Treatment Method Shows Local Control of Cervical Cancer

Excellent local control (LC) and survival was shown with the use of computed-tomography (CT)-planned high-dose-rate (HDR) intracavitary brachytherapy (BT) for patients with stage 1 or 2 cervical carcinoma, according to the findings of a recent study published in Gynecologic Oncology.

With a median follow-up of 30 months, no patients experienced local-only recurrence.

“We found that, of nine patient characteristics and various RT prognostic factors tested in a univariate analysis, tumor size and total external beam radiation therapy (EBRT) plus BT dose were initially the most significant prognostic factors for predicting any recurrence (AR),” Akila N. Viswanathan, M.D., executive vice chair, Johns Hopkins Radiation Oncology and Molecular Radiation Sciences, and her colleagues wrote in the study.

However, a bivariate model showed that total EBRT plus BT dose were no longer significant when adjusted for tumor size, the authors wrote. The authors of the study found large tumor size to be a prognostic factor for increased risk of recurrence outside the radiation field and worse progression-free survival (PFS) and overall survival (OS). Patients with tumors larger than 4 cm were three times more likely to develop regional or distant recurrence, compared with patients who had tumors smaller than 4 cm.

Moreover, the researchers also found that a volume-optimized plan treated a smaller area than a standard, Point A plan for these patients.

A total of 150 patients were treated for stage 1/2 cervical cancer using HDR CT-planned BT between April 2004 and October 2014 at Brigham and Women’s Hospital. One-hundred twenty-eight women met eligibility criteria for the current study, as they had stage 1/2 disease, were treated with CT-based BT, and were not treated with interstitial BT.

Patients were staged according to the International Federation of Gynecology and Obstetrics (FIGO) guidelines. Clinical examination reports provided information about tumor size, which was also subsequently confirmed using CT or MR. Small and large tumor size were defined as up to 4 cm and more than 4 cm, respectively.

For the BT procedure, patients were placed under general anesthesia and immobilized for applicator insertion, CT scanning and treatment. A physician assessed the location, size and firmness of residual disease at the time of brachytherapy. All contouring was performed by the treating physician, who also carried out the final treatment plan evaluation to maximize dose coverage and minimize dose to the organs at risk (OAR) (bladder, rectum, and sigmoid). Contouring per previously published guidelines included a clinical tumor volume (CTV) that encompassed the palpable disease, the contoured cervix to at least a height of approximately 3 cm along the tandem and laterally to the edge of the visualized cervix and parametrial regions. Point A was recorded, but not used for dose specification.

Pelvic recurrence sites were classified as either “true pelvis” (cervix, uterine corpus, vagina and parametria) or “pelvic nodes” (external and internal iliac, obturator and perivesical nodes). Regional recurrence (RR) was defined as failure in the para-aortic and inguinal nodes. Distant recurrence (DR) was defined as metastasis outside of the loco-regional sites as evidenced through PET-CT or MRI.

The primary endpoints included PFS — defined as no evidence of disease progression after tumor biopsy, and subdivided into PFS true pelvis (local control) and PFS pelvic nodes (local and regional control, or pelvic control [PC]) — and OS, which was defined as the period from the date of biopsy until the date of death from any cause.

Thirty-eight patients (30 percent) had stage 1 disease, while 90 women (70 percent) had stage 2 cervical cancer. The overall median tumor size at the time of diagnosis was 3.8 cm (range, 0-6 cm), with stage 1 tumors yielding a smaller median size (2.9 cm; range, 0-7.6 cm) than stage 2 tumors (4.0 cm; range, 0-10 cm). Lymph node involvement was recorded in 40 patients (31 percent), 32 of whom (80 percent) had stage 2 disease.

Chemotherapy was administered to 114 patients (89 percent) and mainly included a platinum-based regimen of concurrent cisplatin or carboplatin. At the earliest, BT began in the fourth week of EBRT and was delivered in a dedicated BT suite with CT imaging done immediately after insertion. A total of 630 fractions were analyzed, with each patient receiving a median of five fractions (range, three to five). The median per-fraction prescription dose was 5.5 Gy (range, five to seven), and the median average of Point A (fraction 1) was 5.0 Gy (range, 2.9-nine). The cumulative EBRT plus BT dose to 90 percent of the tumor volume (D90) in EQD2 was 83.7 (range, 66.7-114.7), and the median cumulative doses (Gy3) to 2cm³ (D2cc) were 75.1 Gy for bladder, 63.9 Gy for rectum, and 59.4 Gy for sigmoid.

The median follow-up time was 30 months (range, 3.8-129.7). Eighteen of 128 evaluable patients (14 percent) had documented disease recurrence or progression, 15 of whom had stage 2 disease at diagnosis. No patients relapsed in the true pelvis (LR) only. Six patients (5 percent) demonstrated LR plus PR, RR, and/or DR. Of these, three experienced concomitant LR and PR (pelvic sidewall, pelvic node and pelvic mass), one had LR plus PR plus DR, one had LR plus PR plus RR plus DR, and one patient with a 6-cm primary lesion at diagnosis had residual disease at the end of the treatment.

One patient (1 percent) had PR plus RR, and three women (2 percent) had RR plus DR. Eight patients (6 percent) had DR only, five of whom had tumors larger than 4 cm.

Overall, of the 18 patients who experienced a relapse, 14 (78 percent) had a DR. The overall two-year rate of LC was 96 percent, PFS was 88 percent, and OS was 88 percent.

When these results were broken down by tumor size (up to 4 cm vs. larger than 4 cm), the two-year LC rates were 98 percent versus 93 percent, the PFS rates were 95 percent versus 76 and the OS rates were 91 percent versus 84 percent, respectively.

There were 28 deaths overall in the study (22 percent). Causes of death included recurrence or metastasis (14 patients; 11 percent), respiratory failure (one patient; 1 percent), metastasis of a secondary cancer (six patients; 5 percent), sepsis (one patient; 1 percent), and cardiac arrest (one patient; 1 percent). The causes of five patients’ deaths (4 percent) were unknown.

A univariate analysis showed no differences in median age at diagnosis, median length of follow-up, median gravid status, stage, lymphovascular invasion, lymph node positivity (biopsy or PET), tumor grade, use of chemotherapy, histology, race and smoking history between patients with AR and those with no recurrence. Large tumor size was significantly associated with AR. There were no significant prognostic factors associated with OS.

The authors also looked at outcomes at two years by receipt of chemotherapy. For patients treated with chemotherapy (114 patients) or without chemotherapy (14 patients), LC rates were 97 percent versus 91 percent, PFS rates were 88 percent versus 85 percent, and OS rates were 93 percent versus 87 percent, respectively.

Among the 14 women treated without chemotherapy, three (21 percent) experienced a relapse, two (14 percent) of whom had combined LR (cervix and vagina) and PR (pelvic nodes and sidewall) and one (7 percent) who had DR to the spine.

Among the rest of the patients who were treated with chemoradiation, no differences were identified between those with NR (99 patients; 87 percent) and those with AR (15 patients; 13 percent) in either baseline characteristics or clinical outcomes, with the one exception of median age at diagnosis. For those with NR, the median age at diagnosis was 53 years, and for those with AR, the median age was 47 years.

No significant differences were found in terms of median total brachytherapy D90 dose (EQD2), BT dose (EQD2), V100 target coverage, cumulative D90 or cumulative EBRT and BT dose (EQD2), between patients who had NR and those who had AR.

The median fraction-1 Point A dose was significantly lower for those with NR than for those with AR (5.0 ± 1.0 vs 5.5 ± 1.0 Gy, respectively).

Although a univariate analysis of radiation therapy doses showed that tumor volume receiving 100 percent of prescribed dose (V100) target coverage, point A dose, and total EBRT plus BT dose were predictors of AR, the effect of V100 target coverage on AR lost its significance after the authors adjusted for tumor size. Thus, tumor size remained as the only predictor for AR.

Moreover, after tumor size was accounted for, the association between EBRT plus BT (EQD2) dose and AR became less significant, and tumor size was, again, the only predictor for AR. Also, Point A dose was a significant predictor for AR after adjustment for tumor size.

Genitourinary toxicities (GU) were observed in this study, including bladder spasm, incontinence, stenosis, urinary frequency and urgency and dysuria. Gastrointestinal (GI) toxicities included diarrhea without prior colostomy, hemorrhoid pain, constipation, nausea, and ulcer.

Twenty-one patients (16 percent) experienced grade 2 or higher acute toxicity after receiving BT. Of those women, six (5 percent) had GI toxicities, while 12 (9 percent) had GU adverse events, and three patients (2 percent) experienced vaginal toxicities. Two patients (2 percent) also experienced grade 2 or higher late toxicity, including one (1 percent) with GI and one (1 percent) with GU adverse events. There were no acute or late grade 3 or higher toxicities.