|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 15 (August 1), 2004: pp. 3120-3125 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.195
Duration of Response to Second-Line, Platinum-Based Chemotherapy for Ovarian Cancer: Implications for Patient Management and Clinical Trial DesignFrom the Departments of Hematology/Medical Oncology and Gynecology/Obstetrics and the Taussig Cancer Center, The Cleveland Clinic Foundation, Cleveland, OH; and The University of Texas M.D. Anderson Cancer Center, Houston, TX Address reprint requests to Maurie Markman, MD, The University of Texas M.D. Anderson Cancer Center, Mail Box 121, Houston, TX 77030; e-mail: mmarkman{at}mdanderson.org
PURPOSE: Limited information is available regarding the influence of the duration of a prior response on the length of a subsequent response to platinum chemotherapy in recurrent ovarian cancer. PATIENTS AND METHODS: We retrospectively reviewed the medical records of women with ovarian cancer treated at the Cleveland Clinic from 1993 through April 2003 who received two or more platinum-based regimens for recurrence of the malignancy. Patients were considered to have responded to second-line therapy if they satisfied specific criteria, including favorable effects on both measurable or assessable disease. RESULTS: A total of 211 platinum-based regimens were administered to 176 women with recurrent ovarian cancer during this time period, with a response being observed in 125 treatment episodes (59%). Only four (3%) of 121 currently assessable secondary responses were of longer duration than the prior response in a specific individual. In three of these four cases, the platinum-based regimen used in the second-line approach included a drug that had not been used in that patient's primary chemotherapy program. CONCLUSION: The length of a prior response to platinum-based therapy in ovarian cancer is highly predictive of the upper limit of the duration of response to a subsequent platinum program, assuming the same or similar drugs are used. Knowledge of this clinical parameter may assist in developing optimal management for an individual patient and may potentially be exploited in clinical trial designs examining novel maintenance strategies with both cytotoxic and cytostatic agents in women who achieve a secondary response to a platinum-based regimen.
It has long been recognized that individuals with malignant disease who respond to chemotherapy and who experience a long treatment-free interval before the initiation of a second-line treatment program may respond again to the same drug(s) as used in the initial treatment regimen.1,2 Ovarian cancer is no exception to this highly clinically relevant observation. A number of studies have revealed that secondary responses to platinum-based chemotherapy occur in this setting in as many as 50% to 80% of patients, based on the duration of the treatment-free interval.3-12 For example, in one report, ovarian cancer patients with a treatment-free interval of between 5 and 12 months experienced a response rate of 27%, whereas 59% of individuals whose time away from chemotherapy exceeded 24 months responded to second-line, platinum-based therapy.7 However, what is less well documented is the duration of the secondary responses, particularly the relationship of this clinical parameter to the length of the initial response to platinum therapy. The specific question to be asked is, "Can the duration of the second response in an individual patient be reasonably accurately predicted based on knowledge of the length of the prior response or treatment-free interval?" To directly address this issue and its implications for patient management, we report here the experience of the Gynecologic Cancer Program of the Cleveland Clinic with 176 ovarian cancer patients who received platinum-based treatment in the second-line setting.
Patients included in this retrospective analysis had a diagnosis of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer (all considered to be ovarian cancer in future discussions in this report). They had to have received one or more second-line chemotherapy regimens with a platinum (cisplatin or carboplatin) agent at the Cleveland Clinic from 1993 through April 2003 and were also required to have either measurable or assessable disease (see below in this section). Patients had to have been treated with at least one second-line, platinum-based chemotherapy regimen during this time period. However, primary chemotherapy may have been administered before these inclusive dates, and this treatment may have been given at another institution. Patients were considered to have received a separate treatment program with a platinum-based regimen (either a single-agent or combination chemotherapy program) if the treatment-free interval between the last dose of the initial therapy and the initiation of the second-line treatment was at least 4 months. Thus, patients who continued to receive platinum beyond the initial planned five- to six-course program (eg, persistent elevation of CA-125 and slowly resolving symptoms) were not considered to have received a second-line program unless they had treatment discontinued for at least 4 months. All patients who received even a single treatment with a platinum agent in the second-line setting were included in this analysis. Patients were also included if they had second-line platinum therapy discontinued because of the development of a hypersensitivity reaction or a strongly positive carboplatin skin test.13,14
Patients were considered to have achieved a response to second-line, platinum-based therapy if they satisfied one or both of the following requirements: (1) a reduction in measurable disease (either by physical examination or radiographic evaluation) as defined by standard criteria ( The durations of primary and secondary responses were defined as the period of time from the initiation of treatment (in a patient responding to therapy) until documentation of disease progression (eg, development of new measurable disease or enlargement of existing disease, sustained rise in the CA-125 antigen level,19 and appearance of new symptoms believed to be a result of progressive cancer).
Patient Characteristics A total of 176 patients were identified in our program who met the previously described criteria for inclusion in this retrospective analysis. The median age of the patient population was 61 years (range, 38 to 88 years). This study included 131, 41, and four patients with ovarian, primary peritoneal, and fallopian tube cancers, respectively. Characteristics of the prior platinum-based treatment programs administered to this patient population and the regimens used in the second-line setting are listed in Table 1. Twenty-four patients received more than two platinum-based programs (total of 35 regimens beyond a second platinum management strategy).12 Thus, this analysis includes a total of 211 assessable regimens for documentation of both the occurrence and duration of response.
Response Rate In 125 (59%) of the 211 second-line, platinum-based treatment regimens included in this series, there was evidence of a response of measurable or assessable (by CA-125 criteria) disease. Response was determined by changes in measurable disease or assessable disease only in 42% and 58% of patients, respectively. Consistent with other reports demonstrating the importance of the duration of the previous remission, or treatment-free interval, in influencing the opportunity of a patient to achieve a subsequent response, the response rate in women with a prior response duration of 18 months or more (75%) was more than double the response rate observed in individuals with a previous response duration of less than 12 months (33%; Table 2).
Sixteen patients were unable to continue second-line carboplatin, despite exhibiting evidence of a response, because of the development of a hypersensitivity reaction or a markedly positive carboplatin skin test.13,14 As previously noted, these responses and their duration are included in this analysis, despite the fact that the patient may have subsequently received another agent (most frequently paclitaxel) before developing disease progression. To date, four patients who exhibited a secondary response to a platinum program remain without evidence of disease progression. Of the 121 episodes of secondary response for which it is currently possible to evaluate the length of the response, in all but four occasions (3%), the duration of the later response was shorter than the initial or previous remission. Of note, in three of the four cases where the subsequent platinum response was longer than the prior response, the patient had received a different regimen than what was used with the previous program (eg, paclitaxel was substituted for cyclophosphamide). For patients who received and responded to three or more such second-line programs, the durations of the subsequent responses (with the one exception described in the following paragraph) were shorter than the immediately preceding response. The case history of the single patient in our series who experienced a longer duration of a later response compared with an earlier remission when treated with only single-agent carboplatin is instructive. In this individual, the duration of response to primary carboplatin-paclitaxel chemotherapy was 24 months. With recurrence, the patient was again treated with a carboplatin-based combination regimen, but the patient developed right upper quadrant pain and a modest elevation of the serum CA-125 level 8 months after second-line treatment was initiated. A computed tomography scan of the abdomen was unremarkable, except for gallstones. Because of the pain and elevated CA-125, carboplatin was initiated. The pain resolved over several weeks, and the CA-125 level declined (current duration of response, 14+ months). However, on the basis of the nonspecific signs and symptoms (including the fact that CA-125 can increase in the presence of peritoneal inflammation), and the strong predictive value revealed in the current analysis associated with knowledge of an individual patient's prior platinum response duration, it is uncertain at this point whether the abdominal pain and CA-125 abnormalities observed in this woman at the time of her second relapse were a result of actual tumor progression or rather a self-limited episode of acute choleocystitis. Although this series demonstrated that the population of patients with more prolonged previous response durations experienced longer secondary remissions than the subgroup with shorter prior response durations, we were unable to accurately predict the relative duration of the subsequent response in individual patients based on the duration of their previous response (Table 3). Thus, although the length of the secondary response for a patient with a previous response duration of less than 12 months was always relatively short, patients with a previous response duration of more than 24 months who responded to second-line platinum seemed to be equally likely to experience either a prolonged (eg, > 12 months) or a limited (eg, < 6 months) remission.
Treatment-Free Interval An attempt was made to independently evaluate the impact of the treatment-free interval on the duration of clinical responses. Unfortunately, an insufficient number of patients in this retrospective series received extended treatment courses to permit any reasonable statement regarding the impact of this interval on the time to disease progression in an individual patient.
Several clinically relevant statements can be made regarding the results of this retrospective examination of secondary responses of patients with epithelial ovarian cancer to platinum-based therapy. First, we have again confirmed the importance of the duration of prior response in defining the opportunity for secondary responses to platinum-based treatment.5-7 Although this clinical parameter is not necessarily identical to the commonly used term of treatment-free interval, for responding patients whose therapy is routinely discontinued after six courses of cytotoxic drugs (as occurred in the majority of individuals included in the current analysis), it is reasonable to suggest that the two features measure similar biologic attributes of the cancer. For example, the statement that a patient who received six courses of carboplatin-paclitaxel and who recurred 12 months later experienced a treatment free-interval of 12 months is equivalent to describing the duration of response in this individual to be approximately 16 to 18 months. Second, we have demonstrated that the duration of response to the initial or prior platinum-based chemotherapy regimen is highly predictive of the upper limit of the duration of response to a subsequent platinum treatment program, assuming that the same or similar drugs are used as in the previous treatment program. This information should be helpful in discussing management options with ovarian cancer patients being considered for second-line chemotherapy. However, it is important to note that the large majority of patients in our series received either single-agent carboplatin in the second-line setting or the same drug regimen (carboplatin-paclitaxel) used in the previous course of chemotherapy. In addition, for patients who exhibited an objective response, treatment was frequently discontinued after six courses of therapy. Therefore, it is possible that if platinum had been delivered in combination with an agent not previously administered to that individual or if the drug had been continued in the responding patient population, the duration of response might have been longer. Although the more prolonged duration of response in three patients in our series who received a combination platinum-based regimen that included an agent not delivered as a component of their primary therapy supports this hypothesis, far more data will be required to demonstrate the validity of this analysis. The experience of other institutions that may have routinely used a different management strategy (eg, standard use of combination chemotherapy or continuation of platinum in responding patients) with second-line platinum therapy in ovarian cancer would be of interest in evaluating this issue.8-10 Also relevant to this discussion are recently reported data demonstrating that the delivery of single-agent maintenance/consolidation paclitaxel to women with advanced ovarian cancer who achieved a clinically defined complete response to primary chemotherapy can substantially prolong the time to subsequent disease progression.20 It is reasonable to postulate that patients who achieve a complete or partial response to second-line, platinum-based treatment may experience clinical benefit from some form of maintenance therapy.21 A randomized trial designed to specifically address this issue would be of considerable interest. However, although prolonging second-line therapy or adding a new drug may improve the duration of response, either approach also has the potential to increase both the toxicity (eg, bone marrow suppression and peripheral neurotoxicity) and the cost of treatment without having any meaningful impact on the patient's quality of life, time to symptomatic disease progression, or overall survival. Only randomized trials can define the genuine benefits of these alternative management strategies. Third, in our series, we have been unable to accurately predict the duration of secondary responses to platinum chemotherapy for individual patients based on the length of the initial or immediately preceding remission. Although this may have been because of the limited number of patients in each previous response duration category (eg, < 12 months and > 24 months), it is also possible that the inherent substantial heterogeneity associated with the recurrent tumor (eg, rate of growth of platinum-resistant cells present within the sensitive tumor cell population) makes it unrealistic that a reliable predictive model for individual patient management can be developed. Finally, it is appropriate to comment on the potential implications of our findings for clinical trial design for second-line chemotherapy of ovarian cancer. It is well recognized that this clinical setting has been important in the development of a number of cytotoxic agents currently used in standard oncologic practice (eg, cisplatin, carboplatin, paclitaxel, topotecan, and liposomal doxorubicin). In fact, the antineoplastic activity of several of these drugs was initially demonstrated in ovarian cancer patients who were defined as being resistant to the primary chemotherapy regimens used during specific eras (eg, cisplatin in patients failing alkylating agents22 and paclitaxel and topotecan in platinum resistance23,24). Current efforts in drug development for ovarian cancer have been required to specifically focus initially on the platinum-resistant patient population in an attempt to define an acceptable degree of antineoplastic activity worthy of further investigation. This is because of the fact that even finding a relatively high objective response rate in women with recurrent, potentially platinum-sensitive disease would lead to the obvious question of whether the same (or even a greater) level of activity might have been observed if either carboplatin or cisplatin had been administered to the patient population rather than the experimental drug. Therefore, unless activity is documented in the setting of resistant disease, it would be appropriately argued that there should be limited interest in the agent. The results of the current analysis suggest the potential utility of an alternative clinical trial design in patients with recurrent ovarian cancer after an initial response to platinum-based chemotherapy. Because the duration of secondary responses in patients with platinum-sensitive ovarian cancer are shorter than the initial or prior responses (assuming use of the same regimen, or single-agent platinum treatment), if an experimental drug produces a respectable response rate and a reasonable percentage of those responses (eg, > 20% to 25%) exceed in duration the individual patient's prior response to platinum-based therapy, this observation might be accepted as strong evidence that the new agent has produced a biologic effect that would not have not been anticipated if platinum had been administered in this setting. It is appropriate to suggest that this hypothesis be tested in the future in a clinical trial. Furthermore, the use of duration of second response criteria has several advantages in the development of new therapies in ovarian cancer. First, it allows a larger patient population to be used in more definitive studies of novel strategies in the management of this malignancy (ie, individuals with potentially platinum-sensitive disease). Second, it may permit critically important data regarding relative antineoplastic efficacy, compared with platinum, to be obtained in well-designed phase II trials, rather than always requiring far more expensive and time-consuming phase III studies. At a minimum, the data generated from such an analysis can serve as the basis for the development of a solid hypothesis to be evaluated in a future definitive (randomized phase III) trial. Finally, the use of an individual patient's duration of response may permit an important examination of interesting cytostatic agents in the phase II trial setting. Here, the concern is that this class of agents may not be capable of producing major tumor regressions (as measured by the objective response rate), but rather, they will only retard future tumor growth once a response to cytotoxic chemotherapy is achieved. Thus, a drug with major biologic activity may be discarded because tumor shrinkage is not observed. Although stable disease associated with a good quality of life may have important clinical relevance, the relationship between the existence of this clinical state and a particular antineoplastic drug strategy will be difficult to evaluate outside of the setting of a randomized phase III trial. In contrast, use of duration of response criteria may permit at least a preliminary evaluation of the clinical utility of this class of antineoplastic drugs. For example, if a patient receives second-line treatment with carboplatin, followed by a novel cytostatic agent, and the duration of this secondary remission is 18 months, in contrast to only 12 months for the primary response, it would be reasonable to conclude that the experimental agent contributed substantially to the longer progression-free interval, despite the lack of evidence for any tumor shrinkage associated with use of this drug. The attractiveness of using the treatment-free interval to define the opportunity for secondary responses is based on the objective nature of this clinical parameter. However, as oncologists begin to explore a variety of maintenance or consolidation strategies, it may become more difficult to define what is meant by treatment free (eg, does the term include freedom from therapy with both cytotoxic and cytostatic drugs?). Thus, in the future, it may be more meaningful to discuss the time to disease progression from initiation of primary chemotherapy until documented disease progression, rather than the treatment-free interval, in attempting to optimize the benefits required of a second-line treatment program in a phase II clinical trial. Further discussion of this point, on the basis of the experience of other centers using second-line, platinum-based chemotherapy for recurrent ovarian cancer, would be of interest.
The authors indicated no potential conflicts of interest.
1. Fisher RI, DeVita VT, Hubbard SP, et al: Prolonged disease-free survival in Hodgkin's disease with MOPP reinduction after first relapse. Ann Intern Med 90:761-763, 1979 2. Batist G, Ihde DC, Zabell A, et al: Small-cell carcinoma of the lung: Reinduction therapy after late relapse. Ann Intern Med 98:472-474, 1983 3. Seltzer V, Vogl S, Kaplan B: Recurrent ovarian carcinoma: Retreatment utilizing combination chemotherapy including cis-diamminedichloroplatinum in patients previously responding to this agent. Gynecol Oncol 21:167-176, 1985[CrossRef][Medline] 4. Gershenson DM, Kavanagh JJ, Copeland LJ, et al: Re-treatment of patients with recurrent epithelial ovarian cancer with cisplatin-based chemotherapy. Obstet Gynecol 73:798-802, 1989[Medline] 5. Hoskins PJ, O'Reilly SE, Swenerton KD: The ‘failure free interval’ defines the likelihood of resistance to carboplatin in patients with advanced epithelial ovarian cancer previously treated with cisplatin: Relevance to therapy and new drug testing. Int J Gynecol Cancer 1:205-208, 1991[CrossRef] 6. Gore ME, Fryatt I, Wiltshaw E, et al: Treatment of relapsed carcinoma of the ovary with cisplatin or carboplatin following initial treatment with these compounds. Gynecol Oncol 36:207-211, 1990[CrossRef][Medline] 7. Markman M, Rothman R, Hakes T, et al: Second-line platinum therapy in patients with ovarian cancer previously treated with cisplatin. J Clin Oncol 9:389-393, 1991[Abstract] 8. Gronlund B, Hogdall C, Hansen HH, et al: Results of reinduction therapy with paclitaxel and carboplatin in recurrent epithelial ovarian cancer. Gynecol Oncol 83:128-134, 2001[CrossRef][Medline]
9. Rose PG, Fusco N, Fluellen L, et al: Second-line therapy with paclitaxel and carboplatin for recurrent disease following first-line therapy with paclitaxel and platinum in ovarian or peritoneal carcinoma. J Clin Oncol 16:1494-1497, 1998
10. Dizon DS, Hensley ML, Poynor EA, et al: Retrospective analysis of carboplatin and paclitaxel as initial second-line therapy for recurrent epithelial ovarian carcinoma: Application toward a dynamic disease state model of ovarian cancer. J Clin Oncol 20:1238-1247, 2002
11. Cantu MG, Buda A, Parma G, et al: Randomized controlled trial of single-agent paclitaxel versus cyclophosphamide, doxorubicin, and cisplatin in patients with recurrent ovarian cancer who responded to first-line platinum-based regimens. J Clin Oncol 20:1232-1237, 2002 12. Markman M, Kennedy A, Webster K, et al: Continued chemosensitivity to cisplatin/carboplatin in ovarian carcinoma despite treatment with multiple prior platinum-based regimens. Gynecol Oncol 65:434-436, 1997[CrossRef][Medline]
13. Markman M, Kennedy A, Webster K, et al: Clinical features of hypersensitivity reactions to carboplatin. J Clin Oncol 17:1141-1145, 1999
14. Zanotti KM, Rybicki LA, Kennedy AW, et al: Carboplatin skin testing: A skin-testing protocol for predicting hypersensitivity to carboplatin chemotherapy. J Clin Oncol 19:3126-3129, 2001 15. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 16. Markman M, Kennedy A, Webster K, et al: Phase 2 trial of liposomal doxorubicin (40 mg/m2) in platinum/paclitaxel-refractory ovarian and fallopian tube cancers and primary carcinoma of the peritoneum. Gynecol Oncol 78:369-372, 2000[CrossRef][Medline] 17. Markman M, Kennedy A, Webster K, et al: Phase 2 evaluation of topotecan administered on a 3-day schedule in the treatment of platinum- and paclitaxel-refractory ovarian cancer. Gynecol Oncol 79:116-119, 2000[CrossRef][Medline]
18. Markman M, Kennedy A, Webster K, et al: Combination chemotherapy with carboplatin and docetaxel in the treatment of cancers of the ovary and fallopian tube and primary carcinoma of the peritoneum. J Clin Oncol 19:1901-1905, 2001
19. Rustin GJS, Nelstrop AE, Tuxen MK, et al: Defining progression of ovarian carcinoma during follow-up according to CA-125: A North Thames Ovary Group study. Ann Oncol 7:361-364, 1996
20. Markman M, Liu PY, Wilczynski S, et al: Phase III randomized trial of 12 versus 3 months of single-agent paclitaxel in patients with advanced ovarian cancer who attained a clinically defined complete response to platinum/paclitaxel-based chemotherapy: A Southwest Oncology Group and Gynecologic Oncology Group trial. J Clin Oncol 21:2460-2465, 2003 21. Eltabbakh GH, Piver MS, Hempling RE, et al: Prolonged disease-free survival by maintenance chemotherapy among patients with recurrent platinum-sensitive ovarian cancer. Gynecol Oncol 71:190-195, 1998[CrossRef][Medline] 22. Katz ME, Schwartz PE, Kapp DS, et al: Epithelial carcinoma of the ovary: Current strategies. Ann Intern Med 95:98-111, 1981 23. McGuire WP, Rowinsky EK, Rosenshein NB, et al: Taxol: A unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111:273-279, 1989
24. ten Bokkel Huinink W, Gore M, Carmichael J, et al: Topotecan versus paclitaxel for the treatment of recurrent epithelial ovarian cancer. J Clin Oncol 15:2183-2193, 1997 Submitted May 29, 2003; accepted April 29, 2004.
This article has been cited by other articles:
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
50% reduction in the sum of the products of the perpendicular diameters of measurable tumor masses)
