Anthony Fyles

Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer

BACKGROUND The optimal fractionation schedule for whole-breast irradiation after breast-conserving surgery is unknown. METHODS We conducted a study to determine whether a hypofractionated 3-week schedule of whole-breast irradiation is as effective as a 5-week schedule. Women with invasive breast cancer who had undergone breast-conserving surgery and in whom resection margins were clear and axillary lymph nodes were negative were randomly assigned to receive whole-breast irradiation either at a standard dose of 50.0 Gy in 25 fractions over a period of 35 days (the control group) or at a dose of 42.5 Gy in 16 fractions over a period of 22 days (the hypofractionated-radiation group). RESULTS The risk of local recurrence at 10 years was 6.7% among the 612 women assigned to standard irradiation as compared with 6.2% among the 622 women assigned to the hypofractionated regimen (absolute difference, 0.5 percentage points; 95% confidence interval [CI], -2.5 to 3.5). At 10 years, 71.3% of women in the control group as compared with 69.8% of the women in the hypofractionated-radiation group had a good or excellent cosmetic outcome (absolute difference, 1.5 percentage points; 95% CI, -6.9 to 9.8). CONCLUSIONS Ten years after treatment, accelerated, hypofractionated whole-breast irradiation was not inferior to standard radiation treatment in women who had undergone breast-conserving surgery for invasive breast cancer with clear surgical margins and negative axillary nodes. (ClinicalTrials.gov number, NCT00156052.)

Oxygenation predicts radiation response and survival in patients with cervix cancer

BACKGROUND AND PURPOSE Hypoxia appears to be an important factor in predicting tumor relapse following radiation therapy. This study measured oxygenation prior to treatment in patients with cervix cancer using a polarographic oxygen electrode to determine if oxygenation was an important prognostic factor with regard to tumor control and survival. MATERIALS AND METHODS Between May 1994 and June 1997, 74 eligible patients with cervix cancer were entered into an ongoing prospective study of tumor oxygenation prior to primary radiation therapy. All patients were evaluated with an Eppendorf oxygen electrode during examination under anesthesia. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of pO2 readings of <5 mm Hg (abbreviated as HP5). RESULTS The HP5 ranged from 2 to 99% with a median of 52%. With a median follow-up of 1.2 years, the disease-free survival (DFS) rate was 69% for patients with HP5 of < or =50% compared with 34% for those with HP5 of >50% (log-rank P = 0.02). Tumor size above and below the median of 5 cm was also significantly related to DFS (P = 0.0003) and patients with bulky hypoxic tumors had a significantly lower DFS (12% at 2 years) than either bulky oxygenated or non-bulky oxygenated or hypoxic tumors (65%, P = 0.0001). CONCLUSIONS Hypoxia and tumor size are significant adverse prognostic factors in a univariate analysis of disease-free survival in patients with cervix cancer. A high risk group of patients with bulky hypoxic tumors have a significantly higher probability of relapse and death.

Hypoxia: importance in tumor biology, noninvasive measurement by imaging, and value of its measurement in the management of cancer therapy.

PURPOSE The Cancer Imaging Program of the National Cancer Institute convened a workshop to assess the current status of hypoxia imaging, to assess what is known about the biology of hypoxia as it relates to cancer and cancer therapy, and to define clinical scenarios in which in vivo hypoxia imaging could prove valuable. RESULTS Hypoxia, or low oxygenation, has emerged as an important factor in tumor biology and response to cancer treatment. It has been correlated with angiogenesis, tumor aggressiveness, local recurrence, and metastasis, and it appears to be a prognostic factor for several cancers, including those of the cervix, head and neck, prostate, pancreas, and brain. The relationship between tumor oxygenation and response to radiation therapy has been well established, but hypoxia also affects and is affected by some chemotherapeutic agents. Although hypoxia is an important aspect of tumor physiology and response to treatment, the lack of simple and efficient methods to measure and image oxygenation hampers further understanding and limits their prognostic usefulness. There is no gold standard for measuring hypoxia; Eppendorf measurement of pO(2) has been used, but this method is invasive. Recent studies have focused on molecular markers of hypoxia, such as hypoxia inducible factor 1 (HIF-1) and carbonic anhydrase isozyme IX (CA-IX), and on developing noninvasive imaging techniques. CONCLUSIONS This workshop yielded recommendations on using hypoxia measurement to identify patients who would respond best to radiation therapy, which would improve treatment planning. This represents a narrow focus, as hypoxia measurement might also prove useful in drug development and in increasing our understanding of tumor biology.

Tumor Hypoxia Has Independent Predictor Impact Only in Patients With Node-Negative Cervix Cancer

PURPOSE This prospective clinical study was begun in 1994 to validate the independent prognostic impact of tumor hypoxia in patients with cervix cancer treated with definitive radiation therapy. PATIENTS AND METHODS Between May 1994 and January 1999, 106 eligible patients with epithelial cervix cancer had tumor oxygen pressure (PO(2)) measured using the Eppendorf probe. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of PO(2) readings less than 5 mm/Hg (abbreviated as HP(5)) and the median PO(2). RESULTS The median HP(5) in individual patients was 48%, and the median PO(2) was HP(5). Progression-free survival (PFS) for patients with hypoxic tumors (HP(5) > 50%) was 37% at 3 years versus 67% in those patients with better oxygenated tumors (P =.004). In multivariate analysis, only tumor size (risk ratio [RR], 1.33; P =.0003) and evidence of pelvic nodal metastases on imaging studies (RR, 2.52; P =.0065) were predictive of PFS. However, an interaction between nodal status and oxygenation was observed (P =.006), and further analysis indicated that HP(5) was an independent predictor of outcome in patients with negative nodes on imaging (P =.007). There was a significant increase in the 3-year cumulative incidence of distant metastases in the hypoxic group (41% v 15% in those with HP(5) < 50%; P =.0023), but not in pelvic relapse (37% v 27%; P =.12). CONCLUSION Tumor hypoxia is an independent predictor of poor PFS only in patients with node-negative cervix cancer, in addition to tumor size. Its impact appears to be related to an increased risk of distant metastases rather than to an effect on pelvic control.

The effect of treatment duration in the local control of cervix cancer.

A significant effect of treatment duration on pelvic control was found in 830 patients with cervix cancer treated by radical radiation therapy. Using three methods of analysis, the loss of control consistently approximated 1% per day of treatment prolongation beyond 30 days, although analysis of stage subgroups showed that this effect was predominantly manifested in Stages III/IV compared with Stages I/II. In multivariate analyses using both a logistic regression and a Cox regression model, stage (p = 0.0001 for Stage I/IIA and 0.0036 for Stage IIB relative to Stage III/IV) treatment time (p = 0.0001), and age (p = 0.0067) were independently correlated with pelvic control. Exclusion from analysis of patients with delays due to tumour or treatment related complications, intercurrent illness or manifestations of poor tumour response did not significantly change the magnitude of the time effect nor the ranking of the significant covariates. These results are consistent with the occurrence of accelerated repopulation and warrant further investigation, preferably in a randomized trial of accelerated versus conventionally fractionated radiation therapy.

Interim Cosmetic and Toxicity Results From RAPID: A Randomized Trial of Accelerated Partial Breast Irradiation Using Three-Dimensional Conformal External Beam Radiation Therapy

PURPOSE To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation therapy (3D-CRT) with whole-breast irradiation (WBI). PATIENTS AND METHODS Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis. RESULTS Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001). CONCLUSION 3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.

Consensus Guidelines for Delineation of Clinical Target Volume for Intensity-Modulated Pelvic Radiotherapy for the Definitive Treatment of Cervix Cancer

PURPOSE Accurate target definition is vitally important for definitive treatment of cervix cancer with intensity-modulated radiotherapy (IMRT), yet a definition of clinical target volume (CTV) remains variable within the literature. The aim of this study was to develop a consensus CTV definition in preparation for a Phase 2 clinical trial being planned by the Radiation Therapy Oncology Group. METHODS AND MATERIALS A guidelines consensus working group meeting was convened in June 2008 for the purposes of developing target definition guidelines for IMRT for the intact cervix. A draft document of recommendations for CTV definition was created and used to aid in contouring a clinical case. The clinical case was then analyzed for consistency and clarity of target delineation using an expectation maximization algorithm for simultaneous truth and performance level estimation (STAPLE), with kappa statistics as a measure of agreement between participants. RESULTS Nineteen experts in gynecological radiation oncology generated contours on axial magnetic resonance images of the pelvis. Substantial STAPLE agreement sensitivity and specificity values were seen for gross tumor volume (GTV) delineation (0.84 and 0.96, respectively) with a kappa statistic of 0.68 (p < 0.0001). Agreement for delineation of cervix, uterus, vagina, and parametria was moderate. CONCLUSIONS This report provides guidelines for CTV definition in the definitive cervix cancer setting for the purposes of IMRT, building on previously published guidelines for IMRT in the postoperative setting.

Prognostic factors in patients with cervix cancer treated by radiation therapy: results of a multiple regression analysis

A retrospective analysis of 965 patients with invasive cervix cancer treated by radiation therapy between 1976 and 1981 was performed in order to evaluate prognostic factors for disease-free survival (DFS) and pelvic control. FIGO stage was the most powerful prognostic factor followed by radiation dose and treatment duration (P values = 0.0001). If the analysis was limited to patients treated with radical doses of 75 Gy or more, dose was no longer significant. Young age at diagnosis, non-squamous histology and transfusion during treatment were also adverse prognostic factors for survival and control. Para-aortic nodal involvement on lymphogram was associated with a reduction in DFS (P = 0.0027), whereas pelvic lymph node involvement alone was not. In patients with Stage I and IIA disease, tumour size was the most powerful prognostic factor for survival (P = 0.0001) and the extent of pelvic sidewall involvement was significant in patients with Stage III tumours (P = 0.007). Histological grade appeared to be a predictive factor but was only recorded in 712 patients. These features should be considered in the staging of patients and in the design of clinical trials.

MicroRNA-301 Mediates Proliferation and Invasion in Human Breast Cancer

Several microRNAs have been implicated in human breast cancer but none to date have been validated or utilized consistently in clinical management. MicroRNA-301 (miR-301) overexpression has been implicated as a negative prognostic indicator in lymph node negative (LNN) invasive ductal breast cancer, but its potential functional impact has not been determined. Here we report that in breast cancer cells, miR-301 attenuation decreased cell proliferation, clonogenicity, migration, invasion, tamoxifen resistance, tumor growth, and microvessel density, establishing an important oncogenic role for this gene. Algorithm-based and experimental strategies identified FOXF2, BBC3, PTEN, and COL2A1 as candidate miR-301 targets, all of which were verified as direct targets through luciferase reporter assays. We noted that miR-301 is located in an intron of the SKA2 gene which is responsible for kinetochore assembly, and both genes were found to be coexpressed in primary breast cancer samples. In summary, our findings define miR-301 as a crucial oncogene in human breast cancer that acts through multiple pathways and mechanisms to promote nodal or distant relapses.

Concurrent radiation and chemotherapy in vulvar carcinoma

Between June 1984 and February 1988 the role of radiation with concurrent infusional 5-fluorouracil with or without mitomycin C (CT-RT) was examined in 33 patients with vulvar cancer. The median duration of follow-up is 16 months (range 5 to 45 months). Nine received adjuvant postsurgical CT-RT and none has relapsed in the radiation field. Seven are alive disease free. Two have died of distant metastases. Of the 9 receiving definitive primary CT-RT, 6 had initial complete response with subsequent vulvar relapse developing in 3. Seven of the 9 remain disease free after CT-RT alone (in 3) or with the addition of a local excision of residual or recurrent disease (in 6). One patient did not respond to CT-RT and required a radical vulvectomy and groin node dissection. Fifteen received CT-RT for disease recurrence following primary surgery. Disease was present in the vulva only in 11, vulva and inguinal nodes in 1 and nodes only in 3. Eight of the 15 had a complete response and no relapses occurred in the treated sites. Four of the 8 dying of disease developed pulmonary metastases. Serious late complications developed in 2 patients, 1 avascular hip necrosis and 1 proctitis requiring a defunctioning colostomy. CT-RT appears tolerable and may contribute to enhanced locoregional control in recurrent or advanced disease. As initial therapy it may allow lesser surgery with preservation of normal anatomy in selected primary vulvar cancers.