Epithelial ovarian cancer is the most common cause of death among gynecological malignancies in the Western world. Approximately 75% of patients with ovarian cancer show an advanced disease at diagnosis, with a 5-year survival rate of 25% to 30%. Although multimodality treatment regimens have resulted in a greater number of responses and have prolonged both progression-free and overall survival rates, the overall cure rate of the disease has not changed dramatically. More than 75% of patients respond to first-line chemotherapy, but approximately 75% of them eventually develop disease recurrence and die of their disease.1
The treatment of recurrent ovarian cancer, also defined as second-line or salvage treatment, has long been recognized as an important element in the overall management of patients with this disease. The life expectancy after first relapse is now longer than in the past, and ovarian cancer could be considered a chronic disease. Most patients are candidates for second-line or salvage therapy and may also be on therapy for prolonged periods.2,3
According to current dogma in ovarian cancer treatment, the potential for platinum sensitivity is the most important factor in planning second-line treatment.4 Patients with ovarian cancer who experience a durable response to platinum induction chemotherapy (>6 months) have a high probability of responding to platinum retreatment again and the likelihood of response dependents on the treatment-free interval (TFI).5 Carboplatin-paclitaxel combination is, by now, the standard treatment of recurrent platinum-sensitive ovarian cancer.6 Nevertheless, also these patients experience repeated disease recurrences, and further chemotherapy alternatives are needed. Furthermore, patients relapsing between 6 and 12 months after treatment with a platinum compound are now considered partially platinum sensitive.
In the last decade, a large amount of drugs with significant activity in recurrent ovarian cancer have been identified. Even the most promising new second-line drugs have demonstrated response rates ranging only from 10% to 30% with short response duration.7-10 To maximize the benefits of second-line or salvage treatment, alternative novel agents and combination chemotherapy are increasingly being recognized as potential therapeutic approaches. In the last few years at our institution, we carried out a phase II trial to evaluate feasibility, efficacy, and toxicity of gemcitabine and vinorelbine combination in recurrent ovarian carcinoma.
Gemcitabine (2′,2′-difluorodeoxycytidine [dFdC]) is a nucleoside analogue of deoxycytidine. After sequential phosphorylation by deoxycytidine kinase to the triphosphate dFdCTP, gemcitabine is incorporated into DNA, causing masked chain termination.11 The diphosphate dFdCDP also functions as an inhibitor of ribonucleotide reductase.12 In ovarian cancer, the efficacy of gemcitabine as single-agent or combination therapy has been evaluated in several clinical trials and tumor remission has been observed in patients with sensitivity and resistance to both platinum and paclitaxel.9,13-15 The most frequently occurring dose-limiting toxicities are hematological.
Vinorelbine is a semisynthetic vinca alkaloid. It exerts its biologic effect like other vinca alkaloids by inhibiting the microtubule assembly, resulting in mitotic spindle dissolution and metaphase arrest in dividing cells.16 Compared with vincristine and vinblastine, vinorelbine is equally active on mitotic microtubules and less active on axonal microtubules, suggesting a better efficacy-toxicity ratio.17 The activity of vinorelbine in the treatment of ovarian cancer has already been demonstrated by some phase II studies using vinorelbine as single agent in recurrent disease.10,18-20 Both phases I and II studies have been conducted to assess the feasibility and efficacy of vinorelbine combined with other cytotoxic agents in recurrent ovarian cancer.21-23
Gemcitabine and vinorelbine combination has been widely used in advanced non-small cell lung cancer (NSCLC) and in advanced or metastatic breast cancer and less frequently in other malignancies.24 Pharmacokinetic studies in head and neck cancer have shown that the association does not alter the pharmacokinetic profile of either drug.25
The rationale of our phase II study was based on the antitumoral activity of the 2 drugs in ovarian cancer, the different mechanisms of action and especially the nonoverlapping toxicity pattern. We adopted the schedule consisting in vinorelbine at 25 mg/m2 followed by gemcitabine at 1000 mg/m2, 1:8:21 in accordance with the experience of medical oncologists on NSCLC and breast cancer.26,27
The aim of the present study was to evaluate the role of gemcitabine and vinorelbine combination in the treatment of platinum-sensitive recurrent ovarian cancer.
PATIENTS AND METHODS
Eligibility criteria required that patients had a histologically proven diagnosis of epithelial ovarian carcinoma with a recurrent disease either bidimensionally measurable on computed tomographic (CT) scan (≥2 cm) or assessable on CT scan with elevated cancer antigen 125 test (CA-125) levels (≥twice the upper limit of normal) on 2 baseline determinations. Lesions as ascites and small peritoneal implants were considered radiographically assessable but not measurable.
Patients with platinum-sensitive disease recurring after 1 or more lines of platinum-based chemotherapy were included. The length of platinum-free interval (PFI) was evaluated and classified as between 6 and 12 months or more than 12 months.
Further inclusion criteria were a life expectancy of more than 12 weeks; an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less; and adequate hematological, renal, and hepatic functions at baseline (absolute neutrophil count ≥ 1.500/μL, serum creatinine level ≤ 1.5 mg/dL, total bilirubin level ≤ 1.5 mg/dL, and aspartate and alanine aminotransferases ≤ 2 times the upper limit of normal level or ≤ 5 times the upper limit of normal in case of metastatic liver disease).
Patients were excluded from the protocol if they had received previous treatment with gemcitabine and vinorelbine, showed evidence of a concomitant second malignancy, or contraindication to chemotherapy treatment.
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines and was approved by the local ethics committee. Written informed consent was required from each patient before study entry.
The chemotherapy schedule consisted of intravenous (iv) infusion of vinorelbine at 25 mg/m2 followed by gemcitabine at 1000 mg/m2 on days 1 and 8 every 3 weeks. Vinorelbine was administered by 10-minute iv infusion and gemcitabine by 30-minute iv infusion.
Dexamethasone at 8 mg and tropisetron at 5 mg were administered iv in 30 minutes before study drugs.
The treatment duration was at the discretion of the investigator, although it was recommended that responding patients should receive at least 6 courses of chemotherapy. The treatment was discontinued in case of progressive disease or unacceptable toxicity.
Response and Toxicity Assessment
Before study entry, baseline standard assessments were performed including a complete history, physical examination, laboratory assessments of hematological, renal, and hepatic functions, ECOG performance status evaluation, instrumental evaluation with CT scan at the pelvis and abdomen, and 2-view chest x-ray. Serum chemistries and liver function tests were monitored on days 1 and 8 of every cycle. A physical examination and CA-125 evaluation were performed every cycle, whereas a CT scan was done after the third and sixth cycles of chemotherapy.
At study entry, patients were evaluated to detect measurable and nonmeasurable lesions. Measurability of tumor lesions at baseline was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST).
The RECIST and the CA-125 criteria were adopted to classify responses and to determine the best overall response.28,29 A minimum of 3 cycles were required to assess the response.
Responses according to PFI were assessed.
Toxicity was graded according to the National Cancer Institute Common Toxicity (NCI-CT) criteria.30
The study was designed as a single-institution phase II study. The primary end point of the study was response to treatment. Toxicity, time to progression, and survival were secondary end points.
Progression-free survival for all patients was recorded from the date of protocol entry until disease progression, death from any cause, or date of last follow-up. Overall survival was calculated from the date of study entry until death from any cause or date of last follow-up. Progression-free survival and survival times were calculated with the Kaplan-Meier product-limit method.
Analyses were performed using the SPSS software (version 12, SPSS Inc, Chicago, Ill).
Thirty-nine patients were eligible for the study. They were enrolled from 1998 to 2003.
Patient characteristics are summarized in Table 1. Median age was 59 years, and the most common tumor histologic diagnosis was papillary serous adenocarcinoma (84.5%). At first diagnosis, 87.2% of patients were at International Federation of Gynecology and Obstetrics (FIGO) stage IIIC. All patients underwent prior up-front or interval debulking surgery and first-line platinum-based chemotherapy.
PFI was between 6 and 12 months in 13 patients (33.3%) and more than 12 months in 26 patients (66.7%). Most of the patients (71.8%) had received 2 or more previous lines of platinum-based chemotherapy.
Altogether, 34 patients (87.2%) had measurable disease and 5 (12.8%) nonmeasurable but assessable disease. Thirty-seven (94.9%) had a peritoneal relapse, and 2 (5.1%) of them had hepatic metastasis.
Treatment and Dosing
A total of 238 triweekly cycles were administered. All the patients received 3 or more courses of chemotherapy. The median number of courses administered per patient was 6 (range, 3-9).
Three patients (7.7%) required 1-week treatment delay because of toxicity. Four cycles were delayed because of inadequate hematological recovery (granulocytes < 1.5 × 109/L and thrombocytes < 100 × 109/L). One cycle was delayed at patient's request. In 5 patients (12.8%), day 8 was not administered owing to inadequate hematological recovery. Only 1 patient (1.8%) required dose reduction because of hematological toxicity.
Planned dose intensity was maintained in 98% of patients. Total mean dose per cycle was 1859 mg/m2 for gemcitabine and 46 mg/m2 for vinorelbine.
All 39 patients enrolled in our study were evaluated for toxicity.
Toxicity is reported in Table 2 as the worst grade per patient according to the NCI-CT criteria.
Neutropenia was the most frequently encountered toxicity, with grade 3 or 4 observed in 9 patients (23%). The mean neutrophil nadir was 0.9 × 109/L. No sepsis or fever related to neutropenia was observed. No hospitalization was required. No blood or platelet transfusion was needed. No hematological growth factor was administered.
Non-hematological toxicity was mild and manageable. Gastrointestinal disturbance was the predominant non-hematological toxicity with abdominal pain, constipation, and diarrhea. The only grade 3 non-hematological toxicity was hepatic toxicity in 2 patients (5.1%).
Response and Survival
Of the 39 patients enrolled into the study, 19 patients obtained an objective response to treatment (48.7%; 95% confidence interval [CI], 24.2%-73.2%). Six patients (15.4%; 95% CI, 4%-26.6%) had a complete response, with disappearance of any measurable or evaluable disease and with normalization of CA-125 serum level. Thirteen partial responses (33.3%%; 95% CI, 13.1%-50%) were registered. Nineteen patients (48.7%; 95% CI, 32.0%-65.4%) showed a stable disease, and 1 (2.6%, 95% CI, 1.5%-3.5%) had a progression.
Responses according to PFI are summarized in Table 3.
For all responders, the median time to response was 12 weeks (range, 5.1-18.6 weeks) and the median duration of response was 38 weeks (range, 8.2-67.6 weeks).
The median progression-free survival was 32.7 weeks (95% CI, 21.6-43.8), and the median overall survival from on-study was 78.1 weeks (95% CI, 37.1-119.1).
A number of questions related to treatment approaches have emerged as a consequence of the chronic nature of ovarian cancer.4 One important question is whether combination chemotherapy could produce better results than single-agent therapy in patients with recurrent ovarian cancer. Historically, sequential single-agent therapies have been administered, and the selection of which individual agent to use has primarily been based on toxicity considerations.3 Although the use of combinations has been usually discouraged in the recurrent setting, it is conceivable that the rationalized choice of drugs with different mechanisms of action and toxicity patterns might increase the chance of response and favorably effect the clinical outcome.31 The results of 2 parallel randomized trials (International Collaborative Ovarian Neoplasm 4, ICON 4, and Arbeitsgemeinschaft Gynaekologische Onkologie, AGO) suggest that paclitaxel plus platinum chemotherapy improves survival and progression-free survival in patients with platinum-sensitive relapsed ovarian cancer compared with conventional platinum-based chemotherapy.32 In another randomized trial, comparing the combination of carboplatin and gemcitabine versus single-agent carboplatin, the combination regimen produced a significantly longer progression-free survival than the control arm.33 In patients who are not candidate to a platinum rechallenge, combination chemotherapy has been evaluated in the last few years.
Preclinical studies have shown that gemcitabine-based combinations increase cytotoxicity and can potentially overcome drug resistance. These characteristics make gemcitabine an attractive partner for combination with other cytostatic agents.14 Our study showed that gemcitabine and vinorelbine combination is feasible. To our knowledge, this is the first study evaluating this combination in ovarian cancer. We did not perform a phase I study but adopted the schedule consisting in vinorelbine at 25 mg/m2 followed by gemcitabine at 1000 mg/m2, 1:8:21 in accordance with the experience of medical oncologists on NSCLC and breast cancer. In NSCLC, several phase I dose-finding studies have been performed, and the proposed dose for expansion and future studies was 25 mg/m2 vinorelbine and 1000 mg/m2 gemcitabine on days 1 and 8 every 21 days.26 The same schedule has been used in breast cancer with promising results.27 As in ovarian cancer, treatment options in patients with NSCLC remain limited after platinum-based chemotherapy. The combination of gemcitabine plus vinorelbine is also active and well tolerated in patients with NSCLC recurring after taxane-platinum therapy34 and seems to be appropriate for patients unsuitable for cisplatin-based chemotherapy because of physical or clinical contraindications.
In our study, the response rate was 48.7%, with a median response duration of 38 weeks and a survival of 78 weeks. This result is better than those obtained with gemcitabine or vinorelbine single agents. In phases I and II studies with gemcitabine as single agent, the overall response rates varied from 14% to 22%, with a median survival of 6 to 9 months.9,13 Response rates of 15% to 30% have been obtained in clinical trials on administration of vinorelbine to patients with recurrent ovarian cancer.10,18-20 Furthermore, our results are better than those obtained with other combinations including gemcitabine or vinorelbine.
Pegylated liposomal doxorubicin (PLD) is a promising drug in recurrent ovarian cancer.8 In a phase II study to evaluate the activity of gemcitabine and PLD combination, the response rate was 34.3%, with a median response duration of 22 weeks.35 In a multicenter phase II study, evaluating the combination of vinorelbine and PLD in pretreated patients, we obtained a 37% overall response with a progression-free survival and a overall survival of 5.5 and 9 months, respectively.23 Our population was surely more favorable compared with these single-agent or combination studies, including both patients with platinum-sensitive and platinum-resistant diseases. Nevertheless, our results are encouraging also if they are compared with the recently published studies on platinum containing regimens in patients with platinum-sensitive disease.
In the ICON4-AGO trial comparing paclitaxel plus carboplatin versus conventional platinum-based chemotherapy, overall and progression-free survivals of 29 and 13 months, respectively, were reported in the paclitaxel plus platinum arm.32 In the trial comparing the combination of carboplatin and gemcitabine versus single-agent carboplatin, the combination regimen produced a 47.2% response rate with a progression-free survival of 8.6 months and an overall survival of 18 months.33 PLD and carboplatin combination was highly active in patients in late relapse after a first- or second-line with platinum-taxane-based regimens: a 63% response rate with a progression-free survival of 9.4 months and an overall survival of 32 months were reported in a phase II trial.36 PLD and carboplatin combination has been compared with the standard arm carboplatin plus paclitaxel in a recently closed intergroup trial. The higher number of previous lines and the absence of a platinum compound in our combination make our results more attractive. Furthermore, in a phase II study of gemcitabine and oxaliplatin in patients with recurrent ovarian cancer, an overall best response rate of 20% was reported (9.5% in patients with platinum-resistant disease and 24.1% in patients with platinum-sensitive disease).37 The author concluded that the combination is active, but the regimen is unsatisfactory for further study owing to the modest response and the relatively high toxicity. Despite oxaliplatin being a platinum compound, our combination had a better response rate.
Several factors have been shown to affect response to second-line therapy, including duration of response to platinum induction chemotherapy, TFI, and PFI.3,5 These factors are interrelated, and PFI and TFI are often the same.38 Tumor response rates are directly related to the PFI among all the agents currently used in second-line therapy.4,5 In addition, in our study, patients with a PFI of more than 12 months had a better response than patients with a PFI of 6 to 12 months. Ovarian cancers that relapse 6 to 12 months after treatment with a platinum compound are considered partially platinum-sensitive. Phase III studies of combination regimens versus platinum monotherapy and comparing various non-platinum agents administered as monotherapy generally do not analyze separately patients with platinum-sensitive or partially platinum-sensitive disease. A platinum-taxane combination or single-agent PLD is recommended by the United Kingdom National Institute for Health and Clinical Excellence in this subset of patients.38 Gemcitabine and vinorelbine combination could be an alternative treatment.
The high response rate (61.5%) in patients with a PFI of more than 1 year makes our combination competitive with all the experimented platinum combination.32,33,36 Patients who developed hypersensitivity reactions to carboplatin or in which platinum is contraindicated are possible candidates to gemcitabine plus vinorelbine administration.
Platinum-free interval is the most critical predictor of sensitivity to platinum rechallenge. It has been proposed that extending the PFI with intervening non-platinum therapy increases the efficacy of a later retreatment with platinum in platinum-sensitive recurrent ovarian cancer. This hypothesis is based on data from small series, and although it has not been validated prospectively, this strategy has entered general practice. This strategy provides an alternate sequence plan with greater recognition of the chronic nature of relapsed ovarian cancer.4 The hypothesis has been questioned by the Study of an Ovarian Cancer Cohort Recurred after First-Line Treatment: a Retrospective Survey (SOCRATES), which retrospectively assessed the pattern of care of a cohort of patients with recurrent platinum-sensitive ovarian cancer observed in the years 2000 to 2002 in 37 Italian centers.39 For the retrospective nature of the SOCRATES study, further data are required. In the meantime, gemcitabine and vinorelbine combination could have a place in prolonging the PFI.
Nineteen patients (48.7%) showed a stable disease during the treatment with our combination. In view of the chronic nature of recurrent ovarian cancer, the achievement of stable disease with maintenance of good performance status is considered an acceptable goal for many patients.2
As therapy is palliative in relapsed disease, quality of life and other factors must be considered in addition to response rates and survival times. The aim of management in this setting was to provide maximum time without symptoms of disease or treatment related toxicity.3 In our study, a quality-of-life evaluation was not formerly performed, but the toxicity was lower than in other second-line schedules. The absence of alopecia and the very low incidence of fatigue (1 case, grade 1 and 1 case, grade 2) are indirect signs of a good quality of life associated with our proposed treatment. Toxicity was mainly hematological, principally neutropenia, which was manageable and non-cumulative. No hospitalization was required, and no blood or platelet transfusion and no hematological growth factors were needed. Considering the potentially high costs of toxicity management, this aspect should not be forgotten in this kind of patients.
The most frequently reported dose-limiting toxicities of gemcitabine are hematological, with neutropenia occurring more often than thrombocytopenia. Nonhematological toxicities include transient increase of liver enzymes, myalgia, fatigue, and gastrointestinal disorders. In our series, the only grades 3 and 4 toxicities were grade 3 neutropenia (17.9%), grade 4 neutropenia (5.1%), and grade 3 hepatic toxicity (5.1%). Despite the combination with vinorelbine, the observed toxicity was less forced than described by Mutch et al40 and Ferrandina et al41 for gemcitabine as single agent in 2 recently published phase III trials on recurrent disease. On the other hand, Villella et al42 reported lower grades of toxicity than ours with platinum and gemcitabine combination. Nevertheless, our toxicities were quite similar to those described when gemcitabine is combined with carboplatin.33,43
The issue of how many treatment regimens to use in patients with ovarian cancer has been an area of controversy. Patients frequently have to make a decision about either continuing to be treated with chemotherapy or receiving supportive care only.3 In a study of treatment preferences in recurrent ovarian cancer, most women indicated a desire for continuing aggressive treatment despite understanding that it was associated with poor outcomes.44 In our study, 71.8% of the patients were treated after 2 previous lines of chemotherapy. Nevertheless, the response rate was quite high and the toxicity low.
In conclusion, gemcitabine and vinorelbine combination is effective and well tolerated in recurrent platinum-sensitive ovarian cancer. It may represent an option in the management of these patients because of the chronic nature of the disease. At first recurrence, gemcitabine and vinorelbine combination could be administered to patients who experienced previous allergic reactions to carboplatin or in which platinum is contraindicated. At further recurrences, patients treated with previous lines of platinum-based chemotherapy could benefit from gemcitabine and vinorelbine administration. Furthermore, the combination could be proposed to prolong the PFI or to treat patients with partially platinum-sensitive disease.
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