Does Adjuvant Chemotherapy Improve Outcome

Because of a relatively low rate of cancer recurrence in early ovarian cancer, the challenge of clinical trials has been to accrue enough patients to have the power to detect a clinically meaningful impact of adjuvant chemotherapy on either cancer recurrence or survival. The most notable studies indicating significant effects of adjuvant chemotherapy compared with observation are listed in Table 8-3.

In 1980, the GOG reported that an 18-month course of melphalan significantly reduced the recurrence rate compared with either observation or pelvic radiation therapy.5 This result is surprising owing to the fact that the trial design was three arms and included only 86 patients with a large proportion of stage Ia grade 1 cancers, a group of patients who benefit the least from adjuvant chemotherapy.

All four trials found that adjuvant chemotherapy significantly reduced the risk of cancer recurrence by an absolute value of 8% to 18%. Only one study, however, also demonstrated a significant benefit on overall survival; the ICON (International Collaborative Ovarian Neoplasm)-1 trial reported an absolute improvement of 9%. The GOG trial did not report overall survival, and the GICOG trial was likely underpowered to detect a significant difference. ACTION found an absolute improvement in overall survival of 7%, very similar to ICON-1, but not reaching statistical significance despite comparable sample size.

Table 8-3. Randomized Controlled Trials Showing Benefit of Adjuvant Chemotherapy in

Early-Stage Ovarian Cancer

Table 8-3. Randomized Controlled Trials Showing Benefit of Adjuvant Chemotherapy in

Early-Stage Ovarian Cancer

RFS %

OS %

Trial

N

Stage and Grade

Treatment

Drug vs. No Drug

Drug vs. No Drug

GOG

86

Stages IA, B, C

Melphalan 18 mo.

94 vs 83

Not reported

(Hreshchyshyn

Grades 1, 2, 3

P < .05

et al, 1980)5

GICOG (Bolls

83

Stages IA, B

Cisplatin 6 cycles

83 vs 65

88 vs 82

et al, 1995)7

Grades 1, 2, 3

P = .028

P = .77

ICON-1 (Colombo

477

Stages IA, B, C; ?II

Carboplatln 6 cycles

73 vs 62

79 vs 70

et al, 2003)14

Grades 1, 2, 3

P = .01

P = .03

ACTION (Trlmbos

448

Stages IA, B

Platinum minimum 4

76 vs 68

85 vs 78

et al, 2003)9

Grades 2, 3

cycles

P = .02

P = .1

Stages IC and IIA All clear cell

Stages IC and IIA All clear cell

OS, overall survival; RFS, recurrence-free survival.

Time since relapse (years)

Figure 8-4. Progression-free survival after platinum-based chemotherapy for first relapse after surglcal-only treatment of stage I ovarian cancer. (From Kolomainen DF, A'Hern R, Coxon FY, et al: Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 21[16]:3113-3118, 2003.)

Time since relapse (years)

Figure 8-4. Progression-free survival after platinum-based chemotherapy for first relapse after surglcal-only treatment of stage I ovarian cancer. (From Kolomainen DF, A'Hern R, Coxon FY, et al: Can patients with relapsed, previously untreated, stage I epithelial ovarian cancer be successfully treated with salvage therapy? J Clin Oncol 21[16]:3113-3118, 2003.)

Other than sample size, two other reasons might explain the fact that a reduction in the rate of cancer recurrence does not translate into improvement in overall survival. "Salvage" chemotherapy for cancer recurrence in the observation arms of these trials most likely impacted the survival for those patients, thus dampening the survival difference between the two arms. In fact, platinum-based chemotherapy for first recurrences in stage I observation groups provides 5-year progression-free survivals of 24% to 42%10,15 (Fig. 8-4). In our opinion, the primary end point of trials in early ovarian cancer should be recurrence-free survival, since this outcome most closely approximates a true cure of the disease. Although treatment of first relapse may affect overall survival, most of these patients whose cancers recur will die of their disease.

Table 8-4. Survival After Adjuvant Chemotherapy or Observation by Completeness of Surgical Staging: The ACTION Trial

N RFS P Value OS P Value

Complete Surgical Staging

Observation 75 80%

Chemotherapy 76 83%

Incomplete Surgical Staging

Observation 147 65%

Chemotherapy 148 78%

.009

CI, confidence interval; HR, hazard ratio; OS, 5-year overall survival; RFS, 5-year recurrence-free survival. Data from Trimbos JB, Vergote I, Bolis G, et al: Impact of adjuvant chemotherapy and surgical staging in early-stage ovarian carcinoma: European Organisation for Research and Treatment of Cancer-Adjuvant ChemoTherapy in Ovarian Neoplasm trial. J Natl Cancer Inst 95(2):113-125, 2003.

A further explanation for trials not finding significant differences in overall survival could be the inconsistency in the degree of surgical staging. ICON-1,14 which did report an overall survival difference between treatment and observation, did not require surgical staging as defined by GOG. Thus, the cohort undoubtedly included microscopic or occult advanced disease. Adjuvant chemotherapy is more likely to impact occult advanced disease than true pathologic stage I disease. The ACTION trial data may support this theory.9 That trial encouraged complete surgical staging, and approximately one third of the patients underwent "optimal" surgical staging. A subanalysis of the optimally staged patients found no difference in either recurrence-free survival (83% versus 80%) or overall survival (87% versus 89%) between treatment and observation arms. On the other hand, for the group of nonoptimally staged patients, both recurrence-free and overall survivals were significantly better for the treated patients (78% versus 65%, P = .009; 84% versus 75%, P = .03, respectively) (Table 8-4). The caveat on the data from ACTION is that the number of patients in the optimally staged analysis was 151, perhaps too small to detect a significant difference. The precision of the estimated difference in recurrence rates between observation and chemotherapy in this optimal subset is wide, 0.5 to 2.4. However, a meta-analysis of randomized controlled trials that reported at least a modified surgical staging operation also did not detect a significant overall survival difference between adjuvant chemotherapy and no treatment with a more narrow precision (HR 0.81; 95% CI, 0.58-1.21).16 These data suggest that adjuvant chemotherapy benefits nonoptimally staged patients but may not benefit optimally staged patients. Once again, this is likely due to the inclusion of occult stage III patients in cohorts not undergoing complete surgical staging.

Further evidence of the importance of thorough surgical staging on the decision for adjuvant chemotherapy comes from a non-randomized Canadian study.17 Among 94 patients who underwent staging operations by gynecologic oncologists following a fixed protocol, 60 patients had surgical-pathologic stage I. During expectant management, only 10% of these 60 patients had recurrenceā€”all being serous or clear cell histology. On the other hand, the recurrence rate was 25% among 25 unstaged patients managed expectantly owing to lack of risk factors. Attaining this type of thorough and regimented staging operation in a multi-institutional, randomized trial would be ideal and rewarding, but probably not feasible.

10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment