Abstract
Due to the high recurrence rates of ovarian carcinoma, the treatment of recurrent disease is currently one of the most challenging topics in the clinical setting. Ovarian cancer patients who do not respond to initial chemotherapy or who relapse after achieving a response are generally incurable. Treatment goals after failure of first-line treatment for ovarian cancer include: (a) controlling or preventing disease-related symptoms, (b) maintaining quality of life by choosing an effective treatment with low toxicity potential, and (c) prolonging progression-free survival. In contrast to the adjuvant situation in which prospective randomized phase III trials have established the current standard, only a few randomized trials are available for patients with recurrent disease. In addition, a series of agents has been shown to have clinical activity in recurrent ovarian cancer, including topotecan, pegylated liposomal doxorubicin, gemcitabine and oral etoposide. It has also been demonstrated that re-treatment with a platinum drug and taxane has been associated with a significant clinical activity in patients with “sensitive” (treatment-free interval >6 months) recurrent disease. The role of antihormonal therapy is still unclear. These possible treatments for recurrent ovarian cancer require prospective randomized trials comparing efficacy, toxicity and quality of life.
Currently, the standard of care for primary advanced ovarian cancer is a radical surgery with the primary aim of maximal tumor reduction and a combination therapy with platinum and taxane. Despite the initially favorable response, however, 65% of these patients recur in the first three years (1, 2). Ovarian cancer patients who do not respond to initial chemotherapy or who relapse after achieving a response are generally incurable.
However, further responses to either the same or different drugs are possible. There are various agents with antitumor activity against ovarian cancer, but there seems to be no definite standard approach for second-line treatment in these collective patients. The main treatment goals after failure of first-line treatment for ovarian cancer are the controlling or preventing of disease-related symptoms, maintaining quality of life by choosing an effective treatment with low toxicity potential, prolonging progression-free survival and the consideration of patients' preferences. It is problematic that, despite the availability of validated questionnaires, their routine use in the clinical setting has been not established so far. This paper describes the implementation of a questionnaire designed to obtain information on patients' preferences and on doctor-patient communication for ovarian cancer patients.
Patients and Methods
In order to identify the patients' preferences and to address the information needs focusing on doctor patient communication of ovarian cancer patients, a multicenter German survey was performed via print or internet version: “Expression II Ovar” was based on the experience and results from Expression I (3). Before starting this study in a multicenter setting, the questionnaire was tested for comprehensibility and reproducibility in a single center pilot study (at the Charité Hospital in the Virchow University Hospital Campus) involving 20 patients with primary (25%) and recurrent (75%) ovarian cancer (4). The average duration of an interview was approximately 25 minutes (range 15-40 minutes). Patients were assured at the start of the interview that their replies would be in no way detrimental to their care or clinical management. The median age of this patient population was 62 years (range 41 to 83 years). On a 10-item Likert scale with scores ranging from 1 to 10, the patients were requested to rate different topics during the conversation with their doctors.
Results
In regard to the competence of the physician, the median score was 8.4 points, for the shared decision process 8 points, for consideration of a patient's question 8.2 points, for the general understanding of information 7.9 points, and for completeness of all information 7.3 points (Figure 1).
Seventy five percent of the patients wanted to know details about the possible side-effects and discomforts during treatment. Detailed information about life expectancy was requested from 50% of the patients interviewed.
This questionnaire was subsequently posted in the internet after suitable technical preparation, but the paper version is continually used in parallel with the internet survey. A link to the study was also set up on the websites of various medical associations, patient self-help groups and interest groups. The internet survey opened in May 2008 and about 500 patients have responded via the online and paper versions. In June 2009, the survey will close and the data will be analyzed. A European survey to compare the results from different countries will be initiated in October 2009.
Recurrent ovarian cancer patients were classified based on the disease-free interval after adjuvant primary chemotherapy as platinum-sensitive and platinum-resistant (5). Platinum-resistant are those patients who show a relapse of the disease within 6 months of therapy, or a progression during primary first-line therapy. Platinum-sensitive are those patients with a longer (>6 months) treatment-free interval (5). The response rates and duration of responses differ significantly between patients considered to be sensitive and those considered to be resistant. The treatment-free interval determines the choice of second-line treatment. But it must be underlined that this definition can only be used in cases of adequate primary treatment, defined by optimal surgery and chemotherapy.
Platinum-sensitive patients. A large randomized phase III trial demonstrated a superiority of combined carboplatin and paclitaxel over platinum monotherapy in platinum-sensitive patients (6). In the AGO-ICON IV-trial, which includes 802 patients, the platinum-based combination demonstrated an improved impact on progression-free survival and on overall survival.
However, the cumulative neurotoxicity of platinum and paclitaxel precludes administration to patients with residual neurological deficits (7, 8). Therefore various working groups are looking for new platinum-based combinations to improve the therapeutical index.
Pfisterer et al. in a large randomized AGO-GCIG trial compared single-agent carboplatin with a combination of carboplatin plus gemcitabine (the total number of patients enrolled was 356) and demonstrated a significant benefit in progression-free survival for the combination therapy (9). Data on overall survival in the treated populations were not available, although this study was not specifically powered to observe any survival difference between the regimens.
To decide which combination can be offered to patients with platinum-sensitive ovarian cancer the toxicities remaining from adjuvant treatment (e.g. neurological symptoms) should be considered and the preference of the patient (e.g. alopecia, treatment schedule) included.
To analyze further therapy options for these patient groups, two large multicenter trials have already been conducted.
The AGO (Arbeitsgemeinschaft Gynäkologische Onkologie; www.ago-ovar.de) and GCIG (Gynecologic Cancer Intergroup) have finished the enrolment for their multi-national randomized phase-III-trial comparing pegylated liposomal doxorubicin (CAELYX®) and carboplatin versus paclitaxel and carboplatin in patients having a relapse of >6 months. The results of this study including 976 patients are presented in ASCO 2009. The paclitaxel and pegylated liposomal doxorubicin (CAELYX®) combination was well-tolerated with lower severe toxicities. After a median of 21 months, progression-free survival was 11.3 months in the paclitaxel plus CAELYX® group versus 9.4 months in the paclitaxel plus carboplatin group.
In a phase I and II clinical trial, pemetrexed (ALIMTA®) in combination with carboplatin will be evaluated in platinum-sensitive patients with recurrent ovarian cancer. This study also includes patients with primary peritoneal cancer and is currently recruiting participants in five countries (Argentina, Canada, Germany, Poland and Sweden).
The NOGGO (North Eastern Society of Gynecologic Oncology; www.NOGGO.de) and the AGO conducted a randomized phase-III-trial comparing the promising combination of topotecan and carboplatin with the established treatment regimes carboplatin and taxane or carboplatin and gemcitabine. The study design is shown in Figure 2. Currently 528 patients from 127 centers in Germany and Austria are included in this trial.
Platinum-resistant patients. Approximately 30% of the ovarian cancer patients are platinum resistant; out of these patients 5 to 10% progressed while on platinum therapy and 15 to 25% shortly after platinum treatment (e.g. within 6 months) (10, 11). Current chemotherapy in platinum-resistant ovarian cancer patients has demonstrated minimal to no improvements at all in survival. For this patient population, it is the symptom control and quality of life which represent the real goal of the second-line therapy. There are various agents with antitumor activity against ovarian cancer, but none of these are yet claimed to be a definite standard for second-line treatment in these collective patients.
The choice of second-line chemotherapy will be mostly influenced by response rates, the different toxicity profiles of the active agents and also the patients' preferences (12) (Table I). Furthermore the current tumor symptoms and toxicities remaining should be integrated into the decision of the next therapy, and the palliative situation discussed seriously with the patient and family.
Patient-doctor communication; ESGO 2007.
Chemotherapeutic agent with response rates and cumulative toxicity.
For this patient group, usually a single-agent therapy is chosen to control symptoms without producing more toxicity. Sehouli et al. demonstrated in a randomized phase III trial, which compared topotecan versus topotecan and etoposide and versus topotecan and gemcitabine, that a combination therapy showed no benefit in survival for the platinum-resistant patient group, but indeed generated a much higher toxicity than a single-agent therapy (13).
Design of the HECTOR trial.
Design of the TOWER study.
Is there any difference concerning efficacy between the various agents, or is there no difference?
The AGO presented a randomized phase III trial comparing topotecan versus treosulfan (14). Overall, 378 patients with recurrent ovarian cancer, predominantly in second-line situation and some patients in third-line situation were included in this multicenter trial. Treosulfan showed a significantly better toxicity profile than topotecan did, but the median overall survival for topotecan was 18 months and 14 months for treosulfan.
In this connection, it should be noted that in the NOGGO preference study, patients having a recurrent ovarian, tube or peritoneal carcinoma and aged 65 years or more were asked about their preference of an oral or peritoneal administration of treosulfan, whereby the compliance, tolerability and efficacy were to be examined prospectively. Only when a patient's preference was missing would a randomization list be taken into account. All patients anticipating a third-line therapy can be accepted, this study is still open for recruitment.
In various studies topotecan has demonstrated antitumor activity in relapsed ovarian cancer with a tolerable toxicity profile. It shows no cross-resistance to paclitaxel and carboplatin and especially no overlapping or cumulative toxicity (15, 16).
Based on large phase III trials, topotecan appears to be as effective as paclitaxel and liposomal doxorubicin (17, 18).
Relapsed ovarian cancer is frequently treated with topotecan for which the standard dose and schedule are 1.25-1.5 mg/m2 daily for five consecutive days every 3 weeks. Different study groups are also evaluating a weekly application of topotecan to improve the therapeutical index (19, 20). The potential benefits of weekly administration are reduced toxicity without any significant deficit of antitumor activity and greater patient convenience and quality of life.
The NOGGO conducted a randomized multicenter trial to evaluate this hypothesis.
Between January 2006 and 2008, 194 patients with resistant ovarian cancer were enrolled into this trial comparing the conventional schedule with a weekly schedule. The study design is demonstrated in Figure 3.
According to the statistical Gehan design of this study, a safety and first efficacy analysis was defined and the first interim analysis was presented by Sehouli et al. at ASCO 2007 (21). The data showed no significant differences in tolerability or response between both treatment arms. The final analyses are already finished and will be presented at the ASCO meeting of 2009.
Pegylated liposomal doxorubicin is also an effective and well-tolerated agent in the treatment of recurrent ovarian cancer. Gordon et al. (18) compared in a randomized phase-III trial topotecan with pegylated liposomal doxorubicin as single-agent therapy in recurrent ovarian cancer patients. The results were not able to show a significant benefit for any one of these agents concerning overall or progression-free survival. However palmar-plantar erythrodysesthesia (PPE) is a typical and commonly noted adverse event of pegylated liposomal doxorubicin, and often represents the dose-limiting toxicity, thus compromising somewhat the patient's quality of life. Previous investigations showed that a biweekly schedule with splitting of the dosage into 20 mg/m2 every two weeks is associated with a low incidence of PPE and is well tolerated in pre-treated patients with relapsed ovarian cancer (22, 23).
The MITO group compared a single agent therapy with gemcitabine given in a dose of 1,000 mg/m2 on day 1, 8 and 15 every 28 days with pegylated liposomal doxorubicin at a dose of 40 mg/m2 given on day 1 every 28 days in recurrent ovarian cancer patients (24). Overall, 128 patients (60% platinum-resistant) were included in this trial. Both treatment regimes showed a favorable but different toxicity profile, but concerning overall or progression-free survival, no significant difference was demonstrated.
It is important to note that no evidence-based data exist which justify a combination treatment or platinum re-treatment outside of clinical studies for this palliative patient group.
Role of hormonal treatment. Although in 70% of all ovarian cancer cases a positive estrogen receptor and in 50% a positive gestagen receptor can be demonstrated, the role of hormonal therapy and hormone receptor in the treatment of ovarian cancer remains unclear (25). Du Bois et al. (26) evaluated in a randomized trial if second-line chemotherapy with treosulfan in resistant ovarian cancer patients can offer any benefit compared with a less toxic hormonal treatment with leuprorelin acetate. After 2.5 years of accrual, an interim analysis was performed. In the presence of any suspected lack of efficacy, the recruitment was stopped early and the 78 patients already enrolled were followed-up until the final analysis. Both treatment arms demonstrated a favorable toxicity profile. After a median observation period of 22.5 months, the median survival time was 36 and 30 weeks in the treosulfan and leuprorelin arm, respectively.
Kristensen et al. (27) presented at the ASCO meeting of 2008 a randomized study of chemotherapy versus hormonal treatment in patients with ovarian cancer resistant or refractory to platinum and taxane. Two hundred and twenty-five out of the 241 randomized patients were treated with tamoxifen (40 mg daily, for 83 patients), paclitaxel (80 mg/m2 weekly, for 72 patients), or pegylated liposomal doxorubicin (40 mg/m2 every 4 weeks, for 86 patients). Both treatment arms were well tolerated. The chemotherapy arm showed a slightly better progression-free interval with a median of 87 days versus a median of 62 days in the hormonal treatment arm. In overall survival, a minimal difference was shown, with a median overall survival of 328 days in the chemotherapy arm and 278 days in the tamoxifen arm.
New agents on the horizon. There are also novel approaches including molecular biological agents (e.g. bevacizumab, sunitinib) in the treatment concepts of ovarian cancer patients. Defining molecular biological targets in ovarian cancer patients will be the future direction to develop more effective and individual therapies, but the combination of targeted therapies and systemic chemotherapy seems to be the most promising strategy.
In fact, the results of studies including the new agents are disappointing, hence more clinical trials are needed to define the role of all known antibodies and inhibitors and to individualize therapy to patients who would benefit from it.
Conclusion
Platinum-resistant patients (<6 months):
No benefit of combination versus single agent therapy was observed.
Agents which were effective included topotecan, pegylated liposomal doxorubicin, or gemcitabine.
In taxane-naive patients, paclitaxel is also effective.
The role of hormonal treatment remains nonetheless unclear.
Platinum-sensitive patients:
Re-induction treatment with a platinum-based combination therapy with paclitaxel or gemcitabine is now considered to be the standard second-line treatment for patients with platinum-sensitive ovarian cancer
The main conclusion for recurrent ovarian cancer still remains that more patients are needed in randomized trials to generate data which can support therapy decisions in the clinical management of these palliative patients.
Footnotes
-
This work was presented in part at the 'VII. International Symposium of the North-Eastern German Society of Gynecologic Oncology (NOGGO)' at the 8th International Conference of Anticancer Research, 17-22 October 2008, Kos, Greece.
- Received January 7, 2009.
- Revision received March 17, 2009.
- Accepted May 4, 2009.
- Copyright© 2009 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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