Introduction
Uterine cervical cancer is among the most lethal malignancies affecting women worldwide. For early invasive cervical cancer, radical hysterectomy plays a pivotal role in patient outcome, and it is widely accepted that it should be expedited. However, patients must occasionally suffer long wait times due to patient overload of skilled oncologists and qualified facilities. For patients with life-threatening cancers, these progressively longer wait times prior to initial surgery represent a serious problem. The effect of delays between the onset of symptoms and the initial treatment is highly controversial and, unfortunately, cannot be investigated in randomized controlled trials due to major ethical issues.
In breast cancer, delays of 3–6 months prior to initial surgical treatment are associated with poorer survival (1). Recently, Elit et al (2) retrospectively analyzed 9,417 patients with uterine cancer regarding the association between their wait time for surgery and their prognosis, and found that patients with wait times of >12 weeks had worse survival compared with those with wait times of <12 weeks. Thus, the evidence that delays should be kept to a minimum is compelling.
Generally, neoadjuvant chemotherapy (NAC) aims to reduce the size or extent of the cancer prior to a more radical treatment, making later procedures easier and more likely to succeed. In addition, NAC may attack micrometastatic disease. NAC regimens for cervical cancer treatment have been developed, although to date there has been little clear evidence of any survival benefits for any of them. NAC has been performed to reduce cervical tumor bulk prior to radical hysterectomy (3). The drugs used for NAC are generally administered systemically in multiple cycles. However, Japanese researchers have been developing a special method for intra-arterial neoadjuvant chemotherapy (IANAC) delivered directly to the tumor, with the aim to expose the tumor to higher drug concentrations than would systemic intravenous delivery, while decreasing the systemic side effects (3). Thus, the idea that IANAC administered during the wait time prior to a delayed surgery may inhibit tumor growth and remove micrometastatic disease with minimum side effects, may be highly appealing to gynecological oncologists. Indeed, when informed of such potential benefits, patients often prefer an early start to this therapy, when faced with long wait times to initial surgery.
In this study, we retrospectively analyzed 12 cases of operable stage IB1-IIB cervical cancer who were treated with single-dose IANAC during their wait for subsequent radical hysterectomy, in order to better understand the efficacy and safety of IANAC for this purpose.
Discussion
Our study demonstrated that single-dose IANAC, delivered while waiting for radical hysterectomy, was not associated with an objective benefit for patients with stage IB-IIB cervical cancer. In our study, there were no significant differences in DFS or 3-year survival rates between the IANAC and PS groups. A multivariate analysis revealed that the wait time until surgery (≥45 vs. <45 days) or the use or of IANAC did not affect DFS. Only the type of histology (squamous vs. non-squamous) was found to be an independent prognostic factor for DFS. Surprisingly, we observed distal recurrences more frequently in the IANAC rather than in the PS control group, with a statistically significant difference. This may indicate that IANAC may promote new spreading of tumor cells, rather than the hoped for effect of eradicating pre-existing micrometastases.
Previous studies, usually performed with 3 cycles of platinum and taxanes, have shown the benefits of IANAC for controlling bulky cervical cancer. IANAC was effective at reducing tumor bulk, with reduced toxicity (relative to intravenous treatments), with safety and improved prognosis (3,5–9).
In ovarian cancer, >3 cycles of NAC are required to efficiently control the primary as well as the distant tumors. In early-stage ovarian cancer, 6 cycles of adjuvant carboplatin and paclitaxel significantly reduced recurrence, compared with 3 cycles). This result suggested that, to vanquish micrometastases of hardier cancer cells, repeated administrations of chemotherapy are required. Therefore, if IANAC use is inevitable, multiple cycles of administration is clearly preferable to a single dose, as was attempted in this study.
Due to the high ratio of patients with technically difficult surgical needs to the low numbers of fully skilled gynecologic oncologists and hospitals with advanced facilities, wait times for cancer surgeries have increased, causing serious problems for the patients. These longer wait times for surgery may cause the patient anxiety, thereby negatively affecting prognosis. For patients to cope with longer wait times, concurrent chemoradiotherapy (CCRT) may be the most reasonable option. The evidence for the efficacy of CCRT in cervical cancer is well established; therefore, in order to start therapy early, some patients have been treated with CCRT instead of surgery. However, some patients prefer to undergo surgery instead of CCRT, due to the long-lasting side effects of radiation. In such cases, multiple cycles of IANAC, followed by radical hysterectomy, may be a viable option. The limitations of our study were the relatively small number of IANAC cases, the retrospective design that may cause bias, and the relatively short follow-up period.
In conclusion, although single-dose IANAC may help reduce patient anxiety and permit earlier surgery (compared with multiple cycles of IANAC), its survival benefit is equivocal and it should not be performed lightly. Furthermore, it is recommended that single-cycle IANAC should not be performed without careful consideration. It is likely that multiple-cycle IANAC will perform better than a single dose for controlling distant micrometastases, as higher response rates and better prognosis were previously reported using ≥3 cycles.