High-dose, single-fraction image-guided intensity-modulated radiotherapy for metastatic spinal lesions.

PURPOSE: To report tumor control and toxicity for patients treated with image-guided intensity-modulated radiotherapy (RT) for spinal metastases with high-dose single-fraction RT. METHODS AND MATERIALS: A total of 103 consecutive spinal metastases in 93 patients without high-grade epidural spinal cord compression were treated with image-guided intensity-modulated RT to doses of 18-24 Gy (median, 24 Gy) in a single fraction between 2003 and 2006. The spinal cord dose was limited to a 14-Gy maximal dose. The patients were prospectively examined every 3-4 months with clinical assessment and cross-sectional imaging. RESULTS: The overall actuarial local control rate was 90% (local failure developed in 7 patients) at a median follow-up of 15 months (range, 2-45 months). The median time to local failure was 9 months (range, 2-15 months) from the time of treatment. Of the 93 patients, 37 died. The median overall survival was 15 months. In all cases, death was from progression of systemic disease and not local failure. The histologic type was not a statistically significant predictor of survival or local control. The radiation dose was a significant predictor of local control (p = 0.03). All patients without local failure also reported durable symptom palliation. Acute toxicity was mild (Grade 1-2). No case of radiculopathy or myelopathy has developed. CONCLUSION: High-dose, single-fraction image-guided intensity-modulated RT is a noninvasive intervention that appears to be safe and very effective palliation for patients with spinal metastases, with minimal negative effects on quality of life and a high probability of tumor control.

Epidermal growth factor receptor signaling in adenocarcinomas with bronchioloalveolar components.

BACKGROUND: Epidermal growth factor receptor (EGFR) has gained importance in non-small cell lung cancer given impressive responses to agents targeting this molecule, particularly in bronchioloalveolar carcinoma (BAC) and adenocarcinomas, mixed subtype, with BAC components (adeno/BAC). This study assesses EGFR signaling in these tumors. METHODS: One hundred fifty tumors were classified as BAC or adeno/BAC. Tumor marker expression was determined by immunohistochemistry. Correlations with expression were examined for all tumors (BAC and adeno/BAC), and by BAC and adeno/BAC subset analyses. RESULTS: Positive immunophenotype was observed in 40.6% of tumors for EGFR, 51.3% for p-AKT, 58.7% for p-ERK, and 28.0% for PTEN, with increased overexpression of EGFR (p = 0.025) and p-AKT (p < 0.0001) in adeno/BAC. Epidermal growth factor receptor immunophenotype was greater in never-smokers (p = 0.008) and correlated with improved overall survival (p = 0.018). On subset analysis, EGFR correlated with improved overall survival (p = 0.05) and disease-free interval (p = 0.044) only in adeno/BAC. Epidermal growth factor receptor independently predicted improved disease-free interval in adeno/BAC (p = 0.03; hazard ratio, 0.47; 95% confidence interval, 0.23 to 0.94). CONCLUSIONS: Overexpression of EGFR in lung adenocarcinomas with components of BAC histology correlate with never-smoker status and improved overall survival and disease-free interval. Epidermal growth factor receptor immunophenotype may be a useful predictor of clinical outcomes in this tumor subset.

Salvage re-irradiation for recurrent head and neck cancer.

PURPOSE: To present a retrospective review of treatment outcomes for recurrent head and neck (HN) cancer patients treated with re-irradiation (re-RT) at a single medical center. METHODS AND MATERIALS: From July 1996-September 2005, 105 patients with recurrent HN cancer underwent re-RT at our institution. Sites included were: the neck (n = 21), nasopharynx (n = 21), paranasal sinus (n = 18), oropharynx (n = 16), oral cavity (n = 9), larynx (n = 10), parotid (n = 6), and hypopharynx (n = 4). The median prior RT dose was 62 Gy. Seventy-five patients received chemotherapy with their re-RT (platinum-based in the majority of cases). The median re-RT dose was 59.4 Gy. In 74 (70%), re-RT utilized intensity-modulated radiation therapy (IMRT). RESULTS: With a median follow-up of 35 months, 18 patients were alive with no evidence of disease. The 2-year loco-regional progression-free survival (LRPFS) and overall survival rates were 42% and 37%, respectively. Patients who underwent IMRT, compared to those who did not, had a better 2-year LRPF (52% vs. 20%, p < 0.001). On multivariate analysis, non-nasopharynx and non-IMRT were associated with an increased risk of loco-regional (LR) failure. Patients with LR progression-free disease had better 2-year overall survival vs. those with LR failure (56% vs. 21%, p < 0.001). Acute and late Grade 3-4 toxicities were reported in 23% and 15% of patients. Severe Grade 3-4 late complications were observed in 12 patients, with a median time to development of 6 months after re-RT. CONCLUSIONS: Based on our data, achieving LR control is crucial for improved overall survival in this patient population. The use of IMRT predicted better LR tumor control. Future aggressive efforts in maximizing tumor control in the recurrent setting, including dose escalation with IMRT and improved chemotherapy, are warranted.

A comparison of intensity-modulated radiation therapy and concomitant boost radiotherapy in the setting of concurrent chemotherapy for locally advanced oropharyngeal carcinoma.

PURPOSE: The aim of this study was to compare toxicity/efficacy of conventional radiotherapy using delayed accelerated concomitant boost radiotherapy (CBRT) vs. intensity-modulated radiotherapy (IMRT) in the setting of concurrent chemotherapy (CT) for locally advanced oropharyngeal carcinoma. METHODS AND MATERIALS: Between September 1998 and June 2004, a total of 293 consecutive patients were treated at our institution for cancer of the oropharynx. Of these, 112 had Stage III/IV disease and squamous cell histology. In all, 41 were treated with IMRT/CT and 71 were treated with CBRT/CT, both to a median dose of 70 Gy. Most common CT was a planned two cycles given every 3 to 4 weeks of cisplatin, 100 mg/m2 i.v., but an additional cycle was given to IMRT patients when possible. Both groups were well-matched for all prognostic factors. RESULTS: Median follow-up was 46 months (range, 3-93 months) for the CBRT patients and 31 months (range, 20-64 months) for the IMRT group. Three-year actuarial local-progression-free, regional-progression-free, locoregional progression-free, distant-metastases-free, disease-free, and overall survival rates were 85% vs. 95% (p = 0.17), 95% vs. 94% (p = 0.90), 82% vs. 92% (p = 0.18), 85% vs. 86% (p = 0.78), 76% vs. 82% (p = 0.57), and 81% vs. 91% (p = 0.10) for CBRT and IMRT patients, respectively. Three patients died of treatment-related toxicity in the CBRT group vs. none undergoing IMRT. At 2 years, 4% IMRT patients vs. 21% CBRT patients were dependent on percutaneous endoscopic gastrostomy (p = 0.02). Among those who had > or =20 months follow-up, there was a significant difference in Grade > or =2 xerostomia as defined by the criteria of the Radiation Therapy and Oncology Group, 67% vs. 12% (p = 0.02), in the CBRT vs. IMRT arm. CONCLUSION: In the setting of CT for locally advanced oropharyngeal carcinoma, IMRT results in lower toxicity and similar treatment outcomes when compared with CBRT.

Evaluation of postradiotherapy PSA patterns and correlation with 10-year disease free survival outcomes for prostate cancer.

PURPOSE: To describe the prostate-specific antigen (PSA) pattern profiles observed after external beam radiotherapy with and without short-term neoadjuvant androgen deprivation therapy (ST-ADT) and to report the association of established posttreatment PSA patterns with long-term disease-free survival outcomes. METHODS AND MATERIALS: A total of 1,665 patients were treated with conformal external beam radiotherapy for clinically localized prostate cancer. Of 570 patients who had the requisite>10 consecutive PSA measurements for statistical analysis, 194 patients received a median of 3 months of ADT before radiotherapy and 376 were treated with radiotherapy alone. The median follow up was 103 months. RESULTS: In the group treated with ST-ADT, three distinct postradiotherapy PSA patterns were identified: a stable trend (44%), an increasing trend followed by stabilization of the PSA (25%), and an increasing trend (31%). Among the subgroup that demonstrated a rising and subsequent stabilizing patterns, PSA levels had gradually risen to a median value of 0.9 ng/mL after therapy, stabilized, and remained durably suppressed. The only identified trends among patients treated with external beam radiotherapy without ST-ADT were declining PSA levels followed by stable PSA trends or declining patterns followed by rising levels. Patients whose PSA levels stabilized after an initial rise or those with slowly rising PSA profiles had a lower incidence of distant metastasis compared to those with accelerated rises after therapy. CONCLUSIONS: For those treated with external beam radiotherapy in conjunction with ST-ADT, a significant percentage who develop a rising PSA after treatment are expected to manifest subsequent stabilization at plateaued levels of approximately 1.0 ng/mL, which can remain durably suppressed. The likelihood of distant metastasis in these patients is low despite the PSA stabilization at levels 1.0 ng/mL or higher and comparable to outcomes observed for those with lower nonrising PSA values.

Guidelines and selection criteria for secondary cytoreductive surgery in patients with recurrent, platinum-sensitive epithelial ovarian carcinoma.

BACKGROUND: The benefit of cytoreductive surgery for patients with recurrent epithelial ovarian cancer has not been defined clearly. The objective of this study was to identify prognostic factors for survival in patients who underwent secondary cytoreduction for recurrent, platinum-sensitive epithelial ovarian cancer and to establish generally applicable guidelines and selection criteria. METHODS: The authors reviewed all patients who underwent secondary cytoreduction for recurrent epithelial ovarian cancer from 1987 to 2001. Potential prognostic factors were evaluated in univariate and multivariate analyses. RESULTS: In total, 157 patients underwent secondary cytoreduction, and 153 of those patients were evaluable. After secondary cytoreduction, the median follow-up was 36.9 months (range, 0.2-125.6 months), and the median survival was 41.7 months (95% confidence interval, 36.0-47.2 months). For patients who had a disease-free interval prior to recurrence of between 6 months and 12 months, the median survival was 30 months compared with 39 months for patients who had a disease-free interval between 13 months and 30 months and 51 months for patients who had a disease-free interval >30 months (P = .005). For patients who had a single site of recurrence, the median survival was 60 months compared with 42 months for patients who had multiple sites of recurrence and 28 months for patients who had carcinomatosis (P <.001). The median survival for patients who had residual disease that measured < or =0.5 cm was 56 months compared with 27 months for patients who had residual disease that measured >0.5 cm (P <.001). On multivariate analysis, disease-free interval (P = .004), the number of recurrence sites (P = .01), and residual disease (P <.001) were significant prognostic factors. CONCLUSIONS: In the authors' analysis of secondary cytoreduction for recurrent epithelial ovarian cancer, a significant survival benefit was demonstrated for residual disease that measured < or = 0.5 cm. The disease-free interval and the number of recurrence sites should be used as selection criteria for offering secondary cytoreduction.

Use of cigarette-smoking history to estimate the likelihood of mutations in epidermal growth factor receptor gene exons 19 and 21 in lung adenocarcinomas.

PURPOSE: Lung adenocarcinomas with mutations in exons 19 and 21 of the epidermal growth factor receptor gene (EGFR) demonstrate sensitivity to gefitinib or erlotinib. Investigators have reported an association between EGFR mutations and the amount and duration of cigarette smoking, with the highest incidence of mutations seen in never smokers. METHODS: EGFR exon 19 and 21 mutation status was determined in 265 tumor samples using direct sequencing, polymerase chain reaction (PCR), or PCR-based restriction fragment length polymorphism analysis. A detailed smoking history was obtained. Patients were categorized as never smokers (< 100 lifetime cigarettes), former smokers (quit > or = 1 year ago), or current smokers (quit < 1 year ago). RESULTS: We detected EGFR mutations in 34 (51%) of 67 never smokers (95% CI, 38% to 64%), 29 (19%) of 151 former smokers (95% CI, 13% to 27%), and two (4%) of 47 current smokers (95% CI, 1% to 16%). Significantly fewer EGFR mutations were found in people who smoked for more than 15 pack-years (P < .001) or stopped smoking less than 25 years ago (P < .02) compared with individuals who never smoked. The number of smoking pack-years and smoke-free years predicted the prevalence of EGFR mutations (areas under receiver operating characteristic curve = 0.78 and 0.77, respectively). CONCLUSION: The likelihood of EGFR mutations in exons 19 and 21 decreases as the number of pack-years increases. Mutations were less common in people who smoked for more than 15 pack-years or who stopped smoking cigarettes less than 25 years ago. These data can assist clinicians in assessing the likelihood of exon 19 and 21 EGFR mutations in patients with lung adenocarcinoma when mutational analysis is not feasible.

Clinical course of patients with non-small cell lung cancer and epidermal growth factor receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib.

PURPOSE: In patients with non-small cell lung cancer (NSCLC), mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase domain have been associated with sensitivity to erlotinib and gefitinib. We undertook this study to explore the relationship between EGFR mutation type and clinical variables, including treatment with gefitinib and erlotinib. EXPERIMENTAL DESIGN: In patients with NSCLC, EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by nonsequencing PCR-based methods from paraffin blocks of tissue obtained before treatment. The results were correlated with clinical information (sex, pathologic subtype, race/ethnicity, treatment, and overall survival). RESULTS: The two most common EGFR mutations were identified in 24% (70 of 291; 95% confidence interval, 26%-38%) of tumors from patients with NSCLC. EGFR mutation was associated with Asian ethnicity (P = 0.0023) and being a "never smoker" (P = 0.0001). Among patients with EGFR mutations, 39% (27 of 70) had EGFR L858R, whereas 61% (43 of 70) had an EGFR exon 19 deletion. After treatment with erlotinib (n = 12) or gefitinib (n = 22), patients with EGFR mutations had a median overall survival of 20 months. After treatment with erlotinib or gefitinib, patients with EGFR exon 19 deletions had significantly longer median survival than patients with EGFR L858R (34 versus 8 months; log-rank P = 0.01). CONCLUSIONS: EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations.

Identification of prognostic factors after positive second-look surgery in epithelial ovarian carcinoma.

OBJECTIVE: The objective of this study was to identify independent prognostic factors for survival in patients with epithelial ovarian cancer who had persistent disease identified at second-look surgery. METHODS: We performed a retrospective chart review of all patients with epithelial ovarian cancer who had positive findings at second-look surgery between June 1991 and June 2002. All patients achieved a complete clinical remission after a prescribed course of primary therapy. Survival was determined from the time of second-look surgery until last follow-up or death. RESULTS: The study included a total of 262 patients, with a median age of 54 years (range, 22-80). Of the 262 patients, 166 (63%) had died of disease. Records of initial (salvage) treatment after the positive second-look surgery were available for 243 patients. Therapies included the following: intraperitoneal (IP) cisplatin, 71 (29%); IP cisplatin combined with a second drug, 53 (22%); IP therapy other than cisplatin, 29 (12%); intravenous (IV) chemotherapy, 50 (21%); IP and IV therapy, 35 (14%); and oral chemotherapy, 5 (2%). Of the 13 potential prognostic factors analyzed, only 2 factors emerged that, when combined, were significant--residual disease after primary surgery and size of persistent disease found at second-look surgery. Patients with

Mesorectal lymph node involvement and prognostic implications at total pelvic exenteration for gynecologic malignancies.

OBJECTIVES: To determine the incidence and prognostic implications of positive mesorectal lymph nodes in patients undergoing total pelvic exenteration for recurrent gynecologic malignancies. METHODS: We performed a retrospective chart review of all patients who had undergone total pelvic exenteration for a gynecologic malignancy between July 1992 and December 2003. Patient charts were reviewed for information regarding demographics, site of cancer, histology, pathology report, and time to recurrence. RESULTS: Fifty-eight women had undergone total pelvic exenteration for recurrent gynecologic malignancies during the study period and 57 were available for analysis. Primary cancer site was as follows: cervix, 37 (65%); vagina, 8 (14%); vulva, 5 (9%); and uterine corpus, 7 (12%). In 30 patients (53%), the mesorectal lymph node status was pathologically evaluated. Of these 30 patients, 3 (10%) had positive mesorectal lymph nodes at the time of total pelvic exenteration. All 3 patients had rectal wall involvement (rectal submucosa, 2; rectal mucosa, 1), and all 3 patients recurred within 4 months of pelvic exenteration. The median time to recurrence after surgery was 2.4 months in those patients with positive mesorectal lymph nodes compared with 7.3 months in those with negative mesorectal lymph nodes (P = 0.005). When individually adjusted for other prognostic variables, such as margin status, tumor grade, lymphovascular space involvement, primary cancer site, and histologic type, a finding of positive mesorectal lymph nodes was associated with a shorter time to recurrence of disease (all P < 0.05). CONCLUSIONS: Mesorectal lymph node involvement is a common finding at total pelvic exenteration, particularly in patients with rectal wall involvement. Patients with positive mesorectal lymph nodes appear to have a worse outcome with a shorter time to recurrence of disease.

The relationship of pathologic tumor regression grade (TRG) and outcomes after preoperative therapy in rectal cancer.

PURPOSE: To examine the relationship between tumor regression grade (TRG) and outcomes in patients with rectal cancer treated with preoperative therapy. METHODS AND MATERIALS: Specimens from 144 patients with cT3,4 rectal cancer who had received preoperative radiation +/- chemotherapy and had a minimum follow-up of 3 years were retrospectively reviewed. TRG, which involves examining the residual neoplastic cells and scoring the degree of both cytological changes, including nuclear pyknosis or necrosis and/or eosinophilia, as well as stromal changes, including fibrosis (either dense or edematous) with or without inflammatory infiltrate and giant-cell granulomatosis around ghost cells and keratin, was quantified in five grades according to the Mandard score (Cancer 1994;73:2680-2686). The greater the response, the lower the TRG score. The median follow-up was 72 months (range, 40-143 months). RESULTS: Of the 144 patients, 19% were TRG1, 12% were TRG2, 21% were TRG3, 46% were TRG4, and 1% were TRG5. To simplify the analysis, TRG was combined into two groups: TRG1-2 and TRG3-5. By univariate analysis, none of the pretreatment factors examined, including age, circumference, length, distance from the anorectal ring, pretreatment T and N stage, and INDpre (defined as the pretreatment reference index size based on digital rectal examination), had an impact on 5-year outcomes, including local control, metastases-free survival, disease-free survival, and overall survival. Postoperative parameters, including pathologic T stage (pT), pathologic N stage (pN), and TRG, did significantly influence 5-year outcomes. These included local failure: pT0-2: 5% vs. pT3-4: 19%, p = 0.007; pN0: 7% vs. pN1-3: 26%, p = 0.002; TRG1-2: 2% vs. TRG3-5: 17%, p = 0.013; metastasis-free survival: pT0-2: 86% vs. pT3-4: 62%, p = 0.005; pN-: 86% vs. pN*: 42%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 66%, p = 0.004; disease-free survival: pT0-2: 83% vs. pT3-4: 54%, p = 0.001; pN0: 80% vs. pN1-3: 39%, p < 0.001; TRG1-2: 91% vs. TRG3-5: 58%, p < 0.001; and overall survival: pT0-2: 85% vs. pT3-4: 65%, p = 0.007; pN0: 86% vs. pN1-3: 45%, p < 0.001; TRG1-2: 89% vs. TRG3-5: 68%, p = 0.004. By multivariate analysis combining all pre- and posttreatment parameters, only pN (p < 0.001) and TRG (p = 0.005) significantly predicted disease-free survival. Furthermore, TRG predicted the incidence of pathologic nodal involvement (p < 0.0001). CONCLUSIONS: By univariate analysis, TRG is a predictor for local failure, metastases-free survival, and overall survival. By multivariate analysis, it predicts improved disease-free survival. Given the ability of TRG to predict those patients with N* disease, it may be helpful, in combination with other clinicopathologic factors, in selecting patients for a more conservative procedure, such as local excision rather than radical surgery, after preoperative therapy.

Pilot study prospectively evaluating the use of the measurement of preoperative sonographic endometrial thickness in postmenopausal patients with endometrial cancer.

OBJECTIVE: The value of sonographic evaluation of the endometrial thickness as a screening or a prognostic tool for endometrial cancer remains controversial. The objective of this study was to prospectively evaluate the endometrial thickness in women with known endometrial cancer to assess the predictive value of this modality and its preoperative use in this disease. DESIGN: In a prospective, nonrandomized trial, 29 patients with pathologically confirmed endometrial cancer had preoperative transvaginal ultrasound and endometrial thickness evaluated. Body mass index (BMI) and endometrial thickness were recorded and correlated with surgical and pathologic information. RESULTS: The median age at diagnosis of endometrial cancer was 61.6 years (range, 48-87 years). Tumor grade was as follows: grade 1, 23; grade 2, 3; and grade 3, 3. All patients had an endometrial stripe of 5.0 mm or more. The median preoperative sonographic endometrial stripe was 12.0 mm (range, 5.0-32.0 mm). After surgery, 25 patients (86%) were diagnosed with International Federation of Gynecology and Obstetrics (FIGO) stage I disease (IA, 8; IB, 14; IC, 3), 2 (7%) with stage II disease, and 2 (7%) with stage III disease. Median BMI was 33 (range, 20-56). The patients' BMIs were found to be directly associated with endometrial thickness (rank correlation = 0.39; P = 0.03). Stage was only marginally associated with endometrial thickness (correlation 0.23; P = 0.07). Sonographic endometrial thickness was not associated with depth of myometrial invasion. No correlation was found between endometrial thickness and patient age or tumor grade. CONCLUSIONS: Although patients with endometrial cancer and a high BMI are likely to have a thickened endometrial stripe, endometrial thickness does not correlate with tumor grade or stage. The use of preoperative transvaginal ultrasound in diagnosed endometrial cancer appears limited.

Ten-year experience with laparoscopy on a gynecologic oncology service: analysis of risk factors for complications and conversion to laparotomy.

OBJECTIVE: The purpose of this study was to analyze our initial 10-year experience with laparoscopy and to determine risk factors for complications and conversions to laparotomy for technical difficulty. STUDY DESIGN: We reviewed the charts of all laparoscopic procedures from January 1991 through December 2000 and divided the procedures into 4 levels on the basis of the degree of difficulty: level I, diagnostic; level II, procedures on the uterus and/or adnexa; level III, second look operations for malignancy; and level IV, lymphadenectomies/other complex procedures. Complications were graded from 1 (mild) to 5 (death). Standard univariate and multivariate analyses were performed. RESULTS: We identified 1451 evaluable procedures. The number of complications was as follows: grades 1 to 5, 129 complications (9%); grades 3 to 5, 36 complications (2.5%). On multivariate analysis, older age ( P = .03), previous radiation ( P = .03), and malignancy ( P = .006) were associated with an increased risk of complications grades 3 to 5. Complication rates for grades 3 to 5 for patients with malignancy versus benign disease was 4% versus 1%, respectively. Technical difficulty led to conversion to laparotomy in 105 cases (7%). Previous abdominal surgery ( P < .001) significantly increased the rate of conversion to laparotomy; more complex, higher procedure levels were associated with a significant decrease in conversions ( P = .005). CONCLUSION: Both simple and complex laparoscopic procedures can be performed by a gynecologic oncology service with a low rate of complications and conversions to laparotomy. Older age, malignancy, previous radiation therapy, and previous abdominal surgery were identified as significant risk factors for complications and/or conversion and should be taken into account in patient selection, preoperative counseling, and surgical planning.

SCCRO expression correlates with invasive progression in bronchioloalveolar carcinoma.

BACKGROUND: Overexpression of squamous cell carcinoma-related oncogene (SCCRO) is associated with invasive progression and poor outcomes in non-small cell lung cancer. We assessed the role of SCCRO as a tumor marker in bronchioloalveolar carcinoma (BAC), a subtype of adenocarcinoma exhibiting evidence of histologic tumor progression. We hypothesized that SCCRO expression would correlate with invasive tumor phenotypes and worse survival in BAC. METHODS: We classified 150 tumors as pure BAC, BAC with focal invasion, or adenocarcinoma with BAC features. A tissue microarray was constructed from areas of benign lung, BAC, and invasive adenocarcinoma in these tumors. Squamous cell carcinoma-related oncogene expression was graded by immunohistochemistry from 0 to 3 (absent, low, moderate, or high), with positive SCCRO phenotype defined as grade 3. Squamous cell carcinoma-related oncogene specificity was determined by Wilcoxon rank test and area under the receiver-operator curve, survival by the Kaplan-Meier method, and correlation with prognostic factors by log-rank test. RESULTS: Of the 86.0% (129 of 150) of specimens suitable for analysis, positive SCCRO phenotype was seen in 16.3% (21 of 129) and was 100.0% specific for tumor versus benign tissue (area under receiver-operator curve, 0.92). Positive SCCRO phenotype was greater in tumors with increasing degrees of invasive histologic type (7.0% pure BAC, 13.6% BAC with focal invasion, and 28.6% adenocarcinoma with BAC features; p = 0.02). Low-level SCCRO expression was present in 83.9% (99 of 118) of benign tissues and correlated with tobacco use and poor survival (p = 0.05). CONCLUSIONS: Squamous cell carcinoma-related oncogene is a marker of invasive tumor progression in BAC. Low-level expression in adjacent benign lung predicts worse survival, and may represent field cancerization or host-tumor effects.

Breast cancer metastatic to abdomen and pelvis: role of surgical resection.

OBJECTIVE: The purpose of this study was to describe the characteristics and outcome of women with metastatic breast cancer to the abdomen and pelvis, and to assess the role of surgical resection of abdominal and pelvic metastasis in this disease. METHODS: We retrospectively reviewed the medical records of 59 women with documented metastatic breast cancer to the abdomen or pelvis who had exploratory surgery by the Gynecology Service between 1986 and 2001. RESULTS: Exploratory surgery was performed a median of 5 years (range, 0-25 years) after initial diagnosis of breast cancer. Median survival from diagnosis of abdominal disease was 23 months, and 5-year survival was 24%. Survival was 36 months for optimally debulked patients (<2 cm of residual disease) and 20 months for suboptimally debulked patients (P = 0.07). Patients diagnosed 5 or more years after initial breast cancer diagnosis had a median survival of 36 months versus 17 months if diagnosed earlier (P < 0.01). On multivariate analysis the time to recurrence of breast cancer in the abdomen and optimal debulking were both significant variables. Hazard ratio for dying of disease if recurring before 5 years was 2.7 (CI 1.45-5.03) [P < 0.01]. Hazard ratio for dying of disease if suboptimal debulking was achieved was 2.14 (CI 1.13-4.02) [P = 0.02]. CONCLUSIONS: The disease pattern of metastatic breast carcinoma to the abdomen and pelvis does not appear to effect survival. Survival in patients where optimal debulking is achieved and in those recurring late is improved. Surgical resection of metachronous metastatic breast cancer to the abdomen and pelvis may be an important component of the management of this disease and should be considered in candidate patients.

Predictors of biochemical outcome with salvage conformal radiotherapy after radical prostatectomy for prostate cancer.

PURPOSE: To identify predictors of biochemical outcome following radiotherapy in patients with a rising prostate-specific antigen (PSA) after radical prostatectomy for prostate cancer. PATIENTS AND METHODS: One hundred fifteen patients with a rising PSA after radical prostatectomy received salvage three-dimensional conformal radiotherapy (3D-CRT) alone or with neoadjuvant androgen deprivation. Tumor-related and treatment-related factors were evaluated to identify predictors of subsequent PSA failure. RESULTS: The median follow-up time after 3D-CRT was 42 months. The 4-year actuarial PSA relapse-free survival, distant metastasis-free survival, and overall survival rates were 46%, 83%, and 95%, respectively. Multivariate analysis, which was limited to 70 patients receiving radiation without androgen deprivation therapy, showed that negative/close margins (P =.03), absence of extracapsular extension (P <.01), and presence of seminal vesicle invasion (P <.01) were independent predictors of PSA relapse after radiotherapy. Neoadjuvant androgen deprivation did not improve the 4-year PSA relapse-free survival in patients with positive margins, extracapsular extension, and no seminal vesicle invasion (P =.24). However, neoadjuvant androgen deprivation did improve PSA relapse-free survival when one or more of these variables were absent (P =.03). CONCLUSIONS: Salvage 3D-CRT can provide biochemical control in selected patients with a rising PSA after radical prostatectomy. Among patients with positive margins and no poor prognostic features, 77% achieved PSA control after salvage 3D-CRT. Salvage neoadjuvant androgen deprivation therapy may improve short-term biochemical control, but it requires further study.

Clinical pattern and pathologic stage but not histologic features predict outcome for bronchioloalveolar carcinoma.

BACKGROUND: The histologic criteria defining bronchioloalveolar carcinoma (BAC) were recently revised, but it is unclear whether these criteria predict clinical behavior. This study determined the outcome of resected BAC in relationship to clinical and radiologic disease pattern, and pathologic features. METHODS: Between 1989 and 2000, 100 consecutive surgically treated patients with adenocarcinomas exhibiting various degrees of BAC features were retrospectively studied. Histology was reviewed; tumors were classified as pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features. Clinical and radiologic pattern were classified as unifocal, multifocal, or pneumonic. Demographic data, tumor stage, and outcome were recorded. Survival was analyzed by the Kaplan-Meier method, and prognostic factors were determined by the log-rank test. RESULTS: Patient median age was 65, and 74% of the patients were female. Pure BAC, BAC with focal invasion, and adenocarcinoma with BAC features occurred in 47, 21, and 32 patients, respectively. Unifocal disease occurred in 64 patients, multifocal in 29, and pneumonic in 7. Seventy-one patients had stage I/II tumors, 22 had stage III/IV, and 7 patients had Stage X tumors. Overall 5-year survival was 74%. There was no significant difference in survival among the three histologic subtypes. The pneumonic pattern had significantly worse survival compared with unifocal and multifocal patterns. Pathologic stage predicted survival, with 5-year survivals for I/II and III/IV of 83.7% and 59.6%, respectively. CONCLUSIONS: Clinical pattern and pathologic stage, but not the degree of invasion on histologic examination predict survival. Multifocal disease is associated with excellent long-term survival after resection. The favorable survival of stage III/IV BAC indicates that the current staging system does not fully describe this disease in patients undergoing resection because of its distinct tumor behavior.

Dose-volume factors contributing to the incidence of radiation pneumonitis in non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy.

PURPOSE: To analyze acute lung toxicity data of non-small-cell lung cancer patients treated with three-dimensional conformal radiation therapy in terms of dosimetric variables, location of dose within subvolumes of the lungs, and models of normal-tissue complication probability (NTCP). METHODS AND MATERIALS: Dose distributions of 49 non-small-cell lung cancer patients treated in a dose escalation protocol between 1992 and 1999 were analyzed (dose range: 57.6-81 Gy). Nine patients had RTOG Grade 3 or higher acute lung toxicity. Correlation with dosimetric and physical variables, as well as Lyman and parallel NTCP models, was assessed. Lungs were evaluated as a single structure, as superior and inferior halves (to assess significance of dose to upper and lower lungs), and as ipsilateral and contralateral lungs. RESULTS: For the whole lung, Grade 3 or higher pneumonitis was significantly correlated (p 0.5 for superior lung indices, and >0.1 for contralateral lung indices studied). CONCLUSIONS: For these patients, commonly used dosimetric and NTCP models are significantly correlated with >or= Grade 3 pneumonitis. Equivalently strong correlations are found in the lower portion of the lungs and the ipsilateral lung, but not in the upper portion or contralateral lung.

Risk group dependence of dose-response for biopsy outcome after three-dimensional conformal radiation therapy of prostate cancer.

BACKGROUND AND PURPOSE: We fit phenomenological tumor control probability (TCP) models to biopsy outcome after three-dimensional conformal radiation therapy (3D-CRT) of prostate cancer patients to quantify the local dose-response of prostate cancer. MATERIALS AND METHODS: We analyzed the outcome after photon beam 3D-CRT of 103 patients with stage T1c-T3 prostate cancer treated at Memorial Sloan-Kettering Cancer Center (MSKCC) (prescribed target doses between 64.8 and 81Gy) who had a prostate biopsy performed >or=2.5 years after end of treatment. A univariate logistic regression model based on D(mean) (mean dose in the planning target volume of each patient) was fit to the whole data set and separately to subgroups characterized by low and high values of tumor-related prognostic factors T-stage (or=T2c), Gleason score (6), and pre-treatment prostate-specific antigen (PSA) (10 ng/ml). In addition, we evaluated five different classifications of the patients into three risk groups, based on all possible combinations of two or three prognostic factors, and fit bivariate logistic regression models with D(mean) and the risk group category to all patients. Dose-response curves were characterized by TCD(50), the dose to control 50% of the tumors, and gamma(50), the normalized slope of the dose-response curve at TCD(50). RESULTS: D(mean) correlates significantly with biopsy outcome in all patient subgroups and larger values of TCD(50) are observed for patients with unfavorable compared to favorable prognostic factors. For example, TCD(50) for high T-stage patients is 7Gy higher than for low T-stage patients. For all evaluated risk group definitions, D(mean) and the risk group category are independent predictors of biopsy outcome in bivariate analysis. The fit values of TCD(50) show a clear separation of 9-10.6Gy between low and high risk patients. The corresponding dose-response curves are steeper (gamma(50)=3.4-5.2) than those obtained when all patients are analyzed together (gamma(50)=2.9). CONCLUSIONS: Dose-response of prostate cancer, quantified by TCD(50) and gamma(50), varies by prognostic subgroup. Our observations are consistent with the hypothesis that the shallow nature of clinically observed dose-response curves for local control result from a patient population that is a heterogeneous mixture of sub-populations with steeper dose-response curves and varying values of TCD(50). Such results may eventually help to identify patients, based on their individual pre-treatment prognostic factors, that would benefit most from dose-escalation, and to guide dose prescription.

Long-term results of combined-modality therapy in resectable non-small-cell lung cancer.

PURPOSE: Assessment of long-term results of combined-modality therapy for resectable non-small-cell lung cancer is hampered by insufficient follow-up and small patient numbers. To evaluate this, we reviewed our collective experience. PATIENTS AND METHODS: This study was a retrospective chart review recording demographics, tumor stage, treatment, and outcome of consecutive patients undergoing surgery. Survival was analyzed by Kaplan-Meier, and prognostic factors were analyzed by log-rank and Cox regression. RESULTS: From January 1993 to December 1999, 470 patients were treated, with follow-up in 446: 27 stage I, 55 stage II, 316 stage III, 43 stage IV (solitary M1), and five uncertain. Chemotherapy was mitomycin/vinblastine/cisplatin (174 patients [39.0%]), carboplatin/paclitaxel (148 [33.2%]), and other combination (124 [27.8%]); 75 patients (16.8%) received induction radiation. Resection was complete in 77.4%, incomplete in 8.3%, attempted but with gross residual disease afterward in 1.8%, and not performed in 12.6%. Pathologic complete response occurred in 20 patients (4.5%). With median follow-up of 31.0 months for patients still alive, median and 3-year survival for pathologic stages 0, I, II, III, and IV were more than 90 months, 73%; 42 months, 52%; 23 months, 35%; 16 months, 28%; and 16 months, 23% (P <.001). In a multivariate analysis, age, complete resection, pathologic stage, and pneumonectomy, but not induction regimen, significantly influenced survival. CONCLUSION: Although pathologic complete response outside the protocol setting is low, survival of this large patient cohort is comparable to that of patients in published combined-modality trials. Survival is significantly influenced by patient age, complete resection, pathologic stage, and pneumonectomy. These results can help guide standard clinical practice and emphasize the need for novel induction regimens.