Reviewers: John Han-Chih Chang, MD
Source: Conclusion: This study demonstrates that for patients with locally advanced carcinoma of the cervix, the combination of 5-FU and CF with RT offers patients better PFS and overall survival than HU, and with manageable toxicity.
Background / Discussion / CritiqueThe article focused on the GOG 85 study (conducted in conjunction with the Southwest Oncology Group - SWOG protocol 8695). As described above, the patients enrolled into this study had clinical FIGO stages IIB to IVA. That means the extent of disease was at least parametrial disease (IIB) or more extending to the lower 1/3rd of the vagina (IIIA) or had a nonfunctioning kidney, hydronephrosis, or pelvic side wall involvement (IIIB). Stage IVA is invasion of the bladder and/or rectum. As expected, as the incidence of pelvic and para-aortic lymph node metastases increases significantly, the overall survival decreases. Historically, the most utilized treatment for locally advanced lesions such as the ones included in this trial are usually treated with primary RT alone. A substantial local failure rate is seen (20 - 50% in stage IIB up to 50 - 75% for the more advanced stages).
In the late 1970's, literature grew on the possibility of combining chemotherapy (ChT) with RT to improve outcome in locally advanced malignancy of the cervix. In prior GOG trials, the agent of choice had been HU. It was compared in a prospective and randomized fashion with placebo or misonidazole (hypoxic cell sensitizer). It was found to significantly affect local control and survival. Thus, it became the measuring stick for subsequent ChT agents.
As of late, cisplatin has been supplanting HU, largely on the basis of this and another prospective randomized trial (GOG 120). The GOG protocol 120 was a three-arm phase III trial comparing locally advanced patients without lymph node metastases (same stages as the trial currently being reviewed here) treated with RT + weekly cisplatin versus RT + 5-FU, cisplatin and HU versus RT + HU. Both arms with the cisplatin did better than the RT + HU alone arm in survival (Rose et al, NEJM 1999; 340: 1144).
GOG 85 is obviously an earlier trial that, since it's publishcation, may place the final nail in HU's coffin for use in cervical cancer. Median follow-up was fairly substantial at 8.7 years. Seventy-six (43%) of the CF arm patients havehad disease progression, while 53% (101) of the HU arm patients have progressed or recurred. This is statistically significant along with the survival (45% of CF patients have died versus 57% of the HU patients). The authors cite relative risks of progression and survival of CF compared to HU of 0.79 and 0.74, respectively. The largest difference seen in the site of progression was failures in the pelvis (25% for CF versus 30% for HU). As mentioned in the abstract, severe (grade 3) or life threatening (grade 4) hematologic toxicities of treatment were much more common (24%) in HU patients than CF patients (4%). The opposite was true of grade 3 - 4 gastrointestinal effects with the CF arm having 8% versus 4% in the HU arm.
A few minor points of note in the article are as follows. Slightly more patients were of adenocarcinoma or adenosquamous variety in the CF arm. It is not quite clear that such a small difference in histology would cause a significant effect on outcome. Some have postulated that squamous cell lesions are more favorable. Thus, in this case, since the CF arm had an improved outcome, the argument to use CF becomes even more compelling. There was a slight difference in pathological determination of pelvic lymph node status. More of the CF arm patients had known pathologic lymph node negativity than the HU patients. This may skew the data in favor of the CF patients. Of those that were supposed to receive 81 Gy to point A, more patients were able to achieve within 15% of the prescribed dose in the CF arm than the HU arm. However, the opposite was true of those that were to receive 61 Gy to point A. This, along with the histologic and lymph node status issues, is probably of little significance when interpreting the data.
Based on the data presented here and the prior mentioned GOG 120 study, cisplatin has emerged as the proven standard. Other studies have demonstrated cisplatin's clear efficacy over radiation alone in lymph node positive disease(Radiation Therapy Oncology Group - RTOG 9001) and bulky IB tumors (GOG 123). The measuring stick has again been established, but we are far from being done. Future studies will focus on novel agents to produce even better outcomes, since we are hardly at 100% or even 80% long-term survivors. Perhaps taxanes will help provide the next answer.