|Year : 2012 | Volume
| Issue : 1 | Page : 169-175
Biweekly peglated liposomal doxorubicin/oxaliplatin for ovarian cancer resistant to taxane-platinum treatment: A Phase II study
MA Salah-Eldin1, HA Wahba2, AA Halim2
1 Department of Medical Oncology, Oncology Center, Mansoura University, Mansoura, Dakahliya, Egypt
2 Department of Clinical Oncology and Nuclear Medicine, Faculty of Medicine, Mansoura University, Mansoura, Dakahliya, Egypt
|Date of Web Publication||25-Jul-2012|
M A Salah-Eldin
Department of Medical Oncology, Oncology Center, Mansoura University, Mansoura, Dakahliya
Source of Support: None, Conflict of Interest: None
Aim: The aim of this Phase II study was to evaluate the activity and safety of biweekly pegylated liposomal doxorubicin (PLD) and oxaliplatin (L-OHP) in patients with platinum-taxane resistant ovarian cancer. Materials and Methods : Treatment consisted of PLD (20 mg/m 2 ) on Day 1; and L-OHP (50 mg/m 2 ) administered on Days 1 and 2, every two weeks. Response to therapy was assessed using the Response Evaluation Criteria in Solid Tumors RECIST ; toxicity was evaluated by the National Cancer Institute Common Toxicity Criteria. Results: Forty patients pretreated with platinum/taxane chemotherapy, with a median age of 61 years, were recruited for the study. Thirty-eight patients were available for response evaluation: three complete responses and nine partial responses were registered; resulting in an overall response rate of 31.5%. Twenty-eight patients gained clinical benefit (73.7%) from this chemotherapy regimen. Median time to progression (TTP) and overall survival (OS) were 5.5 and 10 months respectively. The hematological and non-hematological toxicity profile was favorable. No Grade 4 toxicity was observed. Major toxicities included Grade 3 neutropenia (13.2%), Grade 2 palmar-plantar erythrodysesthesia (7.9%), and Grade 1-2 neuropathy in 15.8% of patients. Conclusion: Biweekly PLD and L-OHP combination has high activity, with less than anticipated adverse toxicity, for treatment of platinum-resistant ovarian cancer. A comparison of the doublet PLD/L-OHP with single-agent treatment is warranted.
Keywords: Oxaliplatin, ovarian cancer, peglated liposomal doxorubicin, resistant, relapse
|How to cite this article:|
Salah-Eldin M A, Wahba H A, Halim A A. Biweekly peglated liposomal doxorubicin/oxaliplatin for ovarian cancer resistant to taxane-platinum treatment: A Phase II study. Indian J Cancer 2012;49:169-75
|How to cite this URL:|
Salah-Eldin M A, Wahba H A, Halim A A. Biweekly peglated liposomal doxorubicin/oxaliplatin for ovarian cancer resistant to taxane-platinum treatment: A Phase II study. Indian J Cancer [serial online] 2012 [cited 2020 Jun 2];49:169-75. Available from: http://www.indianjcancer.com/text.asp?2012/49/1/169/98944
| » Introduction|| |
Despite the advances in surgical efforts and the achievement of high response rates with platinum/ taxane front-line treatment,  ovarian cancer remains the most lethal gynecologic malignancy, with a five-year survival rate of 25-30% in advanced stage disease. 
In the majority of patients presenting with advanced epithelial ovarian cancer (EOC), the disease recurs, and will need some form of salvage chemotherapy.  The choice of the drug or drug combinations to be used at recurrence is conditioned by the duration of platinum-free interval (PFI); indeed, patients with a PFI > six months are considered platinum-sensitive and exhibit a 27-59% rate of response to platinum-based rechallenge, according to the duration of PFI,  while patients with platinum-resistant disease who respond poorly to treatment with platinum agents initially and have a short interval to recurrence, do poorly. Current treatment options include pegylated liposomal doxorubicin (PLD), topotecan, etoposide, gemcitabine, and vinorelbine, with response rates to single-agent therapy ranging from 14-27% and median TTP from 3 to 23 weeks. ,,,,,,
When single-agent PLD was administered to women with refractory ovarian cancer, overall response (OR) was 12.3%, median progression-free survival (PFS) was 9.1 weeks, and median overall survival (OS) was 35.6 weeks. , PLD is approved by the Food and Drug Administration and other regulatory authorities for treating recurrent ovarian cancer in a dose of 50 mg/m 2 , however, investigations demonstrated lower incidence of palmar-plantar erythrodysesthesia (PPE) and stomatitis by decreasing the total dose to 40 mg/m 2 with comparable survival rates.  A potentially successful approach is biweekly application of PLD; as demonstrated in recent years in patients with recurrent ovarian cancer, this dose-splitting reduced the incidence of toxicity while retaining efficacy in platinum-refractory disease. ,
Oxaliplatin (L-OHP) is a platinum analogue with non-cross-resistance characteristics with first- and second-generation platinum compounds such as cisplatin and carboplatin and has known activity in colorectal cancer.  It was brought into clinical evaluation in ovarian cancer because of the in vitro and in vivo antitumor activity observed in experimental models resistant to cisplatin. As single agent at 130 mg/m 2 every three weeks, the objective response rates range from 16-29% in patients treated after failure of one or two regimens. 
The ICON4 trial demonstrated that combination chemotherapy regimens are more effective than monotherapy regimens in patients with advanced ovarian cancer.  Preclinical studies conducted by W. Zoli demonstrated synergy with sequential PLD and oxaliplatin in cancer cell lines, even in platinum-resistant cells (unpublished data). Mavroudis et al., conducted a Phase I study of the combination of these two drugs. 
Results of initial Phase II studies that used the combination of PLD and L-OHP to treat patients with advanced ovarian cancer were reported. , In these studies, the feasibility of four-weekly and three-weekly schedules of PLD plus oxaliplatin in resistant disease was addressed, with an OR of 28.6% and 12.5%; TTP of 5.9 and 5.8 months; and OS of 6.4 and 11.2 months in both studies, respectively. The results of these trials suggest that PLD and L-OHP showed promising preliminary antitumor activity, were well tolerated and have a manageable toxicity profile in women with relapsed advanced ovarian cancer, regardless of platinum sensitivity.
In view of these beneficial effects, we conducted a Phase II study to evaluate the efficacy and toxicity profile of PLD 20 mg/m 2 ; d1, combined with L-OHP 50 mg/m 2 on Days 1 and 2, every two weeks in patients with resistant ovarian cancer previously treated with a platinum/taxane regimen.
| » Materials and Methods|| |
This is a non-comparative prospective Phase II study, aimed at evaluating the activity and toxicity of a biweekly schedule of pegylated liposomal doxorubicin (PLD; Caelyx, Schering-Plough International, Kenilworth, NJ, USA) plus oxaliplatin (Eloxatin, Sanofi-Synthelabo Inc., Paris, France), in recurrent ovarian cancer after first-line platinum/taxane therapy. This study was designed with stringent inclusion criteria for platinum sensitivity, including only patients with platinum-resistant disease.
The primary end point was to assess the antitumor activity of PLD/L-OHP combination in patients with platinum/taxane-resistant ovarian cancer. The main criterion for efficacy was objective response rate; secondary criteria were time to progression, and overall survival. Our secondary objective was to determine the type, severity, and frequency of adverse events associated with PLD/L-OHP treatment in these patients.
Patients were eligible for the study if they had histologically confirmed epithelial ovarian cancer with the following: (i) age more than 18 years, (ii) Eastern Cooperative Oncology Group performance status less than or equal to 2, (iii) previous treatment with only one platinum/taxane regimen, (iv) progression of disease while on platinum-containing first-line therapy; or treatment-free interval less than six months from the discontinuation of the first-line chemotherapy, (iv) radiological evidence of measurable (> 2 cm) lesions, (vi) life expectancy of three months or greater, (vii) adequate baseline bone marrow function "absolute neutrophil count ≥ 1500/ml, platelet count ≥ 100.000/ml", (viii) adequate baseline hepatic function "serum bilirubin ≤ 2.0 mg/d, transaminase aspartate aminotransferase, alanine transaminase ≤ 2.0 the upper limit of institutional normal", (ix) adequate renal function "creatinine ≤ 1.5 mg/dl", and (ix) adequate cardiac function "left ventricular ejection fraction ≥ 50%".
Patients were excluded if they had other malignancies, peripheral neuropathy as determined by the National Cancer Institute Common Toxicity Criteria grade greater than 2, severe co-morbid conditions, or lacked the ability to comply with the requirements of the protocol. This Phase II study, conducted in accordance with the Declaration of Helsinki, was approved by the local Ethics Committee.
Patients received PLD 20 mg/m 2 diluted in 250 ml of 5% dextrose on Day 1 followed by oxaliplatin 50 mg/m 2 over 2 h in 500 ml of 5% glucose on Days 1 and 2 (total dosage in two days: 100 mg/m 2 ) administered by intravenous infusion every two weeks. Premedication was given in the form of methylprednisolone (20 mg intravenous) and a 5-HT 3 antagonist in 100 cm 3 of saline.
Treatment was given for a minimum of two cycles in the absence of disease progression, unacceptable toxicity or patient refusal. Granulocyte colony-stimulating factor and erythropoietin were used if febrile neutropenia or Grade 3 anemia was recorded in the earlier course of chemotherapy.
Evaluation of response was done after two courses to determine whether treatment should be continued, and repeated every two cycles. After six cycles; treatment could be continued for a further three cycles if clinical benefit could be expected.
Given that this study involved two agents, dose adjustments were made for each agent if a distinction in toxicity could be made. If both agents were believed to be causing toxicity, a dose reduction was performed for both groups of agents. If Grade 3 or 4 myelosuppression occurred, the PLD dose was decreased by 10%; in cases of Grade 3 or 4 gastrointestinal toxicity the dose of L-OHP was withheld; subsequent doses, decreased by 20%, were resumed when toxicity was resolved. In case of paresthesia with pain or functional decrease, every oxaliplatin infusion was reduced by 25% for an event lasting more than seven days, or discontinued if paresthesia with functional impairment became persistent. Treatment was suspended until toxicity resolved to Grade 1 or less in patients experiencing Grade 2 or greater palmar-plantar erythrodysesthesia (PPE) or stomatitis. Treatment was discontinued when Grade 2 or greater hematological or non-hematological toxicity persisted for more than two weeks. Treatment was also discontinued in case of left ventricular ejection fraction less than 45% or a 20% decrease from the baseline.
Response was evaluated initially by physical examination, abdomino-pelvic computed tomography (CT) scan, chest X-ray and CA 125 . Objective responses were evaluated using the RECIST.  Toxicity was graded using the National Cancer Institute Common Toxicity Criteria after each cycle of treatment.  All documented side-effects were included regardless of their relationship to the study treatment.
The primary end point was assessment of antitumor activity. The main criterion for efficacy was objective response rate; secondary criteria were time to progression, and overall survival. Our secondary objective was to determine the type, severity, and frequency of adverse events. For descriptive statistics of qualitative variables, the frequency distribution procedure was run with calculation of the number of cases and percentages. Overall survival was defined as the time elapsed from initiation of treatment to the date of death or date of last follow-up. Time to progression (TTP) was estimated from initiation of treatment to the documentation of disease progression or the date of last follow-up. Survival rates were estimated by the Kaplan-Meier product-limit estimator. Comparison of survival was performed by the log rank test. Data were analyzed on a personal computer running SPSS for Windows (Statistical Package for Social Scientists, release 15; SPSS Inc., Chicago, Illinois, USA)
| » Results|| |
Between June 2008 and June 2010, 40 ovarian cancer patients, with a median age of 61 years (range, 37-74 years) were enrolled into the study at two institutions. [Table 1] summarizes the demographic profile. Baseline CA 125 levels ≥40 IU/ml were reported in 65% of patients. All patients had been pretreated with platinum and taxane, and 27.5% had achieved complete response (CR) to prior treatment.
A total of 208 cycles of chemotherapy were administrated for 38 evaluable patients, with a median of five courses (range 1-9) per patient. The major cause for early discontinuation was disease progression Nine patients had dose reductions and eight cycles were delayed because of Grade 3 neutropenia and gastrointestinal toxicity.
This analysis was based on 40 patients, including two patients not assessable for response, because they did not meet the eligibility criteria. In all assessable patients, overall confirmed response at the end of treatment was seen in 12 patients; with three patients achieving complete response (CR), while nine (23.6%) had partial remission (PR). Sixteen patients (42.1%) remained stable, and 10 patients (26.3%) progressed [Table 2]. The median TTP was 5.5 months (range 0.5-14 months, 95% CI: 1.2-9.6) [Figure 1]. Median overall survival was 10 months (range 3-25 months, 95% CI: 5.9- 13.3) [Figure 2]a. The median OS was 19, 10 and 5 months for responsive, stable and progressive disease, respectively. And the difference was statistically significant (P<0.0001) [Figure 2]b.
|Figure 2a: Median overall survival|
Figure 2b: Median OS for patients with responsive disease versus stable and progressive disease (P < 0.0001)
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No treatment-related deaths were observed. As far as hematologic toxicity is concerned [Table 3] Grade 3 neutropenia occurred in five patients (13.2%), febrile neutropenia in two patients, and anemia in 10 patients. Granulocyte colony-stimulating factor was necessary for three patients. There was no Grade 4 hematologic toxicity. Myelosuppression was usually brief and manageable with dose adjustments or treatment delay.
This schedule is associated with a favorable non-hematologic toxicity profile. Overall, non-hematologic toxicities were primarily Grade 1 or 2; with no Grade 4 adverse reactions [Table 3]. The reported rate of PPE was 23.7%, none of which was Grade 3-4; Grade 1-2 diarrhea was seen in seven patients (18.4%). Grade 1-2 neuropathy was observed in six patients (15.8%), but in only one of them (2.6%) the symptoms were severe enough to compromise the activities of daily living. Most alopecia was Grade 1. No clinical evidence of cardiotoxicity was registered during the study.
| » Discussion|| |
Patients with platinum-resistant/recurrent ovarian cancer have few therapeutic options with response rates ranging from 14-27% using non-cross-resistant chemotherapeutic agents.  Based on the results of randomized trials, there is no agreement on appropriate second-line therapy, as no single agent or combination has proved beneficial in terms of either response rate or median survival.  Therefore, the search for the optimal chemotherapy is an ongoing process.
Owing to the poor performance status that patients with resistant ovarian cancer usually have, palliation of their disease may require a chemotherapy regimen that is devoid of excessive toxicity. Therefore, we have chosen two drugs, PLD and L-OHP that have shown some activity and are not inferior to their more toxic parent compounds.
This Phase II study shows that the combination of PLD/ L-OHP is active in earlier treated patients with ovarian cancer refractory to platinum-taxane administration, and achieves an overall response rate of 31.5%. These results are encouraging when compared with other chemotherapeutic agents, that is, liposomal pegylated doxorubicin or topotecan and weekly paclitaxel, or gemcitabine used alone, which achieve objective overall response rates of only 10-20% in clinical trials conducted in the same setting. ,,,
The regimen used in this study was remarkably well tolerated by our patients regarding hematological and non-hematological toxicities. There were no treatment-related deaths. The main cause of treatment delay was hematological toxicity. The main toxic reaction was Grade 3 neutropenia recorded in five patients, but only two of them developed febrile neutropenia.
One of the major concerns in PLD-based regimens is represented by non-hematological toxicities; in particular, PPE. , In our study, it was low-grade and easily managed in all patients; PPE did not exceed Grade 2, which represents a very favorable result. In this patient population, we used premedication with corticosteroids (methylprednisolone 20 mg i.v) in order to prevent allergic reactions.
Although it has to be acknowledged that comparison across non-randomized Phase II studies is difficult, especially in light of the heterogeneity and patient selection issues, our study was accompanied with a lower toxicity profile when compared with the three-weekly regimen [Table 4],  especially for Grade 3-4 neutropenia (13.2% versus 38%), and Grade 2 PPE (7.9% versus 13.2%). This was probably due to the different administration schedule.
Considering the current widespread use of the carboplatin/paclitaxel combination as first-line chemotherapy,  and, above all, the significant proportion and duration of residual neurotoxicity after this regimen,  much attention has to be focused on the choice of drugs to be used for rechallenge of platinum-resistant disease. With single agent oxaliplatin at 130 mg/m 2 every three weeks, 29 out of 48 patients had peripheral neuropathy at the end of treatment with 23% experiencing Grade 3 toxicity.  Among regimens utilizing L-OHP-based combinations [Table 4], an overall Grade 1-2 neurotoxicity rate of 25.5-50% has been documented. , The study regimen of fractionated biweekly PLD/L-OHP presents far less neurotoxicity, with Grade 1-2 neuropathy observed in 15.8% of cases; severe symptoms that compromised the activities of daily living were recorded in one patient only. One possible reason of the recorded low rate of severe neuropathy could be found in the fractionated administration of L-OHP.  However, the issue of residual neurotoxicity in the choice of salvage chemotherapy would become clinically less relevant than before, on the basis of the results of the MITO-2 study,  demonstrating the equivalence of carboplatin/PLD versus carboplatin/ paclitaxel in front-line therapy.
The median time to progression of 5.5 months and the median OS of 10 months in resistant or refractory patients treated with PLD/L-OHP in our study, appears comparable to survival durations reported in earlier trials of liposomal pegylated doxorubicin, topotecan or weekly paclitaxel used as single agents. , However, median PFS and OS, in contrast to disease control, may not be the most relevant end-points for trials conducted in patients with refractory or resistant ovarian cancer. Many studies in resistant ovarian cancer patients have failed to find a median PFS or OS advantage for combinations of doxorubicin or epirubicin with paclitaxel over paclitaxel alone, or for doublets including topotecan over topotecan alone, suggesting that non-platinum single-agent therapy might be the most appropriate treatment in this setting. ,
If we consider our patient population, biweekly PLD/L-OHP combination induced response or stable disease in 73.6% of the cases, allowing prolonged disease control with acceptable side-effects in a majority of patients. The high response rate reported in our patients might be of value in a selected population of treatment-resistant patients who complain of symptoms and need rapid relief. This should be confirmed in other trials in which long-term improvement of symptoms could be a relevant end-point to compare the benefits of combination with those of single-agent therapy.
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[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]
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