protocol was approved by the institutional ethic committee. Staging procedures included: blood chemistries, physical examination, chest X-ray, abdomen-pelvic CT scan. Patients received G 1000 mg/m2 (day 1,8) and E 60 mg/m2 (day 1) every 3 weeks for 6 cycles, or disease progression, unacceptable toxicity or withdrawal due to other reasons. Patients showing objective response after 6 cycles continued to a maximum of 9 cycles. All pts received anti-emetic medication and steroids. Treatment was delayed and/or doses reduced in case of grade 4 neutropenia or ‡ grade 3 thrombocytopenia or grade 1–2 renal toxicity. G-CSF support was allowed in the case of prolonged leucopenia (> 7 days) or febrile neutropenia in the prior cycle. Objective responses and toxicity were the primary end points. Time to progression, time to response, and overall survival were the secondary end points.
v196 | Galligioni et al.
Tumor assessment was performed, according to RECIST Criteria, £ 28 days before treatment, after 3 and 6 cycles, and subsequently until disease progression. Serological Response was assessed according to Rustin criteria and toxicity according the NCI criteria. Haematological and biochemical parameters were measured on day 1 of each treatment cycle. Time to progression was defined as the time from the first day of treatment until objective progression, or the last date of patient contact. Time to response was defined as the time from the first day of treatment until objective response was documented and response duration from that time to progression. Overall survival as defined as the time from the first day of treatment until death from any cause or the last date of patient contact.
data analysis The Simon two-stage design was planned: if fewer than 16 responses are obtained among the first 46 patients, then the accrual will terminate and the association of G and E is will rejected. Otherwise, accrual will continue to a total of 65 pts. At the end of the second stage, the drug combination will be rejected if the observed responses will be less than 26.
results The study is still open and preliminary results have been recently presented [28]. From June 2002 to February 2005, we have enrolled 30 patients with 1–4 previous chemotherapy regimens (median 1) and a median platinum free interval of 6 months (range 0–12), a median age of 59 years [43–74), and 0–2 (median 1) ECOG performance status. The FIGO stage and number of patients were III/13 and IV/17 respectively. Histology was serous in 21 patients, endometrioid in 2, unclassified adenocarcinoma in 5, tuba in 1 and peritoneal in 1 (Table 1). Cumulatively, 149 cycles were administered (median 6). Among the 27 patients evaluable for response (2 too early, 1 with early worsening of general conditions and progression after 1 dose), 1 complete and 12 partial responses were observed, for an overall response rate of 48%. Nine pts (33%) had stable disease and 5 (18%) progressed (Table 2). The serological responses were substantially in accord to the objective responses and are reported in table 3. Median time to progression was 8 months (range 1.5–23). Among responding patients, the median time to response was 10 weeks (range 8–20) with a median duration of 8 months (range 4.5–12). Major (grade 3–4) toxicities on 29 evaluable patients included: leucopenia 27%, neutropenia 58%, thrombocytopenia 3%, anemia 10%, liver 13%, and mucositis 7%. Eight patients (27%) received G-CSF support, and 3 (10%) blood transfusions (Table 4).
discussion Based on our preliminary results, this G/E combination with a 48% RR and 33% of stabilizations appears effective and safe in these platinum-resistant/refractory patients.
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with a fixed dose 30 mg/m2 of PLD on day 1 of a 28-day cycle. Overall 5 complete responses (36%), 1 partial (7%) and 5 stable disease (36%), were observed [20]. In a different phase I study, on 23 heavily pretreated women, 5 of whom platinum-sensitive, the MTD was reached at 1000 mg/m2 for G on days 1 and 8 and at 30 mg/m2 for PLD. Five partial responses (21%) and 5 stable disease (21%) were observed [21]. G at 2000 mg/m2 combined with PLD 20 mg/m2 every other week, was administered to 16 pts, with at least 4 previous chemotherapy regimens, obtaining 3 complete (19%) and 4 partial responses (25%). Toxicity was high, mainly for stomatitis or palmo-plantar erythrodysesthesia, and 53% of patients had to discontinue therapy. A prospective phase II trial is now underway with these doses in less pretreated patients [22]. Furthermore, 25 heavily pretreated patients, 8 platinumrefractory/resistant and 17 platinum-sensitive, had received PLD 25 mg/m2 on day 1 and G 650 mg/m2 on days 1 and 8, every 21 days. The overall RR was 64%; six patients had stable disease and the median overall survival was 13 months. Toxicity grade 3/4 included neutropenia in 60% of patients, thrombocytopenia in 32%, anemia in 24% and PPE in 12% [23]. Finally, in a phase II study with G/PLD combination on 67 evaluable patients, a 34% RR, with a 10% of complete responses, was reported with manageable toxicity. Among resistant patients, the observed 25% RR favourably compares to the 18– 12% achievable in phase II and III trials with PLD [5, 25] or with G alone [26], as does the 38% disease stabilisation [24]. Recent studies in fact have demonstrated that patients with partial responses and with stable disease after second line chemotherapy, have a similar survival benefit [27].
Annals of Oncology
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Annals of Oncology
Table 1. Patient demographics Patients
Table 3. Serological response 30 (n)
Table 2. Responses on 27 evaluable patients n Objective response Complete response Partial response Stable disease Progressive disease Median duration of response (range), months Sites of response Peritoneum Liver Pelvic and/or aortic lymph nodes Pelvic node Axillary lymph nodes Ascites
13 1 12 9 5 8
(48%) (2.7%) (44.4%) (33.3%) (18.5%) (4.5–12)
8 3 2 2 1 1
This study is still open, so it is too early for any survival evaluation. However, the response duration and the time to progression observed so far are comparable to those of the
Volume 17 | Supplement 5 | May 2006
Serological response
1 RC 12 RP
1 7 1 2 2 7 2 5
9 SD 5 PRO
RC RC RP 50% RP 75% NA SD RP 50% PRO
Table 4. Drug-related grade 3/4 toxicities Adverse event
n (%)
Cycles
Leucopenia Neutropenia Thrombocytopenia Anemia Liver Mucositis Nausea/vomiting
8 15 1 3 4 2 1
6% 20% 1.3% 2% 3.3% 1.3% 1.3%
(27.5) (51.7) (3.4) (10.3) (13.7) (6.8) (3.4)
literature and indicate that patients did benefit from this treatment at the cost of reasonable toxicity. Despite the 54% incidence of Gr 3–4 neutropenia in fact, no febrile neutropenia was observed. Similarly, no cardiotoxicity was reported and others non-haematological toxicities, apart alopecia, were minor. Finally, as the approach to recurrent ovarian cancer is evolving in to a treatment of a chronic disease, not only effective and well-tolerated regimens but also affordable costs are important components of medical decision. [29] The cost of PLD however is substantial. In contrast, the average cost per cycle of E is approximately 2.5 times lower than PLD and may represent a more convenient choice in this context of non curative cancer treatments. In conclusion, our results are still preliminary but the G/E combination that we have studied appears a valid approach in recurrent OC patients and may deserve future studies.
disclosures Dr Galligioni has indicated no financial relationships with companies whose products are mentioned in this article.
references 1. Ozols RF. Recurrent ovarian cancer: evidence-based treatment. J Clin Oncol 2002; 20(5): 1161–1163. 2. Kaye SB. Lancet 2003; 361: 2094–5. 3. Rose PG, Blessing JA, Mayer AR, Homesley HD. Prolonged oral etoposide an second line therapy for platinum-therapy resistant and platinum sensitive ovarian carcinoma: a Gynecologic Oncology Group Study. J Clin Oncol 1998; 16: 405–410. 4. Markman M. Second-line treatment of ovarian cancer with single-agent gemcitabine. Semin Oncol 2002; 29(S1): 9–10.
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Median age (range), years 59 (43–74) Eastern Cooperative Oncology Group performance status 0 15 1 13 2 2 No. prior chemotherapy regimen 1 17 2 10 3 2 4 1 Sites of recurrence Peritoneum 21 Liver 12 Pelvic and/or aortic lymph nodes 10 Pelvic nodes 2 Ascites 2 Axillary lymph nodes 1 Inguinal lymph nodes 1 Sovraclavear lymph nodes 1 Lung 1 Spleen 1 Histological type Serous 21 Endometrioid 2 Unclassified adenocarcinoma 5 Carcinoma of tuba 1 Peritoneal carcinoma 1 Histological grade 1 0 2 6 3 21 Unknown 3 Platinum-free interval <6 months 21 ‡6 < 12 months 6
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