Bulky stage IB cervical cancers have a poorer prognosis than smaller stage I cervical cancers. For the Gynecologic Oncology Group, we conducted a trial to determine whether weekly infusions of ...cisplatin during radiotherapy improve progression-free and overall survival among patients with bulky stage IB cervical cancer.
Women with bulky stage IB cervical cancers (tumor, > or =4 cm in diameter) were randomly assigned to receive radiotherapy alone or in combination with cisplatin (40 mg per square meter of body-surface area once a week for up to six doses; maximal weekly dose, 70 mg), followed in all patients by adjuvant hysterectomy. Women with evidence of lymphadenopathy on computed tomographic scanning or lymphangiography were ineligible unless histologic analysis showed that there was no lymph-node involvement. The cumulative dose of external pelvic and intracavitary radiation was 75 Gy to point A (cervical parametrium) and 55 Gy to point B (pelvic wall). Cisplatin was given during external radiotherapy, and adjuvant hysterectomy was performed three to six weeks later.
The relative risks of progression of disease and death among the 183 women assigned to receive radiotherapy and chemotherapy with cisplatin, as compared with the 186 women assigned to receive radiotherapy alone, were 0.51 (95 percent confidence interval, 0.34 to 0.75) and 0.54 (95 percent confidence interval, 0.34 to 0.86), respectively. The rates of both progression-free survival (P<0.001) and overall survival (P=0.008) were significantly higher in the combined-therapy group at four years. In the combined-therapy group there were higher frequencies of transient grade 3 (moderate) and grade 4 (severe) adverse hematologic effects (21 percent, vs. 2 percent in the radiotherapy group) and adverse gastrointestinal effects (14 percent vs. 5 percent).
Adding weekly infusions of cisplatin to pelvic radiotherapy followed by hysterectomy significantly reduced the risk of disease recurrence and death in women with bulky stage IB cervical cancers.
Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. ...Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible.
To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs.
A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network.
Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between.
Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact).
Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related.
In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding.
clinicaltrials.gov Identifier: NCT00832000.
In 1986, a protocol comparing primary radiation therapy (RT) plus hydroxyurea (HU) to irradiation plus fluorouracil (5-FU) and cisplatin (CF) was activated by the Gynecologic Oncology Group (GOG) for ...the treatment of patients with locally advanced cervical carcinoma. The goals were to determine the superior chemoradiation regimen and to quantitate the relative toxicities.
All patients had biopsy-proven invasive squamous cell carcinoma, adenocarcinoma, or adenosquamous carcinoma of the uterine cervix. Patients underwent standard clinical staging studies and their tumors were found to be International Federation of Gynaecology and Obstetrics stages IIB, III, or IVA. Negative cytologic washings and para-aortic lymph nodes were required for entry. Patients were randomized to receive either standard whole pelvic RT with concurrent 5-FU infusion and bolus CF or the same RT plus oral HU.
Of 388 randomized patients, 368 were eligible; 177 were randomized to CF and 191 to HU. Adverse effects were predominantly hematologic or gastrointestinal in both regimens. Severe or life-threatening leukopenia was more common in the HU group (24%) than in the CF group (4%). The difference in progression-free survival (PFS) was statistically significant in favor of the CF group (P = .033). The sites of progression in the two treatment groups were not substantially different. Survival was significantly better for the patients randomized to CF (P = .018).
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.
Abstract Objective A randomized phase III trial was conducted to determine if neoadjuvant chemotherapy (NACT) prior to radical hysterectomy and pelvic/para-aortic lymphadenectomy (RHPPL) could ...improve progression-free survival (PFS) and overall survival (OS), as well as operability, with acceptable levels of toxicity. Adjuvant radiation therapy was prescribed for specific surgical/pathological risk factors for both regimens. Methods Eligible patients were required to have bulky FIGO Stage IB cervical cancer, tumor diameter ≥ 4 cm, adequate bone marrow, renal and hepatic function, and performance status ≤ 2. Prospective random allocation was to either NACT (vincristine-cisplatin chemotherapy every 10 days for 3 cycles) before exploratory laparotomy and planned RHPPL (NACT + RHPPL), or RHPPL only. Results The study was closed prematurely, because of slow accrual, after 291 patients were enrolled, three were ineligible; thus 288 were eligible and randomly allocated to RHPPL ( N = 143) or NACT + RHPPL ( N = 145). There were no notable differences between regimens with regard to patient age, race, performance status, or tumor size. The median follow-up time is 62 months among living patients. The NACT + RHPPL group had very similar recurrence rates (relative risk: 0.998) and death rates (relative risk: 1.008) when compared to the RHPPL group. There were 79% that had surgery in the RHPPL group compared to 78% in the NACT RHPPL group. There were 52% who received post op RT in the RHPPL group compared to 45% in the NACT + RHPPL group (not statistically significant). Conclusion There is no evidence from this trial that NACT offered any additional objective benefit to patients undergoing RHPPL for suboptimal Stage IB cervical cancer.
Episodic ataxia type 1 (EA1) is a rare autosomal potassium channelopathy, due to mutations in
KCNA1
. Patients have childhood onset of intermittent attacks of ataxia, dizziness or imbalance. In order ...to quantify the natural history of EA1, its effect on quality of life and in preparation for future clinical trials, we set up an international multi-centre study of EA1. We recruited thirty-three participants with EA1: twenty-three completed 1-year follow-up and eighteen completed 2-year follow-up. There was very little accumulation of disability or impairment over the course of the 2 years of the study. The outcome measures of ataxia (SARA and functional rating of ataxia) and the activities of daily living scale were largely stable over time. Self-reported health-related quality of life (SF-36) scores were lower across all domains than controls, in keeping with a chronic condition. Physical subdomain scores appeared to deteriorate over time, which seems to be driven by the female participants in the study. This is an interesting finding and warrants further study. Attacks of EA1 reported by participants in real time via an interactive voice response system showed that symptoms were not stereotyped; however, attack duration and frequency was stable between individuals. This large prospective study is the first ever completed in subjects with EA1. We document the natural history of the disorder over 2 years. These data will enable the development of outcome measures for clinical trials of treatment.
To evaluate outcome in patients with clinical stage I/II papillary serous (PS) or clear cell (CC) endometrial carcinoma treated with whole abdominal radiotherapy.
After total abdominal hysterectomy ...with bilateral salpingo-oophorectomy, pelvic/para-aortic lymph node sampling, and peritoneal washings, eligible patients received radiotherapy (RT) to the abdomen (3000 cGy at 150 cGy/day) with a pelvic boost (1980 cGy at 180 cGy/day).
Among 21 PS patients (median age: 68 years), one refused therapy, and another received a non-protocol vaginal boost. In total, eight patients died of disease (DOD) between 9.6 and 35.2 months. Five others died due to protocol treatment (1), toxicity from subsequent chemotherapy (1), intercurrent disease (1), and unknown cause (2). Five-year progression-free survival (PFS) was 38%. Among treated patients who DOD, sites of recurrence included lung (2), lung/vagina (1), abdomen/pelvis (1), vagina (1), and abdomen (2).
Among 13 CC patients (median age: 63 years), one received pelvic RT only and died with intercurrent disease. Five others died due to DOD (3), intercurrent disease (1), and unknown cause (1). Five-year PFS was 54%. Among patients who DOD, sites of recurrence included lung (1), vagina (1), and unknown (1).
Grade 3/4 toxicities for both histologic groups included gastrointestinal (three grade 4; three grade 3), hematologic (one grade 4), and cutaneous (one grade 3).
Over half of the treatment failures were within the radiation field. Systemic chemotherapy, radiosensitizing chemotherapy, or sequential radiation and chemotherapy should be considered in future adjuvant trials for these patients.
To evaluate, in a randomized clinical trial, the role of adjuvant hysterectomy after standardized radiation in improving progression-free survival and survival for patients with “bulky” stage IB ...cervical cancer.
A total of 256 eligible patients with exophytic or “barrel” shaped tumors measuring ≥4 cm were randomized to either external and intracavitary irradiation (RT,
N = 124) or attenuated irradiation followed by extrafascial hysterectomy (RT + HYST,
N = 132). Twenty-five percent of patients had tumors with a maximum diameter of ≥7 cm.
Tumor size was the most pronounced prognostic factor followed by performance status 2 and age at diagnosis. Hysterectomy did not increase the frequency of reported grade 3 and 4 adverse effects (both groups, 10%). The majority of these adverse effects were from the gastrointestinal or genitourinary tracts exclusively. There was a lower cumulative incidence of local relapse in the RT + HYST group (at 5 years, 27% vs. 14%). There were no statistical differences in outcomes between regimens except for the adjusted comparison of progression-free survival, although all indicated a lower risk in the adjuvant hysterectomy regimen (unadjusted relative risk URR of progression, 0.77,
P = 0.07; URR of death,
P = 0.26, both one tail).
Overall, there was no clinically important benefit with the use of extrafascial hysterectomy. However, there is good evidence to suggest that patients with 4-, 5-, and 6-cm tumors may have benefitted from extrafascial hysterectomy (URR of progression; 0.58; URR of death, 0.60).
Objectives.The objectives of this study were to assess efficacy and toxicity of the combination of bleomycin, etoposide, and cisplatin (BEP) in this Phase II trial as first-line therapy for ovarian ...stromal malignancies.
Methods.Patients with incompletely resected Stages II–IV or recurrent cancer underwent surgical debulking. There were two bleomycin-related deaths early in the trial; thus, the initial schedule of bleomycin (20 units/m2× 9 weeks for a maximum dose of ≤30 units × 9) was changed, without subsequent mortality. The final dose schedule was 20 units/m2bleomycin iv push day 1 every 3 weeks × 4, 75 mg/m2etoposide days 1–5 every 3 weeks × 4 and 20 mg/m2cisplatin days 1–5 every 3 weeks × 4. The frequency of negative second-look surgery was the primary outcome measure.
Results.Seventy-five women were entered; 18 were excluded. Grade 4 myelotoxicity occurred in 61% of the patients. The end point used for response was negative second-look laparotomy. Thirty-seven percent (14/38) of the patients undergoing second-look laparotomy had negative findings. The six complete responders were of long median duration (24.4 months). Patients with measurable disease were at the highest risk of progression and death.
Conclusions.BEP appears to be an active combination regimen for first-line chemotherapy of malignant tumors of the ovarian stroma. Myelotoxicity was tolerable.
Purpose: A multicenter trial of chemoradiation therapy to evaluate the feasibility of extended field radiation therapy (ERT) with 5-fluorouracil (5-FU) and cisplatin, and to determine the ...progression-free interval (PFI), overall survival (OS), and recurrence sites in patients with biopsy-confirmed para-aortic node metastases (PAN) from cervical carcinoma.
Methods and Materials: Ninety-five patients with cervical carcinoma and PAN metastases were entered and 86 were evaluable: Stage I—14, Stage II—40, Stage III—27, Stage IVA—5. Seventy-nine percent of the patients were followed for 5 or more years or died. ERT doses were 4500 cGy (PAN), 3960 cGy to the pelvis (Stages IB/IIB), and 4860 cGy to the pelvis (Stages IIIB/IVA). Point A intracavitary (IC) doses were 4000 cGy (Stages IB/IIB), and 3000 cGy (Stages IIIB/IVA). Point B doses were raised to 6000 cGy (ERT + IC) with parametrial boost. Concomitant chemotherapy consisted of 5-FU 1000 mg/m2/day for 96 hours and cisplatin 50 mg/m2 in weeks 1 and 5.
Results: Eighty-five of 86 patients completed radiation therapy and 90% of patients completed both courses of chemotherapy. Gynecologic Oncology Group (GOG) grade 3–4 acute toxicity were gastrointestinal (18.6%) and hematologic (15.1%). Late morbidity actuarial risk of 14% at 4 years primarily involved the rectum. Initial sites of recurrence were pelvis alone, 20.9%; distant metastases only, 31.4%; and pelvic plus distant metastases, 10.5%. The 3-year OS and PFI rate were 39% and 34%, respectively, for the entire group. OS was Stage I—50%, Stage II—39%, and Stage III/IVA—38%.
Conclusions: Extended field radiation therapy with 5-FU and cisplatin chemotherapy was feasible in a multicenter clinical trial. PFI of 33% at 3 years suggests that a proportion of patients achieve control of advanced pelvic disease and that not all patients with PAN metastases have systemic disease. This points to the importance of assessment and treatment of PAN metastases.
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