A feasibility study of low-dose, prolonged oral topotecan in patients with advanced ovarian, fallopian tube, or primary peritoneal serous cancer who have attained a complete clinical response following platinum-based chemotherapy
Amy H. Comander, MD, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215, USA. Email: firstname.lastname@example.org
To determine the tolerability of oral maintenance topotecan when administered to patients with advanced ovarian, fallopian tube, and primary peritoneal serous cancers who have achieved a complete clinical response after first-line platinum-based therapy. Oral topotecan was given at a starting dose of 0.4 mg/m2/dose, twice a day (BID) for 21 consecutive days out of 28 days. The dose was subsequently increased to 0.5 mg/m2/dose, twice a day as tolerated. If the patient experienced toxicities during cycle 1 or subsequent cycles, doses were delayed and/or reduced. The lowest dose allowed on protocol was 0.3 mg/m2/dose twice daily. Thirteen patients were enrolled in the study, representing a total of fifty-nine cycles of oral topotecan. The starting dose of 0.4 mg/m2 by mouth (PO) BID for 21 days was generally difficult for patients to tolerate, usually due to progressive anemia and fatigue, and a dose reduction to 0.3 mg/m2 was necessary in 10/13 patients. A median of six cycles was administered, although 6 of 13 patients could not tolerate the planned 6 cycles due to toxicity. Hematologic toxicity was the most common side effect, although there were no episodes of febrile neutropenia. Diarrhea was the most common nonhematologic side effect, occurring in 8 of 13 patients. Six patients were removed from the study prior to completing the planned six cycles of therapy, after receiving a median number of 2.5 cycles of treatment. This dose and schedule of oral topotecan does not appear to be feasible in this patient population.
Most patients with advanced epithelial ovarian cancer are destined to relapse, despite achieving an initial complete clinical response to first-line, platinum-based chemotherapy(1). While second-line treatments may provide effective palliation and extend survival for some patients, they are not curative. One potential strategy to improve survival in this disease is to consider the use of maintenance therapy after achievement of a complete response. Unfortunately, drugs such as paclitaxel, altretamine, epirubicin, or intravenous topotecan in the maintenance setting have not yet been associated with an improvement in survival(2).
By definition, residual microscopic disease that remains after first-line therapy is relatively resistant to taxanes and platinum agents. However, other drugs that exert their effects through potentially non–cross resistant mechanisms might prove to be more effective in this setting. In this regard, topotecan is an S-phase specific topoisomerase I inhibitor with activity in patients with recurrent ovarian cancer who are either refractory, resistant, or sensitive to initial platinum-based treatment(3–5). Intravenous topotecan has been studied in the maintenance setting in two separate randomized trials thus far, neither of which showed an advantage for maintenance therapy(6,7). However, only four cycles of topotecan were administered in these studies, and patients with persistent disease after first-line therapy were included. Thus, these studies did not examine the role of topotecan in a purely maintenance setting, but rather addressed the ability of this drug to control clinically apparent, platinum-refractory disease in a subset of patients.
Being an S-phase specific agent, it is possible that topotecan’s effectiveness may be schedule dependent. For instance, a randomized phase II trial of intravenous topotecan administered weekly (1.75 mg/m2 over 24 h weekly) compared to daily for 5 days (1.5 mg/m2 over 30 min daily, days 1–5), showed inferiority of the weekly regimen, suggesting that more continuous exposure to this drug may be necessary for optimal effectiveness(8). More recent data using higher doses of weekly topotecan in the range of 4 mg/m2 per week intravenously demonstrate activity in the recurrent disease setting, although this has not yet been compared to the 5-day regimen in a randomized trial(9). In addition to intravenous administration, topotecan is available as an oral formulation for investigational use. Oral administration of this drug might provide the potential benefit of more continuous daily dosing, and the oral formulation has been shown to be active in patients with relapsed ovarian cancer(10,11). Oral topotecan bioavailability ranges 32–44% and it is associated with less myelosuppression, but generally more diarrhea, when compared to the intravenous drug(12).
In view of the potential advantages of oral topotecan as a maintenance strategy, we sought to determine the maximally tolerated dose (MTD) of this drug when administered orally for up to 21 days per 4-week cycle, in patients with advanced ovarian, fallopian tube, and primary peritoneal serous cancers who have achieved a complete clinical response after first-line platinum-based therapy.
Materials and methods
Patients with histologically confirmed epithelial carcinoma of the ovary, fallopian tube cancer, or primary peritoneal cancer were eligible for this study. All patients underwent an initial exploratory laparotomy with tumor debulking, and patients with FIGO stages IIIB, IIIC, or IV at the time of initial laparotomy were eligible. Patients must have received a minimum of five courses of first-line, platinum-based chemotherapy and begin the protocol no sooner than 21 days following their last dose of prior chemotherapy. All patients were required to have achieved a clinically defined complete response following first-line treatment (ie, no evidence of cancer by history or physical examination, CA-125 ≤ 35 units/mL, and no evidence of residual cancer on computed tomography scan of the abdomen/pelvis and chest x-ray, within 30 days prior to registration). Concomitant chemotherapeutic agents, immunotherapy, hormonal therapy, radiation therapy, surgery, or other antitumor treatment were not allowed. Patients were excluded if they had received prior chemotherapy (other than first-line chemotherapy for ovarian, fallopian tube, or primary peritoneal cancer) for any other malignancy within the past 3 years, or if they had received prior abdominal or pelvic radiation. Other eligibility criteria included age at least 18 years; Eastern Cooperative Oncology Group performance status 0–2; granulocyte count at least 1200/mm3, and platelet count at least 90,000//mm3; total bilirubin less than or equal to the institutional upper limit of normal; and alkaline phosphatase, asparatate aminotransferase (AST), and alanine aminotransferase (ALT) less than 1.5 × upper limit of normal. As topotecan is renally excreted, patients were required to have a calculated creatinine clearance of at least 60 mL/minute(13). The study was approved by the Institutional Review Board of the Beth Israel Deaconess Medical Center. Written informed consent that fulfilled all institutional, state, and federal regulations was obtained from all patients prior to beginning protocol therapy.
Treatment and study design
Oral topotecan was administered at a starting dose of 0.4 mg/m2/dose by mouth (PO) twice a day (BID) for 21 consecutive days out of 28 days, for a planned six cycles of treatment as tolerated. The BID dosing schedule was based upon data from Creemers et al.(12), who determined the MTD and safety of this treatment schedule. The dose was subsequently increased to 0.5 mg/m2/dose PO BID if the previous cycle was well tolerated (see below). No further dose escalations beyond 0.5 mg/m2/dose were permitted. If any cycle was poorly tolerated, subsequent doses were held and/or delayed and/or dose reduced as described below. The lowest permissible topotecan dose was 0.3 mg/m2/dose PO BID. Erythropoietin was permitted at the discretion of the treating physician. Granulocyte colony stimulating factor was not permitted during oral topotecan administration.
Hematologic indications for dose reductions and dose delays were as follows: on days 8 and 15, if the ANC was less than 500/mm3, and/or platelets were less than 25,000/mm3, and/or the patient experienced fever and neutropenia, oral topotecan doses were held, and counts were monitored weekly until hematologic toxicity resolved (absolute neutrophil count [ANC] at least 1200/mm3 and platelets at least 90,000/mm3). The topotecan dose was then subsequently reduced by 0.1 mg/m2/dose PO BID, and the day of reinstitution of therapy was called day 1 of the next cycle. If the day 1 ANC was less than 1200/mm3, and/or platelets were less than 90,000/mm3 for a given cycle, the cycle was delayed. Counts were monitored weekly until hematologic toxicity resolved (ANC at least 1200/mm3 and platelets at least 90,000/mm3). The next cycle was resumed with a topotecan dose reduced by 0.1 mg/m2/dose, PO BID. If the required delay was greater than 3 weeks, the patient was taken off study.
Nonhematologic indications for dose reductions and dose delays were as follows: if the creatinine increased by 50% compared with baseline, topotecan was held. Creatinine and blood counts were monitored weekly until the creatinine returned to within 0.1 mg/dL of baseline. For any grade 2 diarrhea (increase of 4–6 stools/day over pretreatment number of stools/day), loperamide was administered. If the diarrhea resolved within 24 h, oral topotecan was continued at the same dose, but the patient was no longer a candidate for subsequent dose escalation. If the diarrhea continued for more than 24 h despite loperamide, or if it was grade 3/4, oral topotecan was held until diarrhea resolved. In that event, patients were given supportive care with antidiarrheal agents and intravenous hydration as needed, and the topotecan was dose reduced by 0.1 mg/m2/dose, PO BID for subsequent cycles. For any other grade 3 or grade 4 nonhematologic toxicity, oral topotecan was held, and toxicity was monitored on a weekly basis, or more frequently as clinically indicated until toxicity resolved to less than or equal to grade 1. For all nonhematologic toxicities, if the required delay was greater than 3 weeks, the patient was taken off study.
Dose-limiting toxicity (DLT) was defined as any of the following: failure to achieve an ANC of at least 1200/mm3 or platelets of at least 90,000/mm3, despite a delay of up to 3 weeks; ANC less than 500/mm3 on days 8 or 15 despite dose reduction; fever and neutropenia despite dose reduction; platelets less than 25,000/mm3 on days 8 or 15 despite dose reduction; failure to recover renal or hepatic function despite a delay of up to 3 weeks; unexpected life-threatening toxicity of any kind; or irreversible grade 3 or grade 4 nonhematologic toxicity.
Twenty patients were to be enrolled in the trial. The primary outcome was to determine whether greater than 80% of patients could tolerate the regimen, as defined by the ability to receive greater than four cycles of oral topotecan. With 20 patients, if an 80% tolerability rate was observed, then the 90% confidence interval would be between 0.60–0.93. That is, there would be a 90% chance that the true tolerability rate falls between 60% and 93%.
Thirteen patients with advanced ovarian or primary peritoneal cancer were enrolled in the study, with their clinical features shown in Table 1. All patients had undergone initial exploratory laparotomy with tumor debulking, and all patients had received a minimum of five courses of first-line taxane/platinum-based chemotherapy prior to protocol entry. All patients had an Eastern Cooperative Oncology Group performance status of zero at the time of enrollment. Most patients had ovarian carcinoma (11/13, 85%), and the majority of patients had stage IIIC disease (10/13, 77%). Twelve out of 13 patients were optimally cytoreduced to less than or equal to 1 cm of residual disease at the time of initial debulking surgery. The median duration of the time between the end of primary chemotherapy and the beginning of oral topotecan maintenance was 2 months (range 1–9 months).
Table 1. Patient characteristics
|Number of patients enrolled||13|
|Number of patients evaluable for toxicity||13|
|ECOG performance status|
| Primary peritoneal cancer||2|
| Papillary serous||12|
| Less than 1 cm||12|
| Greater than or equal to 1 cm||1|
Fifty-nine cycles of chemotherapy were administered to 13 patients throughout the course of this trial. A median of six cycles was administered (range 1–6), although 6 out of 13 patients could not tolerate the planned six cycles due to toxicity. Per protocol, the dose was adjusted based upon patient tolerance. Table 2 shows dose adjustments made at the time of cycle two, after tolerance of cycle one could be assessed. Four patients tolerated a dose increase to 0.5 mg/m2, for a median of 2.5 cycles. Three patients remained at the dose of 0.4 mg/m2, for a median of three cycles. One patient started at 0.3 mg/m2, the dose was increased to 0.4, and she was subsequently taken off study due to side effects (described in detail below). This starting dose was approved by the protocol chairperson, based upon myelosuppression experienced by the patient during previous chemotherapy. Five patients required a dose reduction to 0.3 mg/m2, for a median of four cycles. However, an additional four patients required dose reduction to 0.3 mg/m2 for cycles beyond cycle two. Therefore, a total of ten patients required dose reduction to 0.3 mg/m2 during the entire course of treatment.
Table 2. Dose adjustmentsa
|Dose increased to 0.5 mg/m2||4/13 (31)||2.5|
|Dose remained at 0.4 mg/m2||3/13 (23)||3|
|Dose reduced to 0.3 mg/m2||5/13 (38)b||4|
Hematologic toxicity was the most common side effect. As shown in Table 3, grade 3 neutropenia was seen in 5% of cycles, although there were no episodes of febrile neutropenia. Grade 2 anemia was observed in 25% of cycles, and grade 3 anemia was seen in 2% of cycles. One patient required a dose reduction due to grade 3 anemia. Grade 4 thrombocytopenia was observed in one patient during the first cycle of oral topotecan. This patient required two platelet transfusions (for platelet counts of 22,000/mm3 and 15,000/mm3), as well as a transfusion of packed red blood cells for grade 3 anemia. She was subsequently taken off the trial after one cycle. Two patients each required transfusions of two units of packed red blood cells while they were undergoing treatment. A third patient required transfusions of two units of packed red blood cells for grade 2 anemia during each of cycles two through six, for a total of 10 units of packed red blood cells for this patient. Darbopoetin-alpha (Aranesp, Amgen, Thousand Oaks, CA) was used in 2 of 13 patients for hemoglobin less than 11 g/dL, at a dose of 200 mcg subcutaneously every 2 weeks. However, administration of this drug did not appear to improve hemoglobin levels. One patient enrolled in the trial 9 months after completion of primary chemotherapy. By excluding this outlier from the analysis, the incidence of grade 1 neutropenia decreased from 29% (Table 3) to 22%. All other grades of hematologic toxicity were unchanged.
Table 3. Most frequently observed toxicitiesa
|Neutropeniab||17 (29)||5 (9)||3 (5)||0|
|Hemoglobinc||22 (46)||15 (25)||1 (2)||0|
|Thrombocytopeniad||12 (20)||2 (3)||0||1 (2)|
|Diarrheae||6 (11)||3 (5)||5 (9)||0|
|Nausea/vomiting||10 (17)||4 (7)||1 (2)||0|
|Elevated alkaline phosphatase||1 (2)||0||0||0|
Diarrhea was the most common nonhematologic side effect, occurring in 8 of 13 patients, with 9% of patients experiencing grade 3 diarrhea (Table 3). Two patients were removed from the study due to grade 3 diarrhea. One patient was admitted on day 9 of cycle one with nausea, vomiting, and diarrhea, which responded to supportive measures within 24 h. Three patients required dose reductions, and four patients required dose delays, due to diarrhea. The median day of onset of diarrhea was day 19 of a given cycle, and the median duration of diarrhea was 5 days. There was not a clear relationship between drug dose and severity of diarrhea, although patient numbers were small. Intermittent nausea and vomiting (grade 2 and 3) were observed in 7% and 2% of cycles, respectively, and two patients required dose reductions due to grade 1–2 nausea. Creatinine levels did not change by more than 10% during the course of treatment in any patient. One patient enrolled in the trial 9 months after completion of primary chemotherapy. By excluding this outlier, there was no change in the observed nonhematologic toxicities.
Reason for protocol withdrawal
Six patients were removed from the study prior to completing the planned six cycles of therapy, after receiving a median number of 2.5 cycles (range 1–5 cycles). Table 4 shows the reasons for patient removal from the study. Four of the six patients removed early from the study experienced simultaneous toxicities, with grade 2–3 myelosuppression and grade 1–3 diarrhea as the most common side effects, despite dose reduction to 0.3 mg/m2. One patient requested to be removed for grade 2 nausea. A sixth patient was removed due to disease progression. No treatment-related deaths were observed.
Table 4. Reasons for withdrawal
|5||3||Neutropenia, grade 3; anemia, grade 2; diarrhea, grade 3|
|6||2||Nausea, grade 2|
|8||2||Neutropenia, grade 3; diarrhea, grade 3|
|11||1||Thrombocytopenia, grade 4; nausea and diarrhea, grade 2|
|13||5||Diarrhea, grade 1; anemia, grade 2|
Remission duration was not the primary end point of the study, since this was not an efficacy trial. However, 2 of 13 patients remain in clinical remission following completion of first-line chemotherapy. The first patient has been in remission for 55 months, and began protocol treatment with topotecan 9 months after completion of first-line chemotherapy. The second patient has been in remission for 31 months, and began protocol treatment 2 months after completion of first-line chemotherapy (Table 5). Nine of 13 patients relapsed, at a median of 5 months from completing the study (range 0–15 months), and three of the relapsed patients have died. Two patients were lost to follow-up.
Table 5. Patient outcomes
|11||59||IIIC||1||Not known||Not known|
We conducted this feasibility study in order to determine the tolerance of oral topotecan when used in the maintenance setting for patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal serous cancers. The starting dose of 0.4 mg/m2 PO BID for 21 days was generally difficult for patients to tolerate, usually because of progressive anemia and fatigue, and a dose reduction to 0.3 mg/m2 PO was eventually required in 10 out of 13 patients during the course of protocol treatment (cycle two or beyond). Despite dose reduction, continued transfusion dependent anemia, fatigue, myelosuppression, diarrhea were frequent toxicities that prevented 6 of 13 patients (46%) from completing the planned six cycles of the trial. There appeared to be a loose relationship between diarrhea and myelosuppression, with three of the five patients who experienced grade 3 diarrhea also developing grade 3 myelosuppression. Conversely, among the eight patients who had grade 2 or less diarrhea, two patients had grade 3 or greater myelosuppression. Due to the small numbers of patients in this study, it is difficult to know whether this relationship is statistically significant, or due to chance alone. Only 7 out of 13 patients (54%) received the planned six cycles of oral topotecan. The patients entered in our study had a performance status of zero, and therefore were expected to have the best chance of tolerating the oral topotecan regimen. Nonetheless, the observed toxicity profile was unacceptable, even for this optimal group. Thus, a decision was made to terminate this study prior to enrollment of 20 patients, since it was deemed too difficult for patients to tolerate.
Similar toxicities have been reported in other studies of oral topotecan. In a phase I study of oral topotecan administered BID for 21 days to adult patients with solid tumors, the DLT was reached at a dose of 0.6 mg/m2 BID and consisted of grade 3–4 diarrhea(12). Diarrhea occurred at a median of 15 days and lasted for a median of 8 days, resulting in dehydration that required hospitalization in all three patients who received 0.6 mg/m2 BID. Other toxicities included leukopenia, thrombocytopenia, nausea, and vomiting, although these were not generally dose limiting. The MTD was determined to be 0.5 mg/m2 BID for 21 days every 4 weeks, and a median of two cycles was administered. In another phase I study of oral topotecan in patients with solid tumors, the drug was administered once or twice daily for 10 days every 3 weeks(14). Among the patients who received topotecan BID for 10 days, DLT was reached at 0.8 mg/m2, and consisted of grade 4 myelosuppression and grade 4 diarrhea. The MTD was 0.8 mg/m2, and a median number of two cycles was administered. In a phase II study using oral topotecan as second-line chemotherapy in patients with advanced ovarian cancer, oral topotecan was administered at a dose of 2.3 mg/m2 for 5 days every 21 days(10). Grade 4 neutropenia, grade 4 thrombocytopenia, and grade 3–4 anemia was observed in 50.4%, 22.1%, and 29.2% of patients, respectively. The most frequent nonhematologic toxicities were grade 1 or 2 nausea, vomiting, and/or diarrhea. The median number of cycles administered was four. In our study, patients received a median number of six cycles of oral topotecan, whereas the median number of cycles administered in these reports ranged 2–4(10,12,14). Since our patients were in a complete remission at the beginning of oral topotecan treatment, it is possible that they were able to tolerate more cycles of treatment due to the absence of disease progression.
Other trials have assessed the role of maintenance therapy with single agent drugs such as altretamine, epirubicin, topotecan, or paclitaxel in patients responsive to first-line platinum-based chemotherapy(2). In a single arm study, oral altretamine was given for 14 of 28 days for six cycles in patients with stage III epithelial ovarian cancer who achieved a complete clinical remission following platinum-based first-line therapy(15). The 2-year survival in this study was 75%, and the authors concluded that further evaluation of maintenance chemotherapy, either with altretamine or other agents, was warranted. However, they acknowledged that the value of altretamine as maintenance therapy could not be determined with confidence, since the use of paclitaxel-containing first-line therapy could have been partly responsible for the favorable outcome. Likewise, maintenance treatment with epirubicin was studied in an Italian randomized phase II trial(16). Patients with advanced epithelial ovarian cancer who achieved complete pathologic response at second-look laparotomy/laparoscopy or complete clinical response after platinum-based chemotherapy were given consolidation treatment with epirubicin 120 mg/m2 every 3 weeks for four cycles. Administration of epirubicin did not improve overall survival when compared to observation alone(16), although the study was not sufficiently powered to exclude a small but potentially important benefit. Finally, in a phase III intergroup trial (Gynecologic Oncology Group/Southwest Oncology Group), patients with advanced ovarian cancer who achieved a complete clinical response were randomized to receive three versus twelve cycles of paclitaxel maintenance therapy(17). Median PFS was prolonged by 7 months (P= 0.0023) in patients who received 12 months of paclitaxel, although no overall survival benefit was observed. It will be difficult to assess overall survival as an end point, since crossover occurred after study closure. An update of these data continues to show no survival advantage for the entire group, although subset analysis showed a longer survival with 12 months of paclitaxel for a population of patients who entered into maintenance therapy with a CA-125 of less than or equal to 10 IU/mL(18).
Two randomized studies have investigated the role of intravenous topotecan as a maintenance strategy(6). In a phase III trial conducted by the Arbeitsgemeinschaft Gynaekologische Onkologie and Groupe d’Investigateurs Nationaux pour l’Etudes des Cancers Ovariens, patients with stages IIB–IV epithelial ovarian cancer who achieved a complete or partial response after six cycles of paclitaxel and carboplatin were randomized to either surveillance or four cycles of intravenous topotecan (1.25 mg/m2 per day administered intravenously on days 1–5 every 3 weeks)(7). An interim analysis showed no statistical difference in progression-free survival between the two arms. In a second randomized study, patients with stage IC–IV disease who achieved a complete or partial response after first-line paclitaxel and platinum-based chemotherapy received either observation or maintenance treatment with intravenous topotecan 1.5 mg/m2 per day administered intravenously on days 1–5 every 3 weeks for four cycles(6). Maintenance with topotecan did not improve the progression-free survival or overall survival. Since both of these studies included patients who achieved only a partial response following first-line chemotherapy, the value of topotecan as a maintenance strategy, as opposed to treatment of platinum-refractory disease, could not be precisely determined. Furthermore, the inclusion of patients with early-stage disease in both studies potentially reduces the statistical power to determine whether a survival advantage could be detected in patients receiving maintenance therapy.
Although the dose and schedule of oral topotecan used in our study is not feasible as a maintenance strategy, the concept of administering a potentially non–cross resistant agent in this setting remains attractive. In this regard, the Gynecologic Oncology Group is performing two randomized trials, one attempting to further define the role of taxanes in the maintenance setting, and the other to address the possible role of novel agents such as maintenance single agent bevacizumab. The use of other non–cross resistant agents such as liposomal doxorubicin deserves investigation as well. The identification of an effective maintenance strategy would represent an important advance in the treatment of patients with advanced ovarian cancer.
We would like to thank Dr Anna Berkenblit for assistance in the design of this study, and Ms Diane Desousa for data management support. Data management support provided in part by Glaxo Smith Kline, Inc.