Prognosis in HIV-infected patients with non-small cell lung cancer.

BACKGROUND: We conducted a population-based study to evaluate whether non-small cell lung cancer (NSCLC) prognosis was worse in HIV-infected compared with HIV-uninfected patients. METHODS: Using the Surveillance, Epidemiology and End Results (SEER) registry linked to Medicare claims, we identified 267 HIV-infected patients and 1428 similar controls with no evidence of HIV diagnosed with NSCLC between 1996 and 2007. We used conditional probability function (CPF) analyses to compare survival by HIV status accounting for an increased risk of non-lung cancer death (competing risks) in HIV-infected patients. We used multivariable CPF regression to evaluate lung cancer prognosis by HIV status adjusted for confounders. RESULTS: Stage at presentation and use of stage-appropriate lung cancer treatment did not differ by HIV status. Median survival was 6 months (95% confidence interval (CI): 5-8 months) among HIV-infected NSCLC patients compared with 20 months (95% CI: 17-23 months) in patients without evidence of HIV. Multivariable CPF regression showed that HIV was associated with a greater risk of lung cancer-specific death after controlling for confounders and competing risks. CONCLUSION: NSCLC patients with HIV have a poorer prognosis than patients without evidence of HIV. NSCLC may exhibit more aggressive behaviour in the setting of HIV.

Setting priorities for occupational cancer research and control: synthesis of the results of occupational disease surveillance studies.

The objectives of this paper were 1) to identify occupations with potentially high cancer risk by combining the results of 12 major occupational disease surveillance studies, 2) to develop a quantitative methodology for accomplishing the first objective, and 3) to make recommendations concerning priorities for occupational cancer research and control on the basis of the results of this analysis in conjunction with other available epidemiologic, industrial hygiene, toxicologic, and employment data. It was suggested that the first priority be the investigation and control of occupational exposure to asbestos, particularly in the automobile repair and construction industries. Of the 34 occupational groups found to be at high risk for lung cancer in this analysis, 18 have potential asbestos exposure. The second priority was suggested to be research into the consistent lung-cancer excess found among motor vehicle drivers. This excess may be due to occupational exposure to diesel and gasoline engine exhaust, to cigarette smoking, or to both of these factors.

Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the esophagus and gastric cardia.

BACKGROUND: Incidence rates for adenocarcinomas of the esophagus and gastric cardia have risen steeply over the last few decades. To determine risk factors for these tumors, we conducted a multicenter, population-based, case-control study. METHODS: The study included 554 subjects newly diagnosed with esophageal or gastric cardia adenocarcinomas, 589 subjects newly diagnosed with esophageal squamous cell carcinoma or other gastric adenocarcinomas, and 695 control subjects. Estimates of risk (odds ratios [ORs] and corresponding 95% confidence intervals [CIs]) were calculated for the four tumor types separately and for esophageal and gastric cardia adenocarcinomas combined. RESULTS: Risk of esophageal and gastric cardia adenocarcinomas combined was increased among current cigarette smokers (OR = 2.4; 95% = 1.7-3.4), with little reduction observed until 30 years after smoking cessation; this risk rose with increasing intensity and duration of smoking. Risk of these tumors was not related to beer (OR = 0.8; 95% CI = 0.6-1.1) or liquor (OR = 1.1; 95% CI = 0.8-1.4) consumption, but it was reduced for drinking wine (OR = 0.6; 95% CI = 0.5-0.8). Similar ORs were obtained for the development of noncardia gastric adenocarcinomas in relation to tobacco and alcohol use, but higher ORs were obtained for the development of esophageal squamous cell carcinomas. For all four tumor types, risks were higher among those with low income or education. CONCLUSIONS: Smoking is a major risk factor for esophageal and gastric cardia adenocarcinomas, accounting for approximately 40% of cases. IMPLICATIONS: Because of the long lag time before risk of these tumors is reduced among ex-smokers, smoking may affect early stage carcinogenesis. The increase in smoking prevalence during the first two thirds of this century may be reflected in the rising incidence of these tumors in the past few decades among older individuals. The recent decrease in smoking may not yet have had an impact.

Body mass index and risk of adenocarcinomas of the esophagus and gastric cardia.

BACKGROUND: Incidence rates have risen rapidly for esophageal adenocarcinoma and moderately for gastric cardia adenocarcinoma, while rates have remained stable for esophageal squamous cell carcinoma and have declined steadily for noncardia gastric adenocarcinoma. We examined anthropometric risk factors in a population-based case-control study of esophageal and gastric cancers in Connecticut, New Jersey, and western Washington. METHODS: Healthy control subjects (n = 695) and case patients with esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma (n = 589) were frequency-matched to case patients with adenocarcinomas of esophagus or gastric cardia (n = 554) by 5-year age groups, sex, and race (New Jersey only). Classification of cases by tumor site of origin and histology was determined by review of pathology materials and hospital records. Data were collected using in-person structured interviews. Associations with obesity, measured by body mass index (BMI), were estimated by odds ratios (ORs). All ORs were adjusted for geographic location, age, sex, race, cigarette smoking, and proxy response status. RESULTS: The ORs for esophageal adenocarcinoma rose with increasing adult BMI. The magnitude of association with BMI was greater among the younger age groups and among nonsmokers. The ORs for gastric cardia adenocarcinoma rose moderately with increasing BMI. Adult BMI was not associated with risk of esophageal squamous cell carcinoma or noncardia gastric adenocarcinoma. CONCLUSIONS: Increasing prevalence of obesity in the United States population may have contributed to the upward trends in esophageal and gastric cardia adenocarcinomas.

A conformational change in phosphoglycerate dehydrogenase induced by a shift in pH.

The fluorescence of NADH bound to phosphoglycerate dehydrogenase (3-phosphoglycerate: NAD+ oxidoreductase, EC 1.1.1.95) decreased by 42% between pH 8.5 and 7.0 Serine, an allosteric inhibitor, quenched the fluorescence of enzyme-bound NADH by 29% at pH 8.5, but not at all at pH 7.0. The kinetics of the fluorescence change which occurred when the pH of an enzyme-NADH solution was rapidly shifted from 8.5 to 7.0 was measured using stopped-flow fluorimetry. The kinetics were first order, with a rate constant of 2.83 s-1. This rate constant was similar in magnitude to the rate constants for fluorescence quenching at pH 8.5 by saturating concentrations of serine and glycine, another allosteric inhibitor (Dubrow, R. and Pizer, L.I. (1977) J. Biol. Chem. 252, 1527-1538). These results indicate that the conformation of phosphoglycerate dehydrogenase at pH 7.0 is similar to, but not identical with, the serine-induced conformation at pH 8.5.

Phase II study of fluorouracil and recombinant interferon alfa-2a in previously untreated advanced colorectal carcinoma.

We conducted a phase II clinical trial of fluorouracil (5FU) and recombinant interferon alfa-2a (rIFN alpha-2a) in 52 previously untreated patients with bidimensionally measurable metastatic colorectal cancer. During week 1, 5FU was administered as a continuous intravenous infusion, 750 mg/m2/d for 5 consecutive days. Intravenous bolus administration of 5FU 750 mg/m2 was given weekly for 7 weeks starting on day 12. rIFN alpha-2a (Roferon; Hoffman-LaRoche, Nutley, NJ), 9 x 10(6) U, was administered subcutaneously three times weekly during weeks 1 to 8. Patients were evaluated for response on week 9. Of 52 patients enrolled in the study, 51 were assessable for toxicity, and 45 were assessable for response. Fifteen patients experienced partial response, and one patient achieved a clinical complete response for an overall response rate of 35% (95% confidence interval [CI], 22%, 50%). Median duration of response is 7.5 months (range, 4 to 11 months). Seventy percent of patients entered on the study are alive with a median follow-up duration of 7 months. Twenty-five percent of patients developed grade 4 toxicity, and 82% developed grade 3 toxicity. One drug-related death in the presence of sepsis was reported, and two treatment-related seizures occurred. Our experience with this schedule produced a lower response rate with greater toxicity than previously reported. Current randomized trials comparing this schedule of 5FU with rIFN alpha-2a to 5FU plus folinic acid (leucovorin) or single-agent 5FU may determine its role in the treatment of advanced colorectal carcinomas.

Therapy for metastatic colorectal cancer with hepatic artery infusion chemotherapy using a subcutaneous implanted pump.

Sixty-two patients with metastatic colorectal carcinoma involving the liver were treated by hepatic intra-arterial chemotherapy using an implantable infusion pump. The 53 patients with metastases confined to the liver had a median survival (MS) of 17 months and an objective response rate of 32%. Four patients (8%) demonstrated a complete response (CR), with normal abdominal computed tomography (CT) scan results and plasma carcinoembryonic antigen (CEA) levels, and 13 patients (25%) demonstrated a partial response (PR), with at least a 50% decrease in the liver lesions by CT scan and at least a 50% decrease in CEA levels. Thirty patients (57%) had stable disease (S), and six patients (11%) had no response (NR). Nine patients with extrahepatic tumor plus hepatic metastases had an MS of only 4.9 months. None of these patients had an objective response, and only four patients had S. Quality of response was clearly associated with longevity. Forty patients treated with floxuridine (FUDR) and mitomycin (M) (F + M) showed a 20% objective response rate, while the 13 patients treated with FUDR and dichloromethotrexate (DCMTX) (F + D) attained a 69% objective response rate. Although F + D treatment appears to be superior, there may have been selection biases that make such an observation only preliminary. Twenty-six (49%) of the 53 patients developed hepatitis during infusion chemotherapy, which resolved after temporary cessation of the chemotherapy. Of the 17 patients with CR or PR, 12 patients (71%) had hepatitis, whereas only 14 (39%) of the 36 patients with S or NR had hepatitis. Eleven patients had evidence of peptic ulceration by endoscopic examination during the infusion chemotherapy. All the ulcers healed after chemotherapy was discontinued.

Risk of female breast cancer associated with serum polychlorinated biphenyls and 1,1-dichloro-2,2'-bis(p-chlorophenyl)ethylene.

This case-control study was designed to investigate the relationship between polychlorinated biphenyls (PCBs) and 1,1-dichloro-2,2'-bis(p-chlorophenyl)ethylene (DDE) and breast cancer risk in Connecticut. Cases were incident breast cancer patients who were either residents of Tolland County or who had a breast-related surgery at the Yale-New Haven Hospital in New Haven County. Controls were randomly selected from Tolland County residents or from patients who had newly diagnosed benign breast diseases or normal tissue at Yale-New Haven Hospital. A total of 475 cases and 502 controls had their serum samples analyzed for PCBs and DDE in 1995-1997. The age- and lipid-adjusted geometric mean serum level of DDE was comparable between the cases (460.1 ppb) and controls (456.2 ppb). The geometric mean serum level of PCBs was also comparable between cases (733.1 ppb) and controls (747.6 ppb). After adjustment for confounding factors, odds ratios of 0.96 (95% confidence interval, 0.67-1.36) for DDE and 0.95 (95% confidence interval, 0.68-1.32) for PCBs were observed when the third tertile was compared with the lowest. Further stratification by parity, lactation, and menopausal and estrogen receptor status also showed no significant association with serum levels of DDE or PCBs. The results by PCB congener groups also showed no major increased risk associated with any of the congener groups. Our study does not support the hypothesis that DDE and PCBs, as encountered through environmental exposure, increase the risk of female breast cancer.

Environmental exposure to hexachlorobenzene (HCB) and risk of female breast cancer in Connecticut.

Earlier studies have provided inconclusive results relating hexachlorobenzene (HCB), an organochlorine fungicide, to female breast cancer risk. The current study, with a total of 304 breast cancer cases and 186 controls recruited in Connecticut between 1994 and 1997, examined the association by directly comparing breast adipose tissue levels of HCB between incident breast cancer cases and noncancer controls. The cases and controls were patients who had breast biopsies or surgery at the Yale-New Haven Hospital (New Haven, CT) and histologically diagnosed either as breast cancer or benign breast disease. Information on major known or suspected risk factors for breast cancer was obtained through in-person interview by trained interviewers. No significant difference in mean breast adipose tissue levels of HCB was observed between breast cancer patients (21.0 ppb) and controls (19.1 ppb) in this large case-control study. The risk also did not vary significantly by menopausal status, estrogen or progesterone receptor status of the breast cancer cases, breast cancer histology, stage of diagnosis, or type of benign breast disease. Among parous women who reported ever breast feeding, an odds ratio (OR) of 0.5 [95% confidence interval (CI), 0.2-1.4] was observed when the highest quartile was compared with the lowest quartile. However, no association was observed among parous women who reported never breast feeding (OR = 0.7; 95% CI, 0.3-1.7 for the fourth quartile). For nulliparous women, the adjusted OR was 2.1 (95% CI, 0.5-8.8) for the third tertile when compared with the lowest based on few subjects. Therefore, our study does not support a positive association between environmental exposure to HCB and risk of breast cancer.

Nutrient intake and risk of subtypes of esophageal and gastric cancer.

Incidence rates for adenocarcinoma of the esophagus and gastric cardia have been rising rapidly. We examined nutrient intake as a risk factor for esophageal and gastric cancers in a population-based case-control study in Connecticut, New Jersey, and western Washington state. Interviews were completed for cases with histologically confirmed esophageal adenocarcinoma (n = 282), adenocarcinoma of the gastric cardia (n = 255), esophageal squamous cell carcinoma (n = 206), and noncardia gastric adenocarcinoma (n = 352), along with population controls (n = 687). Associations between nutrient intake and risk of cancer were estimated by adjusted odds ratios (ORs), comparing the 75th versus the 25th percentile of intake. The following nutrients were significantly inversely associated with risk of all four tumor types: fiber, beta-carotene, folate, and vitamins C and B6. In contrast, dietary cholesterol, animal protein, and vitamin B12 were significantly positively associated with risk of all four tumor types. Dietary fat [OR, 2.18; 95% confidence interval (CI), 1.27-3.76] was significantly associated with risk of esophageal adenocarcinoma only. Dietary nitrite (OR, 1.65; 95% CI, 1.26-2.16) was associated with noncardia gastric cancer only. Vitamin C supplement use was associated with a significantly lower risk for noncardia gastric cancer (OR, 0.60; 95% CI, 0.41-0.88). Higher intake of nutrients found primarily in plant-based foods was associated with a reduced risk of adenocarcinomas of the esophagus and gastric cardia, whereas higher intake of nutrients found primarily in foods of animal origin was associated with an increased risk.

Use of aspirin and other nonsteroidal anti-inflammatory drugs and risk of esophageal and gastric cancer.

Regular users of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are at reduced risk of colon cancer, but the evidence for protective effects of NSAIDs elsewhere in the digestive tract is scant. We investigated the association between the use of NSAIDs and risk of esophageal and gastric cancer, using data from a large population-based, case-control study. Cases were individuals, ages 30-79 years, diagnosed with esophageal adenocarcinoma (n = 293), esophageal squamous cell carcinoma (n = 221), gastric cardia adenocarcinoma (n = 261), or noncardia gastric adenocarcinoma (n = 368) in three areas with population-based tumor registries. Controls (n = 695) were selected by random digit dialing and through the rosters of the Health Care Financing Administration. After controlling for the major risk factors, we found that current users of aspirin were at decreased risk of esophageal adenocarcinoma [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.24-0.58], esophageal squamous cell carcinoma (OR, 0.49; 95% CI, 0.28-0.87), and noncardia gastric adenocarcinoma (OR, 0.46; 95% CI, 0.31-0.68), but not of gastric cardia adenocarcinoma (OR, 0.80; 95% CI, 0.54-1.19), when compared to never users. Risk was similarly reduced among current users of nonaspirin NSAIDs. The associations with current NSAID use persisted when we excluded use within 2 or 5 years of reference date, which might have been affected by preclinical disease in cases, and when we restricted analyses to subjects reporting no history of chronic gastrointestinal symptoms. Our findings add to the growing evidence that the risk of cancers of the esophagus and stomach is reduced in users of NSAIDs, although whether the association is causal in nature is not clear.

Risk of esophageal and gastric adenocarcinomas in relation to use of calcium channel blockers, asthma drugs, and other medications that promote gastroesophageal reflux.

Incidence of adenocarcinomas of the esophagus and gastric cardia has risen dramatically over the past 2 decades in the U. S., for reasons that are not yet clear. A number of common medications (e.g., calcium channel blockers, tricyclic antidepressants, and certain asthma medications) promote gastroesophageal reflux by relaxing the lower esophageal sphincter (LES). Reflux is thought to increase cancer risk by promoting cellular proliferation, and by exposing the esophageal epithelium to potentially genotoxic gastric and intestinal contents. Recent studies have suggested that calcium channel blockers may also increase cancer risk by inhibiting apoptosis. Using personal interview data from a multicenter, population-based case-control study conducted between 1993 and 1995 in three areas of the U. S., we evaluated whether the use of LES-relaxing drugs was associated with increased risk of adenocarcinomas of the esophagus and gastric cardia. Cases of esophageal adenocarcinoma (n = 293) and gastric cardia adenocarcinoma (n = 261) were compared with general population controls (n = 695). Information on additional case groups of esophageal squamous cell carcinoma (n = 221) and noncardia gastric cancer (n = 368) were also available for comparison. Overall, 27.4% of controls had used one or more of these drugs for at least 6 months, compared with 30.2% of esophageal adenocarcinoma and 23.8% of gastric cardia adenocarcinoma cases. The adjusted odds ratios (ORs) for ever use were 1.0 [95% confidence interval (CI) = 0.7-1.5] and 0.8 (95% CI = 0.5-1.1), respectively. There was little evidence of increasing risk with increasing duration of use of all LES-relaxing drugs together. We found an increased risk of esophageal adenocarcinoma among persons reporting use of asthma drugs containing theophylline (OR = 2.5; 95% CI = 1.1-5.6) or beta agonists (OR = 1.7; 95% CI = 0.8-3.8). Risks were higher among long-term users (>5 years) of these drugs (OR = 3.1; 95% CI = 0.9-10.3 and OR = 2.3; 95% CI = 0.8-7.0, respectively). In contrast, there was no evidence that the use of calcium channel blockers or other specific groups of drugs increased the risk of any of the cancers studied. These results provide reassuring evidence that the increases in incidence of adenocarcinomas of the esophagus and gastric cardia are not likely to be related to the use of LES-relaxing drugs as a group, or calcium channel blockers in particular, but they do suggest that persons treated for long-standing asthma may be at increased risk of esophageal adenocarcinoma.

Elective groin irradiation is not indicated for patients with adenocarcinoma of the rectum extending to the anal canal.

PURPOSE: To evaluate the inguinal nodal failure rate in patients with locally advanced rectal cancer with anal canal involvement (ACI) treated with pelvic chemoradiation without elective inguinal irradiation. METHODS AND MATERIALS: From 1990 and 1998, 536 patients received preoperative or postoperative chemoradiation for rectal cancer with curative intent; 186 patients had ACI (<4 cm from the anal verge on rigid proctoscopy). Two patients had positive inguinal nodes at presentation. Chemoradiation was delivered preoperatively (45 Gy in 25 fraction) or postoperatively (53 Gy in 29 fractions) with concurrent continuous infusion of 5-fluorouracil (300 mg/m2/d). The inguinal region was specifically irradiated in only 2 patients who had documented inguinal nodal disease. RESULTS: The median follow-up was 50 months. Only 6 of 184 ACI patients who had clinically negative inguinal nodes at presentation developed inguinal nodal recurrence (5-year actuarial rate 4%); 4 of the 6 cases were isolated. Two patients underwent successful salvage. Only 1 died of uncontrolled groin disease. Local control was achieved in both patients with inguinal nodal disease at presentation, but both died of metastatic disease. Only 3 patients with tumors >4 cm from the verge developed inguinal recurrence (5-year actuarial rate <1%). CONCLUSIONS: Inguinal nodal failure in rectal cancer patients with ACI treated with neoadjuvant or adjuvant chemoradiation is not high enough to justify routine elective groin irradiation.

Preoperative infusional chemoradiation therapy for stage T3 rectal cancer.

PURPOSE: To evaluate preoperative infusional chemoradiation for patients with operable rectal cancer. METHODS AND MATERIALS: Preoperative chemoradiation therapy using infusional 5-fluorouracil (5-FU), (300 mg/m2/day) together with daily irradiation (45 Gy/25 fractions/5 weeks) was administered to 77 patients with clinically Stage T3 rectal cancer. Endoscopic ultrasound confirmed the digital rectal exam in 63 patients. Surgery was performed approximately 6 weeks after the completion of chemoradiation therapy and included 25 abdominoperineal resections and 52 anal-sphincter-preserving procedures. RESULTS: Posttreatment tumor stages were T1-2, N0 in 35%, T3 N0 in 25%, and T1-3, N1 in 11%; 29% had no evidence of tumor. Local tumor control after chemoradiation was seen in 96% (74 out of 77); 2 patients had recurrent disease at the anastomosis site and were treated successfully with abdominoperineal resection. Overall, pelvic control was obtained in 99% (76 out of 77). The survival after chemoradiation was higher in patients without node involvement than in those having node involvement (p = n.s.). More patients with pathologic complete responses or only microscopic foci survived than did patients who had gross residual tumor (p = 0.07). The actuarial survival rate was 83% at 3 years; the median follow-up was 27 months, with a range of 3 to 68 months. Acute, perioperative, and late complications were not more numerous or more severe with chemoradiation therapy than with traditional radiation therapy (XRT) alone. CONCLUSIONS: Excellent treatment response allowed two-thirds of the patients to have an anal-sphincter-sparing procedure. Gross residual disease in the resected specimen indicates a poor prognosis, and therapies specifically targeting these patients may improve survival further.

Tumor downstaging and sphincter preservation with preoperative chemoradiation in locally advanced rectal cancer: the M. D. Anderson Cancer Center experience.

PURPOSE: To evaluate the rates of tumor downstaging after preoperative chemoradiation for locally advanced rectal cancer. MATERIALS AND METHODS: Preoperative chemoradiotherapy (CTX/XRT) that delivered 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2/day) was given to 117 patients. The pretreatment stage distribution, as determined by endorectal ultrasound (u), included uT2N0 in 2%, uT3N0 in 47%, uT3N1 in 49%, and uT4N0 in 2% of cases; endorectal ultrasound was not performed in 13% of cases (15 patients). Approximately 6 weeks after completion of CTX/XRT, surgery was performed. RESULTS: The pathological tumor stages were Tis-2N0 in 26%, T2N1 in 5%, T3N0 in 21%, T3N1 in 15%, T4N0 in 5%, and T4NI in 1%; a complete response (CR) to preoperative CTX/XRT was pathologically confirmed in 32 (27%) of patients. Tumor downstaging occurred in 72 (62%) cases. Only 3% of cases had pathologic evidence of progressive disease. Pretreatment tumor size (< 5 cm vs. > or = 5 cm) was the only factor predictive of tumor downstaging (p < 0.04). A decrease of > 1 T-stage level was accomplished in 45% of those downstaged. Overall, a sphincter-saving (SP) procedure was possible in 59% of patients and an abdominoperineal resection (APR) was required in 41 % of cases. Factors predictive of SP included downstaging (p < 0.03), age > 40 years (p < 0.007), pretreatment tumor distance, 3 to 6 cm from the anal verge (p < 0.00001), tumor size <6 cm (p < 0.02), mobility (p < 0.004), tumor stage 6 cm from the anal verge, SP was performed in 14 of the 15 (93%) patients with a CR and 32 of 33 (97%) of patients with residual disease (p < 0.00004). CONCLUSIONS: Significant tumor downstaging results from preoperative chemoradiation allowing sphincter sparing surgery in over 40% of patients whose tumors were located < 6 cm from the anal verge and who otherwise would have required colostomy.

Effective pelvic symptom control using initial chemoradiation without colostomy in metastatic rectal cancer.

PURPOSE: To assess pelvic chemoradiotherapy (CXRT) without colostomy as a component of the multidisciplinary management of patients presenting with metastatic rectal cancer. METHODS AND MATERIALS: Eighty patients with synchronous distant metastases from rectal cancer were treated with initial CXRT. Hypofractionated radiotherapy was administered usually with concurrent 5-FU (92%, 300 mg/m(2)/day, M-F). Three-field belly-board technique was used in 89%. Group 1 had CXRT alone (n = 55). Group 2 (n = 25) patients were selected for primary disease resection, and sometimes HAI chemotherapy (n = 10) or hepatic resection (n = 5). Subsequently, 78% received systemic chemotherapy. RESULTS: Symptoms from primary tumor resolved in 94%. Endoscopic complete clinical response rate was 36%. Two-year survival (11% vs. 46%, p < 0.0001) and symptomatic pelvic control (PC, 81% vs. 91%, p = 0.111) were higher in Group 2, but colostomy-free rate (CFR) was lower (79% vs. 51% p = 0.02). CFR was 87% in Group 1 patients managed initially without fecal diversion (n = 50). Examining all patients using multivariate analysis, pelvic pain at presentation (p < 0.00001), BED (biologic equivalent dose at 2 Gy/fraction) < 35 Gy (p = 0.077), and poor differentiation (0.079) predicted worse PC. Poor differentiation (p = 0.017) and selection for CXRT alone (p < 0.0001) predicted worse survival. There were 4 RTOG of Grade 3 or greater acute complications, 5 severe perioperative complications, and no significant late treatment-related complications. CONCLUSION: Durable PC can be safely achieved without colostomy in most patients presenting with primary rectal cancer and synchronous systemic metastases using hypofractionated pelvic chemoradiation. A BED greater than 35 Gy is recommended. Selected patients appear to benefit from resection of primary disease. Higher doses should be investigated in patients with pelvic pain.

Prospective trial of preoperative concomitant boost radiotherapy with continuous infusion 5-fluorouracil for locally advanced rectal cancer.

RATIONALE: To evaluate the response to a concomitant boost given during standard chemoradiation for locally advanced rectal cancer. METHODS AND MATERIALS: Concomitant boost radiotherapy was administered preoperatively to 45 patients with locally advanced rectal cancer in a prospective trial. Treatment consisted of 45 Gy to the pelvis with 18 mV photons at 1.8 Gy/fraction using a 3-field belly board technique with continuous infusion 5FU chemotherapy (300mg/m(2)) 5 days per week. The boost was given during the last week of therapy with a 6-hour inter-fraction interval to the tumor plus a 2-3 cm margin. The boost dose equaled 7.5 Gy/5 fractions (1.5 Gy/fraction); a total dose of 52.5 Gy/5 weeks was given to the primary tumor. Pretreatment tumor stage, determined by endorectal ultrasound and CT scan, included 29 with T3N0 [64%], 11 T3N1, 1 T3Nx, 2 T4N0, 1 T4N3, and 1 with TxN1 disease. Mean distance from the anal verge was 5 cm (range 0-13 cm). Median age was 55 years (range 33-77 years). The population consisted of 34 males and 11 females. Median time of follow-up is 8 months (range 1-24 months). RESULTS: Sphincter preservation (SP) has been accomplished in 33 of 42 (79%) patients resected to date. Three patients did not undergo resection because of the development of metastatic disease in the interim between the completion of chemoradiation (CTX/XRT) and preoperative evaluation. The surgical procedures included proctectomy and coloanal anastomosis (n = 16), low anterior resection (n = 13), transanal resection (n = 4). Tumor down-staging was pathologically confirmed in 36 of the 42 (86%) resected patients, and 13 (31%) achieved a pathologic CR. Among the 28 tumors (67%) located <6 cm from the anal verge, SP was accomplished in 21 cases (75%). Although perioperative morbidity was higher, toxicity rates during CTX/XRT were comparable to that seen with conventional fractionation. Compared to our contemporary experience with conventional CTX/XRT (45Gy; 1.8 Gy per fraction), improvements were seen in SP (79% vs. 59%; p = 0.02), SP for tumors <6 cm from the anal verge (75% vs. 42%; p = 0.003), and down-staging (86% vs. 62%; p = 0.003). CONCLUSION: The SP rate with concomitant boost radiation has been highly favorable with rates of response which are higher than those previously reported for chemoradiation without administration of a boost. Further evaluation of this radiotherapeutic strategy appears warranted.

Prognostic implications of response to preoperative infusional chemoradiation in locally advanced rectal cancer.

BACKGROUND AND PURPOSE: To evaluate the influence of response to preoperative infusional chemoradiation on outcome parameters among patients with locally advanced rectal cancer. MATERIALS AND METHODS: Preoperative chemoradiotherapy, 45 Gy in 25 fractions over 5 weeks with continuous infusion 5-fluorouracil (300 mg/m2 per day), was given to 117 patients. As determined by pretreatment endorectal ultrasound (EUS), 96% of cases were Stage T3, and 51% had EUS evidence of perirectal adenopathy. Surgery was performed approximately 6 weeks after chemoradiation therapy. Postoperatively adjuvant systemic therapy, consisting of 400-425 mg/m2 of 5-fluorouracil plus 20 mg/m2 leucovorin for 5 days, was administered every 28 days for six cycles. Outcome parameters of local control (LC), freedom from distant metastases (DMC), disease-free survival (DFS) and cancer specific survival (CSS) were evaluated relative to primary tumor characteristics. RESULTS: The final post-treatment pathological tumor stages were complete response in 27%, Tis-2 N0 in 26%, T2 N1 in 5%, T3 N0 in 21%, T3 N1 in 15%, T4 N0 in 5% and T4 N1 in 1%. Down-staging occurred in 61% of cases. The pretreatment primary tumor size only influenced rates of local control (P < 0.03) and had no other influence on outcome parameters. Pretreatment evidence of perirectal lymph node involvement had no impact on outcome parameters. Pathologic evidence of nodal involvement did affect DMC (P < 0.002) and DFS (P < 0.003). Pathologic evidence of response did influence freedom from the development of distant metastases (P < 0.004). On pairwise analysis this relationship held only when responders were compared to non-responders. No difference was observed based on the level of downstaging at the primary tumor. Correspondingly, DFS was improved when non-responders were compared to downstaged patients (P < 0.01). Response to preoperative chemoradiation failed to affect rates of LC or CSS. For the group as a whole, adjuvant chemotherapy improved only CSS (P < 0.03). Adjuvant chemotherapy was given to 74 patients, 36 of whom had responded to preoperative chemoradiation. Improvements were only seen in DFS (P < 0.03) when down-staged patients were compared to the non-responders who received adjuvant chemotherapy. In addition, the DFS rates were lower in the non-responder group who received adjuvant chemotherapy even when they were compared to down-staged patients who did not receive adjuvant chemotherapy (P < 0.04). CONCLUSION: Consistent with other reports, disease free survival and subsequent development of distant metastases is reduced in the more than 60% of patients who respond to preoperative infusional chemoradiation. Evidence of response appears more significant than the degree of response. At present, no impact is seen on cancer specific survival rates. Consideration should be given for strategies that base selection of subsequent adjuvant chemotherapy on response to preoperative chemoradiation.

Growth and development and other risk factors for osteosarcoma in children and young adults.

BACKGROUND: Risk factors for osteosarcoma in young people were investigated in a population-based case-control study among residents of New York State, excluding New York City. METHODS: Cases (n = 130) were diagnosed between 1978 and 1988 at < or = 24 years of age. Controls were randomly selected from birth certificates and were pair matched to cases on year of birth and sex. Exposure information was obtained by telephone interview with a subject and/or parent, and from birth certificates and school and medical records. RESULTS AND CONCLUSIONS: A significant positive association was observed with height one year before diagnosis (P-value for trend = 0.02). No significant associations were observed between osteosarcoma and weight of body mass index one year before diagnosis, birth length, birthweight, gestational age, having reached puberty, having begun growth spurt, age at puberty, age growth spurt began, medical x-rays, antenatal exposures, family history of cancer, birth defects, or parental occupation.

Sunlamp use and the risk of cutaneous malignant melanoma: a population-based case-control study in Connecticut, USA.

BACKGROUND: The relationship between cutaneous malignant melanoma and sunlamp use is examined in a Caucasian population in Connecticut, United States. METHODS: Cases were diagnosed between 15 January 1987 and 15 May 1987 with a first primary cutaneous melanoma. Controls were obtained from the general population, frequency matched to cases by sex and age, through random digit dialling of Connecticut telephone numbers. RESULTS: Of all study subjects, 141 (23%) cases and 95 (19%) controls reported ever having used sunlamps. The crude odds ratio (OR) for developing malignant melanoma after ever having used sunlamps was 1.30 (95% confidence interval [CI]: 0.97-1.74). This was reduced to 1.13 (95% CI: 0.82-1.54) after further adjusting for cutaneous phenotype and recreational sun exposure. Those who used more than one type of sunlamp had a threefold higher risk for melanoma compared to never users. Subgroup analyses showed that sunlamp use was associated with a greater increase in risk for melanoma among those who used sunlamps at home and those who were first exposed to sunlamps prior to 1971. The first use of sunlamps before the age of 25 showed somewhat higher risk for melanoma compared to first use later in life. CONCLUSION: The current study provides limited evidence that use of sunlamps increases the risk of melanoma. For future studies, it is crucial that type of sunlamp, year of first use and amount of exposure are all taken into account. The association between melanoma and tanning with both UV-A and UV-B lamps and tanning under sunlamps early in life merits further investigation.