Study of 962 patients indicates progressive muscular atrophy is a form of ALS.

BACKGROUND: Progressive muscular atrophy (PMA) is clinically characterized by signs of lower motor neuron dysfunction and may evolve into amyotrophic lateral sclerosis (ALS). Whether PMA is actually a form of ALS has important consequences clinically and for therapeutic trials. We compared the survival of patients with PMA or ALS to analyze the clinical features that influence survival in PMA. METHODS: We reviewed the medical records of patients with PMA (n = 91) or ALS (n = 871) from our ALS Center and verified survival by telephoning the families or using the National Death Index. RESULTS: In PMA, patients were more likely to be male (p < 0.001), older (p = 0.007), and lived longer (p = 0.01) than in ALS. Cox model analysis suggested that the risk of death increased with age at onset in both patient groups (p < 0.005). Upper motor neuron (UMN) signs developed in 22% of patients with PMA within 61 months after diagnosis. Demographic and other clinical variables did not differ at diagnosis between those who did or did not develop UMN signs. In PMA, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower forced vital capacity, and lower ALS Functional Rating Scale-Revised score. Noninvasive ventilation and gastrostomy were used frequently in PMA. CONCLUSION: Although patients with progressive muscular atrophy (PMA) tended to live longer than those with amyotrophic lateral sclerosis (ALS), shorter survival in PMA is associated with the same risk factors that predict poor survival in ALS. Additionally, PMA is relentlessly progressive, and UMN involvement can occur, as also reported in imaging and postmortem studies. For these reasons, PMA should be considered a form of ALS.

Preoperative chemotherapy for esophageal cancer with paclitaxel and carboplatin: results of a phase II trial.

OBJECTIVE: Paclitaxel has one of the highest response rates when used as a single agent in patients with esophageal cancer. The combination of paclitaxel and carboplatin has been shown to be a well-tolerated and safe regimen in non-small cell lung cancer. The objective of this study was to determine the efficacy of preoperative paclitaxel and carboplatin in patients with carcinoma of the esophagus. PATIENTS AND METHODS: A phase II trial was initiated in January 1999 and concluded in January 2001. All patients had potentially resectable disease (including clinical T4 lesions). Patients with stage I disease and those with visceral metastases were excluded. All underwent preoperative computed tomography scanning and endosonography for staging. Paclitaxel (200 mg/m(2)) and carboplatin (area under the curve = 6) were given on days 1 and 22. Esophagectomy was carried out on weeks 6 to 8. RESULTS: Twenty-six (11 epidermoid, 15 adenocarcinoma) patients completed the trial. Median age was 61.5 and 85% were men. Preoperative staging showed: stage IIA, 6 patients; stage IIB, 1 patient; and stage III, 19 patients. All patients completed their preoperative chemotherapy. There was no unexpected chemotherapy-related toxicity. A major clinical response was achieved in 16 patients (61%: 19% complete, 42% partial). Resectability was 77% (20/26). A complete pathologic response was seen in 11% of all patients and in 25% of those with epidermoid cancer. Hospital mortality and morbidity were 4 and 27%, respectively. Overall 3-year survival was 48% (64% for resected patients, median not reached). All 6 unresectable patients died within 6 months of exploration. CONCLUSION: Paclitaxel-carboplatin combination is a safe and well-tolerated regimen for esophageal cancer with clinical response rates comparable to historical controls. This regimen may be especially suitable for patients with epidermoid cancer, who had a 25% pathological complete response in this report.

Celecoxib, a selective cyclo-oxygenase-2 inhibitor, enhances the response to preoperative paclitaxel and carboplatin in early-stage non-small-cell lung cancer.

PURPOSE: Preclinical studies suggest that treatment with a selective cyclo-oxygenase-2 (COX-2) inhibitor may augment the antitumor effects of chemotherapy. In this study, patients with non-small-cell lung cancer (NSCLC) were preoperatively treated with celecoxib in combination with chemotherapy. End points were toxicity, response rates, and measurement of intratumoral levels of prostaglandin E2 (PGE2). METHODS: In this phase II trial, 29 patients with stages IB to IIIA NSCLC were treated with two preoperative cycles of paclitaxel and carboplatin, as well as daily celecoxib, followed by surgical resection. Levels of PGE2 in the primary tumors and adjacent normal lung tissue were compared in 17 study patients versus 13 controls, who received preoperative paclitaxel/carboplatin without celecoxib. RESULTS: All patients completed preoperative chemotherapy, and 26 completed preoperative celecoxib. The overall clinical response rate was 65% (48% with partial response; 17% with complete response). Grade 3 or 4 neutropenia was observed in 18 patients (62%). Twenty-eight patients were explored and underwent complete resection of their tumors. There were no complete pathologic responses, but seven patients (24%) had minimal residual microscopic disease. The addition of celecoxib to a regimen of paclitaxel and carboplatin abrogated the marked increase in levels of PGE2 detected in primary tumors after treatment with paclitaxel and carboplatin alone. CONCLUSION: In comparison with historically reported response rates, these data suggest that the addition of a selective COX-2 inhibitor may enhance the response to preoperative paclitaxel and carboplatin in patients with NSCLC. Moreover, treatment with celecoxib 400 mg twice daily was sufficient to normalize the increase in PGE2 levels found in NSCLC patients after treatment with paclitaxel and carboplatin. Confirmatory trials are planned.

Guidelines for the use of spiral computed tomography in screening for lung cancer.

Screening should be considered in lung cancer, more than any other cancer. Not only is the disease highly fatal, essentially incurable, when diagnosed on the prompting of symptoms and/or clinical signs, but its occurrence is also highly concentrated in identifiably high-risk persons. The degree of usefulness of computed tomography (CT)-based screening for lung cancer must be thought of in reference to a particular, presumably optimal, regimen of pursuing early stage diagnosis. This is an algorithm that begins with the initial test ("screening CT") and ends in either discontinuation of the diagnostic pursuit or in diagnosis of lung cancer. A carefully developed, extensively pilot tested and critically reviewed, updated protocol for CT-based screening for lung cancer is presented here. Its implementation is addressed, together with quality assurance. Finally, the associated curability rate for lung cancer is addressed in the light of what is known or can be surmised from evidence already available. However, recommendation for or against screening requires further information. Principally, the patients risk for lung cancer (in the near future) and the patients life expectancy (when spared of death from lung cancer). These two factors influence when, if ever, to begin screening, and if it is initiated, when to discontinue it. Finally, cost-effectiveness of the screening program should also be considered.

Early lung cancer action project: initial findings on repeat screenings.

BACKGROUND: The Early Lung Cancer Action Project (ELCAP) was designed to evaluate the usefulness of annual computed tomography (CT) screening for lung carcinoma. With the baseline results having been reported previously, the focus of the current study was on the early results of the repeat screenings. METHODS: A cohort of 1000 high-risk individuals was recruited for baseline and annual repeat CT screening. At last follow-up, a total of 1184 annual repeat screenings had been performed. A positive result from the screening test was defined as newly detected, one to six noncalcified pulmonary nodules with interim growth. The diagnostic workup of the individuals was guided by recommendations supplied by the ELCAP investigators to the collaborating clinicians. RESULTS: Of the 1184 repeat CT screenings, the test result was positive in 30 (2.5%). In 2 of these 30 cases, the individual died (of an unrelated cause) before diagnostic workup and the nodule(s) resolved in another 12 individuals. In the remaining 16 individuals, the absence of further growth was documented by repeat CT in 8 individuals and further growth was documented in the remaining 8 individuals. All eight individuals with further nodular growth underwent biopsy and malignancy was diagnosed in seven. Six of these seven malignancies were nonsmall cell carcinomas (five of which were Stage IA and one of which was Stage IIIA) and the one small cell carcinoma was found to be of limited stage. The median size dimension of these malignancies was 8 mm. In another two subjects, symptoms prompted the interim diagnosis of lung carcinoma. Neither of these malignancies was nodule-associated but rather were endobronchial; one was a Stage IIB nonsmall cell carcinoma and the other was a small cell carcinoma of limited stage. CONCLUSIONS: False-positive screening test results are uncommon and usually manageable without biopsy; compared with no screening, such screenings permit diagnosis at substantially earlier and thus more curable stages. Annual repetition of CT screening is sufficient to minimize symptom-prompted interim diagnoses of nodule-associated malignancies.

Detection of early-stage lung cancer: computed tomographic scan or chest radiograph?

OBJECTIVE: Computed tomography has recently been proposed as a useful method for the early detection of lung cancer. In this study we compared the stage distribution of lung cancers detected by a computed tomographic scan with that of lung cancers detected by a routine chest x-ray film. METHODS: Two groups of patients with biopsy-proven non-small cell lung cancer were reviewed. In the first group of 32 patients, the tumors were detected by a computed tomographic scan. In a second group (n = 101), the lung cancers were detected on routine chest x-ray films. Patients with pulmonary symptoms or a history of cancer were excluded. RESULTS: There was no difference in age, sex, or cell-type distribution between the 2 groups. A significantly greater number of patients undergoing a computed tomographic scan had stage IA disease compared with those having an x-ray film. Of the 32 patients in the group having a scan, 10 had tumors 1 cm or less in size versus 6 of 101 in the group having a chest radiograph. Additionally, there was a significant reduction in advanced stage disease in the group having a scan. CONCLUSIONS: In this retrospective study, a higher incidence of stage IA lung cancers and significantly fewer cases of more advanced disease were observed in patients screened with computed tomography than in those having a chest radiograph. These data suggest that computed tomographic screening may be of value in improving the survival of patients with non-small cell lung cancer.

Early lung cancer action project: a summary of the findings on baseline screening.

PURPOSE: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low radiation dose computed tomography (low-dose CT) in persons at high-risk for lung cancer. METHODS: Since starting in 1993, the ELCAP has enrolled 1,000 asymptomatic persons, 60 years of age or older, with at least 10 pack-years (1 pack per day for 10 years, or 2 packs per day for 5 years) of cigarette smoking, no prior cancer, and medically fit to undergo thoracic surgery. After a structured interview and informed consent, baseline chest radiographs and low-dose CT were obtained on each subject. The diagnostic work-up of screen-detected noncalcified pulmonary nodules (NCN) was guided by ELCAP recommendations which included short-term high-resolution CT follow-up for the smallest nodules. Baseline RESULTS: On low-dose CT at baseline compared to chest radiography, NCN were detected three times as commonly (23% versus 7%), malignancies four times as commonly (2.7% versus 0.7%), and stage I malignancies six times as commonly (2.3% versus 0.4%). Of the 27 CT-detected cancers, 96% (26/27) were resectable; 85% (23/27) were stage I, and 83% (19 of the 23 stage I) were not seen on chest radiography. Following the ELCAP recommendations, biopsies were performed on 28 of the 233 subjects with NCN; 27 had a malignant and one a benign NCN. Another three individuals underwent biopsy outside of the ELCAP recommendations; all had benign NCNS: No one had thoracotomy for a benign nodule. CONCLUSION: Baseline CT screening for lung cancer provides for detecting the disease at earlier and presumably more commonly curable stages in a cost-effective manner.

Early lung cancer action project: annual screening using single-slice helical CT.

The advent of helical CT imaging held promise for the early diagnosis, and thereby, for enhanced curability of lung cancer--a highly fatal disease. In 1993, the Early Lung Cancer Action Project (ELCAP) was initiated and experimentally screened a cohort of 1,000 high-risk persons. Here we summarize the results of the baseline and annual repeat CT screening of these 1,000 subjects. CT-based screening (compared to traditional radiology) was clearly shown to enhance the detection of lung cancer at earlier and more curable stages. A discussion follows of the meaning of the results and possible future screening protocols.

Early Lung Cancer Action Project: overall design and findings from baseline screening.

BACKGROUND: The Early Lung Cancer Action Project (ELCAP) is designed to evaluate baseline and annual repeat screening by low-radiation-dose computed tomography (low-dose CT) in people at high risk of lung cancer. We report the baseline experience. METHODS: ELCAP has enrolled 1000 symptom-free volunteers, aged 60 years or older, with at least 10 pack-years of cigarette smoking and no previous cancer, who were medically fit to undergo thoracic surgery. After a structured interview and informed consent, chest radiographs and low-dose CT were done for each participant. The diagnostic investigation of screen-detected non-calcified pulmonary nodules was guided by ELCAP recommendations, which included short-term high-resolution CT follow-up for the smallest non-calcified nodules. FINDINGS: Non-calcified nodules were detected in 233 (23% [95% CI 21-26]) participants by low-dose CT at baseline, compared with 68 (7% [5-9]) by chest radiography. Malignant disease was detected in 27 (2.7% [1.8-3.8]) by CT and seven (0.7% [0.3-1.3]) by chest radiography, and stage I malignant disease in 23 (2.3% [1.5-3.3]) and four (0.4% [0.1-0.9]), respectively. Of the 27 CT-detected cancers, 26 were resectable. Biopsies were done on 28 of the 233 participants with non-calcified nodules; 27 had malignant non-calcified nodules and one had a benign nodule. Another three individuals underwent biopsy against the ELCAP recommendations; all had benign non-calcified nodules. No participant had thoracotomy for a benign nodule. INTERPRETATION: Low-dose CT can greatly improve the likelihood of detection of small non-calcified nodules, and thus of lung cancer at an earlier and potentially more curable stage. Although false-positive CT results are common, they can be managed with little use of invasive diagnostic procedures.

The effect of surgical debulking on the response of patients with ovarian carcinoma to chemotherapy.

The role of debulking surgery as an adjuvant to chemotherapy in advanced ovarian carcinoma was examined. Debulking surgery did not alter the overall response rate to chemotherapy. Surgical resection, though, was associated with an increased percentage of complete pathological remissions, particularly in patients receiving efficacious chemotherapy. Whether debulking surgery is causal or a prognostic factor remains conjectural.

The COP-BLAM programs: evolving chemotherapy concepts in large cell lymphoma.

The cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, procarbazine (COP-BLAM) programs of combination chemotherapy were administered to patients with advanced diffuse large cell lymphoma. The original COP-BLAM programs were designed to deliver intense multidrug therapy maximizing tumor kill. COP-BLAM programs IA and IB, easily administered on an outpatient basis, produced identical 73% complete remissions (CRs) and 55% long-term, disease-free survival (DFS). COP-BLAM III, an outgrowth of studies using infusional therapy, differed from COP-BLAM by using infusional bleomycin and vincristine alternated with bolus vincristine. With COP-BLAM III, 84% CRs, 76% "potential cures," and a 65% DFS were produced at a median follow-up time of 50 months. COD-BLAM IV, using four sequential cycles of infusional chemotherapy, high-dose alternating myelosuppressives (doxorubicin, cyclophosphamide), and cycle-active agents (methotrexate, cytarabine, and etoposide) produced 88% CRs, 67% potential cures, and a 64% DFS at a median follow-up of 24 months. COP-BLAM V employs four to six sequential cycles of infusional chemotherapy tailored to the rapidity of response. Preliminary results in patients with high-risk Hodgkin's disease suggest COP-BLAM V may be effective despite the shortened treatment time. In all programs, prognostic factors were critical determinants in the results achieved, particularly age and rapidity of response.

Inadequacy of predicted creatinine clearance as guide to chemotherapy.

Many chemotherapeutic agents are nephrotoxic and/or excreted via the kidney. Thus, careful evaluation of renal function is important since drug dosages are often lowered in patients with impaired renal function. When the creatinine clearance as calculated by the method of Cockcroft and Gault from the patient's age, weight, and serum creatinine was compared to the measured creatinine clearance in the same patients, the correlation coefficient was low (r = 0.40) and the average difference between the predicted and measured creatinine clearance values was 25.3%. Thus, in our patient population, creatinine clearance calculated by the method of Cockcroft and Gault did not correlate well with measured creatinine clearance and thus was not useful as a clinical tool.

Advances in chemotherapy for large cell lymphoma.

Three generations of chemotherapy regimens for the treatment of aggressive lymphomas have evolved in the past decade. The first-generation combination regimen, CVP, also known as COP (cyclophosphamide, vincristine, prednisone), produced maximum long-term survivals in considerably less than 20% of patients. With the MOPP (mechlorethamine, vincristine, procarbazine, prednisone) regimen, 40% of patients achieved complete remission (CR). This signal study was paralleled by other first-generation studies including CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone), HOP (doxorubicin, vincristine, prednisone), CHOP-Bleo/BACOP (CHOP plus bleomycin), and COMLA (cyclophosphamide, vincristine, methotrexate, leucovorin, cytarabine). None of the regimens was shown to be particularly superior to the others. Survival plateaus were seen in approximately 20% to 40% of patients. Second-generation therapies, COP-BLAM (cyclophosphamide, vincristine, prednisone, bleomycin, doxorubicin, procarbazine), ProMACE-MOPP (prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, procarbazine, prednisone), M-BACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, dexamethasone), and m-BACOD (same as M-BACOD, but with a moderate dose of methotrexate and modified leucovorin given on days 8 and 15 instead of just day 10) were characterized by an increasing number of drugs, more frequent administration of myelosuppressive agents, and flexible dose schedules. This new treatment intensity resulted in CRs in excess of 70%. The third generation regimens have been characterized by innovative concepts of chemotherapy, including alternative modes of drug administration, greater use of marrow-sparing, cycle-active, and/or putatively non-cross-resistant agents, and more frequent and/or intense dose administration. These regimens, COP-BLAM III, MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, bleomycin), ProMACE-CytaBOM (ProMACE plus cytarabine, bleomycin, vincristine, methotrexate), and high-dose doxorubicin with cytarabine, have produced over 80% CRs and survival plateaus in excess of 60%. In the COP-BLAM III regimen, 84% of patients achieved a pathologic CR. Overall, 65% of patients are alive, well, and free of disease, and potentially in the survival plateau. COD-BLAM IV (same as COP-BLAM, except dexamethasone is substituted for prednisone) is a new program that further intensifies treatment by using sequential, rather than alternate-cycle, infusions of bleomycin and vincristine. Results are still preliminary, with a short median follow-up of 19 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Six-drug chemotherapy (hexamethylmelamine, doxorubicin, cisplatin, cyclophosphamide, methotrexate, and 5-FU; CHAMP-5) for ovarian carcinoma: alternating sequences of combination regimens.

Twenty-five patients with previously untreated adenocarcinoma of the ovary (International Federation of Gynecology and Obstetrics, stages II, III, and IV) were placed on a six-drug trial (CHAMP-5) for 18 months. This trial consisted of 28-day cycles of hexamethylmelamine, doxorubicin, and cisplatin alternating with hexamethylmelamine, cyclophosphamide, methotrexate, and 5-FU. After a minimum follow-up of 31 months, 14 (56%) of the 25 evaluable patients achieved complete or partial response and nine (36%) achieved complete pathologic response. Although CHAMP-5 is effective in the treatment of ovarian cancer, the results in these patients are not substantially different from those achieved with hexamethylmelamine, doxorubicin, and cisplatin alone.

HAC-Cytoxan (cyclophosphamide) chemotherapy for ovarian carcinoma. Alternating chemotherapy with intensification.

Twenty-two previously untreated patients with adenocarcinoma of the ovary were treated with 28 day cycles of hexamethylmelamine, Adriamycin (doxorubicin), and cisplatin (HAC) for 9 months followed by three monthly cycles of intense intravenous cyclophosphamide. An overall response frequency of 82% (18/22) was achieved. Complete pathologic responses (CPR) documented by second look operations were found in 50% (11/22); however, patients considered to be free of disease (prolonged complete clinical response refusing "second look" and CPR) totaled 59%. Median survival has not been reached after a median follow-up of 34 months. No major or life threatening toxicity was encountered. HAC followed by cyclophosphamide is a highly effective regimen that may be easily administered on an outpatient basis with comparatively little toxicity.

Treatment of advanced endometrial carcinoma with doxorubicin and cisplatin: effects on both untreated and previously treated patients.

Sixteen patients with advanced (International Federation of Gynecology and Obstetrics stage III and IV) adenocarcinoma of the endometrium were treated with twelve 28-day cycles of doxorubicin and cisplatin. Response was achieved in 92% of patients (11 responses among 12 patients) who had received no prior chemotherapy and in 50% (two responses among four patients) of previously treated patients. Median survival was 10 months. Doxorubicin and cisplatin were readily administered on an outpatient basis with comparatively low major toxic effects, primarily hematologic, renal, and gastrointestinal. These results indicate that doxorubicin and cisplatin combination therapy is effective with acceptable toxicity in patients with advanced endometrial carcinoma.

CT of the hyperdense renal cyst: sonographic correlation.

The computed tomographic (CT) appearances of 19 hyperdense renal cysts in nine patients are reported. Sixteen of these cysts were found over a period of only 1 year with state-of-the-art CT equipment. Hyperdense renal cysts are probably more common than suggested by case reports. Their rate of detection can be expected to increase with the wider availability of fast CT scanners using thin collimation. A CT diagnosis of benign hyperdense renal cyst can be made if a lesion meets all of the following criteria: (1) smoothly outlined imperceptible wall with sharp demarcation from the kidney; (2) before intravenous contrast injection, homogeneous internal content with CT numbers 40%-240% higher (70%-240% higher for lesions 10 mm or more in diameter) than renal parenchyma; and (3) after intravenous contrast injection, persistent internal homogeneity and insignificant enhancement (less than 6%) relative to normal renal cortex. For masses exceeding 15 mm in diameter, sonography can be a valuable confirmatory test.

Optimizing metoclopramide control of cisplatin-induced emesis.

Using an original high-pressure liquid chromatographic assay, we measured serum levels of metoclopramide and defined a concentration-response relationship for metoclopramide control of cisplatin-induced emesis. Using a metoclopramide regimen of 2 mg/kg body weight intravenously every 2 hours for four doses, we found that serum levels greater than 850 ng/mL immediately before the third dose were associated with complete control of emesis (less than three episodes) in 78% of patients and partial control (three to five episodes) in 18%. No patient with levels less than 850 ng/mL had complete control of emesis; only 42% had partial control (p less than 0.001). Increases in dosage for patients with low levels and poor responses improved control in four of five patients. Elderly patients had drug levels similar to those of young patients but had fewer episodes of emesis (p = 0.044), suggesting that elderly patients have increased sensitivity to this drug. The metoclopramide dose can be raised up to 2.75 mg/kg with an improvement in emetic control in patients who have an inadequate response to doses of 2 mg/kg and no toxicity.

Treatment of advanced ovarian carcinoma with hexamethylmelamine, doxorubicin, and cis-platinum (HAC): results in both untreated and previously treated patients.

Twenty-two patients with advanced (FIGO stages III and IV) adenocarcinoma of the ovary were treated with 28-day cycles of hexamethylmelamine, doxorubicin, and cis-dichlorodiamine-platinum (II) (HAC). After 45 months, there were 21 evaluable patients. The median survival was 16 months. Response was achieved in 82% (9/11) who had received no prior chemotherapy, and in 50% (5/10) previously treated. HAC therapy was readily administered on an outpatient basis, with comparatively low major toxicities, primarily hematologic, neurologic, and gastrointestinal. These results indicate that HAC therapy is an effective regimen for patients with advanced ovarian carcinoma, regardless of their prior treatment status.