Prospective evaluation of an in vitro radiation resistance assay in locally advanced cancer of the uterine cervix: a Southwest Oncology Group Study.
ABSTRACT To investigate the feasibility of performing a fresh-tissue, in vitro radiation resistance assay (IVRRA) in a cooperative group setting and to assess the association of IVRRA results with clinical outcomes.
Women with Stages IIB-IVA carcinoma of the uterine cervix without obvious para-aortic lymphadenopathy on imaging were eligible. Primary tumor biopsies were shipped to a central testing facility where agar-based cell suspensions were exposed to 300 cGy of RT ± cisplatin and cultured for 5 days. ³H-thymidine incorporation was used to determine percent cell inhibition (PCI) of test specimen compared to that of the untreated control. Tumors were considered to exhibit extreme radiation resistance (ERR), intermediate radiation resistance (IRR) or low radiation resistance (LRR) based on a standard data set from 39 previously studied specimens. Standardized doses of external beam radiation and intracavitary brachytherapy, when feasible, in addition to platinum-based chemotherapy were mandated. Progression-free survival (PFS) was the primary endpoint. Clinical response and overall survival (OS) were secondary endpoints. Clinical investigators were blinded to assay data and vice versa.
Thirty-six patients were enrolled, but analysis was limited to 17 patients whose specimens were adequate for IVRRA. The median follow-up time among patients still alive at last contact was 40 months (range: 0-56 months). There was no association between IVRRA and response. In the Cox model, IRR/ERR tumors showed worse PFS [HR = 11.2 (95% CI 1.3-96, p = 0.03)] and worse OS [HR=11.7 (95% CI 1.4-99.6, p = 0.03)] compared to LRR tumors when IVRRA was performed with RT alone, but there were no associations between IVRRA and PFS or OS when cisplatin was added to the IVRRA.
IVRRA (RT alone) results correlated with PFS and OS in this prospective trial, but follow-up trials are indicated to address feasibility and to confirm results in an expanded cohort. If confirmed, IVRRA could potentially direct molecular identification of novel targeted therapeutic approaches which might counteract radiation resistance.
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ABSTRACT: The Patterns of Care Study (PCS) conducted two national surveys of patients treated in 1973 and 1978 for squamous cell cancer of the uterine cervix. In addition, a survey of patients treated in 1973 from selected large facilities was conducted to establish outcome with "optimal" radiotherapy. The large facility survey consistently reported improved outcome compared to both national average surveys when analyzed by stage and other significant pretreatment factors. That improved outcome was associated with the paracentral (PCS point A) dose and the use of intracavitary irradiation. In this study, we report the pretreatment and treatment factors associated with improved outcome in squamous cell carcinoma of the uterine cervix by analysis of the 1973 and 1978 PCS data. Pretreatment factors associated with improved pelvic control in multivariate analysis include higher Karnofsky Performance Status (KPS) (Stage I and II), older age (Stage I and II), unilateral parametrial involvement (Stage IIB), and unilateral sidewall involvement (Stage III). The only treatment factor associated with improved pelvic control in multivariate analysis is the use of intracavitary irradiation. However, a dose response for infield pelvic control was demonstrated only in Stage III cervix cancer with the highest rate of pelvic control with paracentral (PCS point A) dose greater than 8500 cGy. Multivariate analysis revealed that unilateral parametrial involvement for Stage IIB and unilateral sidewall involvement for Stage III are significant positive prognostic factors with respect to survival after treatment with radiotherapy. No FIGO substage significantly affected survival after radiotherapy. Although FIGO staging is the single most important pretreatment prognostic factor with respect to survival and infield pelvic failure, FIGO substaging deserves reappraisal and further refinement. Major complications were seen in only 9.5% of patients treated with radiotherapy and were stage but not survey related. There is a significant relationship between PCS point A dose and complications with the highest rate of complications for PCS point A dose greater than 8500 cGy. A significant relationship between lateral (external iliac lymph nodes or PCS point P) dose and major complications is also found, and doses greater than 5000 cGy are associated with a significant increase in complications. The PCS has established two sequential national benchmarks of treatment outcome for squamous cell carcinoma of the uterine cervix treated with radiotherapy with respect to survival, infield pelvic control, and complications.(ABSTRACT TRUNCATED AT 400 WORDS)International Journal of Radiation OncologyBiologyPhysics 05/1991; 20(4):667-76. · 4.52 Impact Factor
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ABSTRACT: 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.New England Journal of Medicine 04/1999; 340(15):1154-61. · 51.66 Impact Factor
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ABSTRACT: We compared the effect of radiotherapy to a pelvic and para-aortic field with that of pelvic radiation and concurrent chemotherapy with fluorouracil and cisplatin in women with advanced cervical cancer. Between 1990 and 1997, 403 women with advanced cervical cancer confined to the pelvis (stages IIB through IVA or stage IB or IIa with a tumor diameter of at least 5 cm or involvement of pelvic lymph nodes) were randomly assigned to receive either 45 Gy of radiation to the pelvis and para-aortic lymph nodes or 45 Gy of radiation to the pelvis alone plus two cycles of fluorouracil and cisplatin (days 1 through 5 and days 22 through 26 of radiation). Patients were then to receive one or two applications of low-dose-rate intracavitary radiation, with a third cycle of chemotherapy planned for the second intracavitary procedure in the combined-therapy group. Of the 403 eligible patients, 193 in each group could be evaluated. The median duration of follow-up was 43 months. Estimated cumulative rates of survival at five years were 73 percent among patients treated with radiotherapy and chemotherapy and 58 percent among patients treated with radiotherapy alone (P=0.004). Cumulative rates of disease-free survival at five years were 67 percent among patients in the combined-therapy group and 40 percent among patients in the radiotherapy group (P<0.001). The rates of both distant metastases (P<0.001) and locoregional recurrences (P<0.001) were significantly higher among patients treated with radiotherapy alone. The seriousness of side effects was similar in the two groups, with a higher rate of reversible hematologic effects in the combined-therapy group. The addition of chemotherapy with fluorouracil and cisplatin to treatment with external-beam and intracavitary radiation significantly improved survival among women with locally advanced cervical cancer.New England Journal of Medicine 04/1999; 340(15):1137-43. · 51.66 Impact Factor