Implementing multiplexed genotyping of non-small-cell lung cancers into routine clinical practice.

BACKGROUND: Personalizing non-small-cell lung cancer (NSCLC) therapy toward oncogene addicted pathway inhibition is effective. Hence, the ability to determine a more comprehensive genotype for each case is becoming essential to optimal cancer care. METHODS: We developed a multiplexed PCR-based assay (SNaPshot) to simultaneously identify >50 mutations in several key NSCLC genes. SNaPshot and FISH for ALK translocations were integrated into routine practice as Clinical Laboratory Improvement Amendments-certified tests. Here, we present analyses of the first 589 patients referred for genotyping. RESULTS: Pathologic prescreening identified 552 (95%) tumors with sufficient tissue for SNaPshot; 51% had ≥1 mutation identified, most commonly in KRAS (24%), EGFR (13%), PIK3CA (4%) and translocations involving ALK (5%). Unanticipated mutations were observed at lower frequencies in IDH and ß-catenin. We observed several associations between genotypes and clinical characteristics, including increased PIK3CA mutations in squamous cell cancers. Genotyping distinguished multiple primary cancers from metastatic disease and steered 78 (22%) of the 353 patients with advanced disease toward a genotype-directed targeted therapy. CONCLUSIONS: Broad genotyping can be efficiently incorporated into an NSCLC clinic and has great utility in influencing treatment decisions and directing patients toward relevant clinical trials. As more targeted therapies are developed, such multiplexed molecular testing will become a standard part of practice.

Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older.

Randomized trials of chemoradiation for esophageal cancer have included very few patients age > or = 75. In this retrospective study, we describe the outcomes and toxicity of full-dose chemoradiation in elderly patients with esophageal cancer. Patients, age > or = 75, treated with full-dose chemoradiation for esophageal carcinoma from 2002 to 2008 were retrospectively reviewed. Thirty-four patients were identified with a median age of 79.5 (range 75-89). The median Eastern Cooperative Oncology Group performance status was 1 (range 0-3) and the median Adult Comorbidity Evaluation-27 score was 1 (range 0-3). Twenty-eight patients received definitive and six received neoadjuvant chemoradiation. The median radiation dose delivered was 50.4 Gray (range 3.6-68.4 Gray). Platinum-based chemotherapy was used in 79.4% of patients. Fifty percent of the patients completed all planned radiation therapy (RT) and chemotherapy; 85.3% completed RT. Acute toxicity > or = grade 4 occurred in 38.2% of patients, and 70.6% of the patients required hospitalization, emergency department visit, and/or RT break. Median follow-up was 14.5 months among 7 survivors, and median survival was 12.0 months (95% confidence interval [CI]: 9.7 to 24.1 months). The actuarial overall survival at 2 years was 29.7% (95% CI: 16.6 to 52.6%). There were four treatment-related deaths. The median time to any recurrence was 10.4 months. Nineteen patients had a local and/or distant recurrence. In conclusion, elderly patients experienced substantial morbidity from chemoradiation, and long-term survival was low. Future efforts to improve treatment tolerability in the elderly are needed.

Two-dimensional modelling of benzene transport and biodegradation in a laboratory-scale aquifer.

In this study biodegradation of aqueous benzene during transport in a laboratory-scale aquifer model was investigated by conducting a 2-D plume test and numerical modelling. Benzene biodegradation and transport was simulated with the 2-D numerical model developed for solute transport coupled with a Haldane-Andrews type function for inclusion of an inhibition constant which is effective for high concentrations. Experimental data revealed that in the early stages the benzene plume showed a rather clear shape but lost its shape with increased travel time. The mass recoveries of benzene at 9, 16, and 22 h were 37, 13 and 8%, respectively, showing that a significant mass reduction of aqueous benzene occurred in the model aquifer. The major processes responsible for the mass reduction were biodegradation and irreversible sorption. The modelling results also indicated that the simulation based on the microbial parameters from the batch experiments slightly overestimated the mass reduction of benzene during transport. The sensitivity analysis demonstrated that the benzene plume was sensitive to the maximum specific growth rate and slightly sensitive to the half-saturation constant of benzene but almost insensitive to the Haldane inhibition constant. The insensitivity to the Haldane inhibition constant was due to the rapid decline of the benzene peak concentration by natural attenuation such as hydrodynamic dispersion and irreversible sorption. An analysis of the model simulation also indicated that the maximum specific growth rate was the key parameter controlling the plume behaviour, but its impact on the plume was affected by competing parameter such as the irreversible sorption rate coefficient.

Modeling of growth kinetics for Pseudomonas putida during toluene degradation.

Glucose has been often used as a secondary substrate to enhance the degradation of primary substrate as well as the increase of biomass, especially for the inhibitory range of substrate concentration. In this study, we investigated the effect of glucose concentration on growth kinetics of Pseudomonas putida during toluene degradation for a wide concentration range (60-250 mg/l). Batch microcosm studies were conducted in order to monitor bacterial growth for three different initial concentrations (2, 5, 10 mg/ml) of glucose for a given toluene concentration. Modeling of growth kinetics was also performed for each growth curve of glucose dose using both Monod and Haldane kinetics. Batch studies revealed that bacterial growth showed a distinct inhibitory phase above some limit (approximately 170 mg/l) for the lowest (2 mg/ml) glucose dose, but the degree of inhibition decreased as the glucose dose increased, leading to three different growth patterns. The bacterial growth followed each of the modified Wayman and Tseng, Wayman and Tseng, and Luong model as the glucose dose increased from 2 to 10 mg/ml. This indicates that glucose has a prominent influence on bacterial growth during toluene degradation and that different kinetics should be adopted for each broth condition.

Cytologically negative pericardial effusion complicating combined modality therapy for localized small-cell carcinoma of the lung.

A 17% frequency of cytologically negative pericardial effusion (CNPE), accompanied in some cases by tamponade, occurred a median of 12.6 months from the onset of treatment for localized small-cell carcinoma of the lung. CNPE was apparently caused by toxicity of radiation/chemotherapy treatment rather than recurrent cancer. The occurrence of CNPE does not appear to represent enhanced toxicity of immediate (as opposed to delayed) concurrent chemoradiotherapy, but may be a consequence of the superior survival status of patients treated in this way. The onset of chest pain and/or dyspnea associated with increase in cardiac silhouette and positive echocardiogram allowed accurate diagnosis. Each instance was relatively easily managed by catheter drainage, and, for some patients, with the addition of nonsteroidal antiinflammatory drugs. It is important to recognize the possibility that a radiation/chemotherapy-related syndrome of pericardial effusion/tamponade may occur so that early diagnosis can be made and the risk of fatal tamponade avoided.

Preoperative chemotherapy followed by surgery with possible postoperative radiotherapy in squamous cell carcinoma of the esophagus: evaluation of the chemotherapy component.

Twenty-four patients with squamous cell cancer of the esophagus were entered into a treatment protocol consisting of preoperative chemotherapy (CT), surgical resection (SR), and possible postoperative CT or radiation therapy (RT) beginning August 1981. CT consisted of two cycles of 5-fluorouracil, 1,000 mg/m2, by continuous intravenous infusion for 4 days and cisplatin, 100 mg/m2, on day 4 with mannitol-induced diuresis at 4-week intervals. Postoperatively, RT was administered when resection margins were minimal or if paraesophageal nodes were abnormal; the RT consisted of 5,000 to 5,400 cGy to the tumor area plus a 800- to 1,200-cGy boost to known abnormal tumor margins. Nineteen of 24 patients were resectable (79%). There was one SR death (5%). One of 22 had a normal barium swallow post-CT, no visible tumor at SR, and no pathologic evidence of any residual disease. There was complete radiologic and gross clinical disappearance of tumor post-CT or post-SR in ten of 22 patients (45%). Four of 22 (18%) had greater than or equal to 50% regression, and five of 22 (23%) had no response. Toxicity of CT was mild. Eight of 19 patients (42%) received RT, and six of 19 (32%) received CT postoperatively. Sixteen of 24 (67%) are alive with a median duration of observation of 9.5 months. Eight of 24 (33%) are dead, five of whom had not responded to preoperative CT. Ten of 14 responders are alive and disease free. The mean survival time for nonresponders was 6.70 months and for responders, 20.40 months, with the longest survivor disease free at 45 months.

Neoadjuvant chemotherapy and radiotherapy followed by surgery in stage IIIA non-small-cell carcinoma of the lung: report of a Cancer and Leukemia Group B phase II study.

PURPOSE: This phase II trial was designed to evaluate the feasibility, toxicity, response rates, and survival for neoadjuvant chemotherapy and radiotherapy (RT) followed by surgical resection in newly diagnosed patients with surgically staged IIIA non-small-cell lung carcinoma (NSCLC). PATIENTS AND METHODS: Previously untreated patients with NSCLC underwent bronchoscopy, chest and abdominal computed tomography (CT), bone scan, and surgical staging of the mediastinum. Neoadjuvant treatment consisted of concurrent chemotherapy and RT. Patients then underwent surgical resection, which was followed in turn by additional chemotherapy and RT. Chemotherapy included cisplatin 100 mg/m2 on days 1 and 29, vinblastine 3 mg/m2 on days 1 and 3 and 29 and 31, and fluorouracil (5-FU) 30 mg/kg/d by infusion on days 1 to 3 and 29 to 31 (FVP). RT began on day 1 and included 3,000 cGy in 15 fractions. Surgery took place on day 55, and one more cycle of chemotherapy and an additional 3,000 cGy of RT began on day 85. RESULTS: Forty-one eligible patients (median follow-up, 53 months) were studied. N2 disease was present in 80%, whereas 20% had T3N0 or T3N1 lesions. Response to neoadjuvant chemotherapy and RT included no complete responses (CR), 21 (51%) partial responses (PR) or regressions, 19 (46%) stable disease (SD), and one (2%) progressive disease (PD). Thirty-one patients underwent surgery, and 25 were resected. In four of the 25 resection specimens, no viable tumor was present, whereas in three of the six unresectable patients, extensive biopsy results demonstrated only necrotic tumor. The maximum response achieved using all protocol treatment was 27 (66%) CRs, seven (17%) PRs or regression, six (15%) SDs, and one (2%) PD. Toxicity was substantial and primarily hematologic. There were six (15%) treatment-related deaths, which included three perioperative deaths and three chemotherapy-related toxicity deaths. The Kaplan-Meier curve indicated a 1-year survival of 58% and a median survival of 15.5 months. Nine patients (22%) remain disease-free. CONCLUSIONS: There was a reasonably high rate of PR associated with concurrent neoadjuvant chemotherapy and RT, and a high percentage of patients who ultimately were rendered completely disease-free. However, treatment-related morbidity and mortality was common. Median survival seemed to be only modestly improved beyond that achieved with less intensive means of treatment. However, a group has emerged of patients who enjoy prolonged disease-free survival and possible cure.

Phase I study to determine the maximum-tolerated dose of radiation in standard daily and hyperfractionated-accelerated twice-daily radiation schedules with concurrent chemotherapy for limited-stage small-cell lung cancer.

PURPOSE: An improvement in radiation dose schedule is necessary to increase local tumor control and survival in limited-stage small-cell lung cancer. The goal of this study was to determine the maximum-tolerated dose (MTD) of radiation (RT) in both standard daily and hyperfractionated-accelerated (HA) twice-daily RT schedules in concurrent chemoradiation. METHODS: The study design consisted of a sequential dose escalation in both daily and HA twice-daily RT regimens. RT dose to the initial volume was kept at 40 to 40.5 Gy, while it was gradually increased to the boost volume by adding a 7% to 11 % increment of total dose to subsequent cohorts. The MTD was defined as the radiation dose level at one cohort below that which resulted in more than 33% of patients experiencing grade > or = 4 acute esophagitis and/or grade > or = 3 pulmonary toxicity. The study plan included nine cohorts, five on HA twice-daily and four on daily regimens for the dose escalation. Chemotherapy consisted of three cycles of cisplatin 33 mg/m2/d on days 1 to 3 over 30 minutes, cyclophosphamide 500 mg/m2 on day 1 intravenously (IV) over 1 hour, and etoposide 80 mg/m2/d on days 1 to 3 over 1 hour every 3 weeks (PCE) and two cycles of PE. RT was started at the initiation of the fourth cycle of chemotherapy. RESULTS: Fifty patients were enrolled onto the study. The median age was 60 years (range, 38-79), sex ratio 2.3:1 for male to female, weight loss less than 5% in 73%, and performance score 0 to 1 in 94% and 2 in 6% of patients. In HA twice-daily RT, grade > or = 4 acute esophagitis was noted in two of five (40%), two of seven (29%), four of six (67%), and five of six patients (86%) at 50 (1.25 Gy twice daily), 45, 50, and 55.5 Gy in 1.5 Gy twice daily, 5 d/wk, respectively. Grade > or = 3 pulmonary toxicity was not seen in any of these 24 patients. Therefore, the MTD for HA twice-daily RT was judged to be 45 Gy in 30 fractions over 3 weeks. In daily RT, grade > or = 4 acute esophagitis was noted in zero of four, zero of four, one of five (20%), and two of six patients (33%) at 56, 60, 66, and 70 Gy on a schedule of 2 Gy per fraction per day, five fractions per week. Grade > or = 3 pneumonitis was not observed in any of the 19 patients. Thus, the MTD for daily RT was judged to be at least 70 Gy in 35 fractions over 7 weeks. Grade 4 granulocytopenia and thrombocytopenia were observed in 53% and 6% of patients, respectively, during the first three cycles of PCE. During chemotherapy cycles 4 to 5, grade 4 granulocytopenia and thrombocytopenia were noted in 43% and 29% of patients at 45 Gy in 30 fractions over 3 weeks (MTD) by HA twice-daily RT and 50% and 17% at 70 Gy in 35 fractions over 7 weeks (MTD) by daily RT, respectively. The overall tumor response consisted of complete remission (CR) in 51% (24 of 47), partial remission (PR) in 38% (1 8 of 47), and stable disease in 2% (one of 47). The median survival time of all patients was 24.4 months and 2- and 3-year survival rates were 53% and 28%, respectively. With regard to the different radiation schedules, 2- and 3-year survival rates were 52% and 25% for the HA twice-daily and 54% and 35% for the daily RT cohorts. CONCLUSION: The MTD of HA twice-daily RT was determined to be 45 Gy in 30 fractions over 3 weeks, while it was judged to be at least 70 Gy in 35 fractions over 7 weeks for daily RT. A phase III randomized trial to compare standard daily RT with HA twice-daily RT at their MTD for local tumor control and survival would be a sensible research in searching for a more effective RT dose-schedule than those that are being used currently.

Potential impact on survival of improved tumor downstaging and resection rate by preoperative twice-daily radiation and concurrent chemotherapy in stage IIIA non-small-cell lung cancer.

PURPOSE: The main objectives of this study were (a) to ascertain the feasibility and toxicity of preoperative twice-daily radiation therapy and concurrent chemotherapy, surgery, and postoperative therapy in stage IIIA (N2) non-small-cell lung cancer (NSCLC), and (b) to evaluate tumor response, resection rate, pathologic tumor downstaging, and survival. METHODS: Eligibility included biopsy-proven N2 lesion (stage IIIA) by mediastinoscopy, Karnofsky performance score > or = 70, and weight loss less than 5% in the 3 months before diagnosis. The treatment program consisted of two courses of preoperative cisplatin, vinblastine, and fluorouracil (5-FU); 42 Gy concurrent radiation at 1.5 Gy per fraction in two fractions per day; surgery on day 57; and one more course of postoperative chemotherapy and 12 to 18 Gy of concurrent twice-daily radiation. RESULTS: Forty-two patients with stage IIIA (N2) NSCLC (27 men and 15 women, age 38 to 77 years) were enrolled onto this prospective study. Forty of 42 patients tolerated the intended dose (42 Gy) of preoperative radiation and 37 of 39 resected patients received prescribed postoperative radiation. The intended dose of chemotherapy was given in 100%, 70%, and 60% of patients for the first, second, and third courses of chemotherapy. Marked dysphagia that required intravenous hydration was noted in 14% of patients (six of 42). Myelotoxicities included grade > or = 3 granulocytopenia in 23% and thrombocytopenia in 6% of 113 chemotherapy courses. Febrile neutropenia that required hospital admission was noted in 9% of 113 chemotherapy courses. Surgical resection was performed in 93% of patients. Treatment-related mortality was noted in 7% of patients. The overall survival rates by the Kaplan-Meier method were 66%, 37%, and 37% at 2,3, and 5 years, respectively, with a median follow-up time of 48 months. Pathologic examination of the surgical specimen showed a downward shift in tumor extent from stage IIIA (N2) to stage II (N1) in 33%, to stage I (NO) in 24% (10 of 42), and to stage 0 (TONO) in 9.5%, for a total of 67%. The degree of tumor downstaging was also translated into a survival benefit: 5-year survival rates from the time of surgery were 79%, 42%, and 18% for postoperative tumor stages 0 and I, II, and III, respectively (P = .04). CONCLUSION: Concurrent chemoradiotherapy using twice-daily radiation is an effective induction regimen that resulted in 67% tumor downstaging, and an encouraging 37% 5-year survival rate. The degree of tumor downstaging may be a useful intermediate end point for survival benefit in stage IIIA (N2) NSCLC.

Triphasic perfusion computed tomography in acute middle cerebral artery stroke: a correlation with angiographic findings.

OBJECTIVE: To evaluate the usefulness of triphasic perfusion computed tomography (TPCT) in diagnosing middle cerebral artery (MCA) occlusion and in assessing the perfusion deficit and collateral circulation in patients with acute ischemic stroke. BACKGROUND: Conventional angiography is the criterion standard for the diagnosis of MCA occlusion and for the assessment of perfusion deficit and collateral blood supply. The risk of hemorrhagic transformation after recanalization of occluded arteries by thrombolytic therapy is considered high when pretherapeutic residual flow is markedly reduced. PATIENTS AND METHODS: In 8 patients within 3 hours of onset of acute MCA stroke, precontrast computed tomographic scans were taken, and then TPCT was performed after power-injector controlled intravenous administration of contrast media. Sequential images of early, middle, and late phases were obtained. The whole procedure took 5 minutes. Perfusion deficit on TPCT was graded as "severe" or "moderate," depending on the state of collateral flow. Digital subtraction angiography (DSA) was performed in all patients within 6 hours of acute stroke. Direct intra-arterial urokinase infusion was begun immediately after the angiographic superselection of the MCA occlusion site in 6 of the 8 patients within 7 hours of onset (range, 4.3-6.2 hours). RESULTS: The DSA findings showed occlusion of the MCA stem (n = 1) and at the bifurcation (n = 4). The sites of proximal MCA occlusion could be identified on the early and middle images of TPCT in all 5 patients. On DSA findings, all 8 patients had a zone of perfusion deficit with markedly slow leptomeningeal collaterals and a zone of perfusion deficit with no collaterals. The zone of severe perfusion deficit on TPCT corresponded to the zone of perfusion deficit with no or few collaterals on angiography, and the zone of moderate perfusion deficit on TPCT corresponded to that of perfusion deficit with markedly slow leptomeningeal collaterals. Early parenchymal hypoattenuation on precontrast computed tomography was confined to the zone of severe perfusion deficit on TPCT. The initial National Institutes of Health Stroke Scale score correlated better with the total extent of severe perfusion deficit and moderate perfusion deficit on TPCT than that of severe perfusion deficit alone. After direct intra-arterial thrombolysis within 7 hours of onset, symptomatic hemorrhagic transformation did not develop in 4 patients with small severe perfusion deficit (33% or less of the presumed MCA territory). However, the remaining 2 patients with large severe perfusion deficit (more than 50% of the presumed MCA territory) deteriorated to death with hemorrhagic transformation. CONCLUSIONS: Triphasic perfusion computed tomography is useful for diagnosing proximal MCA occlusion and assessing perfusion deficit and collateral circulation as reliably as DSA. The zone of severe perfusion deficit on TPCT may be presumed to be the ischemic core, and that of moderate perfusion deficit, the penumbra zone. Triphasic perfusion computed tomography may be used as a rapid and noninvasive tool to make thrombolysis safer.

The risk of intradural spinal metastases in patients with brain metastases from bronchogenic carcinomas.

Intradural spinal metastases can develop following dissemination via the cerebrospinal fluid from various primary or secondary brain tumors. Since the risk of intradural spinal metastases has never been formally studied in patients with brain metastases, we reviewed patients with brain metastases from bronchogenic carcinomas and looked for the subsequent development of intradural spinal metastases. Of 160 consecutive patients, only 6 presented intradural spinal metastases, however none were among the 105 patients who had exclusively supratentorial metastases and all intradural spinal metastases were in patients who had lesions in the posterior fossa. In this group, the 1-year actuarial risk of having intradural spinal metastases was 21% (p less than .01 compared with patients who had supratentorial metastases). We could not find any other risk factor for intradural spinal metastases. Recommendations for the group of patients with increased risk of intradural spinal metastases are made.

Importance of radiation dose in achieving improved loco-regional tumor control in limited stage small-cell lung carcinoma: an update.

Between 1974 and 1986, 576 patients (284 limited and 292 extensive stages) were treated at this institution. To keep multiagent chemotherapy (CT) at a uniform intensity, patients who received (a) combined modality approach of both multiagent chemotherapy and thoracic radiotherapy (RT) and (b) greater than or equal to 3 cycles of multiagent chemotherapy (greater than or equal to 3 drugs), were chosen for this analysis. Out of 284 patients with limited Stage small-cell lung carcinoma, there were 154 such patients who met these strict criteria, and the treatment methods for the remaining 130 patients were as follows: (a) chemotherapy alone with radiotherapy reserved for local failure (47 pts); (b) radiotherapy alone (20 pts); (c) surgery +/- adjuvant chemotherapy or radiotherapy (37 pts); (d) modified chemotherapy plus radiotherapy (26 pts). During the 12-year period, the therapeutic factors have evolved. Radiation-dose was increased from 30-40 Gy (time dose fractionation 49-66) in 1974-1977 to 44-52 Gy (time dose fractionation 73-86) in 1978-1986. The target volume for radiotherapy included the primary lesion with a 2-cm margin of normal lung and the mediastinum. Chemotherapy program also evolved from COP, CAV (1974-1977) to MACC, VCE-VCA, PCE-ACE (1978-1986). Fifty of 154 patients (32%) developed loco-regional recurrence (infield failure) and 98% (49/50) of these patients exhibited this by 2.5 years. Survival data of 154 patients were as follows: (a) Median survival time (MST) was 12 M; (b) actuarial survival rates at 2 and 5 years were 21% and 8%, respectively. Fifty percent of these patients died within 12 months (MST 12 M) and were not exposed to the full length of the risk period for loco-regional failure. To take into account the duration of exposure to the risk period, actuarial method was employed to measure the probability of loco-regional failure. Loco-regional failure rates at 2.5 years were 37%, 39%, 49%, 79%, and 84% for 50 Gy, 45 Gy, 40 Gy, 35 Gy, and 30 Gy, respectively. The difference between the recurrence rates of 37% and 79% by 50 Gy and 35 Gy was statistically significant, p less than 0.05. Although the recurrence rates of 37% and 49% by 50 Gy and 40 Gy were not statistically different, there was a strong trend of a better control rate of loco-regional carcinoma by higher radiation doses. The time to recurrence seems also shorter with lower radiation-dose than that of higher radiation doses.(ABSTRACT TRUNCATED AT 400 WORDS)

Improved quality of life of patients with small-cell carcinoma of the lung by elective irradiation of the brain.

About 30% of all patients with small cell undifferentiated carcinoma of the lung will ultimately develop metastases in the brain. It is now well established that elective whole brain irradiation can prevent such metastases, although it does not increase survival time. However, we have found that such treatment does increase the quality of life for these patients. Those with limited disease can survive with a Karnofsky scale of more than 60 for a mean time of 10 months compared with 6 months for an equivalent group treated only when these brain metastases occur. We have also found that treating patients therapeutically does not insure success as 6/16 eventually relapsed in the brain. We conclude that elective brain irradiation in patients with small cell undifferentiated carcinoma of the lung who present with a limited disease is of value because the quality of life is improved significantly.

Effect of postoperative radiotherapy on changes in pulmonary function in patients with stage II and IIIA lung carcinoma.

To assess the pulmonary tolerance to postoperative radiotherapy (RT) in patients with resected lung carcinoma, a prospective study was begun in January 1977, which consisted of (a) initial pulmonary function test (PFT) and arterial blood gases (ABG) at 1 month after surgery, and before beginning of postoperative RT, and (b) follow-up PFT and ABG 1 year after postoperative RT and then every year thereafter. As of December 1987, 137 patients have been enrolled into this study, and 71 patients who were free of recurrence were subjected to the follow-up PFT and ABG. The remaining 66 patients were unable to complete the follow-up studies because of recurrent carcinoma in 60, refusal to participate in the study in 5 patients even in the absence of significant respiratory symptoms, and progressive asbestos-related pleural thickening in 1 patient. The patient characteristics were as follows: Age ranged from 27 to 79 years with the median of 59 years; sex ratio was 1.4 to 1 for male to female; surgical procedures included lobectomy in 49 and pneumonectomy in 22 patients; tumor extent consisted of Stages T1-T2N1M0 in 44, T1-T2N2M0 in 9, and T3N0-N2M0 in 18 patients, respectively. Histologic types included squamous cell carcinoma in 26, adenocarcinoma in 42, small cell carcinoma in 1, and large cell carcinoma in 2 patients. Target volume for RT included the ipsilateral hilum, the mediastinum, and the thoracic inlet including both supraclavicular fossae. A total dose of 54 Gy was delivered in 1.8 Gy of daily fractions, 5 days per week over a period of 6 weeks. Contrary to expectation, there were minor changes in PFT indices in both lobectomy and pneumonectomy patients. The follow-up PFT in the lobectomy group showed small -3% to +2% changes in mean values of ventilatory indices, lung volume, and ABG. The follow-up PFT in the pneumonectomy group also showed small -9% to +13% changes in mean values of ventilatory indices, lung volume, and ABG. Sixteen patients have had more than one PFT during the follow-up period (2 years to 10 years), and there was no significant long term adverse effect of RT on PFT in this subset of patients. Lung scans assessing regional function, which were available in six patients, were not helpful in predicting changes in PFT indices as a result of postoperative RT.

Accelerated radiotherapy followed by chemotherapy for locally recurrent small-cell carcinoma of the lung. A phase II study of Cancer and Leukemia Group B.

Recurrent or persistent small-cell carcinoma of the lung (SCCL) after chemotherapy (CT) alone has shown a poor response to conventional salvage radiotherapy (RT). Accelerated RT is judged more effective than conventional RT for rapidly growing tumors such as SCCL. The objectives of this study were: to determine the tolerability of accelerated RT; and to test the ability of accelerated RT plus CT to achieve local tumor control (LTC) of SCCL recurrent after CT. Patients whose localized tumor was not controlled were selected from Arm III of the Cancer and Leukemia Group B (CALGB) protocol 8083 (Proc. ASCO 2:230, 1984) as eligible for this study. The program of accelerated RT consisted of the delivery of 50.1 Gray (Gy) in 30 fractions over a period of 21 days to the chest. New chemotherapy different from the first began 2 weeks after the completion of RT and was repeated every 3 weeks for 18 months (M). Of 29 potentially eligible patients with locally recurrent SCCL after the first line CT alone from Arm III of the CALBG protocol 8083, 12 were enrolled initially in this study. The analysis of LTC included 11 patients excluding one patient who died 4 weeks after the start of RT from liver metastases. The LTC achieved was as follow: complete remission in 8/11 (72%) and partial remission in 3/11 patients. None of the patients was converted to CR by subsequent chemotherapy. Survival ranged from 2 to 20 M, with a median survival time of 6 M. Tolerance to the subsequent CT, normal tissue reaction to accelerated RT, and the theoretical advantage of accelerated RT over conventional RT for SCCL were evaluated.

Stage III thymoma: pattern of failure after surgery and postoperative radiotherapy and its implication for future study.

PURPOSE: With the conventional approach of surgery and postoperative radiotherapy for patients with Masaoka Stage III thymoma, progress has been slow for an improvement in the long-term survival rate over the past 20 years. The objective of this study was to evaluate the pattern of failure and survival after surgery and postoperative radiotherapy in Stage III thymoma and search for a new direction for better therapy outcome. METHODS AND MATERIALS: Between 1975 and 1993, 111 patients with thymoma were treated at Massachusetts General Hospital. Of these, 32 patients were determined to have Masaoka Stage III thymoma. The initial treatment included surgery for clinically resectable disease in 25 patients and preoperative therapy for unresectable disease in 7 patients. Surgical procedure consisted of thymectomy plus resection of involved tissues. For postoperative radiotherapy (n = 23), radiation dose consisted of 45-50 Gy for close resection margins, 54 Gy for microscopically positive resection margins, and 60 Gy for grossly positive margins administered in 1.8 to 2.0 Gy of daily dose fractions, 5 fractions a week, over a period of 5 to 6.6 weeks. In preoperative radiotherapy, a dose of 40 Gy was administered in 2.0 Gy of daily dose fractions, 5 days a week. For patients with large tumor requiring more than 30% of total lung volume included in the target volume (n = 3), a preoperative radiation dose of 30 Gy was administered and an additional dose of 24-30 Gy was given to the tumor bed region after surgery for positive resection margins. RESULTS: Patients with Stage III thymoma accounted for 29% (32/111 patients) of all patients. The median age was 57 years with a range from 27 to 81 years; gender ratio was 10:22 for male to female. The median follow-up time was 6 years. Histologic subtypes included well-differentiated thymic carcinoma in 19 (59%), high-grade carcinoma in 6 (19%), organoid thymoma in 4 (13%), and cortical thymoma in 3 (9%) according to the Marino and Müller-Hermelink classification. The overall survival rates were 71% and 54% at 5 and 10 years, respectively. Ten of the 25 patients who were subjected to surgery as initial treatment were found to have incomplete resection by histopathologic evaluation. The 5- and 10-year survival rates were 86% and 69% for patients (n = 15) with clear resection margins as compared with 28% and 14% for those (n = 10) with incomplete resection margins even after postoperative therapy, p = 0.002. Survival rates at 5 and 10 years were 100% and 67% for those with unresectable disease treated with preoperative radiation (n = 6) and subsequent surgery (n = 3). Recurrence was noted in 12 of 32 patients and 11 of these died of recurrent thymoma. Recurrences at pleura and tumor bed accounted for 77% of all relapses, and all pleural recurrences were observed among the patients who were treated with surgery initially. CONCLUSION: Incomplete resection leads to poor results even with postoperative radiotherapy or chemoradiotherapy in Stage III thymoma. Pleural recurrence is also observed more often among patients treated with surgery first. These findings suggest that preoperative radiotherapy or chemoradiotherapy may result in an increase in survival by improving the rate of complete resection and reducing local and pleural recurrences.

Simplified measurement of deoxyglucose utilization rate.

UNLABELLED: The reliability of the dose uptake ratio (DUR), a widely used index of 18F-fluoro-2-deoxy-D-glucose (18FDG) metabolism in a variety of tumors, depends on the overall rate of removal of 18FDG from the circulation. Correcting for this factor is important if DUR is to be used quantitatively for pre- and post-treatment assessments of tumors. METHODS: We developed a simplified kinetic method (SKM), based on measured blood curves from a control group, which requires one venous blood sample. We compared the simplified method to the conventional kinetic method and the widely used DUR index in 13 patients with grade 3 or 4 non-small-cell lung carcinoma. Studies were obtained before and after treatment. In all patients, dynamic PET imaging and blood activity measurement was performed for 80 min. The utilization rate of 18FDG (MRDGlc) was calculated by using a three-compartment model and correlated with a 55-min measurement of DUR and with the simplified kinetic method. RESULTS: Coefficients of determination (R2) between MRDGlc and DUR before and after treatment were 0.53 and 0.71, respectively. Using the SKM, these values improved significantly (p < 0.0001) to 0.96 and 0.94, respectively. The pooled pre- and post-treatment coefficient of determination for DUR versus MRDGlc was 0.81; for SKM, it improved significantly (p < 0.001) to 0.98. CONCLUSION: These results indicate that the observed tumor tissue uptake of 18FDG, corrected for blood 18FDG activity and glucose concentration, can reliably predict glucose metabolic rate from a single static image acquired at between 45 min and 1 hr after injection. This has substantial implications for the quantitative use of 18FDG PET to diagnose and manage malignancy.

Lung tumor metastasis to breast detected by fluorine-18-fluorodeoxyglucose PET.

We report a case of breast metastasis from a large-cell bronchogenic adenocarcinoma. Serial 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) was used to monitor the response of the primary lesion to radiation therapy. In the 7-wk interval between studies, an area of markedly increased FDG uptake appeared in the right breast. On subsequent biopsy this proved to be a metastatic deposit from the primary lesion. breast metastasis is uncommon. The ability of FDG-PET to detect metastatic lesions from primary lung tumor is variable. In this case, the finding of the new breast lesion resulted in introduction of chemotherapy to the treatment program.

The dose uptake ratio as an index of glucose metabolism: useful parameter or oversimplification?

UNLABELLED: The dose uptake ratio (DUR) has been used as a quantitative index of glucose metabolism for tumor classification and monitoring response to treatment. In order to provide consistent results, DUR measurements should be made when the concentration of tracer has reached a plateau. The time of this plateau cannot be identified from a single static acquisition. METHODS: In this study, we investigated the changes in DUR as a function of time in eight patients with stage III lung cancer. All patients underwent a quantitative dynamic 18F-FDG PET study before and after treatment and the data were analyzed with a three-compartment model. Using the fitted model parameters, the DUR was predicted at the plateau and intermediate times. RESULTS: Tumor concentrations of 18F-FDG did not reach a plateau within the 90 min of imaging in any of the pre-treatment studies and only in one case post-treatment. The average time to reach 95% of the plateau value pre-treatment was 298 +/- 42 min (range: 130-500 min); in post-treatment, it was 154 +/- 31 min (range: 65-240 min). The difference between the plateau DUR and the 60-min value was 46% +/- 6% pre-treatment and 17% +/- 5% post-treatment. CONCLUSIONS: These data indicate that DUR can vary widely with the time of measurement and that DUR should be interpreted with caution in any individual patient.

Superior sulcus lung tumors: impact of local control on survival.

OBJECTIVES: Our goal was to assess patient survival and response to treatment for superior sulcus tumors treated with combined radiation therapy and surgery when possible, or with radiation alone when surgery was not possible. METHODS: Seventy-three patients were treated for primary non-small cell carcinoma of the superior pulmonary sulcus. Thirty-four patients received combined resection and irradiation. Thirty-nine patients who had extensive primary disease, distant metastases, or who were medically unfit for surgery were treated with radiation alone. Thirty-one patients (91%) assigned to the resection/irradiation group completed treatment. Combined therapy patients routinely received 40 Gy before the operation, with additional postoperative irradiation based on the surgical findings. RESULTS: Overall survival at 5 years was 19% and disease-specific survival was 20% for all patients. Overall survival and disease-specific survival at 5 years for the resection/irradiation group were 33% and 38%, respectively. Significant indicators of poor prognosis included unresected primary disease, low performance score, T4 stage, or positive node status. Eighty-two percent of the patients who received irradiation alone were treated with palliative intent. Freedom from local-regional progression, achieved initially in 66% of these patients, was associated with a median survival of 8 months. Median survival for 7 patients considered for definitive irradiation was 25 months. During the first 18 months, distant failures occurred in approximately 35% of patients in each treatment group. CONCLUSIONS: Selection of medically fit patients with resectable disease for combined surgery and aggressive radiation therapy resulted in a high likelihood of local control. Overall survival for the resection/irradiation group was significantly poorer for patients with T4 stage, nodal disease, or Horner's syndrome. Distant metastases eventually developed in 56% of patients undergoing resection. Median survival in the resection/irradiation group was significantly prolonged for those patients who could tolerate high-dose radiation treatment.