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Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer
Gynecologic Oncology 103 (2006) 195 – 198 www.elsevier.com/locate/ygyno
Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer Maurie Markman a,⁎, Massimo Federico b , P.Y. Liu c , Edward Hannigan d , David Alberts e a
d
University of Texas M.D. Anderson Cancer Center (Mail Box #121), 1515 Holcombe Boulevard, Houston, TX 77030, USA b Universita of Modena e Reggio Emilia, Modena, Italy c Southwest Oncology Group Statistical Office, Seattle, WA 98104, USA Department of Obstetrics and Gynecology, School of Medicine, University of Texas–Galveston, Galveston, TX 77555-0132, USA e University of Arizona Cancer Center, Tucson, AZ 85721, USA Received 22 November 2005 Available online 3 April 2006
Abstract Objective. The relationship between survival and early changes in the serum level of the CA-125 antigen in patients with advanced ovarian cancer remains poorly defined. Methods. To explore this issue, the serum CA-125 values from 101 patients with advanced ovarian cancer who participated in a Southwest Oncology Group trial (SWOG 8412), which compared the systemic delivery of cisplatin/cyclophosphamide vs. carboplatin/cyclophosphamide (both delivered every 28 days for 6 cycles) in suboptimal residual stage III and IV ovarian cancer, were evaluated. All patients in this analysis had CA-125 values available for at least 8 weeks following initiation of chemotherapy. Cox proportional hazards regression was used in multivariate analysis to determine the prognostic significance of the CA-125 concentration. Results. While pretreatment CA-125 values did not correlate with survival, the concentration of this tumor marker 8 weeks after initiation of therapy was a powerful independent prognostic factor. The median survivals for patients (n = 51) with a CA-125 < 35 U/ml, vs. patients (n = 50) with a CA-125 > 35 U/ml, at this time point, were 26 months and 15 months, respectively (P = 0.0001). Further, women with serum CA-125 values <50% of their pretreatment concentration at 8 weeks experienced a median survival of 21 months, compared to only 10 months for individuals with tumor marker levels >50% of their baseline value (P = 0.0003). Conclusion. Reduction in the serum CA-125 concentration over the initial two cycles of platinum-based chemotherapy is a powerful independent predictor of survival for patients with suboptimal stage III or IV ovarian cancer. Patients without significant declines in CA-125 after two cycles of platinum-based chemotherapy have a particularly poor prognosis. © 2006 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Platinum chemotherapy; Serum CA-125 antigen
Currently, the majority of women with advanced ovarian cancer achieve some level of clinical benefit associated with the administration of cytotoxic chemotherapy [1,2]. However, while the overall median survival of patients with the disease has unquestionably improved with the introduction of platinumbased treatment programs, there remains rather remarkable variability in the outcome of individuals with apparently similar tumor grades, morphology, and volume of disease at the initiation of primary anti-neoplastic drug therapy. Unfortunately, ⁎ Corresponding author. Fax: +1 713 563 9586. E-mail address: [email protected] (M. Markman). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.02.024
there are no unique clinical characteristics at initial presentation or known molecular abnormalities that are currently able to clearly define the impact of the primary cytotoxic drug therapy program on an individual patient's survival. Measurement of the serum level of the CA-125 antigen has become a standard component of routine management of women with advanced ovarian cancer [2]. The ease of use of this important laboratory test leads to the obvious question of whether the baseline CA-125 determination, or the subsequent rate of change in the antigen level following several treatment cycles, can provide a reliable early indication of the ultimate effectiveness of cytotoxic drug therapy [3–12].
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The availability of both sequential serum CA-125 levels, and long-term survival data, for patients who participated in a previously reported Southwest Oncology Group (SWOG) randomized phase 3 trial which compared a cisplatin– cyclophosphamide to a carboplatin–cyclophosphamide regimen as primary treatment of “suboptimal” residual stage III and stage IV ovarian cancer, provides an important opportunity to explore this highly clinically relevant issue [13]. Reported here are the results of this evaluation. Methods and materials Patient population The data used in this analysis were generated from an examination of a subgroup of patients who participated in a SWOG randomized phase 3 trial (SWOG 8412) which compared the systemic delivery of cisplatin (100 mg/m2) plus cyclophosphamide (600 mg/m2) to carboplatin (300 mg/m2) plus cyclophosphamide (600 mg/m2) as primary chemotherapy of suboptimal residual stage III or stage IV ovarian cancer [13]. Both treatment programs were delivered on an every 28-day schedule for six cycles. In this trial, “suboptimal residual” stage III disease was defined as the presence of at least one tumor mass >2 cm in diameter remaining within the peritoneal cavity following initial cytoreductive surgery. Details regarding the study design, entry criteria, statistical analysis, and outcome have previously been published [13]. The aim of this phase 3 trial was to examine the equivalence of the two treatment options as primary chemotherapy in advanced ovarian cancer and to confirm the more favorable toxicity profile associated with the carboplatinbased regimen. Both of these objectives were accomplished through the conduct of the trial. The clinical and pathologic response rates, and overall median survivals (17 months and 20 months for the cisplatin and carboplatinbased regimens, respectively; P = 0.88), were not different between the study arms [13]. The principal evaluable population (n = 101) for the current analysis included all individuals who participated in this SWOG trial (total eligible patients sample size: n = 291) for whom baseline serum CA levels were available, as well as values for a minimum of 8 weeks after the initiation of chemotherapy.
Statistical considerations Variables examined in this analysis included the impact on overall survival associated with the following: (a) baseline serum CA-125 level at the initiation of chemotherapy; (b) absolute serum CA-125 level 1 month after the first cycle of chemotherapy; (c) absolute serum CA-125 level 1 month after the second cycle of chemotherapy; (d) change from baseline in serum CA-125 level 1 month after the first cycle of chemotherapy; and (e) change from baseline in serum CA-125 level 1 month after second cycle of chemotherapy. Since treatments were given in 28-day cycles, 1 month after the first and second cycles is equivalent to 4- and 8-weeks post-study entry. Based on previously reported studies, the current patient population was divided into the following discrete “CA-125 antigen” subgroups for (a) baseline determination and absolute levels after the first and second cycle of chemotherapy (≤35 u/ml, vs. >35 to <100 u/ml, vs. ≥100 u/ml); and (b) change from baseline in levels after the first and second cycle of chemotherapy, first as 4 groups (>90% decrease, vs. >50% to 90% decrease, vs. 0% to 50% decrease vs. any increased value), then as 2 groups (>90% decrease vs. ≤90% decrease; or >50% decrease vs. ≤50% decrease). Both univariate survival analyses with CA-125 as categorized above as the only variable and multivariate Cox model analyses were conducted. The Cox model analyses included age (<65 vs. ≥65), performance status (0–1 vs. 2), disease stage (III vs. IV), size of residual disease (measurable vs. non-measurable), and presence/absence of tumor necrosis and stromal sclerosis. To reduce the chance of false-positive findings due to the multiplicity of analyses conducted, P values <0.005 were considered statistically significant.
Results To determine whether the patients included in this analysis, for whom both baseline and follow-up (minimum of 8 weeks) serum CA-125 values were available, differed from other women who participated in this trial and who also survived for a minimum of 8 weeks, but for whom these serum CA-125 levels were incomplete, we examined a number of clinical characteristics of the two populations (Table 1). With the exception of a difference in the proportion of patients who received the cisplatin-based vs. the carboplatin-based program (Table 1), the two groups were quite similar in all other clinical features evaluated, suggesting the outcome of the subgroup analyzed in this report is likely to be representative of the entire study population with the exception of those who did not survive past 8 weeks (8/291 = 3%). Again, as there was no difference in survival between the cisplatin and carboplatin-treated patient populations [13], it would not be expected that an imbalance between the therapies received by the groups in this analysis should influence its outcome. The impact on survival of the various serum CA-125 subgroups, at baseline and at 1 month following the 1st and 2nd chemotherapy cycles, is demonstrated in Tables 2 and 3. Table 4 shows that, compared to the absolute value approach, little was gained by combining the absolute and percent change approaches. A Cox Model analysis including a number of known important variables in advanced ovarian cancer demonstrates the major influence on survival associated with the serum CA-125 antigen level 1 month after the 2nd chemotherapy cycle (Table 5). Discussion Several reasonable conclusions can be drawn from the results of the current analysis of advanced ovarian cancer patients whose serum CA-125 antigen levels were prospectively followed for several months after the initiation of carboplatin + cyclophosphamide or cisplatin + cyclophosphamide chemotherapy. First, the clinical features of the 101 women included in the evaluation appear to be similar to that of the entire study group, suggesting that the results are representative of what would have been found if all patients surviving past 8 weeks had their CA-125 antigen levels available, and these data would have been included in this analysis. A future study, Table 1 Characteristics of patients with serum CA-125 values available at baseline and for ≥8 weeks following initiation of treatment versus patients whose CA-125 levels were incomplete (all patients survived for ≥8 weeks) With CA-125 (n = 101) Without CA-125 (n = 182) Age: <65 PS 0–1 Stage III Non-measurable disease Cisplatin arm Median survival
60% 69% 68% 59% 37% 20 months
56% 68% 73% 55% 56% 19 months (P = 0.83)
M. Markman et al. / Gynecologic Oncology 103 (2006) 195–198 Table 2 Median survival (Months) based on baseline serum CA-125 and absolute serum CA-125 levels 1 month following both 1st and 2nd chemotherapy cycles
≤35 u/ml >35– <100 u/ml ≥100 u/ml
Baseline
1 month after 1st treatment
1 month after 2nd treatment
20 (n = 7) 21 (n = 19) 20 (n = 106) (P = 0.77)
23 (n = 39) 20 (n = 24) 16 (n = 43) (P = 0.11)
26 (n = 51) 20 (n = 20) 14 (n = 30) (P < 0.0001) 26 (n = 51) 15 (n = 50) (P = 0.0001)
≤35 u/ml >35 u/ml
examining a larger sample size and including patients treated with the current chemotherapy “standard” of a platinum agent plus a taxane, will be required to confirm the general findings of this report [1,2]. Second, the absolute baseline level of the serum CA-125 does not appear to be an independent determinant of overall survival, at least within the large group of individuals defined as having “suboptimal” residual stage III or stage IV advanced ovarian cancer. These data are consistent with those of some, but not all other investigators, who have examined this issue. However, our results regarding the lack of major significance for the baseline CA-15 level should not be surprising considering the known marked heterogeneity in the amount of CA-125 produced by individual cancers (as inferred from the serum CA-125 level) with similar tumor volumes (as measured by radiographic or surgical findings). Conversely, clinicians recognize that the finding of relatively modest (<200 u/ml) or very high (>1000 u/ml) levels of the serum CA-125 is a rather poor predictor of the amount of tumor bulk documented following subsequent non-invasive (radiographic) or invasive (surgical) evaluation. In addition, there is no compelling biological reason to suspect that the absolute level of the baseline serum CA-125 should be predictive of either the extent of inherent chemoresistance, or the subsequent development of such resistance, within a given cancer cell population. An ovarian cancer with a low serum antigen level may possess a population of cells with a Table 3 Median survival (Months) based on percentage change from baseline in serum CA-125 1 month following both 1st and 2nd chemotherapy cycles
>90% decrease >50–90% decrease 0–50% decrease Increase (any level from baseline) >90% decrease ≤90% decrease >50% decrease ≤50% decrease
1 month after 1st treatment
1 month after 2nd treatment
33 (n = 24) 19 (n = 39) 14 (n = 16) 9 (n = 9)
21 (n = 39) 20 (n = 29) 12 (n = 6) 9 (n = 11)
(P = 0.19) 33 (n = 24) 17 (n = 64) (P = 0.05)
(P = 0.002)
21 (n = 68) 10 (n = 17) (P = 0.0003)
197
Table 4 Median survival (months) based on combining “best” and “worst” serum CA125 parameters 1 month after 2nd chemotherapy cycle 1 month after 2nd treatment ≤35 u/ml + (>50% decrease) Other >100 u/ml + (≤50% decrease or increase)
26 (n = 51) 17 (n = 33) 9 (n = 13) (P < 0.0001)
high level of resistance, while another tumor whose cells produce large quantities of CA-125 may be exquisitely sensitive to cytotoxic drug therapy. Third, the modest impact on survival associated with the change in serum CA-125 after cycle 1, followed by a highly statistically significant relationship observed between this laboratory value and survival after cycle 2, is consistent with the argument that several treatment courses are required to document, at the clinical level, the net effect of the cytotoxic agents at the molecular and cellular levels. Whether the importance of this time interval is related more to the number of treatment cycles administered (2 vs. 1), or the fact 2 months have passed permitting the removal of dead or dying tumor cells, or a combination of these factors, is an unanswered (but most interesting) question. Finally, it is important to ask if there are potential clinical trial or disease management implications of this analysis. Before addressing this question, it is relevant to again note the findings must be confirmed (or refuted) in a second study, hopefully with all patients having their serum CA-125 levels prospectively evaluated in a manner similar to that reported here. In the absence of such confirmation, any conclusion regarding a possible impact of these treatment-associated changes in the serum CA-125 antigen must be considered to be very preliminary. However, assuming such confirmation, a highly provocative suggestion for a future randomized phase 3 trial would be to prospectively follow a group of patients treated with “standard” platinum–taxane chemotherapy and subsequently randomize those individuals whose serum CA-125 was >35 u/ml 1 month following the 2nd chemotherapy cycle either to (a) continue with Table 5 Cox model analysis Variable
Hazard ratio
95% Confidence interval
P value
Age (≥65 vs. <65) Performance status (2 vs. 0/1) Disease stage (IV vs. III) Measurable disease (Y vs. N) Treatment (cisplatin vs. carboplatin) Tumor necrosis (Y vs. N) Stromal sclerosis (Y vs. N)
0.85 1.40 1.41 0.96 1.26
0.53–1.34 0.85–2.30 0.89–2.21 0.59–1.56 0.79–2.03
0.48 0.18 0.14 0.87 0.33
0.32 1.66
0.14–0.72 0.99–2.79
0.006 0.06
3.0 1.6 1.8
1.7–8.6 0.9–2.8 1.0–3.5
0.0001 0.09 0.07
CA-125 1 month after 2nd cycle: >100 vs. ≤35 u/ml 36–99 vs. ≤35 u/ml >100 vs. 36–99 u/ml
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their current treatment program (e.g., carboplatin + paclitaxel); or (b) to receive an alternative hypothesized “non-cross resistant” chemotherapy strategy. The endpoint of the trial would be both time to disease progression and, most importantly, overall survival. The goal of the study would be to determine if alternating treatment early in a patient whose tumor had demonstrated only modest sensitivity to platinum– taxane chemotherapy would favorably impact outcome. Unfortunately, the current difficulty with initiating such a trial is the absence of candidate chemotherapy programs that have been shown to possess anything beyond a “modest” level of activity in platinum–taxane resistant ovarian cancer [14]. Thus, while the study concept may be of considerable interest for future use, its current relevance is quite limited. Finally, it is appropriate to inquire as to how oncologists may utilize this information to assist them in their routine clinical practice. As there are currently no data to suggest that modifying treatment based on the absolute level, or change in the serum CA-125 from baseline, impacts outcome (except, unfortunately, to document disease progression), it would be inappropriate to suggest that a treating oncologist should alter therapy based solely on these laboratory values. However, if there are other reasons to consider making a major modification in the treatment strategy, specifically excessive toxicity (e.g., development of neuropathy, intense emesis despite aggressive anti-emetic treatment), a slow decline in the CA-125 antigen or continued elevation >35 u/ml may be reasonably used to support this decision. Conversely, for a patient with a similar disquieting side effect profile who has experienced an excellent decline in the serum CA-125 level, it may be appropriate to counsel the individual to consider continuing treatment, perhaps with substantial modifications of the current regimen (e.g., substitution of taxotere for paclitaxel; use of lower-dose weekly carboplatin) [15,16]. Again, while there are currently no prospective randomized phase 3 trial data to document the benefits, or harm, associated with altering treatment following two cycles of chemotherapy based on changes in the serum CA-125 level (except for documented disease progression), very carefully considered use of this clinical feature may assist in individual patient management. Acknowledgment This research was supported in part by NCI grant CA38926.
References [1] Covens A, Carey M, Bryson P, Verma S, Fung MFK, Johnston M. Systemic review of first-line chemotherapy for newly diagnosed postoperative patients with stage II, III, or IV epithelial ovarian cancer. Gynecol Oncol 2002;85:71–80. [2] Markman M. Optimizing primary chemotherapy in ovarian cancer. Hematol/Oncol Clin North Am 2003;17:957–68. [3] Markman M. CA-125: an evolving role in the management of ovarian cancer. J Clin Oncol 1996;14:1411–2. [4] Tuxen MK, Soletormos G, Dombernowsky P. Tumor markers in the management of patients with ovarian cancer. Cancer Treat Rev 1995;21: 215–45. [5] Cooper BC, Sood AK, Davis CS, Ritchie JM, Sorosky JI, Anderson B, et al. Preoperative CA 125 levels: an independent prognostic factor for epithelial ovarian cancer. Obstet Gynecol 2002;100:59–64. [6] Rustin GJS, Gennings JN, Nelstrop AE, Covarrubias H, Lambert HE, Bagshawe KD. Use of CA-125 to predict survival of patients with ovarian carcinoma. J Clin Oncol 1989;7:1667–71. [7] Koper NP, Massuger LFAG, Thomas CMG, Kiemeney LALM, Schijf CPT, Beex LVAM, et al. Prognostic value of serial CA 125 measurements during chemotherapy for patients with advanced ovarian cancer. Int J Gynecol Cancer 1997;7:127–33. [8] Mogensen O. Prognostic value of CA 125 in advanced ovarian cancer. Gynecol Oncol 1992;44:207–12. [9] Latimer JA, Beng CG, Davy MLJ. For stage III epithelial ovarian cancer the initial level of expression of CA 125 does not correlate with survival in women who respond to treatment. Int J Gynecol Cancer 1996;6:380–4. [10] Peters-Engl C, Obermair A, Heinzl H, Buxbaum P, Sevelda P, Medl M. CA 125 regression after two completed cycles of chemotherapy: lack of prediction for long-term survival in patients with advanced ovarian cancer. Br J Cancer 1999;81:662–6. [11] Frasci G, Conforti S, Zullo F, Mastrantonio P, Comella G, Comella P, et al. A risk model for ovarian carcinoma patients using CA 125. Cancer 1996;77:1122–30. [12] van Dalen A, Favier J, Burges A, Hasholzner U, de Bruijn HWA, DoblerGirdziunaiti D, et al. Prognostic significance of CA 125 and TPS levels after 3 chemotherapy courses in ovarian cancer patients. Gynecol Oncol 2000;79:444–50. [13] Alberts DS, Green S, Hannigan EV, O'Toole R, Stock-Novack D, Anderson P, et al. Improved therapeutic index of carboplatin plus cyclophosphamide versus cisplatin plus cyclophosphamide: final report by the Southwest Oncology Group of a Phase III randomized trial in stages III and IV ovarian cancer. J Clin Oncol 1992;10:706–17. [14] Markman M, Bookman MA. Second-line treatment of ovarian cancer. The Oncologist 2000;5:26–35. [15] Vasey PA, Jayson GC, Gordon A, Gabra H, Coleman R, Atkinson R, et al. Phase III randomized trial of docetaxel–carboplatin versus paclitaxel– carboplatin as first-line chemotherapy for ovarian carcinoma. J Natl Cancer Inst 2004;96:1682–91. [16] Markman M, Kulp B, Peterson G, Kennedy A. Weekly carboplatin as a strategy to prevent severe treatment-related emesis. Gynecol Oncol 2000;78:265.
Significance of early changes in the serum CA-125 antigen level on overall survival in advanced ovarian cancer Maurie Markman a,⁎, Massimo Federico b , P.Y. Liu c , Edward Hannigan d , David Alberts e a
d
University of Texas M.D. Anderson Cancer Center (Mail Box #121), 1515 Holcombe Boulevard, Houston, TX 77030, USA b Universita of Modena e Reggio Emilia, Modena, Italy c Southwest Oncology Group Statistical Office, Seattle, WA 98104, USA Department of Obstetrics and Gynecology, School of Medicine, University of Texas–Galveston, Galveston, TX 77555-0132, USA e University of Arizona Cancer Center, Tucson, AZ 85721, USA Received 22 November 2005 Available online 3 April 2006
Abstract Objective. The relationship between survival and early changes in the serum level of the CA-125 antigen in patients with advanced ovarian cancer remains poorly defined. Methods. To explore this issue, the serum CA-125 values from 101 patients with advanced ovarian cancer who participated in a Southwest Oncology Group trial (SWOG 8412), which compared the systemic delivery of cisplatin/cyclophosphamide vs. carboplatin/cyclophosphamide (both delivered every 28 days for 6 cycles) in suboptimal residual stage III and IV ovarian cancer, were evaluated. All patients in this analysis had CA-125 values available for at least 8 weeks following initiation of chemotherapy. Cox proportional hazards regression was used in multivariate analysis to determine the prognostic significance of the CA-125 concentration. Results. While pretreatment CA-125 values did not correlate with survival, the concentration of this tumor marker 8 weeks after initiation of therapy was a powerful independent prognostic factor. The median survivals for patients (n = 51) with a CA-125 < 35 U/ml, vs. patients (n = 50) with a CA-125 > 35 U/ml, at this time point, were 26 months and 15 months, respectively (P = 0.0001). Further, women with serum CA-125 values <50% of their pretreatment concentration at 8 weeks experienced a median survival of 21 months, compared to only 10 months for individuals with tumor marker levels >50% of their baseline value (P = 0.0003). Conclusion. Reduction in the serum CA-125 concentration over the initial two cycles of platinum-based chemotherapy is a powerful independent predictor of survival for patients with suboptimal stage III or IV ovarian cancer. Patients without significant declines in CA-125 after two cycles of platinum-based chemotherapy have a particularly poor prognosis. © 2006 Elsevier Inc. All rights reserved. Keywords: Ovarian cancer; Platinum chemotherapy; Serum CA-125 antigen
Currently, the majority of women with advanced ovarian cancer achieve some level of clinical benefit associated with the administration of cytotoxic chemotherapy [1,2]. However, while the overall median survival of patients with the disease has unquestionably improved with the introduction of platinumbased treatment programs, there remains rather remarkable variability in the outcome of individuals with apparently similar tumor grades, morphology, and volume of disease at the initiation of primary anti-neoplastic drug therapy. Unfortunately, ⁎ Corresponding author. Fax: +1 713 563 9586. E-mail address: [email protected] (M. Markman). 0090-8258/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2006.02.024
there are no unique clinical characteristics at initial presentation or known molecular abnormalities that are currently able to clearly define the impact of the primary cytotoxic drug therapy program on an individual patient's survival. Measurement of the serum level of the CA-125 antigen has become a standard component of routine management of women with advanced ovarian cancer [2]. The ease of use of this important laboratory test leads to the obvious question of whether the baseline CA-125 determination, or the subsequent rate of change in the antigen level following several treatment cycles, can provide a reliable early indication of the ultimate effectiveness of cytotoxic drug therapy [3–12].
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M. Markman et al. / Gynecologic Oncology 103 (2006) 195–198
The availability of both sequential serum CA-125 levels, and long-term survival data, for patients who participated in a previously reported Southwest Oncology Group (SWOG) randomized phase 3 trial which compared a cisplatin– cyclophosphamide to a carboplatin–cyclophosphamide regimen as primary treatment of “suboptimal” residual stage III and stage IV ovarian cancer, provides an important opportunity to explore this highly clinically relevant issue [13]. Reported here are the results of this evaluation. Methods and materials Patient population The data used in this analysis were generated from an examination of a subgroup of patients who participated in a SWOG randomized phase 3 trial (SWOG 8412) which compared the systemic delivery of cisplatin (100 mg/m2) plus cyclophosphamide (600 mg/m2) to carboplatin (300 mg/m2) plus cyclophosphamide (600 mg/m2) as primary chemotherapy of suboptimal residual stage III or stage IV ovarian cancer [13]. Both treatment programs were delivered on an every 28-day schedule for six cycles. In this trial, “suboptimal residual” stage III disease was defined as the presence of at least one tumor mass >2 cm in diameter remaining within the peritoneal cavity following initial cytoreductive surgery. Details regarding the study design, entry criteria, statistical analysis, and outcome have previously been published [13]. The aim of this phase 3 trial was to examine the equivalence of the two treatment options as primary chemotherapy in advanced ovarian cancer and to confirm the more favorable toxicity profile associated with the carboplatinbased regimen. Both of these objectives were accomplished through the conduct of the trial. The clinical and pathologic response rates, and overall median survivals (17 months and 20 months for the cisplatin and carboplatinbased regimens, respectively; P = 0.88), were not different between the study arms [13]. The principal evaluable population (n = 101) for the current analysis included all individuals who participated in this SWOG trial (total eligible patients sample size: n = 291) for whom baseline serum CA levels were available, as well as values for a minimum of 8 weeks after the initiation of chemotherapy.
Statistical considerations Variables examined in this analysis included the impact on overall survival associated with the following: (a) baseline serum CA-125 level at the initiation of chemotherapy; (b) absolute serum CA-125 level 1 month after the first cycle of chemotherapy; (c) absolute serum CA-125 level 1 month after the second cycle of chemotherapy; (d) change from baseline in serum CA-125 level 1 month after the first cycle of chemotherapy; and (e) change from baseline in serum CA-125 level 1 month after second cycle of chemotherapy. Since treatments were given in 28-day cycles, 1 month after the first and second cycles is equivalent to 4- and 8-weeks post-study entry. Based on previously reported studies, the current patient population was divided into the following discrete “CA-125 antigen” subgroups for (a) baseline determination and absolute levels after the first and second cycle of chemotherapy (≤35 u/ml, vs. >35 to <100 u/ml, vs. ≥100 u/ml); and (b) change from baseline in levels after the first and second cycle of chemotherapy, first as 4 groups (>90% decrease, vs. >50% to 90% decrease, vs. 0% to 50% decrease vs. any increased value), then as 2 groups (>90% decrease vs. ≤90% decrease; or >50% decrease vs. ≤50% decrease). Both univariate survival analyses with CA-125 as categorized above as the only variable and multivariate Cox model analyses were conducted. The Cox model analyses included age (<65 vs. ≥65), performance status (0–1 vs. 2), disease stage (III vs. IV), size of residual disease (measurable vs. non-measurable), and presence/absence of tumor necrosis and stromal sclerosis. To reduce the chance of false-positive findings due to the multiplicity of analyses conducted, P values <0.005 were considered statistically significant.
Results To determine whether the patients included in this analysis, for whom both baseline and follow-up (minimum of 8 weeks) serum CA-125 values were available, differed from other women who participated in this trial and who also survived for a minimum of 8 weeks, but for whom these serum CA-125 levels were incomplete, we examined a number of clinical characteristics of the two populations (Table 1). With the exception of a difference in the proportion of patients who received the cisplatin-based vs. the carboplatin-based program (Table 1), the two groups were quite similar in all other clinical features evaluated, suggesting the outcome of the subgroup analyzed in this report is likely to be representative of the entire study population with the exception of those who did not survive past 8 weeks (8/291 = 3%). Again, as there was no difference in survival between the cisplatin and carboplatin-treated patient populations [13], it would not be expected that an imbalance between the therapies received by the groups in this analysis should influence its outcome. The impact on survival of the various serum CA-125 subgroups, at baseline and at 1 month following the 1st and 2nd chemotherapy cycles, is demonstrated in Tables 2 and 3. Table 4 shows that, compared to the absolute value approach, little was gained by combining the absolute and percent change approaches. A Cox Model analysis including a number of known important variables in advanced ovarian cancer demonstrates the major influence on survival associated with the serum CA-125 antigen level 1 month after the 2nd chemotherapy cycle (Table 5). Discussion Several reasonable conclusions can be drawn from the results of the current analysis of advanced ovarian cancer patients whose serum CA-125 antigen levels were prospectively followed for several months after the initiation of carboplatin + cyclophosphamide or cisplatin + cyclophosphamide chemotherapy. First, the clinical features of the 101 women included in the evaluation appear to be similar to that of the entire study group, suggesting that the results are representative of what would have been found if all patients surviving past 8 weeks had their CA-125 antigen levels available, and these data would have been included in this analysis. A future study, Table 1 Characteristics of patients with serum CA-125 values available at baseline and for ≥8 weeks following initiation of treatment versus patients whose CA-125 levels were incomplete (all patients survived for ≥8 weeks) With CA-125 (n = 101) Without CA-125 (n = 182) Age: <65 PS 0–1 Stage III Non-measurable disease Cisplatin arm Median survival
60% 69% 68% 59% 37% 20 months
56% 68% 73% 55% 56% 19 months (P = 0.83)
M. Markman et al. / Gynecologic Oncology 103 (2006) 195–198 Table 2 Median survival (Months) based on baseline serum CA-125 and absolute serum CA-125 levels 1 month following both 1st and 2nd chemotherapy cycles
≤35 u/ml >35– <100 u/ml ≥100 u/ml
Baseline
1 month after 1st treatment
1 month after 2nd treatment
20 (n = 7) 21 (n = 19) 20 (n = 106) (P = 0.77)
23 (n = 39) 20 (n = 24) 16 (n = 43) (P = 0.11)
26 (n = 51) 20 (n = 20) 14 (n = 30) (P < 0.0001) 26 (n = 51) 15 (n = 50) (P = 0.0001)
≤35 u/ml >35 u/ml
examining a larger sample size and including patients treated with the current chemotherapy “standard” of a platinum agent plus a taxane, will be required to confirm the general findings of this report [1,2]. Second, the absolute baseline level of the serum CA-125 does not appear to be an independent determinant of overall survival, at least within the large group of individuals defined as having “suboptimal” residual stage III or stage IV advanced ovarian cancer. These data are consistent with those of some, but not all other investigators, who have examined this issue. However, our results regarding the lack of major significance for the baseline CA-15 level should not be surprising considering the known marked heterogeneity in the amount of CA-125 produced by individual cancers (as inferred from the serum CA-125 level) with similar tumor volumes (as measured by radiographic or surgical findings). Conversely, clinicians recognize that the finding of relatively modest (<200 u/ml) or very high (>1000 u/ml) levels of the serum CA-125 is a rather poor predictor of the amount of tumor bulk documented following subsequent non-invasive (radiographic) or invasive (surgical) evaluation. In addition, there is no compelling biological reason to suspect that the absolute level of the baseline serum CA-125 should be predictive of either the extent of inherent chemoresistance, or the subsequent development of such resistance, within a given cancer cell population. An ovarian cancer with a low serum antigen level may possess a population of cells with a Table 3 Median survival (Months) based on percentage change from baseline in serum CA-125 1 month following both 1st and 2nd chemotherapy cycles
>90% decrease >50–90% decrease 0–50% decrease Increase (any level from baseline) >90% decrease ≤90% decrease >50% decrease ≤50% decrease
1 month after 1st treatment
1 month after 2nd treatment
33 (n = 24) 19 (n = 39) 14 (n = 16) 9 (n = 9)
21 (n = 39) 20 (n = 29) 12 (n = 6) 9 (n = 11)
(P = 0.19) 33 (n = 24) 17 (n = 64) (P = 0.05)
(P = 0.002)
21 (n = 68) 10 (n = 17) (P = 0.0003)
197
Table 4 Median survival (months) based on combining “best” and “worst” serum CA125 parameters 1 month after 2nd chemotherapy cycle 1 month after 2nd treatment ≤35 u/ml + (>50% decrease) Other >100 u/ml + (≤50% decrease or increase)
26 (n = 51) 17 (n = 33) 9 (n = 13) (P < 0.0001)
high level of resistance, while another tumor whose cells produce large quantities of CA-125 may be exquisitely sensitive to cytotoxic drug therapy. Third, the modest impact on survival associated with the change in serum CA-125 after cycle 1, followed by a highly statistically significant relationship observed between this laboratory value and survival after cycle 2, is consistent with the argument that several treatment courses are required to document, at the clinical level, the net effect of the cytotoxic agents at the molecular and cellular levels. Whether the importance of this time interval is related more to the number of treatment cycles administered (2 vs. 1), or the fact 2 months have passed permitting the removal of dead or dying tumor cells, or a combination of these factors, is an unanswered (but most interesting) question. Finally, it is important to ask if there are potential clinical trial or disease management implications of this analysis. Before addressing this question, it is relevant to again note the findings must be confirmed (or refuted) in a second study, hopefully with all patients having their serum CA-125 levels prospectively evaluated in a manner similar to that reported here. In the absence of such confirmation, any conclusion regarding a possible impact of these treatment-associated changes in the serum CA-125 antigen must be considered to be very preliminary. However, assuming such confirmation, a highly provocative suggestion for a future randomized phase 3 trial would be to prospectively follow a group of patients treated with “standard” platinum–taxane chemotherapy and subsequently randomize those individuals whose serum CA-125 was >35 u/ml 1 month following the 2nd chemotherapy cycle either to (a) continue with Table 5 Cox model analysis Variable
Hazard ratio
95% Confidence interval
P value
Age (≥65 vs. <65) Performance status (2 vs. 0/1) Disease stage (IV vs. III) Measurable disease (Y vs. N) Treatment (cisplatin vs. carboplatin) Tumor necrosis (Y vs. N) Stromal sclerosis (Y vs. N)
0.85 1.40 1.41 0.96 1.26
0.53–1.34 0.85–2.30 0.89–2.21 0.59–1.56 0.79–2.03
0.48 0.18 0.14 0.87 0.33
0.32 1.66
0.14–0.72 0.99–2.79
0.006 0.06
3.0 1.6 1.8
1.7–8.6 0.9–2.8 1.0–3.5
0.0001 0.09 0.07
CA-125 1 month after 2nd cycle: >100 vs. ≤35 u/ml 36–99 vs. ≤35 u/ml >100 vs. 36–99 u/ml
198
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their current treatment program (e.g., carboplatin + paclitaxel); or (b) to receive an alternative hypothesized “non-cross resistant” chemotherapy strategy. The endpoint of the trial would be both time to disease progression and, most importantly, overall survival. The goal of the study would be to determine if alternating treatment early in a patient whose tumor had demonstrated only modest sensitivity to platinum– taxane chemotherapy would favorably impact outcome. Unfortunately, the current difficulty with initiating such a trial is the absence of candidate chemotherapy programs that have been shown to possess anything beyond a “modest” level of activity in platinum–taxane resistant ovarian cancer [14]. Thus, while the study concept may be of considerable interest for future use, its current relevance is quite limited. Finally, it is appropriate to inquire as to how oncologists may utilize this information to assist them in their routine clinical practice. As there are currently no data to suggest that modifying treatment based on the absolute level, or change in the serum CA-125 from baseline, impacts outcome (except, unfortunately, to document disease progression), it would be inappropriate to suggest that a treating oncologist should alter therapy based solely on these laboratory values. However, if there are other reasons to consider making a major modification in the treatment strategy, specifically excessive toxicity (e.g., development of neuropathy, intense emesis despite aggressive anti-emetic treatment), a slow decline in the CA-125 antigen or continued elevation >35 u/ml may be reasonably used to support this decision. Conversely, for a patient with a similar disquieting side effect profile who has experienced an excellent decline in the serum CA-125 level, it may be appropriate to counsel the individual to consider continuing treatment, perhaps with substantial modifications of the current regimen (e.g., substitution of taxotere for paclitaxel; use of lower-dose weekly carboplatin) [15,16]. Again, while there are currently no prospective randomized phase 3 trial data to document the benefits, or harm, associated with altering treatment following two cycles of chemotherapy based on changes in the serum CA-125 level (except for documented disease progression), very carefully considered use of this clinical feature may assist in individual patient management. Acknowledgment This research was supported in part by NCI grant CA38926.
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