bluuebunny/crossref_metadata_2025 huggingface dataset:
Anxiety levels in patients randomized to adjuvant therapy versus observation for early breast cancer.
Authors: Cassileth B R , Knuiman M W , Abeloff M D , Falkson G , Ezdinli E Z , Mehta C R
Published: February 2017

We studied anxiety levels in 68 patients who had been randomized to adjuvant chemotherapy v observation on two Eastern Cooperative Oncology Group (ECOG) protocols. All subjects were women who had undergone total or modified radical mastectomy for breast cancer. Immediately before breast protocol randomization and again 3, 6, and 12 months later, patients completed two self-report measures: the State-Trait Anxiety Inventory and the SCL-90. There were no consistent trends in anxiety levels over time. At each test point, patients under observation displayed higher anxiety scores than did patients receiving adjuvant therapy, but these differences failed to attain statistical significance. Power calculations indicate that these results rule out the possibility of major differences in anxiety levels among patients randomized to observation v adjuvant therapy, but a larger patient sample is required before a definitive statement can be made about smaller differences.
Hyperdiploidy and chromosomal rearrangements define the anaplastic variant of Wilms' tumor.
Authors: Douglass E C , Look A T , Webber B , Parham D , Wilimas J A , Green A A , Roberson P K
Published: February 2017

Flow cytometric measurement of the DNA content of Wilms' tumor cells revealed a striking correspondence with the histologic subtype and treatment outcome. In the 48 cases studied, a hyperdiploid DNA content ranging from 1.7 to 3.2 times the result for normal diploid cells distinguished all but one of the ten anaplastic tumors. Lower values, from 1.0 to 1.4 times the diploid DNA content, characterized the nonanaplastic specimens. By Kaplan-Meier analysis, the probability of achieving 3 years of relapse-free survival was significantly lower in the group with higher DNA content (0.42 v 0.87, P less than .01). Analysis of banded chromosomes for a subset of 22 patients contributed important information beyond the flow cytometric study. Cases of anaplasia associated with poorer responses to therapy showed numerous complex translocations, whereas all others lacked such changes. By combining flow cytometric techniques and conventional methods of chromosome analysis, it should be possible to identify those patients with Wilms' tumor who are most likely to fail therapy. The biologic implication of these findings is that the development of clinical drug resistance in Wilms' tumor is a result of the genetic instability of the malignant clone.
The value of hepatic ultrasound and biochemical liver tests in screening for liver metastases.
Authors: Tempero M A , Williams C A , Anderson J C
Published: February 2017

The records of 92 patients with a known diagnosis of extrahepatic cancer who had undergone hepatic ultrasound, biochemical liver tests (alkaline phosphatase, SGOT, lactic dehydrogenase, and bilirubin levels), and subsequent liver biopsy or autopsy within a 6-week period were reviewed. The sensitivity, specificity, and accuracy of the ultrasound and biochemical tests in the detection of metastatic liver disease were calculated. Although there was no significant difference in the sensitivity of either examination, the ultrasound demonstrated higher specificity and accuracy than the biochemical liver tests. The high sensitivity of hepatic ultrasound prevailed even in patients with normal biochemical liver tests. The sensitivity of hepatic ultrasound was significantly lower in patients with lymphoma compared with patients with colorectal cancer (50% v 100%, P less than .05). Notable incidental extrahepatic findings were reported in 25% of the ultrasound examinations. In institutions skilled in sonography, hepatic ultrasound may be a superior tool in the detection of liver metastases in most solid tumors, excluding lymphoma, and offers the additional advantage of simultaneous biliary tract and perihepatic visualization.
A comparison of randomized concurrent control groups with matched historical control groups: are historical controls valid?
Authors: Diehl L F , Perry D J
Published: February 2017

The use of a historical control group is predicated on the assumption that survival and relapse-free survival in the historical control group closely approximate the survival and relapse-free survival in a randomized concurrent control group. This assumption has never been tested. This study compares survival and relapse-free survival in randomized control groups with historical control groups matched for disease, stage, and follow-up. Of the 43 matched control groups, 42% varied by more than 10 percentage points, 21% varied by more than 20 percentage points, and 5% varied by more than 30 percentage points. Of the 18 that varied by greater than 10 percentage points, 17 had superior survival or relapse-free survival in the randomized concurrent control group. This study indicates that the assumption that historical control groups may replace randomized concurrent control groups is not valid.
Analysis of dose intensity for adjuvant chemotherapy trials in stage II breast cancer.
Authors: Hryniuk W , Levine M N
Published: February 2017

We have analyzed the relationship between dose intensity of cyclophosphamide, methotrexate, and fluorouracil (CMF)-containing adjuvant chemotherapy of stage II breast cancer and 3-year relapse-free survival. Studies using only one or two drugs of CMF or melphalan instead of cyclophosphamide were included in the analysis by using simple techniques developed for this purpose. There was a clear-cut relationship between relapse-free survival and dose intensity in trials containing all four prognostic groups: less than 50 years, one to three and more than three positive nodes; and greater than or equal to 50 years, one to three and more than three positive nodes (P less than 10(-5)). Relapse-free survival also correlated with dose intensity for each of the four prognostic groups analyzed separately (P less than .005). Dose intensity was an independently significant correlate of relapse-free survival in multivariate analysis (P less than 10(-5)). This is a retrospective study, and the hypothesis that dose intensity contributes to outcome independently of other variables should be tested prospectively. Methods of increasing dose intensity also require testing in randomized trials before they can be applied to routine clinical practice.
Prognosis of clinical stage I melanoma patients with positive elective regional node dissection.
Authors: Koh H K , Sober A J , Day C L , Lew R A , Kopf A W , Lamar W , Ben Cosimi A , Wood W C , Mihm M C , Malt R A
Published: February 2017

We tested 12 clinical and histologic variables to see which ones best predicted death from melanoma in 66 patients with positive elective regional node dissections (clinical stage I, pathologic stage II [CSI, PSII]). Despite the presence of lymph node metastases, not all patients had poor prognoses. Patients with tumors less than or equal to 3.5 mm and a percentage of positive nodes less than or equal to 20% had a 7-year survival rate of 66%. Within this low-risk group the subset with primary lesions on the trunk or extremities (except hands and feet) had a 7-year survival rate of 76%. This compares with poor 7-year survivals of 29% and 30% observed in other defined high-risk groups. Our results confirm and extend earlier observations concerning the prognoses of CSI, PSII melanoma patients and are relevant to any ongoing and future studies concerning elective regional node dissection (ERND) or adjuvant therapy trials in melanoma.
Analysis of a prospectively randomized comparison of doxorubicin versus 5-fluorouracil, doxorubicin, and BCNU in advanced gastric cancer: implications for future studies.
Authors: Levi J A , Fox R M , Tattersall M H , Woods R L , Thomson D , Gill G
Published: February 2017

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.
Hepatic arterial infusion with floxuridine and cisplatin: overriding importance of antitumor effect versus degree of tumor burden as determinants of survival among patients with colorectal cancer.
Authors: Patt Y Z , Boddie A W , Charnsangavej C , Ajani J A , Wallace S , Soski M , Claghorn L , Mavligit G M
Published: February 2017

Cisplatin (CDDP) was combined with floxuridine (FUDR) and delivered into the hepatic arteries of 29 patients as induction therapy for colorectal cancer metastatic to the liver. Mitomycin C and FUDR combination was substituted after progression or when response had peaked. Chemotherapy was delivered with an Infusaid pump (Infusaid Corp; Norwood, Mass; 14 patients), Medtronic programmable drug administration device (Medtronic, Inc, Minneapolis; two patients), or percutaneously placed catheters (13 patients). Complete disappearance of liver metastases was observed in four patients and 11 additional patients had a partial remission as determined by computed tomography (CT) scan and substantiated at times by angiography, for a total response rate of 52%. Response as determined by imaging techniques coincided with a concurrent decrease in carcinoembryonic antigen (CEA) and improvement in performance status. The severity of tumor burden was correlated with the response to therapy and survival. Among those patients who responded to arterial chemotherapy, differences in disease severity did not significantly influence survival. Median survival among responders with greater than 25% liver replacement by tumor was 14 months (P = .28), compared with 28 months for those patients with less than 25% liver replacement. In contrast, differences in tumor burden significantly affected survival among patients who failed to respond to chemotherapy; median survival among nonresponding patients with greater than 25% liver replacement was 4 months, compared with 8 months for those who had less than 25% liver replacement (P = .01). The presence of minimal extrahepatic disease at the time of initiation of intraarterial treatment did not seem to have a significant detrimental effect on survival. The study suggests that hepatic tumor response to arterial administration of CDDP and FUDR and mitomycin C and FUDR is clinically significant because it overrides the effect of tumor burden on survival among patients who have colorectal cancer with liver metastases and may offer effective palliation.
A trial of combination chemotherapy followed by hormonal therapy for previously untreated metastatic carcinoma of the prostate.
Authors: Seifter E J , Bunn P A , Cohen M H , Makuch R W , Dunnick N R , Javadpour N , Bensimon H , Eddy J L , Minna J D , Ihde D C
Published: February 2017

We administered combination chemotherapy with cyclophosphamide, doxorubicin, and cisplatin to 25 previously untreated patients with metastatic prostate cancer in order to assess the efficacy of chemotherapy before any hormonal manipulation. Hormonal therapy was administered only after progression of disease to chemotherapy. All 25 patients were followed until time of death and all were able to receive hormonal therapy. We did not find substantially improved response rates when combination chemotherapy was applied before endocrine treatment since the 33% objective response rate to chemotherapy was only minimally higher than the response in our patients who had failed hormonal therapy and then received identical or similar chemotherapy. Furthermore, the introduction of intensive combination chemotherapy before hormonal therapy in our study did not result in any striking improvement in overall survival compared with patients who received initial hormonal therapy in many other studies. Responses to chemotherapy were not attributable to suppression of serum testosterone since all 12 patients with partial response (PR) or stable disease (SD) and four of seven patients with no response (NR) had normal testosterone levels at the time of response assessment. The initial use of chemotherapy did not adversely affect the expected high percentage of objective responses (68%) to subsequent hormonal manipulation. The frequency, duration, and quality of responses to hormonal therapy exceeded the responses to chemotherapy. The disappointing responses to chemotherapy reflect the very modest efficacy of even aggressively delivered cytotoxic agents.
Mitomycin C skin toxicity studies in mice: reduced ulceration and altered pharmacokinetics with topical dimethyl sulfoxide.
Authors: Dorr R T , Soble M J , Liddil J D , Keller J H
Published: February 2017

A series of toxicologic and pharmacokinetic studies were performed in BALB/c mice administered intradermal (ID) mitomycin C (MMC) at doses of .015 to 0.25 mg. Dose-dependent skin ulcers were produced at clinically relevant MMC dose levels of .05 and .075 mg (3.6 to 10.7 mg/m2). These doses produced peak ulcers of 0.15 to 0.22 cm2, respectively, one to five days after injection. The integrated ulcer area X time values (area under the curve [AUC] ulceration) were 0.89 and 3.11 cm2 X d. A large number of local pharmacologic adjuvants were found to be ineffective at reducing MMC ulceration after proximal ID injection. These included diphenhydramine, catalase, heparin, hyaluronidase, hydrocortisone, cysteine, N-acetylcysteine, lidocaine, vitamin E, and superoxide dismutase. Also, neither topical heating nor cooling of skin reduced MMC ulcerations. In contrast, a single topical application of a 100% dimethyl sulfoxide (DMSO) solution completely prevented 0.025 mg MMC-induced skin ulceration and significantly reduced .075 mg MMC ulceration (P less than .05 by multiple range tests). Topical DMSO also altered the disposition of ID MMC in mouse skin but not in plasma. Unexpectedly, the DMSO applications slowed MMC elimination from the skin. DMSO significantly increased the AUC for MMC in skin from 0.89 to 2.25 ng/h/mL of tissue (P less than .05). DMSO did not alter the degree of protein binding in skin tissue nor the in vitro chemical stability of MMC in skin tissue homogenates. These results show that experimental MMC-induced skin ulcers in mice can be ameliorated with an immediate application of topical DMSO. This effect is not due to enhanced systemic drug uptake, but may be due to reduced reactivity of MMC with target cellular nucleophiles.
Vascular toxicity associated with antineoplastic agents.
Authors: Doll D C , Ringenberg Q S , Yarbro J W
Published: February 2017

Vascular complications associated with antineoplastic agents are being reported with increasing frequency. Such vascular toxicity is clinically heterogeneous, ranging from asymptomatic arterial lesions to a fatal thrombotic microangiopathic syndrome. Mitomycin is most commonly implicated in the thrombotic microangiopathic syndrome, while bleomycin, either alone or in combination with a vinca alkaloid or cisplatin, appears to be an important cause of Raynaud's phenomenon. Acute arterial ischemic events, ie, myocardial infarction and cerebrovascular accidents, occur most frequently after cisplatin-based combination chemotherapy. Putative mechanisms for such toxicity include drug-induced endovascular damage, perturbation of the clotting system, platelet activation, an abnormality of thromboxane-prostacyclin homeostasis, autonomic dysfunction, vasculitis, and stimulation of fibroblasts. More than one mechanism may be operative in an individual patient. Better documentation of the incidence and types of vascular toxicity and studies to help elucidate the pathogenesis and management of such toxicity are needed.
An analysis of induction and adjuvant chemotherapy in the multidisciplinary treatment of squamous-cell carcinoma of the head and neck.
Authors: Ervin T J , Clark J R , Weichselbaum R R , Fallon B G , Miller D , Fabian R L , Posner M R , Norris C M , Tuttle S A , Schoenfeld D A
Published: February 2017

This study examines the role of combination chemotherapy with surgery and/or radiotherapy in the initial treatment of patients with advanced stage III and IV squamous-cell carcinoma of the head and neck (SCCHN). Two courses of initial (induction) cisplatin, bleomycin, and methotrexate with oral calcium leucovorin (PBM) were used with the principal intent of increasing the effectiveness of subsequent surgery and/or radiotherapy. Following induction chemotherapy and local treatment, disease-free patients who had responded to initial chemotherapy were entered into a randomized trial of adjuvant PBM. The response rates to induction PBM chemotherapy were a complete response (CR) rate of 26% and a partial response (PR) rate of 52%, for an overall response rate of 78%. A response to induction PBM was highly correlated with failure-free survival (P less than .0001). A Cox multistep regression analysis of potential prognostic factors was performed. After adjusting for the significant prognostic factors of performance status, initial tumor size, and primary tumor site, a response to induction chemotherapy remained independently associated with improved survival (P = .0002). The randomized trial of adjuvant chemotherapy demonstrated that such treatment significantly improved failure-free survival by decreasing local-regional failures. The benefit of adjuvant chemotherapy was particularly evident in patients who had a PR to induction chemotherapy (P = .01). The toxicity of this multidisciplinary approach was predictable and acceptable. Surgery and radiotherapy were not compromised by induction or adjuvant chemotherapy. Definitive evidence that chemotherapy can favorably influence survival awaits confirmation of these results by a randomized trial using a control arm of patients treated with conventional surgery and/or radiotherapy alone.
A new technique for placement of tunneled subclavian right atrial catheters: experience with 130 cases.
Authors: Troxell M , Mansour R
Published: February 2017

We have developed a new single step technique for placement of indwelling silastic subclavian right atrial catheters through a short subcutaneous tunnel that is simple, relatively inexpensive, and can be done in the outpatient clinic. Between December 1984 and July 1986, 130 catheters were inserted in 122 patients using this approach for a cumulative total of 8,900 catheter days. Major complications have included five catheter infections with bacteremia, two procedure-related pneumothoraces, one internal jugular vein thrombosis, and one catheter fragment embolization to the right heart (total major complication rate, 6.9%). Minor complications have included five catheter migrations, seven catheter or catheter hub leaks, and two irreversible lumen occlusions (total minor complication rate 10.8%). Damaged or malpositioned catheters can be replaced through the same subcutaneous tract using a guidewire exchange technique. When this has not been possible, we have not encountered technical difficulties (due to subclavian thrombosis or stenosis) prohibiting insertion of a new catheter, even on the same side. These catheters provide reliable venous access for patients requiring frequent blood sampling, intravenous (IV) fluid or blood product administration, chemotherapy, IV narcotics for pain control, long-term antibiotic therapy, or hyperalimentation. They are ideal for infusion of vesicant chemotherapeutic agents and for patients undergoing ambulatory outpatient infusion chemotherapy. They have a low overall morbidity rate and excellent patient acceptance. Catheter maintenance procedures are simple and non-time-consuming. The same technique can be used to place multichannel catheters in patients requiring greater venous access. We now recommend early placement of these catheters in patients who will require frequent phlebotomy or drug administration during the course of their treatment.
Prognostic significance of staging factors of the UICC staging system in childhood rhabdomyosarcoma: a report from the Intergroup Rhabdomyosarcoma Study (IRS-II).
Authors: Lawrence W , Gehan E A , Hays D M , Beltangady M , Maurer H M
Published: February 2017

The need for a pretreatment staging system to accurately assess programs of therapy for the various sites and stages of childhood rhabdomyosarcoma has become apparent as detailed analyses of many factors affecting prognosis and treatment choices have been accomplished through the national cooperative trial, the Intergroup Rhabdomyosarcoma Study (IRS). Initiated in 1972, the IRS has thus far used a clinicopathologic grouping system that is based heavily on therapeutic decisions, particularly on whether or not excision is accomplished and the extent of such an operation. The major problem with this and several other staging classifications now in use is that they depend on pathologic data obtained after surgical treatment has been initiated or rejected. In addition, they do not consider histologic variations of this neoplasm which may be important in estimating prognosis. The large body of clinical data now accumulated in the IRS has provided an excellent opportunity for developing a database for evaluating the International Union Against Cancer (UICC) pretreatment staging system and also the potential for using histologic categories in the staging process. The records of 505 eligible patients entered into the IRS between 1978 and 1982 were used to determine the prognostic impact of a number of pretreatment factors. These included local invasiveness of the primary neoplasm on clinical examination, tumor size, clinical status of regional nodes, clinical or radiologic evidence of distant metastases, and favorable or unfavorable histologic categories. A retrospective assessment of the relationship of these pretreatment observations to survival experience has been carried out. This retrospective study indicates definite prognostic significance for all of the individual factors used on the UICC system except clinical status of regional nodes. Also, these data serve as a basis for considering the possibility of including favorable v unfavorable histology in the pretreatment staging system now being tested prospectively in the ongoing IRS protocols.
Survival from first recurrence: relative importance of prognostic factors in 1,015 breast cancer patients.
Authors: Clark G M , Sledge G W , Osborne C K , McGuire W L
Published: February 2017

Univariate and multivariate analyses of potential prognostic factors for 1,015 women with recurrent breast cancer confirmed that the site of initial recurrence is an important determinant for predicting survival from the time of initial recurrence. However, both estrogen receptor (ER) status and axillary lymph node status at diagnosis, as well as the length of the disease-free interval, provide additional independent information for predicting patient survival after disease recurrence. Involved axillary lymph nodes at the time of initial diagnosis and/or lack of ERs may indicate a highly malignant tumor or a weak host defense, either of which might be related to short survival after relapse. Patients with ER-negative tumors recurred more often in visceral and soft-tissue sites, while patients with ER-positive tumors were more likely to recur in bony sites. However, for each metastatic site, receptor-positive patients had longer survival
A prospective randomized trial of 5-fluorouracil versus 5-fluorouracil and high-dose leucovorin versus 5-fluorouracil and methotrexate in previously untreated patients with advanced colorectal carcinoma.
Authors: Petrelli N , Herrera L , Rustum Y , Burke P , Creaven P , Stulc J , Emrich L J , Mittelman A
Published: February 2017

Seventy-four previously untreated patients with metastatic colorectal adenocarcinoma were prospectively randomized into one of three treatment regimens: (1) 5-fluorouracil (5-FU) 450 mg/m2 as an intravenous (IV) bolus daily for five days or toxicity, then 200 mg/m2 IV bolus every other day for six doses; (2) methotrexate (MTX) 50 mg/m2 in normal saline by IV infusion over four hours followed by an IV bolus of 5-FU 600 mg/m2. This was administered weekly for 4 weeks and then every 2 weeks. (3) Leucovorin 500 mg/m2 in a two-hour IV infusion of normal saline with 5-FU 600 mg/m2 as an IV bolus one hour after the Leucovorin began every week for 6 weeks. The combined complete and partial response rates in the three regimens were 11%, 5%, and 48%, respectively (P = .0009). The median duration of response in the 5-FU and Leucovorin regimen was 10 months. There was no statistically significant difference between the treatment regimens with respect to survival time (P = .6). Toxicity in the 5-FU and Leucovorin regimen was predominantly diarrhea (13 of 30 patients, 40%). In this regimen, eight of 13 patients (52%) who developed diarrhea not only required a dose reduction of 5-FU, but also hospitalization for IV hydration. The predominant toxicity in the 5-FU alone regimen and the 5-FU and MTX regimen was leukopenia. One drug-related death occurred in each regimen.
Conversion by new treatment modalities of nonresectable to resectable hepatocellular cancer.
Authors: Sitzmann J V , Order S E , Klein J L , Leichner P K , Fishman E K , Smith G W
Published: February 2017

Eleven patients with hepatocellular cancer had nonresectable lesions, ten as determined by laparotomy and one by computed tomographic (CT) evidence of inferior vena caval invasion. These patients were treated with a variety of new modalities, particularly radiolabeled antiferritin antibodies. Following treatment, seven of the 11 patients were considered to have converted their lesions to possible resectability. Six patients had complete resections, and one patient was partially resected. All patients had the common features of either nodular massive or nodular multifocal hepatocellular cancer. Relative to the patient's initial status, the quality of life remains high, and a new approach in the treatment of the nodular form of nonresectable hepatoma has been demonstrated. The present rate of such conversion to resectability is unknown. However, with further advances in radiolabeled antibody therapy, these results offer a new opportunity in the management of hepatocellular cancer.
The effects of distance from primary treatment centers on survival among patients with multiple myeloma.
Authors: Lenhard R E , Enterline J P , Crowley J , Ho G Y
Published: February 2017

Twenty-one comprehensive cancer centers participated in a national reporting system of common data items, recording information on all patients seen between 1977 and 1982. There were 240,531 patients who had data abstracted. This report describes 1,479 patients with multiple myeloma. Parameters that may effect the type of treatment given during the initial episode of therapy in the center and the effect of these characteristics on survival were studied. In the univariate analysis, age, treatment, and distance traveled to the center were statistically associated with survival. In a multivariate analysis adjusting for potentially confounding covariates, blacks survive better than whites and the effects of sex and socioeconomic status (SES) on survival approach significance. Survival consistently improved with increasing distance traveled to treatment centers. This may be a serious confounding variable in assessing the results by both single and multiinstitution clinical trials.
A randomized comparison of high-dose versus conventional-dose cyclophosphamide, doxorubicin, and vincristine for extensive-stage small-cell lung cancer: a phase III trial of the Southeastern Cancer Study Group.
Authors: Johnson D H , Einhorn L H , Birch R , Vollmer R , Perez C , Krauss S , Omura G , Greco F A
Published: February 2017

To assess the effect of dose escalation in the treatment of small-cell lung cancer (SCLC), 298 patients with extensive-stage disease were treated with either conventional-dose cyclophosphamide (1,000 mg/m2), doxorubicin (40 mg/m2), and vincristine (1 mg/m2), (CDCAV); or high-dose cyclophosphamide (1,200 mg/m2), doxorubicin (70 mg/m2), and vincristine (1 mg/m2) (HDCAV). No dose attenuation was allowed during the initial three cycles of therapy in either treatment arm. All patients received CDCAV in cycles 4 through 6, during which time dosages were adjusted according to granulocyte and platelet nadirs. No additional chemotherapy was administered until disease progression or relapse was documented. Complete responses were more frequent with HDCAV (22% v 12%; P = .045). However, overall response rate (63% v 53%) and median survival (29.3 v 34.7 weeks) were not significantly different (P greater than .05). HDCAV was substantially more toxic than CDCAV, causing more episodes of life-threatening leukopenia (ie, granulocytes less than 500/microL; 79% v 40%; P less than .05) and infections (15% v 4%; P less than .05). Dose intensification of cyclophosphamide and doxorubicin during induction chemotherapy did not produce any survival benefit compared with conventional dosages of these agents in SCLC patients with extensive-stage disease.
Tumor and liver drug uptake following hepatic artery and portal vein infusion.
Authors: Sigurdson E R , Ridge J A , Kemeny N , Daly J M
Published: February 2017

Anatomic dye injection studies of the blood supply of colorectal hepatic metastases suggest that tumors are supplied predominantly by the hepatic artery. Using 13N amino acids with dynamic gamma camera imaging in patients with colorectal hepatic metastases, it has been shown that hepatic artery infusion results in a significantly greater nutrient delivery to tumor compared with portal vein infusion. However, direct measurements of drug levels in tumor following hepatic artery and portal vein infusion in humans have not previously been reported. Patients with metastatic colorectal cancer confined to the liver received fluorodeoxyuridine (FUdR) through the hepatic artery or through the portal vein. All patients had previously failed systemic chemotherapy. Five patients with hepatic artery catheters were matched (by age, serum lactic dehydrogenase levels, percent hepatic replacement, and tumor size) with five patients with portal vein catheters. At operation, 3H-FUdR (1 microCi/kg) and 99mTc-macroaggregated albumin (MAA) (6 mCi) were injected into the hepatic artery or portal vein. Liver and tumor biopsies were obtained two and five minutes later. 3H and 99mTc were measured per gram tissue by scintillation and gamma counting. The mean liver levels following hepatic artery infusion (23.9 +/- 11.4 nmol/g) and portal vein infusion (18.4 +/- 14.5 nmol/g) did not differ. However, the mean tumor FUdR level following hepatic artery infusion was 12.4 +/- 12.2 nmol/g, compared with a mean tumor FUdR level following portal vein infusion of 0.8 +/- 0.7 nmol/g (P less than .01). This low level of tumor drug uptake after portal vein infusion of FUdR predicts minimal tumor response to treatment via this route. Thus, regional chemotherapy for established colorectal hepatic metastases should be administered through the hepatic artery.
In vivo and in vitro activation of natural killer cells in advanced cancer patients undergoing combined recombinant interleukin-2 and LAK cell therapy.
Authors: Phillips J H , Gemlo B T , Myers W W , Rayner A A , Lanier L L
Published: February 2017

Patients with advanced metastatic cancer were given combined autologous lymphokine activated killer (LAK) cell and recombinant interleukin-2 (rIL-2) therapy on a National Cancer Institute extramural phase II trial. Systemic administration of rIL-2 resulted in pronounced lymphocytopenia. Within two days after completion of in vivo rIL-2 therapy, there was a dramatic increase in absolute numbers of circulating lymphocytes, and cytotoxic activity against tumor cell targets was mediated by peripheral blood lymphocytes, indicating in vivo generation of LAK activity. Patients were leukapheresed and cells cultured for three to four days in rIL-2. rIL-2 cultured cells from all patients demonstrated cytotoxic activity. In order to characterize the effector cell, T cells and natural killer (NK) cells were isolated to greater than 95% purity by flow cytometry. Cytotoxic activity was mediated by rIL-2--activated NK cells, whereas T cells demonstrated no substantial activity. The circulating in vivo cytotoxic effectors detected after in vivo rIL-2 therapy were also shown to be rIL-2--activated NK cells. Results from these studies demonstrate that all patients were capable of generating a cytotoxic response, and that the cytotoxic effector cells were rIL-2--activated NK cells, identified by the phenotype CD3--, Leu 19+.
A programmable and implantable pumping system for systemic chemotherapy: a performance analysis in 52 patients.
Authors: Vogelzang N J , Ruane M , Ratain M J , Dhowlatshahi K , Chodak G W
Published: February 2017

We have prospectively evaluated the performance of the implanted battery-powered Medtronic (Minneapolis) SynchroMed infusion system. Between July 1984 and July 1986, fifty-three SynchroMed pumps were implanted in 52 patients for phase I and II trials of low-dose continuous-infusion doxorubicin (N = 35) or vinblastine (N = 17). The median duration of pump function was 145 days (mean, 180; range, 20 to 787 +) and the systems infused drugs for 61% (range, 32% to 100%) of their patient implant time. During 10,045 patient days (27.5 years) of implantation, there have been no failures of the pump mechanism and pump accuracy was excellent (2.2% error rate in 256 analyzed refills). The median cost of the hospitalization for implantation was +17,140 in 14 analyzed cases. Complications requiring a second surgical procedure occurred with 13 systems (24%). Two of the complications were related to localized cutaneous hypersensitivity to vinblastine, four were directly related to system complications, and seven were secondary to implant procedure problems. Seven patients (13%) requested removal of the device after tumor progression occurred. Based on this experience, the company has made improvements in certain aspects of system design and has implemented a comprehensive user training program to minimize procedure-related problems. The Medtronic SynchroMed is an accurate and sophisticated system that allows infusion of low-dose doxorubicin and of vinblastine for prolonged periods. Extravasation of these vesicant agents must be carefully prevented. The financial cost of this implanted system may limit its use to patients with an expected survival of 5 months or longer.
Favorable outcome of invasive aspergillosis in patients with acute leukemia.
Authors: Burch P A , Karp J E , Merz W G , Kuhlman J E , Fishman E K
Published: February 2017

During a 2-year period, 15 of 110 patients (14%) admitted for intensive therapy of acute leukemia associated with prolonged deep granulocytopenia developed documented invasive aspergillosis (IA). Antemortem diagnosis was accomplished in 14, and 13 of 15 (87%) survived the infection. Because of the high success rate, we reviewed the courses of the 15 patients to assess factors associated with this favorable outcome. Eleven presented with pulmonary IA; early symptoms occurred at a mean 21.6 days of granulocytopenia (less than 100/muL) and included refractory fever in 14 and pulmonary signs or symptoms in 11. Primary necrotic chest wall lesions associated with Hickman catheters developed in four at a mean 11 days of granulocytopenia, followed by pulmonary involvement. All 15 patients had chest radiographs during granulocytopenia, with 14 (93%) demonstrating pulmonary infiltrates and/or nodules at a mean 20.6 days of aplasia. Nine patients had lung computerized tomography (CT) scans, revealing nodular infiltrates in one patient and a characteristic zone of low attenuation surrounding a mass-like infiltrate in seven other patients, which was found to be diagnostic of IA. Subsequent CT scans performed during and following bone marrow recovery showed progression to cavitation followed by either complete resolution or minimal pulmonary scarring. Eleven patients developed IA during empiric amphotericin B (Amp-B) therapy (0.5 mg/kg/d) for fever refractory to antibacterial antibiotics. Fourteen patients received high-dose Amp-B (1.0 to 1.5 mg/kg/d), which was started within a mean of 2.2 days of first clinical findings; 13 survived. Ten patients received 5-fluorocytosine in addition to high dose amp-B. Survival was similar regardless of presentation, as 91% with primary pulmonary IA and 75% presenting with chest wall lesions survived. All 13 surviving patients had complete granulocyte recovery at a mean 33.8 days. Nephrotoxicity (creatinine greater than 2.0 mg/dL) was observed in seven patients during therapy for IA, but was transient in all seven. We conclude IA can be successfully treated in the deeply granulocytopenic patient provided that it is recognized and treated early, and provided that antifungal therapy is aggressive and is continued until granulocyte recovery occurs.
A controlled clinical trial of the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen.
Authors: Meyer B R , O'Mara V , Reidenberg M M
Published: February 2017

A randomized prospective clinical trial was conducted to evaluate the potential utility of adding transdermal scopolamine to a standard regimen of metoclopramide and dexamethasone for the prevention of cisplatin-induced emesis. Thirty-one patients who were about to receive their first cycle of chemotherapy, using a combination regimen including cisplatin at a dose greater than or equal to 60 mg/m2 were randomized to receive an antiemetic regimen of either metoclopramide and dexamethasone alone, or these two drugs plus transdermal scopolamine patches. The mean number of episodes of emesis was .63 +/- 1.31 in the 16 scopolamine-treated patients, and 2.27 +/- 2.66 in the 15 patients who did not receive scopolamine (P less than .01). The scopolamine appeared to inhibit extrapyramidal reactions to the metoclopramide, but the number of cases was too small for statistical significance. We conclude that the addition of transdermal scopolamine to a standard metoclopramide and dexamethasone antiemetic regimen provides additive benefit in the control of cisplatin-induced emesis.
High-dose methotrexate: a critical reappraisal.
Authors: Ackland S P , Schilsky R L
Published: February 2017

High-dose methotrexate (HDMTX) with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology for more than a decade. Administration of HDMTX results in tumoricidal plasma concentrations of the drug without significant host toxicity, provided that plasma MTX levels are monitored and LV rescue is properly administered. The original premise of LV rescue was that the provision of reduced folate to normal cells would circumvent the metabolic block produced by MTX and allow resumption of DNA synthesis, although the presumed therapeutic selectivity of leucovorin has not yet been adequately explained. Despite a strong pharmacologic rationale and a vast clinical experience, HDMTX with leucovorin rescue has not been shown to be unequivocally superior to conventional doses of MTX in any clinical situation except, perhaps, for treatment of osteogenic sarcoma and childhood acute leukemia. While HDMTX is an important component of effective treatment regimens for these diseases, its precise contribution to the success of these regimens remains undefined. Although HDMTX can theoretically overcome all known mechanisms of MTX resistance, no data exist to suggest that this can be accomplished in the clinic. Thus, this well-known but poorly understood treatment regimen must remain a subject of clinical investigation rather than a part of routine clinical practice.
Differences in cerebrospinal fluid penetration of corticosteroids: possible relationship to the prevention of meningeal leukemia.
Authors: Balis F M , Lester C M , Chrousos G P , Heideman R L , Poplack D G
Published: February 2017

The disposition of the synthetic corticosteroids, dexamethasone and prednisolone, in CSF was evaluated following bolus intravenous (IV) and intrathecal (IT) injection in a nonhuman primate model. Steroid concentration in plasma and CSF was measured with a radioimmunoassay following celite column chromatography. The CSF to plasma ratios of dexamethasone and prednisolone following IV bolus administration were 0.15 +/- 0.02 and 0.08 +/- 0.03, respectively. Although peak levels of the two steroids in the CSF reached equally potent levels when administered systemically in equipotent doses, the half-life of prednisolone in the CSF was shorter. In addition, there was a significant difference in the plasma protein binding of the two steroids, which may account for the differences in their CSF pharmacokinetics. Dexamethasone was 70% protein bound over a wide concentration range, while the protein binding of prednisolone was concentration dependent, ranging from 60% at 10 mumol/L to 95% at 0.5 mumol/L and below. After the initial distribution phase in plasma, CSF concentrations of dexamethasone and prednisolone approximated free plasma concentrations, indicating that penetration into the CSF was limited primarily by protein binding. At the plasma concentrations achieved following oral administration of standard doses of prednisone in children, the prednisolone (the active metabolite) is greater than 90% protein bound. The proportionally higher free plasma levels of dexamethasone result in greater penetration into the CSF. These findings may explain the lower rates of meningeal leukemia observed in children receiving dexamethasone instead of prednisone for the treatment of acute lymphoblastic leukemia (ALL).
Metastatic patterns in small-cell lung cancer: correlation of autopsy findings with clinical parameters in 537 patients.
Authors: Elliott J A , Osterlind K , Hirsch F R , Hansen H H
Published: February 2017

Postmortem material from 537 patients included in various protocols of intensive combination chemotherapy or chemoradiotherapy for the management of small-cell anaplastic carcinoma of the lung (SCLC) has been reviewed. Patterns of residual or recurrent disease were analyzed in relation to pretreatment clinical parameters. Residual primary tumor (P less than .05), regional lymph node involvement (P less than .01), hepatic (P less than .01), bone (P less than .05), and renal metastases (P less than .05) were all significantly less frequent among patients with initially limited-stage disease compared with extensively staged patients. The frequency of residual intrathoracic tumor and metastatic pattern did not significantly differ between partial responders (PRs) and nonresponders (NRs). Patients with limited disease achieving a complete remission had a lower frequency of intrathoracic tumor (P less than .001) at autopsy compared with limited-stage PRs. However, for extensive-stage patients the pattern of residual disease was essentially independent of tumor response. Prior surgery was associated with a reduced burden of metastases only in those who underwent a radical resection. The addition of radiotherapy to the primary tumor and mediastinum failed to modify the autopsy distribution of residual tumor compared with that in patients treated with chemotherapy alone. Metastatic patterns were similar with or without prophylactic abdominal radiotherapy, while prophylactic cranial irradiation (PCl) did not prevent the development of cerebral metastases in patients whose systemic response to treatment was either partial or nonexistent. However, a beneficial effect of PCl in compete responders (CRs) was not excluded.
Adjuvant methotrexate escalated to toxicity for resectable stage III and IV squamous head and neck carcinomas--a prospective, randomized study.
Authors: Rentschler R E , Wilbur D W , Petti G H , Chonkich G D , Hilliard D A , Camacho E S , Thorpe R B
Published: February 2017

To determine if adjuvant methotrexate (MTX), escalated weekly to toxicity, could improve disease-free survival (DFS) and overall survival by preventing recurrent disease, 60 patients with potentially resectable stage III or IV squamous head and neck carcinomas were stratified by primary site, stage, and nutritional status, then randomized by pairs to receive or not receive adjuvant MTX. All received standard surgery and postoperative radiation therapy. Five patients were taken off study because of unresectability at the time of surgery, leaving 55 evaluable patients. There were no statistically significant imbalances in known prognostic factors between the two treatment arms. MTX was begun at 40 mg/m2 and escalated 10 mg/m2 weekly (four doses preoperatively; four doses postoperatively, preradiation therapy; eight doses postradiation therapy) to mucosal or hematologic toxicity. The median peak MTX dose achieved was 80 mg/m2. Although three patients were hospitalized with MTX toxicity, none died of MTX toxicity. No patient receiving MTX had disease progression during treatment, and there was no increase in postoperative complications. Thirty-two patients died (median survival, 19 months); 23 patients are alive with median follow-up of 43 months. There was no statistically significant difference in actuarial DFS (P = 1.0) or overall survival (P = .61). Although patients on the MTX arm appeared to have less local and regional recurrences at first recurrence (thus more distant metastases), this did not reach statistical significance (P = .06). There was no significant difference between the sites of recurrence at death or last follow-up (P = .38).