the oncology report (fall 2006) :: gynecologic malignancies

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Gynecologic Malignancies Fall 2006 / THE ONCOLOGY REPORT 61

Gynecologic MalignanciesCommentary by

J. Tate Thigpen, MD

I n the current National Com-prehensive Cancer Network (NCCN) guidelines, chemother-

apy is almost an afterthought in the treatment of women with carcino-sarcoma. However, a study showing a reduction in recurrence rates and mortality could change that.

Chemotherapy is superior to radiotherapy for carcinosarcoma of the uterusStudy results could have “significant impact” on when and where chemotherapy is used

significant impact in perhaps alter-ing the choice of when and where chemotherapy is used in a number of stages of disease, especially ear-ly-stage tumors that are optimally debulked.

In a study of 206 women, the probability of relapse at 5 years was 58% in patients who under-went whole abdominal irradiation (WAI) and 52% in those who re-ceived chemotherapy. The recur-rence rate in the chemotherapy group was 18% lower than in the radiotherapy group, which was not statistically significant. The death rate was 53% in patients in the chemotherapy arm of the trial and 63% in those in the radiotherapy arm, reported Aaron Wolfson, MD, professor of radiation oncology at the University of Miami.

T he probability of survival at 5 years was 34% in patients who underwent WAI and

47% in patients who received che-motherapy. The adjusted death rate was 30% lower with chemotherapy, which approached statistical signifi-cance for overall survival, Dr. Wolf-son said.

The study included women who had stages I–IV carcinosarcoma of the uterus, had undergone surgi-cal staging by means of hysterec-tomy, and had less than 1 cm of residual tumor. Patients were ran-domized to one of two treatment groups. Subjects in the first group underwent WAI at a total dose of 30 Gy to the abdomen and 50 Gy to the pelvis, and patients in the second group received 3 cycles of cisplatin (20 mg/m2/d) and 3 cycles of ifosfamide (Ifex; 1.5 mg/m2/d). The chemotherapy group

also received a loading dose of mesna (Mesnex; 120 mg/m2/d) and a daily regimen of mesna (1.5 g/m2/d) every 3 weeks in combina-tion with the 3 cycles of cisplatin and ifosfamide.

A lthough adjuvant chemo-therapy was more effective than radiotherapy, Dr. Wolf-

son concluded that death most of-ten occurred because of disease pro-gression (53% in the radiotherapy group and 44% in the chemotherapy group). He therefore proposed that future clinical trials include vaginal brachytherapy and additional cycles

of chemotherapy to achieve control of the disease.

The overall poor survival of pa-tients with carcinosarcoma of the uterus calls for further improve-ment of treatment, perhaps by add-ing brachytherapy to chemother-apy, adding chemotherapy cycles, or changing the agents utilized to more contemporary chemothera-peutic agents.

Wolfson AH, Brady MF, Rocereto TF, et al. A Gynecologic Oncology Group random-ized trial of whole abdominal irradiation vs cisplatin-ifosfamide + mesna in optimally debulked stage I–IV carcinosarcoma of the uterus. abstract 5001

Optimally debulked, early-stage tumors may respond to changes in chemotherapy cycles

and agents.

INDEX

CA-125 antigen levels, 65Carboplatin, 62, 63Cisplatin, 61Clinical trials

GOG 0182-ICON5, 62GOG 172, 63GOG 178, 65SWOG 9701, 65

Gemcitabine (Gemzar), 62Ifosfamide (Ifex), 61Irradiation, whole abdominal, 61Lymphadenectomy, 64Mesna (Mesnex), 61Paclitaxel, 62, 63, 65Pegylated liposomal doxorubicin

(Doxil), 62Quality-of-life assessment, 63Topotecan (Hycamtin), 62

Chemotherapy did not defi-nitely improve survival over ra-diotherapy, but the trends were impressive. The study could have

For more meeting reports, visit www.OncologyReport.com© 2006 Elsevier Inc. All rights reserved.

Survival for patients with carcinosarcomas of the uterus is considerably worse than that for patients with endometrial carcinomas. For stage I le-sions, the 5-year mortality is 50%; for all other stages, less than 10% will survive for 5 years. In light of these poor survival rates, the GOG sought to evaluate two different approaches to adjuvant therapy: whole abdominal radiation therapy versus chemotherapy consisting of ifosfamide (Ifex) plus cisplatin. Over 13 years, the GOG was able to accrue sufficient patients to show both superior progression-free and overall survival rates for those patients who received the chemotherapy as opposed to the radiation therapy. These results mark a paradigmatic change in the approach to pa-tients with resected carcinosarcomas from regarding radiation therapy as the standard approach to adjuvant therapy to employing adjuvant chemo-therapy in these patients.

Even more enticing is the fact that the GOG recently reported the results of a trial that showed superior survival for patients receiving ifos-famide plus paclitaxel compared with ifosfamide alone. This study is the first to show an improved survival for combination chemotherapy. A logical extension of these results would be to use the ifosfamide/paclitaxel combi-nation as the standard adjuvant chemotherapy for patients with completely resected uterine carcinosarcomas. These recommendations come on the heels of a recent trial in endometrial carcinoma, which showed that adju-vant chemotherapy for patients with stages III–IVA small-volume residual disease is superior to the previous commonly used adjuvant radiation therapy. Thus, the role of chemotherapy continues to expand for patients with uterine cancers.

—J. Tate Thigpen, MD

Comment

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62 THE ONCOLOGY REPORT / Fall 2006 Gynecologic Malignancies

T he addition of a third drug to standard chemotherapy with a carboplatin-combina-

tion regimen does not appear to im-prove clinical outcomes in patients with advanced ovarian cancer, re-sults of a five-arm randomized clini-cal trial (GOG0182-ICON5) dem-onstrate. Neither progression-free (PFS) nor overall survival improved when a third cytotoxic drug was added to carboplatin and paclitax-el. Three-drug regimens resulted in more hematologic toxicity, although the toxicity was manageable.

“After more than 25 years, plati-num—and particularly carbopla-tin—remains the dominant agent for treatment of advanced ovar-ian cancer, and this has an impact on the evaluation of new agents and potential nonplatinum alter-natives,” concluded Michael A. Bookman, MD, a medical oncolo-gist from Fox Chase Cancer Center in Philadelphia.

Although carboplatin-paclitaxel chemotherapy has emerged as a global standard for epithelial ovar-ian cancer and primary peritoneal cancer, most patients eventually recur with resistant disease. Inves-tigators in the Gynecologic Cancer

Platinum-taxane combination still standard for advanced ovarian cancerAdding a third drug increases toxicity with no apparent improvement in efficacy

Intergroup (GCIG) coordinated this trial through the Gynecologic Oncology Group (GOG) to evalu-ate the effects of adding topotecan (Hycamtin), gemcitabine (Gemzar), or pegylated liposomal doxorubicin (Doxil) to carboplatin-paclitaxel chemotherapy.

“These three drugs clearly have biologic interactions with platinum compounds and can result in en-hanced toxicity to the tumor, as well as the risk of increased toxicity to the host,” said Dr. Bookman. “What was not established was whether there would be any therapeutic advantage to incorporating these newer agents with this particular carboplatin-pacli-taxel combination.”

T he primary objective of the study was to compare the ef-ficacy of each experimental

arm with the control arm of carbo-platin and paclitaxel. Efficacy was defined by overall survival and PFS. A single interim analysis of PFS pro-vided the basis for selecting prom-ising regimens for full accrual. The study protocol did not allow initial use of hematopoietic growth fac-tors. Dose modifications were based on nadir and delayed recovery of

hematologic cell counts. Second-look surgery was not permitted, nor was maintenance or consolidation treatment.

Patients were randomized to five different treatment arms, includ-ing the reference arm. Investigators enrolled 4,312 patients, who were well matched by treatment group for age (58–59 years), stage IV dis-ease (13%–16%), primary peritone-al cancer (13%–15%), and subopti-mal debulking surgery (about 30%). Within the United States, the rate of accrual exceeded predictions, with more than 6% of all women with newly diagnosed advanced-stage disease being enrolled.

The planned interim analysis was triggered by 240 events in the ref-erence arm, and the analysis led to discontinuation of patient accrual. At that point, approximately 80% of patients had completed all 8 cy-cles of therapy.

The median PFS ranged between 15.3 and 16.4 months and did not differ significantly among the treat-ment groups. Median overall sur-vival, the primary outcome, also did not differ, ranging between 39.1 and 42.8 months. In addition, anal-ysis of survival by extent of residual disease failed to reveal an advantage of any experimental regimen over the standard regimen.

R esults of an Italian study cor-roborated the GCIG conclu-sion that adding topotecan

does not improve clinical outcomes in advanced ovarian cancer. A prior study had given some reason for optimism that adding topotecan to carboplatin-paclitaxel might im-prove efficacy (Bolis G et al. Gyne-col Oncol 2001;81:331–333).

Investigators in the multicenter trial randomized 326 patients (suboptimally debulked) to receive carboplatin (area under the curve [AUC] 5) plus paclitaxel (175 mg/m2) or the same doses of carbopla-tin and paclitaxel plus topotecan (1 mg/m2 days 1–3). Regimens were repeated every 21 days for a maximum of 6 cycles.

When the trial ended, median PFS was about 70 weeks in each treatment arm. The overall response rate was nearly 68% in each treat-ment arm, including complete re-sponses in 41% in each arm. About 90% of patients in each treatment group suffered adverse events, and approximately 88% of events were considered possibly related to treat-ment. No patient in either group discontinued therapy because of ad-verse events.

“This study failed to demon-strate that the addition of a third chemotherapeutic agent to standard first-line paclitaxel-carboplatin can increase the secondary endpoints

Bookman, Scarfone, and colleagues present the results of studies evaluat-ing the addition of a third cytotoxic agent to the standard paclitaxel/carbopla-tin chemotherapy for advanced ovarian carcinoma. The GOG0182-ICON5 study is the largest ovarian carcinoma study ever conducted, including 4,312 patients randomized to one of five regimens: a control arm (paclitaxel/carboplatin), two triplets (paclitaxel/carboplatin plus either gemcitabine [Gemzar] or pegylated liposomal doxorubicin [Doxil]), and two sequential doublets (paclitaxel/carboplatin following either topotecan [Hycamtin]/car-boplatin or gemcitabine/carboplatin). The study showed no advantage for any of the four experimental arms over the control of paclitaxel/carboplatin. Results of an Italian study corroborated these findings, indicating that adding a third cytotoxic agent (topotecan) failed to show any advantage.

For practical purposes, these results bring to a close attempts to improve results with the addition of more cytotoxic agents to paclitaxel/carboplatin. Efforts should now turn to more targeted agents in combination with stan-dard paclitaxel/carboplatin. One such ongoing trial is studying the addition of bevacizumab (Avastin) to paclitaxel/carboplatin. Other agents of potential future interest include cetuximab (Erbitux) and TLK 286.


Commentof objective response rate or time to disease progression,” concluded Giovanna Scarfone, MD, a gyneco-logic oncologist from the University of Milan in Italy. “Longer follow-up and analysis of mature data are needed to show whether a triple-drug combination can increase the primary endpoint of overall survival and 3-year survival compared with standard paclitaxel-carboplatin.”

Bookman MA. GOG0182-ICON5: 5-arm phase III randomized trial of paclitaxel and carboplatin vs combinations with gem-citabine, PEG-liposomal doxorubicin, or topotecan in patients with advanced-stage epithelial ovarian or primary peritoneal carcinoma. abstract 5002

Scarfone G, Scambia G, Raspagliesi F, et al. A multicenter, randomized, phase III study comparing paclitaxel/carboplatin versus topotecan/paclitaxel/carboplatin in patients with stage III (residual tumor > 1 cm after primary surgery) and IV ovarian cancer. abstract 5003

After more than 25 years, carboplatin

remains the dominant agent for treating advanced ovarian

cancer.


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All-intraperitoneal chemotherapy regimen shows promise for ovarian cancerA threshold concentration of paclitaxel was maintained longer than with IV dosing

QOL scores may predict risk for serious chemotherapy toxicityOvarian cancer patients with poorest baseline QOL least likely to complete treatment

B aseline quality-of-life (QOL) assessment may help to identify patients with ovar-

ian cancer who have an increased risk of serious toxicities associated with intraperitoneal (IP) chemo-therapy. Patients with the poorest baseline QOL were the least likely to complete the combination in-travenous (IV)-IP chemotherapy regimen used in the Gynecologic

Oncology Group 172 study (Arm-strong DK et al. N Engl J Med 2006;354:34–43). The findings have implications for development of therapeutic regimens to treat ovarian cancer.

In the planning of future tri-als, patient-reported outcomes, such as QOL and symptoms mea-sures, can be useful in treatment planning, decision making, and

supportive care strategies. Con-tinued QOL evaluation is critical to weigh considerable treatment benefits and toxicities and to as-sist in establishing guidelines and safety standards to buffer untow-ard effects.

QOL assessment was includ-ed in the overall study design of GOG 172, a randomized compar-ison of IV versus IP chemotherapy

for patients with optimally de-bulked ovarian cancer. Patient-re-ported QOL, as evaluated by the Functional Assessment of Cancer Therapy–Ovarian (FACT–O) in-strument, showed significantly greater disruption in QOL dur-ing treatment and 3–6 weeks af-terward in women who received IP chemotherapy. However, the difference had disappeared by 12

A n all-intraperitoneal (all-IP) chemotherapy regimen for ovarian cancer has demon-

strated a favorable pharmacokinetic profile and a suggestion of reduced toxicity compared with a combined intravenous (IV)-IP regimen, which was employed in the Gynecologic Oncology Group (GOG) 172 study (Armstrong DK et al. N Engl J Med 2006;354:34–43).

“This study finds our all-IP regi-men to be both feasible and toler-able,” said Carolyn N. Krasner, MD, instructor in medicine from Harvard Medical School in Boston. “The preliminary toxicity analysis is encouraging. Very preliminarily, more patients are able to complete 6 cycles in our study than in GOG 172. The efficacy analysis awaits completion of the trial.”

The regimen is undergoing clini-cal evaluation in a phase II study involving women with newly di-agnosed ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. After optimal surgical de-bulking, patients received carbopla-tin (area under the curve [AUC] 6) and paclitaxel (60 mg/m2). During the first cycle, the drugs were IV; in cycles 2–6, they were IP.

The principal objectives of the pharmacokinetic study were to determine the feasibility of an all-IP regimen, ensure adequacy of systemic drug levels, and examine systemic drug levels achieved with IV versus IP dosing in cycle 1 ver-

sus cycle 2 and IP levels over time (cycle 2 vs cycle 6).

A ssessment of paclitaxel’s pharmacokinetic param-eters showed that IV dosing

in cycle 1 led to a much higher Cmax (2,044 nM) compared with IP ad-ministration in cycles 2 (72 nM) and 6 (69 nM), resulting in a lower AUC for IP dosing. However, the time plasma concentrations exceeded 50 nM, a threshold previously shown to correlate with clinical toxicity, and in vitro antiproliferative effects were similar for both approaches.

The derived pharmacokinetic pa-rameters for free platinum showed a higher Cmax with IV (114 nM) than with IP administration (80 nM cycle 2; 81 nM cycle 6). The AUC was higher than targeted with both IV (9.3 mg-min/mL) and IP admin-istration (125 mg-min/mL).

The all-IP regimen compares favorably with other paclitaxel regimens with respect to systemic exposure to the drug, defined by the time that drug concentration exceeded 50 nM. As derived from the work of Gianni et al (J Clin On-col 1995;13:180–190), standard IV infusion of paclitaxel (175 mg/m2) over 3 hours results in a time > 50 nM of 25 hours. The GOG 172 IV-IP regimen results in a time > 50 nM of 44 hours. The all-IP regimen described by Dr. Krasner resulted in a time > 50 nM of 33 hours.

The all-IP regimen also appears

to have a favorable toxicity profile compared with the GOG 172 regi-men. In GOG 172, which involved 205 patients, rates of grade 3/4 ad-verse events included 46% for gas-trointestinal, 11% for pain, 27% for metabolic, and 76% for leukopenia. In contrast, each of those adverse events occurred at grade 3/4 severity in 4% of patients with the all-IP regi-men. Of 28 evaluable patients, none treated with the all-IP regimen devel-

oped grade 3/4 thrombocytopenia, neurotoxicity, or fatigue, all of which occurred in GOG 172. Every patient in GOG 172 had grade 2 alopecia, whereas no patient did so following treatment with the all-IP regimen.

Krasner CN, Seiden MV, Fuller AF, et al. Pharmacokinetic analysis of an all-intra-peritoneal carboplatin and paclitaxel regi-men in ovarian cancer patients demonstrates favorable systemic bioavailability of both agents. abstract 5008

Although intraperitoneal chemotherapy had been declared the standard of care for patients with small-volume residual ovarian carcinoma, it has been linked to substantial toxicity. Questions as to whether quality of life is impacted by this toxicity and whether dose reductions or modified regimens negatively impact the efficacy of intraperitoneal chemotherapy were ad-dressed by two studies.

Krasner et al approached the problem of intraperitoneal chemotherapy by evaluating a carboplatin-based, rather than a cisplatin-based, regimen. An effec-tive pattern of systemic exposure for both agents was seen with a schedule of weekly paclitaxel plus every-3-week carboplatin. Wenzel et al presented results of a quality-of-life (QOL) study of the patients on the third major GOG study of intraperitoneal therapy. These data suggest that QOL scores on the FACT–Ovarian can predict the likelihood of any given patient tolerating the intraperito-neal regimen. Patients in the lowest of four quartiles were the least likely to toler-ate intraperitoneal therapy. Selecting only those patients in the higher quartiles could markedly improve tolerance to such treatment.

These two studies represent further building blocks in the design of tolerable intraperitoneal regimens that maintain the efficacy advantage. Until ongoing study results are available, intraperitoneal chemotherapy should be used outside clinical trials only after a thorough discussion of the poten-tial toxicities of the therapy with patients, and one of the tested regimens should be employed to ensure that efficacy is maintained.


Comment


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64 THE ONCOLOGY REPORT / Fall 2006 Gynecologic Malignancies

months. Consistent with the QOL data, significantly more grade 3+ toxicity occurred in patients treated with IP chemotherapy, specifically fatigue, neurotoxicity, and abdominal pain.

Substantially fewer patients in the IP chemotherapy arm of GOG 172 completed the planned 6 cycles of therapy. The difference in com-pletion rates emerged during the first cycle of therapy and increased with subsequent cycles; only 42% of patients in the IP arm completed

tients with higher FACT–O scores were significantly more likely to complete more IP cycles (odds ra-tio [OR], 1.27; P < 0.001) and to tolerate 6 cycles of IP therapy (OR, 1.31; P = 0.002). Moreover, pa-tients who had FACT–O scores ≤ 92 were significantly more likely not to complete 6 cycles of IP chemother-apy than were patients with higher scores (OR, 4.46; P < 0.001).

Furthermore, comparison of QOL and toxicity showed that patients with higher baseline FACT–O scores

all 6 cycles of therapy, compared with 83% of patients who received IV chemotherapy.

I n addition to assessment of QOL by the FACT–O scale, neurotox-icity and abdominal discomfort

were assessed by FACT subscales, which included items pertinent to the two types of adverse events. Of 205 patients randomized to receive IP therapy, 198 completed the base-line QOL assessment.

The analysis showed that pa-

D ata from a large-scale, popu-lation-based retrospective analysis of lymphadenec-

tomy reaffirmed the value of com-prehensive staging and lymph node dissection for women with endome-trioid uterine cancer who are at sig-nificant risk for extrauterine spread, said Thomas Herzog, MD, professor of clinical obstetrics and gynecology at Columbia University in New York.

Lymphadenectomy improves survival for high-risk women with endometrioid uterine cancerLittle benefit, however, is seen in women with stage I disease

enectomy did not confer a survival benefit to patients with stage I en-dometrioid cancer, reported Nita Karnik Lee, MD, clinical instruc-tor in the department of obstetrics and gynecology of Stanford Uni-versity School of Medicine in Palo Alto, California. Although there was a trend toward improved sur-vival in women with stage I grade C disease who underwent lymph-adenectomy (81.7%) versus those who had not (76.5%; P = 0.07), the overall 5-year DSS rate for pa-tients with stage I cancer was simi-lar in the two groups.

T he study evaluated data from the National Cancer Insti-tute’s Surveillance Epidemi-

ology End Results (SEER) database on 39,396 women with endometri-oid uterine cancer who were treated between 1988 and 2001. A total of 27,063 women did not undergo lymphadenectomy, and 20% of these patients had grade I disease. The proportion of patients with stage I cancer with grade I histology or with tumors limited to the endo-metrium was significantly higher in the group that did not have lymph-adenectomy.

Although the study demonstrated the need for comprehensive staging and surgery for most patients with

endometrioid uterine cancer, ques-tions remain. Was the survival bene-fit due to therapeutic lymphadenec-tomy or stage migration? Do these patients have true surgical stage I disease, or are we missing patients who otherwise would be upstaged being missed? Furthermore, while proponents of lymphadenectomy are defining subgroups of patients

who would benefit from wide lymph node dissection, opponents argue that the procedure could ex-pose as many as 85% of patients to unnecessary morbidity and cost, concluded Dr. Herzog.

Karnik Lee N, Wu H, Cheung MK, et al. The impact of lymphadenectomy in women with endometrioid uterine cancer: a study of 39,396 women. abstract 5000

The study by Karnik Lee et al is yet one more attempt to determine whether lymphadenectomy offers patients with endometrial carcinoma a therapeutic benefit. Although the data suggest an advantage for lymphad-enectomy, the nature of the dataset makes it impossible to draw definitive conclusions for three important reasons.

First, the study is not a randomized trial but rather a retrospective re-view of a database; hence, one cannot determine why certain patients un-derwent lymphadenectomy and others did not. Such factors as patient per-formance status may have entered into the decision and biased the results in favor of the lymphadenectomy group.

Second, the fact that a patient has undergone a lymphadenectomy sug-gests that the staging procedure was likely more detailed, and perhaps more accurate, than procedures that do not include a lymphadenectomy. This consideration tends to yield the illusion of improved survival stage for stage in the lymphadenectomy patients, an improvement resulting solely from stage migration.

Third, phase III or randomized trials on lymphadenectomy in breast cancer have shown no benefit for axillary lymphadenectomy. By extension, it seems unlikely that lymphadenectomy in patients with endometrial carci-noma would be associated with a survival advantage.


Comment

were significantly less likely to de-velop severe fatigue (OR, 0.81; P = 0.037) or neurotoxicity (OR, 0.76; P = 0.004). Baseline scores on the FACT–O subscales for neurotoxicity and abdominal discomfort did not correlate with development of grade 3/4 adverse events.

Wenzel LB, Huang HQ, Armstrong DK, et al. Baseline quality of life as a pre-dictor of tolerance to intraperitoneal che-motherapy for advanced epithelial ovar-ian cancer: a Gynecologic Oncology Group study. abstract 5007

Questions about the utility of

lymphadenectomy remain despite improvement

in survival.

For women with grade II or higher disease, there was a marked benefit in 5-year disease-specific survival (DSS) of 8%; for patients with stage III disease, lymphade-nectomy improved the 5-year DSS by 11%; and for patients with stage IV cancer, the procedure was associated with a 25% improve-ment in DSS. However, lymphad-


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M ore may not necessarily mean better with respect to the impact of mainte-

nance chemotherapy on overall sur-vival in ovarian cancer. However, the debate is far from over.

In patients who achieved a clini-cal complete response with primary chemotherapy, 12 months of main-tenance therapy with paclitaxel led to suggestive evidence of superiority over 3 months, but the data did not provide definitive proof. Specifical-ly, an unplanned exploratory analy-sis suggested that more prolonged maintenance therapy may reduce the risk of relapse in patients with pretreatment CA-125 antigen levels < 10 U/mL.

No definitive survival benefit seen with prolonged maintenance paclitaxel Inadequate sample size might have doomed a potential benefit in ovarian cancer

ficient to produce a major favorable impact on survival, with the extent of persistent chemotherapy-sensi-tive cancer, but not when larger tu-mor volumes are present.”

Patients were eligible for the tri-al if they had a histologically con-firmed diagnosis of ovarian cancer or primary peritoneal cancer and had achieved a clinical complete re-sponse with 5 or 6 cycles of primary platinum-paclitaxel chemotherapy. Complete response was defined as a normal CT scan, normal physical examination, CA-125 antigen level ≤ 35 U/mL, and no symptoms sug-gesting active disease.

Patients were randomized to re-ceive 3 versus 12 monthly cycles of paclitaxel (175 mg/m2) administered by 3-hour infusion. Initially, the pri-mary endpoint was progression-free survival (PFS), and the computed sample size was 450 patients. How-ever, the trial ended prematurely when a planned interim analysis showed approximately a 50% im-provement in PFS in favor of 12 cy-cles of paclitaxel (Markman M et al. J Clin Oncol 2003;21:2460–2465).

When the trial ended, too few clinical events had occurred to de-termine whether 12 months of pa-clitaxel maintenance led to better overall survival than did 3 months. With the passage of more time, revisiting the issue of overall sur-vival seems appropriate, added Dr. Markman.

A n updated analysis showed that 12-cycle paclitaxel maintenance therapy re-

sulted in a median PFS of 22 months versus 14 months for 3-

cycle therapy (P = 0.01). Median overall survival for the 12-cycle arm was 53 months, compared with 46 months for the 3-cycle arm (P = 0.27). After adjustment for stratification factors, a hazard ratio of 0.84 emerged in favor of the 12-cycle arm, but the value did not achieve statistical significance (P = 0.30).

“It is unfortunately clear that the total sample size available for evaluation is simply inadequate to make any definitive statements regarding the impact of this man-agement approach on overall sur-vival,” Dr. Markman concluded. The Gynecologic Oncology Group has initiated a prospective clini-

cal evaluation of baseline levels of CA-125 antigen as a predictor of relapse following clinical com-plete remission in ovarian cancer. Earlier this year, Dr. Markman and colleagues published evidence linking higher baseline levels of CA-125 antigen to an increased risk of relapse after complete re-mission in patients with ovarian cancer (Markman M et al. J Clin Oncol 2006;24:1454–1458).

Markman M, Liu P, Wilczynski S, et al. Survival of ovarian cancer patients treat-ed on SWOG9701/GOG178: 12 versus 3 cycles of monthly single-agent paclitaxel (PAC) following attainment of a clinically defined complete response to platinum/PAC. abstract 5005

The first successful attempt at maintaining a complete remission in ovarian cancer was reported at ASCO 2003 and consisted of a study from the SWOG and the GOG evaluating prolonged maintenance therapy with paclitaxel. The initial report of this trial showed a significant reduction in the recurrence rate and a significant prolongation of progression-free sur-vival. This follow-up report confirmed those earlier observations (median progression-free survival, 22 months with 12 cycles and 14 months with 3 cycles) and also presented a first analysis of survival, showing median rates of 53 months with 12 cycles and 46 months with 3 cycles. This differ-ence was not statistically significant, but the analysis was based on only 146 events, not the 190 events required by the protocol design; hence, a final evaluation of survival must await sufficient events to permit a meaningful analysis. An unplanned subset analysis suggested that the patients who ben-efit the most from maintenance paclitaxel are those who experience a drop in the CA-125 level to < 10 U/mL as a part of their initial clinical complete remission. Also of note in this presentation was a 9% dropout rate, which is remarkably low and suggests that both arms were well tolerated. Since this is the only approach shown to produce clear benefit, all patients achieving a clinical complete remission should be offered the option of prolonged main-tenance therapy with paclitaxel.


CommentThe total sample size is simply inadequate

to make any definitive statements.

“It is reasonable to speculate that the patient population with pre-maintenance CA-125 antigen levels ≤ 10 U/mL had the lowest total body burden of residual malignant cells and, perhaps more importantly, the most chemotherapy-sensitive dis-ease,” revealed Maurie Markman, MD, vice president for research from The University of Texas M. D. Anderson Cancer Center in Hous-ton. “These data strongly suggest that 12 additional monthly cycles of single-agent paclitaxel may be suf-


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