Serum galactosyltransferase as a prognostic marker in patients with solid tumors.

The serum level of galactosyltransferase was measured in a group of 218 patients with a variety of solid tumors and most with advanced disease. The pretreatment enzyme level showed little potential as a diagnostic tumor marker, and its change with treatment did not reflect the initial response. There was, however, a significant correlation between the length of survival and the pretreatment enzyme level. Patients with normal levels survived over twice as long as those with elevated levels. When Cox's proportional hazards regression analysis was used to compare the prognostic potential of galactosyltransferase with a number of known clinical indicators of prognosis, the variable most related to survival was performance status (P less than 10(-4) followed by galactosyltransferase (P = 0.01) and then the extent of disease (P = 0.03). The other variables, such as previous therapy, the type, site, and size of primary tumor, did not contribute significantly to the relationship with survival. The pretreatment level of galactosyltransferase is therefore a relatively independent prognosticator of survival and, as such, could be potentially useful in patient management by increasing the accuracy of the initial assessment of prognosis.

A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis.

Forty-four patients with documented meningeal carcinomatosis (small-cell lung carcinoma [SCLC], 29%; breast carcinoma, 25%) were treated in a prospective randomized trial with intrathecal methotrexate (MTX) 15 mg or MTX plus cytosine arabinoside (Ara-C) 50 mg/m2. Most patients received intrathecal hydrocortisone (HC) each treatment to minimize arachnoiditis. Overall response was 55%. Seven patients achieved complete response. Response to MTX was superior to combined MTX/Ara-C, but not significantly so (61% v 45%; P greater than .10). Response was more frequent if drugs were administered via Ommaya reservoir than by lumbar puncture (65% v 48%; P greater than .10). Concurrent radiotherapy to the CNS was associated with significantly better response (73% v 35%; P less than .05). Small-cell lung carcinoma patients showed the best response (69%). Overall median survival for the whole group was 8 weeks, but responders fared better than nonresponders (median survival, 18 v 7 weeks; P less than .05). Nausea and vomiting were the most common toxicities encountered (45%), but rarely proved limiting. An unusual, previously undocumented reaction to intrathecal HC was noted. MTX is moderately effective in nonleukemic meningeal carcinomatosis, but the addition of Ara-C does not appear to improve results. Pretreatment factors did not predict outcome in this trial.

Analysis of a prospectively randomized comparison of doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: implications for future studies.

A multi-institutional cooperative study of patients with locally advanced, recurrent, or metastatic gastric adenocarcinoma who had not previously received chemotherapy was conducted, prospectively randomizing patients to receive either doxorubicin or the three-drug combination, 5-fluorouracil (5-FU), doxorubicin (Adriamycin; Adria Laboratories, Columbus, Ohio), and BCNU (FAB). The 187 evaluable patients were initially stratified according to the presence of measurable or evaluable disease and performance status. There was a significantly higher response rate observed for FAB (40%) compared with doxorubicin (13%) among the 145 measurable-disease patients. Duration of response and survival were significantly longer for FAB in the measurable-disease group, but for the total patient population an early advantage for FAB in time to disease progression and survival was lost with continued follow-up. Median survival was 33 weeks for patients receiving FAB and 19 weeks for those receiving doxorubicin. Significant pretreatment factors adversely affecting survival included poor performance status, weight loss of greater than 10%, and more than two sites of metastases. Toxicity was not severe in either treatment arm, and only thrombocytopenia occurred significantly more often with FAB. It is contended that in the treatment of advanced gastric cancer, chemotherapy only exerts a relatively short-term and modest beneficial effect, most apparent in patients with intermediate tumor bulk. 5-FU remains the most active single agent, and combination chemotherapy has not yet proven its overall worth. Further studies are indicated comparing the most active combinations with 5-FU using optimal doses and schedules, and consideration must be given to the incorporation of no-treatment controls.

Effective salvage chemotherapy with etoposide, dactinomycin, and methotrexate in refractory germ cell cancer. Australasian Germ Cell Trial Group.

Fifty-one patients with advanced germ cell malignancy who had either failed to achieve complete remission with initial cisplatin, vinblastine, and bleomycin chemotherapy or who had relapsed after complete response (CR) to this therapy and then proven refractory on retreatment, were treated with etoposide (75 mg/m2 for 3 days), dactinomycin (1 mg/m2 day 1), and methotrexate (30 mg/m2 day 1) (EAM) every 3 weeks. Courses were continued until maximum response without empirical limit, and if complete remission was achieved, two courses of consolidation therapy were given before cessation of treatment. Thirteen patients (25%) were complete responders with residual masses containing fibrosis or benign teratoma being subsequently resected in seven patients. Two patients had persisting viable carcinoma within residual masses that were completely resected, leaving no evidence of disease (NED); the combined CR plus NED rate was 29%. The only pretreatment factor significantly influencing this response rate was tumor volume. Toxicities were moderate, with leukopenia being observed in 28% of patients, but it was severe in only 2%. There was one death from septicemia. Severe nausea and vomiting occurred in only 9% of patients and treatment-related stomatitis was observed in 42%. All patients achieving CR plus NED have been followed for a minimum of 5 years and no relapses have occurred, suggesting that these patients are cured. Unlike other regimens of salvage chemotherapy, this treatment program did not contain cisplatin and it is contended that a completely noncrossresistant drug regimen based on etoposide provides the opportunity to further improve the curability of patients with advanced germ cell cancer.

A prospective study of cisplatin-based combination chemotherapy in advanced germ cell malignancy: role of maintenance and long-term follow-up.

Two hundred fifty-three patients with advanced germ cell malignancy received initial chemotherapy with cisplatin, vinblastine, and bleomycin followed by surgical resection of residual masses if possible. Patients achieving complete remission (CR) were prospectively randomized to receive 6 months maintenance therapy with vinblastine or no further treatment. CR was achieved in 183 patients (72%) and a further eight patients (4%) had complete resection of residual viable malignancy (no evidence of disease [NED]). Pretreatment factors having a significant adverse influence on response by univariate analysis included extragonadal origin of the tumor, poor performance status, advanced lung or lung and abdominal disease, and elevated serum levels of human chorionic gonadotropin (HCG) and alpha-fetoprotein (AFP) greater than 1,000 ng/mL. Multivariate regression analysis indicated the independent prognostic factors of significance were advanced lung or advanced lung and abdominal disease, total tumor diameter greater than 10 cm, and a serum level of HCG greater than 1,000 ng/mL. Of the toxicities encountered, myelosuppression was significant, being exacerbated by radiotherapy, and seven deaths occurred from septicemia. Bleomycin pulmonary toxicity occurred in 46% of patients and was severe in 4%, resulting in eight deaths. With a median follow-up of 64 months, relapses have occurred in 25 patients with no significant difference between those patients receiving or not receiving maintenance vinblastine. Eight of these relapses occurred beyond 1 year and four beyond 2 years of follow-up. Presently, 68% of the total patient population is alive and disease-free, with 84% of the CR and NED patients alive and 81% alive and disease-free. It is concluded that with prolonged follow-up, vinblastine maintenance therapy does not improve treatment outcome. Moreover, late relapses occur, cautioning against premature pronouncements of cure.

The importance of bleomycin in combination chemotherapy for good-prognosis germ cell carcinoma. Australasian Germ Cell Trial Group.

PURPOSE: In an effort to maintain the excellent long-term results achieved with combination chemotherapy for good-prognosis germ cell carcinoma, but to reduce the toxicities encountered, a randomized trial was conducted comparing cisplatin and vinblastine with or without bleomycin. PATIENTS AND METHODS: Two hundred eighteen assessable patients with a good prognosis were randomized to receive induction chemotherapy with cisplatin 100 mg/m2 intravenously (IV) day 1 and vinblastine 6 mg/m2 IV days 1 and 2 every 3 weeks (PV) with or without bleomycin 30 mg intramuscularly (IM) weekly (PVB) for a maximum of 12 weeks. Once maximum response was achieved, patients with a complete remission (CR) received two courses of consolidation chemotherapy, while those with residual abnormalities and normal tumor markers underwent surgical resection whenever possible. RESULTS: Toxicities encountered in this study were clearly greater for those patients who received bleomycin, with significantly more leukopenia, thrombocytopenia, anemia, alopecia, and renal and pulmonary toxicities. The proportion of patients who achieved CR and had no evidence of disease (resection of all viable malignancy) was 89% for PV and 94% for PVB (P = .29). After a minimum of 4 years of follow-up, relapses have occurred in 7% of patients who received PV and 5% who received PVB. A total of five patients on each therapy arm were successfully treated with further salvage chemotherapy and surgery. Thus, deaths from progressive malignancy have occurred in 15% of patients on PV and 5% on PVB (P = .02), a rate that was partly offset by the higher proportion of toxic deaths with PVB (P = .06). CONCLUSION: Despite the toxicities encountered with bleomycin in cisplatin-based combination chemotherapy for these patients, complete deletion of this drug compromises therapeutic efficacy.

Phase II trial of a 3-hour infusion of paclitaxel in previously untreated patients with advanced non-small-cell lung cancer.

PURPOSE: To determine the antitumor activity and toxicity of paclitaxel administered as a 3-hour infusion in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Fifty-one patients with advanced measurable or assessable NSCLC and performance status 0 to 2 who had not received prior chemotherapy were treated with paclitaxel 175 mg/m2 over 3 hours with premedication. Cycles were repeated every 3 weeks for a maximum of nine cycles. Most patients had prior radiotherapy (57%), extrathoracic metastatic disease (65%), and measurable disease (75%). Twenty-two percent had previously untreated stage III disease. RESULTS: The objective response rate was five of 51 (10%; 95% confidence interval, 3% to 21%). No subgroup with a higher response rate could be identified. There were no complete responses (CRs) and all responses lasted less than 5 months. Treatment was well tolerated with brief World Health Organization (WHO) grade IV neutropenia in only 16% of patients. Grade III/IV myalgia/athralgia occurred in 22% of patients. No significant hypersensitivity reactions occurred. CONCLUSION: The antitumor activity of this dose and schedule appears inferior to that reported in previously published phase II trials in NSCLC that used higher doses of paclitaxel infused over 24 hours, although confidence intervals for response overlap. Determining the optimal dose and schedule for using paclitaxel in NSCLC requires further investigation, and these results should caution against using shorter infusions outside appropriate clinical trials.

Management of mycosis fungoides--current status and future prospects.

Current knowledge concerning the course of mycosis fungoides and recognized prognostic factors have been reviewed. Those factors with prognostic significance at the time of biopsy diagnosis include age and the clinical findings of skin tumors, ulceration or palpable lymphadenopathy. During the course of disease, the development of skin tumors, ulceration or palpable lymphadenopathy were each associated with a poor prognosis and median survival was only 12 months if all those clinical parameters were present. Patients who developed overt visceral mycosis fungoides rarely survived more than a few months. Lymphocytopenia and the presence of malignant lymphoma in biopsied lymph nodes were also poor prognostic findings. The various modalities of therapy for proven mycosis fungoides were reviewed. Topical therapy and external irradiation were generally of symptomatic benefit only, but two recent studies have shown that aggressive use of topical nitrogen mustard and electron beam therapy are associated with long-term responses in patients with disease confined to the skin. Single agent chemotherapy often resulted in transient responses in advanced and refractory mycosis fungoides. Future approaches to the management of mycosis fungoides have been suggested. These include a thorough review of the histological features, a thorough and systematic pretreatment evaluation and randomized studies of the various treatment modalities including combination therapy in appropriately staged patients.

Long-term follow-up of a randomised trial of combined chemoradiotherapy induction treatment, with and without maintenance chemotherapy in patients with small cell carcinoma of the lung.

The toxicity and efficacy of concomitant chemotherapy and radiotherapy as induction therapy was evaluated in patients with previously untreated small cell carcinoma of the lung (SCLC), and in responding patients the value of maintenance chemotherapy was examined. 202 patients received induction chemotherapy with cisplatin and etoposide (EP), in combination with cranial and local radiotherapy. 85 patients (42%) developed grades III and IV myelosuppression, the main toxicity of induction treatment. Of the 154 responding patients, 129 were randomised to maintenance chemotherapy with vincristine, doxorubicin and cyclophosphamide (VAC) or no further treatment. The response rate for the limited disease patients (LD) was 87%, 62% achieving a complete response (CR) and the response rate for extensive disease patients (ED) was 68%, with 26% achieving a CR. 17 patients (11%) completed 10 courses of maintenance chemotherapy. 32 patients (57%) developed grade III and IV neutropenia. Median survival for all patients was 53 weeks (LD, 70 weeks; ED, 42.5 weeks). There was no significant difference in overall survival (OS) or disease-free survival (DFS) in the two randomisation arms. This study shows that EP combined with radiotherapy is an effective induction regimen in SCLC. Maintenance chemotherapy with VAC is not associated with increased survival but has significant toxicity after such induction treatment.

Meningeal carcinomatosis in small cell carcinoma of the lung.

Cerebral and meningeal metastases are increasingly important complications in small cell anaplastic carcinoma of the lung. In a study at this institution, 60 evaluable patients received intensive chemotherapy without prophylactic cranial irradiation or other prophylactic measures. The complete plus partial remission rate was 78 percent with a median survival of 49+ weeks (range eight to 106+ weeks) for those with a complete response and 18+ weeks (range six to 67 weeks) for those with a partial response, all of which are comparable to other reported series. In 11 patients (18 percent) meningeal carcinomatosis has developed. Forty-two percent of the patients with a relapse have exhibited meningeal carcinomatosis and in 27 percent of the patients with a relapse it was the only site of relapse. Cerebral metastases occurred in 27 percent of those who had a relapse, and in 12 percent this was the sole site of relapse. Simultaneous meningeal carcinomatosis and cerebral metastases occurred in 8 percent of the patients with a relapse. The median time to meningeal relapse was 27 weeks (range 12 to 60 weeks) compared with 25+ weeks (six to 106+ weeks) over-all, and the median survival was 28 weeks (range 14 to 82 weeks) compared with 25+ weeks (two to 106+ weeks) for the whole group with small cell carcinoma of the lung. Meningeal involvement in small cell carcinoma of the lung must now be considered a sanctuary site of equal importance to cerebral metastases. To prevent and treat this complication will necessitate evaluation of all available modalities, including cranial and spinal irradiation, intrathecal chemotherapy and systemic agents that readily cross the blood-brain barrier.

Determining the time and day of photography.

Photographs taken by crime victims and perpetrators are at times important evidence. Their time of photography may also affect their value as such. Three methods of determining when a picture was taken by using the content of the picture are presented. The methods utilize solar direction-measured from shadows in the photograph, identifying flowering wild plants and correlating cloudiness with meteorological observations. Solar direction is the most accurate and involved method and therefore is the main part of this paper. A case using all three methods is described.

Forensic identification of a rapist using unusual evidence.

This case report demonstrates a rape case, where no semen, hair, or fingerprints were left by the perpetrator at the crime scene, but rather uncharacteristic biological and physical evidence in the form of a lollipop and a pair of glasses. Three separate forensic laboratories collaborated using conventional forensic methods of PCR DNA typing, photography, and toolmark comparisons to provide investigators with scientific evidence which in turn was instrumental in bringing a violent criminal to justice. The importance of evaluating each item of evidence and realizing its forensic value is stressed in this case report.

Current status of treatment for breast cancer.

Recent developments in the treatment of early stage breast cancer include mature data from randomised trials that indicate limited surgery with breast irradiation provide comparable survival to total or radical mastectomy. For patients undergoing radical mastectomy while post-operative radiotherapy should not be routine, when more than four axillary lymph nodes are involved at surgery or the primary tumour involves the medial quadrants, then local recurrence rates are significantly reduced by this radiotherapy. Overview statistical metanalyses of data from adjuvant therapy trials has confirmed that cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy reduced the risk of death by 24 +/- 6% compared to controls for premenopausal women. Whereas, administration of tamoxifen for more than one year to postmenopausal women with positive axillary lymph nodes and positive hormone receptor levels resulted in a 18 +/- 4% reduction in mortality. Similar adjuvant treatments in women with negative axillary lymph nodes but other adverse prognostic factors improves disease-free but not as yet overall survival. In advanced disease, the success of hormone manipulation is dependant on the presence and amount of oestrogen and progesterone receptor protein in either the primary breast tumour or a biopsied metastasis. If a response is achieved, this will be complete in 5-20% of patients with a median survival in excess of 18 months for responding patients and 25% remaining alive and disease-free beyond 30 months. Combination chemotherapy for patients with negative hormone receptors or aggressive disease achieve response in 50-60% of patients. Current activity to improve the therapeutic index of chemotherapy include less toxic analogs, priming hormones and high dose chemotherapy.

Management of germ cell carcinoma: state of the art.

The management of all stages of germ cell carcinomas is fairly well defined with generally high rates of cure. In stage I disease surveillance and chemotherapy on relapse is as successful as initial adjuvant chemotherapy. More than 95% of patients will survive. In stage II disease either three to four cycles of chemotherapy, or retroperitoneal node dissection and subsequent chemotherapy if more than six nodes are positive or nodes are > 2 cm diameter, or there is extra nodal extension, are equivalent with survival > 95%. For stage III disease, a new international prognostic classification has determined that the level of tumour markers, presence of non pulmonary visceral disease, or a mediastinal primary, indicate a poorer prognosis. Long term follow up studies reveal an overall percentage of relapses (4-5%) beyond two years and the need for long term follow up.