Reviewers: John Han-Chih Chang, MD
Source: Gynecology Oncology 1999; Volume 72: pages 215 ? 219
Ovarian cancer has become one of the most dreaded diseases to treat, because of the very poor survival in the epithelial types (the subject of this article). In the early stages, ovarian cancer can be managed with surgery alone, and reported survivals have been documented at 85 ? 95%, when there has not been breech of the ovarian capsule by tumor (stages IA and IB). Many studies have demonstrated that most of these patients do not need further adjuvant therapy (chemotherapy or radiation therapy). Unfortunately, most (70%) present with stage III and IV disease (abdominal or distant spread). Survival for this group of advanced patients is 5 ? 45% based on extent of disease. The mainstay of treatment has been surgery for resection or debulking of the primary tumor.
Adjuvant chemotherapy (ChT) in the postoperative setting for intermediate to high-risk patients (stages IC to IV) seems to improve outcome. Most have defined platinum-based ChT as the standard of care postoperatively for these patients. The role of taxane chemotherapeutic agents is starting to be elucidated and appears very promising. What has not been well defined is the role of radiation therapy (RT) in the postoperative setting. RT can be given via a radioactive colloid solution directly to the abdominal cavity or with external beam radiation therapy.
This article attempts to address the issue of RT with a randomized trial for the intermediate to high-risk population with ovarian cancer. The data presented are from the University of Graz in Austria.
Between 1985 and 1992, 94 patients with stage IC to IV ovarian cancer had radical surgery consisting of a total abdominal hysterectomy and bilateral salpingo-oophorectomy, omentectomy and pelvic and para-aortic lymphadenectomy. ChT followed with carboplatin (400 mg/m2 IV day 1), epirubicin (70 mg/m2 IV day 1) and prednimustine (100 mg/day on days 3 ? 7) for 6 cycles on an every 28 days regimen.
All 94 patients completed the 6 cycles of ChT and were evaluated clinically with a physical exam, computed tomography scan (CT scan) and tumor markers. No second look surgery was performed. Sixty-four were deemed to be without clinical evidence of disease. These were then randomized to RT (arm 1) or observation (arm 2).
The RT consisted of whole abdominal radiation therapy to 30 Gy in 1.5 Gy fractions. Kidney and liver shielding was done after a certain doses (15 and 19 Gy, respectively). Patients then went on a two week break and then received a diaphragmatic and pelvic field boost to a final total dose of 42.6 and 51.6 Gy (including the initial whole abdominal dose), respectively. Those that had para-aortic lymph node disease also had a boost to a total dose of 42.6 Gy.
Table 1 in the paper demonstrates the similarity of the two treatment arms in age, stage, residual tumor, lymph node status, histological grade and size of primary.
Overall and relapse free survival were superior (statically significant) in the RT arm for the entire group and especially for the stage III patients.
Relapse Free Survival
Overall: no RT
61% (p = 0.029)
33% (p = 0.029)
56% (p = 0.013)
26% (p = 0.013)
Stage III: RT
Stage III: no RT
58% (p = 0.012)
26% (p = 0.012)
54% (p = .00061)
19% (p = 0.0061)
Cox multivariate analysis found a positive prognostic value of RT. The adverse prognostic factors were para-aortic lymph node involvement and larger size of the primary tumor.
All 32 patients received some degree of fatigue, nausea, cramping, diarrhea, anorexia and abdominal bloating. Grade 3 leukopenia (lowering of WBC's to 1000 ? 2000) was seen in 6. Treatment was discontinued in 5 patients in whom the myelosuppresion was persistent. One patient required surgery for bowel obstruction 5 months after RT.
On the surface, if you take this paper at face value, it appears that this is the wave of the future. We must now treat all stage IC ? IV patients with RT. Being a radiation oncologist, I would want to believe this to be true. BUT:
First of all, there are TOO few patients in stages IC, II and IV to make a definite conclusion about the benefit in those stages. Stages IC and II are considered intermediate risk patients who derive benefits from both ChT and RT alone. No randomized trial has demonstrated convincingly that both are more beneficial than single modality in the postoperative setting. For stage IV disease, it remains fairly controversial whether RT adds anything to adjuvant chemotherapy in the postoperative setting.
My biggest problem with this trial ? was it truly randomized? I found their prior reference Pickel et al, Am J Clin Oncol 1991; Volume 14: pages 184 ? 187. It gives data from their PILOT NONRANDOMIZED trial beginning in 1985 ending in 1987. It curiously overlaps with their randomized trial period (1985 ? 1992). In their toxicity data discussions, both mention a patient having treatment related bowel obstruction 5 months after radiation. The rest of the toxicity sections in both manuscripts were nearly identical. This calls into serious question the validity of the initial patients enrolled in this trial.
A paper that seemed so promising, initially, becomes one that is inconclusive due to factors that may have biased the data. All we can truly conclude from this paper is that some patients may benefit from RT in addition to ChT. We still need a randomized trial of platinum and taxane based ChT with or without RT to help answer the question.