Distant Disease-free Survival Rates Research Articles

Five-year outcome of concurrent radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer: single-institution experience

BACKGROUND AND OBJECTIVESWe aimed to evaluate long-term treatment outcomes and toxicity profile of combined radiotherapy and chemotherapy in Saudi women with locally advanced cervical cancer.DESIGN AND SETTINGSRetrospective study in a tertiary care cancer center in Riyadh, Saudi Arabia.METHODS AND MATERIALSThe medical records of patients with histopathologically proven, locally advanced cervical cancer were analyzed. These patients received three-dimensional conformal radiotherapy with concurrent chemotherapy followed by high dose rate brachytherapy in our center between July 2007 and April 2012. The data regarding the safety profile, response rates, occurrence of locoregional or distant failure, disease-free survival, and overall survival rates were recorded.RESULTSThe median follow-up period was 60 months (range, 8–66) for 74 patients. The median age of study population was 52.3 years (32–78), and the stage IIB was the predominant stage (49 patients [66.2%]). A total of 45 patients (60.9%) had radiologic-positive pelvic ± para-aortic lymphadenopathy. The 5-year locoregional and distant control rates were 84.3% and 78.5%, respectively. The 5-year disease-free and overall survival rates were 75.7% and 64.5%, respectively. Stage, nodal status, and hemoglobin levels were found to be important prognostic factors for locoregional and distant control. Acute grade 3 hematological and nonhematological toxicities were seen in 4 (5.4%) and 4 (5.4%) patients. Late toxicities were mild, and only 1 (1.4%) patient presented with subacute intestinal obstruction.CONCLUSIONConcurrent chemoradiation in Saudi women with locally advanced cervical cancer showed better locoregional and distant control and survival rates with minimal toxicity.

Breast Cancer Subtype and Distant Recurrence after Ipsilateral Breast Tumor Recurrence

There is little information about the impact of breast cancer subtype on prognosis after ipsilateral breast tumor recurrence (IBTR). One hundred eighty-five patients were classified according to breast cancer subtype, as approximated by estrogen receptor, human epidermal growth factor receptor 2 (HER2), and Ki-67, of IBTR, and we evaluated whether breast cancer subtype was associated with distant recurrence after IBTR. There was a significant difference in distant disease-free survival (DDFS) after IBTR according to breast cancer subtype defined by a cutoff of the Ki-67 index of 20% (p=0.0074, log-rank test). The 5-year DDFS rates for patients with luminal A, luminal B, triple-negative, and HER2 types were 86.3, 57.1, 56.6, and 65.9%, respectively. In addition, breast cancer subtype was significantly associated with distant recurrence after IBTR on adjustment for various clinicopathologic factors (p=0.0027, Cox proportional hazards model). Our study suggests that breast cancer subtype based on immunohistochemical staining predicts the outcomes of patients with IBTR. Further analyses are needed (UMIN-CTR number UMIN000008136).

Molecular Markers Predict Distant Metastases After Adjuvant Chemoradiation for Rectal Cancer

The outcomes of adjuvant chemoradiation for locally advanced rectal cancer are nonuniform among patients with matching prognostic factors. We explored the role of molecular markers for predicting the outcome of adjuvant chemoradiation for rectal cancer patients. The study included 68 patients with stages II to III rectal adenocarcinoma who were treated with total mesorectal excision and adjuvant chemoradiation. Chemotherapy based on 5-fluorouracil and leucovorin was intravenously administered each month for 6-12 cycles. Radiation therapy consisted of 54 Gy delivered in 30 fractions. Immunostaining of surgical specimens for COX-2, EGFR, VEGF, thymidine synthase (TS), and Raf kinase inhibitor protein (RKIP) was performed. The median follow-up was 65 months. Eight locoregional (11.8%) and 13 distant (19.1%) recurrences occurred. Five-year locoregional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival (OS) rates for all patients were 83.9%, 78.7%, 66.7%, and 73.8%, respectively. LRFFS was not correlated with TNM stage, surgical margin, or any of the molecular markers. VEGF overexpression was significantly correlated with decreased DMFS (P=.045), while RKIP-positive results were correlated with increased DMFS (P=.025). In multivariate analyses, positive findings for COX-2 (COX-2+) and VEGF (VEGF+) and negative findings for RKIP (RKIP-) were independent prognostic factors for DMFS, DFS, and OS (P=.035, .014, and .007 for DMFS; .021, .010, and <.0001 for DFS; and .004, .012, and .001 for OS). The combination of both COX-2+ and VEGF+ (COX-2+/VEGF+) showed a strong correlation with decreased DFS (P=.007), and the combinations of RKIP+/COX-2- and RKIP+/VEGF- showed strong correlations with improved DFS compared with the rest of the patients (P=.001 and <.0001, respectively). Molecular markers can be valuable in predicting treatment outcome of adjuvant chemoradiation for rectal cancer patients.

Radiation Treatment in Pathologic N0-N1 Patients Treated with Neoadjuvant Chemotherapy Followed by Surgery for Locally Advanced Breast Cancer

PurposeThis study evaluated the treatment results and the necessity to irradiate the supraclavicular lymph node (SCN) region in pathological N0-N1 (pN0-N1) patients with locally advanced breast cancer treated with neoadjuvant chemotherapy (NAC) followed by surgery and radiotherapy (RT).MethodsBetween 1996 and 2008, 184 patients with initial tumor size >5 cm or clinically positive lymph nodes were treated with NAC followed by surgery and RT. Among these patients, we retrospectively reviewed 98 patients with pN0-N1. Mastectomy was performed in 55%. The pathological lymph node stage was N0 in 49% and N1 in 51%. All patients received adjuvant RT to chest wall or breast and 56 patients (57%) also received RT to the SCN region (SCNRT).ResultsAt 5 years, locoregional recurrence (LRR)-free survival, distant metastasis-free survival, disease-free survival (DFS), and overall survival rates were 93%, 83%, 81%, and 91%, respectively. In pN0 patients, LRR was 7% in SCNRT- group and 5% in SCNRT+ group. In pN1 patients, LRR was 7% in SCNRT- group and 6% in SCNRT+ group. There was no significant difference of LRR, regardless of SCNRT. However, in pN1 patients, there were more patients with poor prognostic factors in the SCNRT+ group compared to SCNRT- group. These factors might be associated with worse DFS in the SCNRT+ group, even though RT was administered to the SCN region.ConclusionOur study showed the similar LRR, regardless of SCNRT in pN0-pN1 breast cancer patients after NAC followed by surgery. Prospective randomized trial is called for to validate the role of SCNRT.

Implications of HER2 Amplification in Small, Node‐Negative Breast Cancers: Do Asians Differ?

We investigated the implications of HER2 amplification in Asian women with small, node-negative breast cancer in low- and middle-income countries (LMCs). We reviewed the charts patients treated between 1989 and 2009 with breast conservation therapy for node-negative breast cancers measuring ≤ 2 cm. Disease-free survival (DFS), ipsilateral breast tumor recurrence (IBTR), distant disease-free survival (DDFS), and overall survival (OS) rates were estimated using the Kaplan-Meier method and were compared by the log-rank test. Potential covariates-age, tumor grade, hormone receptor status--were analyzed by multivariate analysis. A total of 519 patients were studied including 204 (39%) and 315 (61%) patients diagnosed with pT1ab and pT1c tumors, respectively. Median follow-up was 57 months. HER2 amplification was found in 17.1% of all patients and in 16.7% patients with pT1ab tumors. Among patients with T1ab tumors, 73.0 and 9.3% underwent adjuvant hormonal and chemotherapy, respectively; 3 of 34 T1ab patients with HER2-amplified tumors received trastuzumab. HER2 amplification was associated with poorer 5-year DFS (83.7% vs. 95.5%, P < 0.0001), DDFS (87.5% vs. 97.9%, P < 0.0001), and IBTR (8.6% vs. 2.1%, P < 0.0001) rates in patients with pT1 tumors. Multivariate analysis showed that HER2 amplification remained a significant negative prognostic factor for DFS [hazard ratio (HR) 4.1, 95% confidence interval (CI) 2.1-7.8, P < 0.0001], DDFS (HR 6.3, 95% CI 2.4-17.0, P < 0.0001), and IBTR (HR 4.5, 95% CI 2.0-10.0, P < 0.0001) rates. In the pT1ab subgroup, univariate analysis showed that HER2 amplification prognosticated for DFS (85.1% vs. 95.7%, P = 0.022) and IBTR (14.9% vs. 3.5%, P = 0.004) rates but not for the OS (100% vs. 99.2%, P = 0.487) rate. Similar results were obtained after excluding patients given trastuzumab. The decision to use trastuzumab in HER2-amplified pT1ab tumors must balance their poor outcome against intrinsic financial limitations in LMCs. Patient selection criteria needs fine-tuning, and resource-sensitive regimens must be explored.

Locoregional Treatment for Breast Carcinoma After Hodgkin's Lymphoma: The Breast Conservation Option

To report clinical and pathologic characteristics and outcome of breast cancer (BC) after irradiation for Hodgkin's lymphoma (HL) in women treated at the Institut Curie, with a special focus on the breast-conserving option. Medical records of 72 women who developed either ductal carcinoma in situ or Stage I-III invasive carcinoma of the breast after HL between 1978 and 2009 were retrospectively reviewed. Median age at HL diagnosis was 23 years (range, 14-53 years). Median total dose received by the mediastinum was 40 Gy, mostly by a mantle-field technique. Breast cancers occurred after a median interval of 21 years (range, 5-40 years). Ductal invasive carcinoma and ductal carcinoma in situ represented, respectively, 51 cases (71%) and 14 cases (19%). Invasive BCs consisted of 47 cT0-2 tumors (82%), 5 cN1-3 tumors (9%), and 20 Grade 3 tumors (35%). Locoregional treatment for BCs consisted of mastectomy with (3) or without (36) radiotherapy in 39 patients and lumpectomy with (30) or without (2) adjuvant radiotherapy in 32 patients. The isocentric lateral decubitus radiation technique was used in 17 patients after breast-conserving surgery (57%). With a median follow-up of 7 years, 5-year overall survival rate and locoregional control rate were, respectively, 74.5% (95% confidence interval [CI], 64-88%) and 82% (95% CI, 72-93%) for invasive carcinoma and 100% (95% CI, 100 -100%) and 92% (95% CI, 79-100%) for in situ carcinoma. In patients with invasive tumors, the 5-year distant disease-free survival rate was 79% (95% CI, 69-91%), and 13 patients died of progressive BC. Contralateral BC was diagnosed in 10 patients (14%). Breast-conserving treatment can be an option for BCs that occur after HL, despite prior thoracic irradiation. It should consist of lumpectomy and adjuvant breast radiotherapy with use of adequate techniques, such as the lateral decubitus isocentric position, to protect the underlying heart and lung.

Prognostic Value of Pretreatment Carcinoembryonic Antigen After Definitive Radiotherapy With or Without Concurrent Chemotherapy for Squamous Cell Carcinoma of the Uterine Cervix

To evaluate whether pretreatment carcinoembryonic antigen (CEA) levels have a prognostic role in patients after definitive radiotherapy for squamous cell carcinoma (SCC) of the uterine cervix. A retrospective study of 550 patients was performed. The SCC antigen (SCC-Ag) and CEA levels were regarded as elevated when they were ≥2 and ≥5 ng/mL, respectively. A total of 208 patients underwent concurrent chemoradiotherapy (CCRT). The Kaplan-Meier method was used to calculate the distant metastasis (DM), local failure (LF), disease-free survival (DFS), and overall survival (OS) rates. Multivariate analysis was performed using the Cox proportional hazards model. The hazard ratio (HR) with 95% confidence interval (CI) was evaluated for the risk of a poor prognosis. Compared with the patients with normal CEA/SCC-Ag levels, CEA levels ≥10 ng/mL but without elevated SCC-Ag levels was an independent factor for LF (HR, 51.81; 95% CI, 11.51-233.23; p < .001), DM (HR, 6.04; 95% CI, 1.58-23.01; p = .008), DFS (HR, 10.17; 95% CI, 3.18-32.56; p < .001), and OS (HR, 5.75; 95% CI, 1.82-18.18; p = .003) after RT alone. However, no significant role for CEA was noted in patients with SCC-Ag levels ≥2 ng/mL. In patients undergoing CCRT, a CEA level ≥10 ng/mL was an independent factor for LF (HR, 2.50; 95% CI, 1.01-6.21; p = .047), DM (HR, 3.41; 95% CI, 1.56-7.46; p = .002), DFS (HR, 2.73; 95% CI, 1.39-5.36; p = .003), and OS (HR, 3.93; 95% CI 1.99-7.75; p < .001). A SCC-Ag level of ≥40 ng/mL was another prognostic factor for DM, DFS, and OS in patients undergoing not only CCRT, but also RT alone. The 5-year OS rate for CCRT patients with CEA <10 ng/mL and ≥10 ng/mL was 75.3% and 35.8%, respectively (p < .001). CCRT was an independent factor for better OS (HR, 0.69; 95% CI, 0.50-0.97; p = .034). Pretreatment CEA levels in patients with SCC of the uterine cervix provide complementary information for predicting LF, DM, DFS, and OS, except for in patients with abnormal SCC-Ag levels before RT alone. More aggressive therapy might be advisable for patients with CEA levels of ≥10 ng/mL.

Prediction of Residual Disease or Distant Metastasis After Resection of Locally Recurrent Rectal Cancer

It is important to preoperatively identify patients at high risk of relapse at extrapelvic sites or residual disease after salvage surgery for locally recurrent rectal cancer to maximize the survival benefit by indicating whether a surgical approach might be successful. Data from 101 consecutive patients who underwent exploration with curative intent for local recurrence after radical resection of rectal cancer were retrospectively collected. Preoperative factors were examined in univariate and multivariate analyses for their ability to predict resectability and distant disease-free survival. The 5-year disease-specific survival rates of R0, R1, and R2 resection were 43.3%, 19.5%, and 10.0%, respectively (P < .001). In a logistic regression analysis, upper sacral (above the inferior margin of the second sacrum)/lateral invasive type and high-grade lymphatic invasion of the primary tumor were associated with palliative surgery. A Cox regression analysis revealed that upper sacral/lateral invasive type, extrapelvic disease, hydronephrosis at recurrence, and high-grade lymphatic or venous invasion of the primary tumor were associated with a lower distant disease-free survival rate. Patients with one or more of these risk factors had a 3-year distant disease-free survival rate of 6.2% compared with 54.1% for those with none of these risk factors. It was possible to preoperatively identify patients at high risk of relapse or residual disease. This system might be used on an individual basis to select patients with locally recurrent rectal cancer for chemotherapy or radiotherapy before surgical intervention with curative intent.

Prognostic Significance of Neutropenia on Day One of Anthracycline-Based Neoadjuvant Chemotherapy in Operable Breast Cancer

Objectives: It is currently unknown whether neutropenia during neoadjuvant chemotherapy for early breast cancer is associated with prognosis. Methods: We retrospectively analyzed 103 breast cancer patients who were treated with neoadjuvant chemotherapy including epirubicin-based chemotherapy followed by docetaxel. The association between neutropenia due to epirubicin-based chemotherapy and distant disease-free survival (DDFS) was assessed. Results: Thirty-one patients (30%) demonstrated neutropenia during the epirubicin-based regimen. Patients without neutropenia showed a significantly (p = 0.004) lower 5-year DDFS rate (64%) than those with neutropenia (97%). In addition, multivariate analysis showed that neutropenia is an independent prognostic factor for DDFS (p = 0.02). Conclusion: Neutropenia occurring in early breast cancer patients during the initial neoadjuvant treatment is strongly associated with a better prognosis.

Oncoplastic Breast Surgery for Cancer: Analysis of 540 Consecutive Cases

Synchronous plastic and oncological surgery is undertaken to improve the security of excision margins and yield high-quality aesthetic outcomes when conventional breast-conserving therapy either anticipates poor results or is not possible. A total of 540 consecutive patients underwent primary oncoplastic breast surgery for cancer with high tumor-to-breast volume ratios and locations precluding a good aesthetic result with simple tumor excision. A variety of techniques were employed at the Institut Curie between 1986 and 2007, and aesthetic outcomes were assessed on a five-point scale from 1 (excellent) to 5 (poor). The median age was 52 years (range, 28 to 90 years), and median follow-up was 49 months (6 to 262 months). Median tumor size was 29.1 mm (range, 4 to 100 mm), with most patients (72.3 percent) having a brassiere cup size of B or C. Close or involved margins occurred in 18.9 percent, with mastectomy being necessary in 9.4 percent. A satisfactory aesthetic outcome (ratings of 1 to 3) at 5 years was obtained in 90.3 percent. Five-year overall and distant disease-free survival rates were 92.9 and 87.9 percent, respectively, with local recurrence in 6.8 percent. With local recurrence and survival rates similar to those for breast-conserving therapy, this series confirms the safety of oncoplastic breast surgery for tumors both high in volume and difficult in location. Highly satisfactory cosmetic outcomes extend the indications for conservative surgery, further reduce the mastectomy rate, and limit adverse aesthetic sequelae.

Radiation therapy and tamoxifen after breast-conserving surgery: Updated results of a 2 × 2 randomised clinical trial in patients with low risk of recurrence

To study the role of radiotherapy and tamoxifen after breast-conserving surgery (BCS) in patients with a favourable prognosis, a clinical trial was initiated by the German Breast Cancer Study Group (GBSG-V). Between 1991 and 1998, 361 patients (pT 1pN0M0, aged 45–75 years, receptor positive, grades I and II) were randomised to radiotherapy (yes/no) and tamoxifen for 2 years (yes/no) in a 2 × 2-factorial design; the exclusion of seven centres (14 patients) left 347 patients for the analysis. First results after a median follow-up of 5.9 years were published. Herein we present updated results after a median follow-up of about 10 years. Hundred and eleven events concerning event-free survival (EFS) have been observed. Since a strong interactive effect between radiotherapy and tamoxifen has been established, the results are presented in terms of the treatment effects for all four treatment groups separately. Mainly due to the presence of local recurrences, the event rate was much higher in the group with BCS only than in the other three groups. No significant difference could be established between the four treatment groups for distant disease-free survival rates (DDFS). Updated results give further evidence that even in patients with a favourable prognosis, the avoidance of radiotherapy and tamoxifen after BCS increases the rate of local recurrences substantially. Rates are about three times higher in the BCS only group. For the two outcomes EFS and DDFS, no important difference could be seen between the three groups with an additional treatment. However, because of the limited sample size with corresponding low power the strength of evidence for such a comparison is weak.

Intensity-Modulated Radiotherapy in the Treatment of Oropharyngeal Cancer: Clinical Outcomes and Patterns of Failure

To report outcomes, failures, and toxicities in patients treated with intensity-modulated radiotherapy (IMRT) for squamous cell carcinoma of the oropharynx. Between Aug 2001 and Oct 2007, 107 patients were treated with IMRT with curative intent at Stanford University. Twenty-two patients were treated postoperatively, and 85 were treated definitively. Concurrent platinum-based chemotherapy was administered to 86 patients (80%) and cetuximab to 8 patients (7%). The prescribed dose was 66 Gy at 2.2 Gy/fraction for definitively treated cases and 60 Gy at 2 Gy/fraction for postoperative cases. Median follow-up was 29 months among surviving patients (range, 4-105 months). Eight patients had persistent disease or local-regional failure at a median of 6.5 months (range, 0-9.9 months). Six local failures occurred entirely within the high-risk clinical target volume (CTV) (one with simultaneous distant metastasis). One patient relapsed within the high- and intermediate-risk CTV. One patient had a recurrence at the junction between the IMRT and low-neck fields. Seven patients developed distant metastasis as the first site of failure. The 3-year local-regional control (LRC), freedom from distant metastasis, overall survival, and disease-free survival rates were 92%, 92%, 83%, and 81%, respectively. T stage (T4 vs. T1-T3) was predictive of poorer LRC (p = 0.001), overall survival (p = 0.001), and disease-free survival (p < 0.001) rates. Acute toxicity consisted of 58% grade 3 mucosal and 5% grade 3 skin reactions. Six patients (6%) developed grade >or=3 late complications. IMRT provides excellent LRC for oropharyngeal squamous cell carcinoma. Distant metastases are a major failure pattern. No marginal failures were observed.

Noncompliance with adjuvant radiation, chemotherapy, or hormonal therapy in breast cancer patients

Introduction There is little information on patient-driven noncompliance of adjuvant therapies and its consequences. Methods This retrospective study compares clinical, pathological features and outcomes of breast cancer patients who were compliant to recommended radiation, chemotherapy, and hormonal therapies to those who were noncompliant. Results Noncompliance rates for chemotherapy, radiation, and tamoxifen were 31 of 421 (7%), 30 of 855 (4%), and 294 of (37%) respectively. Old age was associated with noncompliance to chemotherapy and radiation, but younger women tend to be more often noncompliant to tamoxifen. Noncompliance with chemotherapy or radiation did not significantly affect 5-year local and distant disease-free survival rates. Noncompliance with tamoxifen was associated with decreased 5-year local and distant disease-free survivals (87% versus 96%, 76% versus 87%, respectively, P < .001). Conclusion Noncompliance with tamoxifen is the most common, resulting in significantly increased risk of local and distant disease recurrence.

Definitive chemoirradiation for resectable head and neck cancer: treatment outcome and prognostic significance of MRI findings

The aim of this study was to evaluate the outcome and prognosticators for patients with resectable head and neck cancer (RHNC) undergoing definitive concurrent chemotherapy and radiotherapy (CCRT). In total, 110 RHNC patients receiving definitive CCRT to defer radical surgery were enrolled. Radiotherapy was given as either 2 Gy once daily with 70 Gy, or 1.2 Gy twice daily with 74.4 Gy. Chemotherapy involved the administration of 5-fluorouracil and cisplatin in two concomitant and two post-radiotherapy adjuvant cycles. 3 months after CCRT, MRI was performed to evaluate the response and determine further treatment plans. Survival outcome was calculated by the Kaplan-Meier method. Log-rank test and Cox regression analyses were used to estimate the significance of prognosticators. 4-year local-regional control, distant metastasis-free survival, disease-free survival and overall survival rates were 76.1%, 85.6%, 67.5% and 53.2%, respectively. Local recurrence (odds ratio = 4.09; p < 0.0001) and T3/T4 stage (odds ratio = 2.34; p = 0.01) were the independent factors associated with poor survival. T stage (odds ratio = 3.29; p = 0.03) and/or remission status on post-CCRT MRI (odds ratio = 7.22; p < 0.0001) were significantly associated with local control, distant metastasis-free survival and disease-free survival. 13 of 20 patients with imaging residuum had local recurrence, compared with 12 of 89 with complete remission (4-year local control rate of 27% vs 86%; p < 0.0001). Post-CCRT MRI may thus be used to predict the chance of a successful non-surgical approach.

Carcinomas arising in the submandibular gland: High propensity for systemic failure

Cancers of the submandibular gland are uncommon and only a few small series have reported patient survival and prognosis. We examined the treatment outcomes of 62 patients with surgically treated submandibular gland carcinomas. All patients underwent surgical excision with/without neck dissection, and 41 received postoperative radiotherapy for high-grade, invasive, positive margin, or regionally metastatic tumors. The locoregional control and survival rates were calculated by the Kaplan-Meier method and prognostic factors were calculated from uni- and multivariate analyses. Of the 62 submandibular gland carcinomas, 19 were adenoid cystic, 11 were mucoepidermoid, and 10 were salivary duct carcinomas, and 8 were carcinomas in pleomorphic adenoma. Actuarial 5-year locoregional control, distant metastasis-free survival, disease-free and overall survival rates were 69.7%, 65.8%, 52.8%, and 56.8%, respectively. In multivariate analysis, T category and histological grading were prognostic for disease-free survival (P < 0.01), and T category and resection margins were prognostic for locoregional control (P < 0.02). Distant metastases were found in 21 patients (33.9%) at initial staging (n = 2) or follow-up (n = 19). Despite effective locoregional treatment, approximately one-third of patients with submandibular gland carcinomas may fail systemically, resulting in poor survival. New, more effective therapies may be required for these patients.

Prognosis After Ipsilateral Breast Tumor Recurrence and Locoregional Recurrences in Five National Surgical Adjuvant Breast and Bowel Project Node-Positive Adjuvant Breast Cancer Trials

Locoregional failure after breast-conserving surgery is associated with increased risk of distant disease and death. The magnitude of this risk in patients receiving chemotherapy has not been adequately characterized. Our study population included 2,669 women randomly assigned onto five National Surgical Adjuvant Breast and Bowel Project node-positive protocols (B-15, B-16, B-18, B-22, and B-25), who were treated with lumpectomy, whole-breast irradiation, and adjuvant systemic therapy. Cumulative incidences of ipsilateral breast tumor recurrence (IBTR) and other locoregional recurrence (oLRR) were calculated. Kaplan-Meier curves were used to estimate distant-disease-free survival (DDFS) and overall survival (OS) after IBTR or oLRR. Cox models were used to model survival using clinical and pathologic factors jointly with IBTR or oLRR as time-varying predictors. Four hundred twenty-four patients (15.9%) experienced locoregional failure; 259 (9.7%) experienced IBTR, and 165 (6.2%) experienced oLRR. The 10-year cumulative incidence of IBTR and oLRR was 8.7% and 6.0%, respectively. Most locoregional failures occurred within 5 years (62.2% for IBTR and 80.6% for oLRR). Age, tumor size, and estrogen receptor status were significantly associated with IBTR. Nodal status and estrogen and progesterone receptor status were significantly associated with oLRR. The 5-year DDFS rates after IBTR and oLRR were 51.4% and 18.8%, respectively. The 5-year OS rates after IBTR and oLRR were 59.9% and 24.1%, respectively. Hazard ratios for mortality associated with IBTR and oLRR were 2.58 (95% CI, 2.11 to 3.15) and 5.85 (95% CI, 4.80 to 7.13), respectively. Node-positive breast cancer patients who developed IBTR or oLRR had significantly poorer prognoses than patients who did not experience these events.

Intensity-modulated radiation treatment for head-and-neck squamous cell carcinoma—the University of Iowa experience

To review the University of Iowa experience with intensity-modulated radiotherapy (IMRT) in the treatment of head-and-neck squamous cell carcinoma. From October 1999 to April 2004, 151 patients with head-and-neck squamous cell carcinoma were treated with IMRT for curative intent. One patient was lost to follow-up 2 months after treatment and therefore excluded from analysis. Of the remaining 150 patients, 99 were treated with definitive IMRT, and 51 received postoperative IMRT. Sites included were nasopharynx, 5; oropharynx, 56; larynx, 33; oral cavity, 29; hypopharynx, 8; nasal cavity/paranasal sinus, 8; and unknown primary, 11. None of the patients treated with postoperative IMRT received chemotherapy. Of 99 patients who had definitive IMRT, 68 patients received concurrent cisplatin-based chemotherapy. One patient received induction cisplatin-based chemotherapy, but no concurrent chemotherapy was given. Three clinical target volumes (CTV1, CTV2, and CTV3) were defined. The prescribed doses to CTV1, CTV2, and CTV3 in the definitive cohort were 70-74 Gy, 60 Gy, and 54 Gy, respectively. For high-risk postoperative IMRT, the prescribed doses to CTV1, CTV2, and CTV3 were 64-66 Gy, 60 Gy, and 54 Gy, respectively. For intermediate-risk postoperative IMRT, the prescribed doses to CTV1, CTV2, and CTV3 were 60 Gy, 60 Gy, and 54 Gy. The median follow-up was 18 months (range, 2-60 months). All living patients were followed for at least 6 months. There were 11 local-regional failures: 7 local failures, 3 regional failures, and 1 failure both in the primary tumor and regional lymph node. There were 16 patients who failed distantly, either with distant metastasis or new lung primaries. The 2-year overall survival, local progression-free survival, locoregional progression-free survival, and distant disease-free survival rates were 85%, 94%, 92%, and 87%, respectively. The median time from treatment completion to local-regional recurrence was 4.7 months (range, 1.8 to 15.6 months). Only one marginal failure was noted in a patient who had extensive tonsil cancer with tumor extension into the orbit and cavernous sinus. Patients with oropharyngeal cancer did significantly better than patients with oral cavity and laryngeal cancer, with a 2-year local-regional control rate of 98%, compared with 78% for oral cavity cancer and 85% for laryngeal cancer (p = 0.005). There was no significant difference in local-regional control for patients who received postoperative radiation or definitive radiation (p = 0.339) and for patients who had chemotherapy or not (p = 0.402). Neither T stage nor N stage had a significant effect on local-regional control (p = 0.722 and 0.712, respectively). Our results have confirmed the effectiveness of IMRT in head-and-neck cancer. It offers excellent outcomes in local-regional control and overall survival. More studies are necessary to further improve the outcomes of laryngeal cancer as well as oral cavity cancer.

Cytoplasmic HuR Expression Is a Prognostic Factor in Invasive Ductal Breast Carcinoma

HuR is a ubiquitously expressed mRNA-binding protein. Intracellular localization of HuR is predominantly nuclear, but it shuttles between the nucleus and the cytoplasm. In the cytoplasm it can stabilize certain transcripts. Because nucleocytoplasmic translocation of HuR is necessary for its activity, it was hypothesized that cytoplasmic HuR expression in cancer cells could be a prognostic marker. To test the significance of HuR in carcinogenesis of the breast, we have investigated HuR expression in a mouse mammary gland tumor model and from 133 invasive ductal breast carcinoma specimens. HuR expression was elevated in the cyclooxygenase-2 transgene-induced mouse mammary tumors, and its expression was predominantly cytoplasmic in the tumor cells. In the human carcinoma samples, high cytoplasmic immunoreactivity for HuR was found in 29% (38 of 133) of the cases. Cytoplasmic HuR expression associated with high grade (P = 0.0050) and tumor size over 2 cm (P = 0.0082). Five-year distant disease-free survival rate was 42% [95% confidence interval (95% CI), 26-58] in cytoplasm-high category and 84% (95% CI, 76-91) in cytoplasm-negative or -low category (P < 0.0001), and high cytoplasmic expression of HuR was an independent prognostic factor in a Cox multivariate model (relative risk 2.07; 95% CI, 1.05-4.07). Moreover, high cytoplasmic HuR immunopositivity was significantly associated with poor outcome in the subgroup of node-negative breast cancer in a univariate analysis (P < 0.0007). Our results show that high cytoplasmic HuR expression is associated with a poor histologic differentiation, large tumor size, and poor survival in ductal breast carcinoma. Thus, HuR is the first mRNA stability protein of which expression associates with poor outcome in breast cancer.

Treatment results of 59 young patients with nasopharyngeal carcinoma

To evaluate the outcome of patients </=30 years old with non-metastatic nasopharyngeal carcinoma and discover adverse prognostic factors. We performed a database search maintained by the Department of Radiation Oncology of Hacettepe University School of Medicine for patients with nasopharyngeal cancer who were </=30 years old at presentation. This search identified 59 (23.7%) patients among 248 patients treated between 1994 and 2001 that met the inclusion criteria for this retrospective study. Patients were staged according to AJCC 1997 classification. There were 1 (2%) patient with stage I, 7 (12%) with stage IIb, 25 (42%) with stage III, 9 (15%) with stage IVA, and 17 (29%) with stage IVB. Thirteen (22%) patients were stage T1, 16 (27%) were T2, 21 (36%) were T3, and 9 (15%) were T4. Nodal staging at presentation was as follows; 7 (12%) N0, 22 (37%) N1, 13 (22%) N2, 13 (22%) N3a, and 4 (7%) N3b. All patients were treated with fractionated external beam radiotherapy (EBRT) to a median dose of 65Gy. While 12 (20.3%) patients were treated with EBRT alone, 47 (79.7%) received chemotherapy beside EBRT. Twenty-five (42.3%) patients older than 17 years of age received brachytherapy boost in addition to EBRT. The median follow-up time for all patients was 46 months (range, 1-111 months). While only 3 patients (5%) developed local recurrence (1/21 T3 and 2/9 T4 patients), 13 patients (22%) developed distant metastases (6/35 N1 and 2 and 7/17 N3 patients). None of the patients had regional failure. Four patients (6.7%) died due to the treatment related toxicity. The actuarial 5-year local control (LC), regional control (RC), distant metastasis-free survival (DMFS) and disease-free survival (DFS) rates were 96%, 100%, 76.5%, and 74.5%, respectively. The actuarial 5-year disease-specific survival (DSS) was 70.6%. DFS at 5 years is significantly longer in patients aged <16 years than ones >17 (90.5% versus 64.7%; p=0.02). Patients aged <16 years had longer 5 year DMFS (90.5% versus 67.7%; p=0.05) with a borderline significance. DMFS is significantly shorter in patients initially presented with N3 disease compared to N0-2 disease (58.8% versus 84.4%; p=0.04). We suggest that RT combined with multiagent chemotherapy is effective in achieving satisfactory DFS and comparable OS in young patients with NPC. Results of both previous series and ours are evoking the necessity of early administration of efficient chemotherapeutic agents in addition to radiotherapy, but indistinct is the precise regimen and the intensity along the radiotherapy. All efforts towards decreasing late side effects of treatment should be encouraged in this long life expected group.

Current status of aromatase inhibitors in the management of breast cancer and critique of the NCIC MA-17 trial.

The third-generation aromatase inhibitors reduce circulating estrogen levels in postmenopausal women and are well tolerated orally for breast cancer. Their role in the management of advanced breast cancer has already been recognized. This article reviews the evidence for their role in the adjuvant treatment of early-stage disease. Three large multicenter trials are reviewed. The ATAC trial compared anastrozole and tamoxifen or a combination of the two, for 5 years from the point of diagnosis. The NCIC trial published the results of letrozole compared with placebo after the completion of 5 years of tamoxifen. Most recently, the Intergroup Exemestane Study reported a comparison of 5 years of tamoxifen vs 2 years of tamoxifen followed by 3 years of exemestane. The aromatase inhibitor arm in each of these studies was associated with improved disease-free survival and good tolerability. Because of the three different settings, cross-trial comparisons of the different aromatase inhibitors are impossible, but in each case the novel therapy appears promising. This review is critical of the early stopping of the NCIC study and recommends more mature follow-up in each case until distant disease-free or overall survival rates can be measured and then correlated with adverse events. The late onset of osteoporotic fractures is a concern that must be addressed before tamoxifen can be abandoned in favor of the aromatase inhibitor in each of the three clinical points: at diagnosis, at midway through a course of tamoxifen, and as an extension to the conventional 5-year period of endocrine therapy.