bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of high-dose combination chemotherapy and autologous bone marrow transplantation for patients with non-Hodgkin's lymphomas who are still responsive to conventional-dose therapy.
Authors: Gribben J G , Goldstone A H , Linch D C , Taghipour G , McMillan A K , Souhami R L , Earl H , Richards J D
Published: February 2017

We commenced a study in September 1981 to investigate the role of high-dose combination chemotherapy in the management of patients with non-Hodgkin's lymphomas who had failed conventional therapy. Fifty patients with diffuse intermediate- and high-grade non-Hodgkin's lymphomas were treated with high-dose combination chemotherapy with autologous bone marrow rescue (ABMT) and have a minimum follow-up of 1 year. Twenty patients had disease that was still responsive to conventional-dose chemotherapy, 15 had achieved a partial response (PR) to first-line therapy, and five were showing PR to salvage therapy after relapse. Twelve of these patients (60%) achieved complete remission (CR) (two following boost radiotherapy) and three patients have nonprogressive masses on computed tomographic (CT) scan as the only abnormality. None of these patients died during the procedure. Twenty-nine patients had disease not responsive to chemotherapy at conventional dosages: 19 had no response to first-line therapy and 10 showed no response to salvage therapy given after relapse. Only three of these patients achieved CR, all of short duration only. Only two patients in this group remain alive more than 2 years after the procedure and both have nonprogressive abnormalities on CT scan. Nine patients (31%) died of sepsis during the procedure. In those patients with disease not responsive to conventional-dose therapy, dose escalation is associated with a high procedure-related mortality and a low response rate. In those patients who still have chemotherapy-responsive disease the response rate is high and mortality is low.(ABSTRACT TRUNCATED AT 250 WORDS)
Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome.
Authors: Gajewski J L , Ho W G , Nimer S D , Hirji K F , Gekelman L , Jacobs A D , Champlin R E
Published: February 2017

One hundred ninety-six patients with acute myelogenous leukemia (AML) were treated with intensive induction chemotherapy using similar daunorubicin/cytarabine/thioguanine regimens. Treatment results of 44 patients who had a documented preleukemic syndrome or cytopenia present for more than 2 months before developing over AML were compared with 152 patients with de novo AML. Eighteen (41%) patients with preleukemia evolving into AML achieved complete remission compared with 111 (73%) patients with de novo AML (P less than .01). Patients with preleukemia-AML had a significantly longer period to recovery of granulocytes. Multivariate analysis indicated that presence of a previous preleukemic syndrome and advancing age were independent poor prognostic indicators for achieving remission. For patients who achieved remission, disease-free survival and overall survival were also inferior for patients with previous preleukemia; disease-free survival was 17 +/- 17% at 3 years compared with 29 +/- 10% in patients with de novo AML (P = .02). These data indicate that intensive chemotherapy has limited efficacy in patients with AML following a preleukemic syndrome. Durable remissions may be achieved in some patients.
Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy.
Authors: Mulhern R K , Horowitz M E , Kovnar E H , Langston J , Sanford R A , Kun L E
Published: February 2017

In an effort to reduce the severity of late neurotoxicities associated with cranial irradiation, 14 infants and young children with malignant brain tumors were given preirradiation chemotherapy for 2 to 22 months (median, 8 months). Prospective neurodevelopmental evaluations were routinely conducted and now extend from 35 to 60 months (median, 41 months) postdiagnosis, and 10 to 52 months (median, 31 months) postirradiation in the 12 surviving children. At the initiation of chemotherapy, less than one fourth of the patients displayed normal performance status or mental functioning on age-corrected tests; the majority remained stable or declined while receiving chemotherapy. Declining mental development and adaptive behavior were noted in six patients following radiation therapy with only two patients now functioning in the normal range for age. The analysis suggests that neurodevelopmental progress is a function of multiple factors, including neurologic and sensorimotor deficits associated with the tumor, surgical intervention, and chemotherapy that antedated radiation therapy. This implies that delaying irradiation will not necessarily improve the patients' functional status. Whether the interval of postponement of irradiation evidenced in this sample will translate into an ultimately better quality of life remains unknown. Given the probable interaction of multiple risk factors, well-controlled prospective clinical trials are needed to definitively analyze this issue.
Variability in the disposition of intraventricular methotrexate: a proposal for rational dosing.
Authors: Strother D R , Glynn-Barnhart A , Kovnar E , Gregory R E , Murphy S B
Published: February 2017

Despite the clinical experience with Ommaya reservoir-facilitated intraventricular methotrexate (MTX) therapy, established age-related dosage guidelines do not exist. In an attempt to design such a schedule, 49 courses of intra-Ommaya MTX (median dose, 6 mg) administered to 12 patients were studied. Using a fluorescence polarized immunoassay (TDx; Abbott, Dallas, TX), the median peak intraventricular CSF MTX concentration (CSF [MTX]) was 423 mumol/L. Median CSF [MTX] at 24 hours was 4.6 mumol/L, and at 48 hours was 1.05 mumol/L. Median MTX half-life (t1/2) was 5.7 hours. A CSF [MTX] greater than 1 mumol/L was maintained for 24 hours in all but one course and for 48 hours in half of the courses. No correlations were found between MTX dose, patient age, [MTX], t1/2 or prior therapy. Considerable intra- and interpatient variability was seen in MTX disposition, emphasizing the need to monitor [MTX] with each course. A schedule for intraventricular MTX with an initial dose of 6 mg and supplemental doses of 6, 4, or 2 mg at 24 and 48 hours according to serial measurements of intraventricular [MTX] should be initiated to provide a minimum CSF [MTX] of 1 mumol/L for 72 hours.
Dose intensity of MOPP chemotherapy and survival in Hodgkin's disease.
Authors: van Rijswijk R E , Haanen C , Dekker A W , de Meijer A J , Verbeek J
Published: February 2017

The association between dose intensity of chemotherapy with the rate of complete remission (CR), the duration of disease-free survival (DFS), and overall survival (OS) was separately analyzed for 67 patients initially treated with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), and for 75 patients in relapse following radiotherapy who had received MOPP as a salvage regimen. In both groups of patients, the fraction of the total dose of mechlorethamine delivered in all cycles divided by the planned dose for six cycles was strongly associated with OS (P = .002 for patients receiving initial MOPP and P = .02 for the salvage group, respectively). B symptoms were independent of drug-derived variables associated with OS (corresponding P values .03 for initial MOPP and .004 for the salvage group). The predictive value of mechlorethamine dosage with regard to OS was retained in an analysis restricted to the patients receiving greater than or equal to six cycles of chemotherapy. In the initial chemotherapy group, mechlorethamine dosage was associated with attainment of CR but none of the variables tested was predictive of DFS. In the salvage chemotherapy group, mechlorethamine dosage was associated with attainment of CR and duration of DFS as well. The results emphasize that, besides tumor characteristics, optimal dosage of chemotherapy is of great importance for survival.
High frequency of benign mediastinal uptake of gallium-67 after completion of chemotherapy in children with high-grade non-Hodgkin's lymphoma.
Authors: Peylan-Ramu N , Haddy T B , Jones E , Horvath K , Adde M A , Magrath I T
Published: February 2017

We observed increased gallium-67 uptake in the mediastinum after completion of chemotherapy in 10 of 62 patients with non-Hodgkin's lymphoma. All 10 were under 15 years of age, yielding a frequency of 43% in this age group. The interval between cessation of chemotherapy and the development of increased gallium-67 uptake ranged from 1 to 8 months, and the abnormality persisted for 2 to 59 months. Serial chest x-rays were performed in all patients, and four of the 10 had transient widening of the mediastinum that remained within normal limits for the children's ages. Three patients had chest computed tomographic (CT) scans at the time of increased gallium-67 uptake, and one of the three had serial scans that showed a mediastinal mass consistent with thymic enlargement. All of the patients were asymptomatic and none were biopsied. All 10 remained well, with a mean follow-up of 52.5 months. The phenomenon we describe is probably due to "rebound" thymic hyperplasia, which is a benign and transient condition. We conclude that abnormal mediastinal gallium-67 uptake after completion of chemotherapy is likely to be benign and transient if the patients are young, have small non-cleaved-cell histology, are without other evidence of lymphoma recurrence, and do not have initial mediastinal involvement. Progressive widening of the mediastinum on chest x-ray is cause for suspicion and requires further evaluation. Serum lactate dehydrogenase (LDH) levels may not be helpful in differentiating a benign from a malignant process.
Patient-controlled analgesia for chronic cancer pain in the ambulatory setting: a report of 117 patients.
Authors: Swanson G , Smith J , Bulich R , New P , Shiffman R
Published: February 2017

Patient-controlled analgesia (PCA) represents a drug-delivery system in which patients self-administer predetermined doses of opiate analgesics. We have taken advantage of recent advances in pump technology and developed a system in which patients with severe pain received a continuous narcotic infusion, along with the capability of PCA bolus for breakthrough pain. All patients were experiencing chronic pain related to cancer and were unable to obtain adequate pain control with either intermittent parenteral, oral, or rectal narcotics. Sixty-nine percent of patients were treated in the home setting, and the majority received morphine sulfate subcutaneously (SQ). Admixture stability studies using high-pressure liquid chromatography (HPLC) showed that dexamethasone, metoclopramide, and haloperidol could be added to the morphine solutions and remain stable for 1 week at room temperature. Of 117 patients entered, 95% received excellent pain control, and side effects were rare, consisting of subcutaneous needle site infection and respiratory depression. Progressive pain due to either advancing disease or development of drug tolerance could be controlled by increasing opiate infusion rates. We conclude that (1) continuous infusion opiate with PCA bolus capability can be initiated and administered safely in the home setting; (2) patients with pain related to malignancy can be managed well with this system; and (3) pain control programs can be designed, implemented, and evaluated in the private practice setting.
Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.
Authors: Bataille R , Chappard D , Marcelli C , Dessauw P , Sany J , Baldet P , Alexandre C
Published: February 2017

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.
Phase I trial of liposomal muramyl tripeptide phosphatidylethanolamine in cancer patients.
Authors: Murray J L , Kleinerman E S , Cunningham J E , Tatom J R , Andrejcio K , Lepe-Zuniga J , Lamki L M , Rosenblum M G , Frost H , Gutterman J U
Published: February 2017

Twenty-eight evaluable patients with metastatic cancer refractory to standard therapy received escalating doses of muramyl tripeptide phosphatidylethanolamine (MTP-PE) (.05 to 12 mg/m2) in phosphatidylserine (PC):phosphatidylcholine (PS) liposomes (lipid:MTP-PE) ratio 250:1). Liposomal MTP-PE (L-MTP-PE) was infused over 1 hour twice weekly; doses were escalated within individual patients every 3 weeks as tolerated for a total treatment duration of 9 weeks. Routine clinical laboratory parameters, acute phase reactants and various immunologic tests were monitored at various time points during treatment. Toxicity was moderate (less than or equal to grade II) in 24 patients with chief side effects being chills (80% of patients), fever (70%), malaise (60%), and nausea (55%). In four patients L-MTP-PE treatment was deescalated due to severe malaise and recurrent fever higher than 38.8 degrees C. The maximum-tolerated dose (MTD) was 6 mg/m2. Significant (P less than .05) increases in WBC count, absolute granulocyte count, ceruloplasmin, beta 2-microglobulin, c-reactive protein, monocyte tumoricidal activity, and serum IL-1 beta were found. Significant decreases in serum cholesterol were also observed. Clearance of intravenously (iv)-infused technetium-99 (99mTc)-labeled liposomes containing MTP-PE in four patients was biphasic; gamma camera scans revealed uptake of radiolabel in liver, spleen, lung, nasopharynx, thyroid gland, and tumor (two patients). No objective tumor regression was seen. In view of its definite immunobiologic activity and lack of major toxicity, additional phase II and adjuvant trials of L-MTP-PE are warranted.
A phase I study of samarium-153 ethylenediaminetetramethylene phosphonate therapy for disseminated skeletal metastases.
Authors: Turner J H , Claringbold P G , Hetherington E L , Sorby P , Martindale A A
Published: February 2017

Thirty-five patients with disseminated skeletal metastases from a variety of tumor types underwent clinical trial of samarium-153 ethylenediaminetetramethylene phosphonate (153Sm-EDTMP) on a day-patient basis. Individual beta radiation dosimetry was based on pharmacokinetic studies of a 20 mCi tracer dose of 153Sm-EDTMP. The retained skeletal activity varied unpredictably from 40% to 95% of the administered dose, but in all patients greater than 98% of the nonosseous activity was cleared in the urine within 6 hours. Prospective calculation of radiation dosimetry in each patient permitted an accurate dosage schedule based upon total red marrow exposure, starting at 100 cGy and escalating to 280 cGy to define the dose-limiting myelotoxicity. Pain was relieved in 22 of 34 evaluable patients (65%) for periods ranging from 4 to 35 weeks, following a single administration of 153Sm-EDTMP. Recurrence of pain responded to retreatment with 153Sm-EDTMP in five of nine patients. The dose-limiting toxicity was myelosuppression manifested particularly by delayed thrombocytopenia. Platelet counts less than 100 x 10(9)/L occurred in 42% of courses when bone marrow radiation absorbed dose exceeded 200 cGy. Myelosuppression was transient and platelet counts had recovered to pretreatment levels within 10 weeks of treatment. 153Sm-EDTMP is effective for the amelioration of pain due to disseminated skeletal metastases particularly with carcinoma of breast or prostate where 83% of patients experienced pain relief. In 15 of the 34 evaluable patients there was evidence of stabilization or regression of skeletal metastases on radiographs and follow-up technetium-99m methylene diphosphonate (99mTc-MDP) bone scans.
Infusion carboplatin treatment of relapsed and refractory acute leukemia: evidence of efficacy with minimal extramedullary toxicity at intermediate doses.
Authors: Meyers F J , Welborn J , Lewis J P , Flynn N
Published: February 2017

Carboplatin (CBDCA) is a second-generation platinum analog with prominent myelotoxicity and modest extramedullary toxicity. We performed a phase I study of CBDCA in adult patients with relapsed acute leukemia. Therapy was administered as a five-day continuous infusion. The initial dose of 875 mg/m2 over five days was escalated in 15% increments to a final dose of 2,100 mg/m2 over five days. Twenty-eight patients received 35 induction courses of CBDCA, including two patients who achieved a complete remission (CR) following the first course, and received a second induction course at the time of relapse. Therapy was well tolerated. No grade 3 or 4 extramedullary toxicity was seen. Myelosuppression was regularly observed, with prolonged myelosuppression at 2,100 mg/m2 over five days being the indication to cease dose escalation. Eight of 28 patients (28.5%) responded to CBDCA therapy (six CR, two partial remission [PR]) or ten of 30 initial induction courses (33.3%). Continuous-infusion CBDCA has an advantage over other therapy for acute leukemia because of its highly selective myelotoxicity and minimal gastrointestinal and renal toxicity. A standard phase II study should be undertaken to establish a more accurate response rate.
A prospective study of Hickman/Broviac catheters and implantable ports in pediatric oncology patients.
Authors: Mirro J , Rao B N , Stokes D C , Austin B A , Kumar M , Dahl G V , Colten M , Balas L , Rafferty M , Hancock M
Published: February 2017

We prospectively studied the continuous function and complication rates of 286 central venous catheters consecutively placed in 264 children and young adults at a single institution over a 19-month period (median follow-up, 376 days). Externalized catheters (91 Hickman [H], 113 Broviac [B]) and implantable ports (n = 82) were compared for complications, including infection and thrombosis. The most frequent major complication of all catheters was infection, although the rates of infection varied with the duration of catheter use and were generally lower than reported by others. Overall, when catheter failures (removal) for infection, obstruction, or dislodgement were considered, ports had a significantly longer failure-free duration of use (P = .0024) than did externalized catheters. Likewise, ports had a significantly longer infection-free (P less than .01) duration of use than H and B catheters. However, differences in patient age and clinical characteristics among the three catheter groups may have affected the outcome. In analysis of pairs matched for diagnosis, therapy, and age, ports had lower infection rates than did B catheters after 100 days (P = .053). This difference became significant at 400 days of catheter use (P = .029). Although there was a trend toward lower rates of infections for ports v H catheters, this difference was not significant. In view of our results in matched pairs, selection of catheter type based on clinical characteristics and patient preferences remains a reasonable therapeutic approach despite the apparent advantages of ports. The superiority of ports for long-term use (greater than 100 days) needs to be confirmed in a large randomized clinical trial.
Two- versus 24-hour infusion of cisplatin: pharmacokinetic considerations.
Authors: Reece P A , Stafford I , Abbott R L , Anderson C , Denham J , Freeman S , Morris R G , Gill P G , Olweny C L
Published: February 2017

The disposition of unchanged cisplatin was compared after two- and 24-hour intravenous (IV) infusion to eight patients with germ cell cancer (dose, 100 mg/m2), 14 patients with head and neck cancer (dose, seven patients 50 mg/m2; seven patients, 100 mg/m2). Patients were randomized to receive either a two- or 24-hour infusion in the first course of treatment and the reverse in the second course. Cisplatin renal clearance, total clearance, and the percentage of the dose excreted unchanged in urine were significantly lower with the longer infusion. Total clearance was 345 +/- 97.0 mL/min/m2 after the two-hour infusion and 268 +/- 70.7 mL/min/m2 after the 24-hour infusion (P less than .0001). Renal clearance was 79.1 +/- 35.3 mL/min/m2 and 34.1 +/- 14.9 mL/min/m2 (P less than .0001). The percentage of the dose excreted unchanged in urine was 22.9 +/- 6.5% and 12.8 +/- 4.0%, respectively (P less than .0001). The ratio of cisplatin renal clearance to creatinine clearance was 1.95 +/- .96 after the two-hour infusion and .90 +/- .40 after the 24-hour infusion (P less than .001). There was only a poor relationship between cisplatin renal clearance and creatinine clearance after a two-hour infusion (r2 = .05, P greater than .1) or 24-hour infusion (r2 = .18, P greater than .05). The severity of emesis was graded on a four-point scale and was significantly less with the 24-hour infusion than with the two-hour infusion (P less than .05). Twenty-four-hour infusion of cisplatin resulted in greater drug retention in patients due to reduced renal clearance, but was also associated with reduced emetic toxicity, probably as a result of lower peak plasma levels.
Male gonadal function after chemotherapy for solid tumors in childhood.
Authors: Aubier F , Flamant F , Brauner R , Caillaud J M , Chaussain J M , Lemerle J
Published: February 2017

The testicular function of 30 adolescent or adult males having undergone polychemotherapy in childhood was assessed by means of a spermogram or testicular biopsy. At the time of examination, the patients were pubertal and had completed chemotherapy between 1 and 20 years previously (mean, 9 years). All patients who were prepubertal or intrapubertal at the time of treatment achieved normal puberty with normal growth. Twenty patients presented with azoospermia and/or severe disturbances in the germinal line on biopsy. This series confirms the toxicity of alkylating agents, in particular that of the mechlorethamine, vincristine, procarbazine, and prednisone combination (MOPP) and that of cyclophosphamide (CPM). However, dactinomycin, vinblastine, and vincristine did not appear to have a toxic effect on spermatogenesis. The prepubertal state did not protect the gonads of 19 patients who were prepubertal at diagnosis: 12 are now sterile as a result of the treatment. An increase in basal follicle-stimulating hormone (FSH) levels gives a good indication of testicular damage, although normal levels do not rule out the possibility of azoospermia.
Bilateral Wilms' tumor: long-term survival and some epidemiological features.
Authors: Coppes M J , de Kraker J , van Dijken P J , Perry H J , Delemarre J F , Tournade M F , Lemerle J , Voûte P A
Published: February 2017

Sixty-seven children with a bilateral Wilms' tumor (BWT) who were registered to the International Society of Pediatric Oncology (SIOP) nephroblastoma trial and studies 1, 2, and 5, conducted between 1971 and 1980, were analyzed. The overall 10-year survival was 64%. While most deaths due to tumor occurred within 3 years after diagnosis of bilateral disease, five patients died after 3 years (20%), three with synchronous and two with metachronous BWT. The survival rates for the 42 children with synchronous BWT (follow-up time, 6 1/2 to 14 years) and the 25 children with metachronous BWT (follow-up time, 5 to 13 years) were 69% and 56%, respectively. Due to an improvement in the synchronous group, overall survival improved over the years: 47%, 72%, and 70%, in SIOP 1, 2, and 5, respectively. Age at diagnosis and most advanced tumor stage affected prognosis. Children presenting a tumor manifestation before the age of 2 years had better prognosis than older children. This difference is significant in synchronous BWT. Prognosis for children with local stage 1 or 2 was better than for those with local stage 3. Median age at initial presentation in BWT was lower than in unilateral nephroblastoma and lower in metachronous BWT than in synchronous BWT. Young children presenting with unilateral nephroblastoma should have a careful follow-up of the contralateral kidney for at least the next 3 1/2 years, as most contralateral tumors will develop during this period.
Three versus five years of maintenance therapy are equivalent in childhood acute lymphoblastic leukemia: a report from the Childrens Cancer Study Group.
Authors: Miller D R , Leikin S L , Albo V C , Sather H , Hammond G D
Published: February 2017

Childrens Cancer Study Group protocol 141 (CCG-141), a randomized trial, was designed in part to compare 3 v 5 years of maintenance therapy, to evaluate the role of late reinduction, and to identify factors that predict relapse after 3 years of continuous complete remission (CCR) in acute lymphoblastic leukemia (ALL). Of 880 patients entered on study, 827 (94%) achieved complete remission and 499 (56.7%) were in CCR after 3 years of maintenance therapy. Boys were required to have negative testicular biopsies before randomization. A total of 481 patients were eligible for the duration of therapy phase of the study. Of the 310 (64.4%) randomly assigned patients, 101 were entered on regimen A: discontinue therapy; 105 on regimen B: reinduction for 4 weeks, then discontinue therapy; and 104 on regimen C: continue maintenance therapy for 2 more years, then discontinue. After a median follow-up of over 72 months, no significant differences in disease-free survival (DFS) or survival were noted in the three regimens. At 6 years from randomization, 93.0%, 89.1%, and 89.1% of patients on regimens A, B, and C, respectively, remained in CCR. Isolated CNS or overt testicular relapses were not significantly different in any of the study regimens. Isolated testicular relapse after a negative biopsy occurred in only two of 137 randomized males (1.5%). DFS (P = .10) and survival (P = .83) were not significantly different for all boys and girls randomized to regimens A, B, or C. The relapse rate was higher in boys than in girls randomized to discontinue therapy (11% v 4%), but the difference was not statistically significant (P = .14). Except for the presence of occult testicular leukemia (TL) in males, no other factors were identified that predicted for adverse events after 3 years of CCR. We conclude that prolongation of maintenance therapy beyond 3 years does not improve survival or decrease the risk of relapse.
Evaluation of optimal duration of chemotherapy in favorable-prognosis disseminated germ cell tumors: a Southeastern Cancer Study Group protocol.
Authors: Einhorn L H , Williams S D , Loehrer P J , Birch R , Drasga R , Omura G , Greco F A
Published: February 2017

Four courses of PVP16B (cisplatin plus etoposide [VP-16] plus bleomycin) has been standard chemotherapy for disseminated germ cell tumors at Indiana University and the Southeastern Cancer Study Group (SECSG) since 1984. We began a random prospective phase III study in patients with favorable-prognosis (minimal and moderate extent) disseminated germ cell tumors comparing four courses of PVP16B over 12 weeks to the identical dose PVP16B administered in three courses over 9 weeks. The categories of minimal and moderate disease constitute approximately two thirds of all disseminated germ cell tumors that require chemotherapy. One hundred eighty-four patients entered this trial, and all patients have a minimal follow-up of 1 year. Overall, 106 of 107 (99%) minimal extent and 73 of 77 moderate patients (95%) achieved an initial disease-free status (NED), confirming the favorable prognostic categories. Eighty-six of 88 patients (98%) randomized to three courses and 93 of 96 randomized to four courses (97%) of PVP16B achieved disease-free status. There have been ten relapses (5%), with five on each arm. Currently, 81 of 88 (92%) and 88 of 96 (92%) patients randomized to three v four courses of PVP16B are continuously disease-free. This study confirms the high cure rate with PVP16B in favorable-prognosis germ cell tumors. The deletion of the fourth course of PVP16B significantly reduces the toxicity, cost, and inconvenience of this curative regimen. We conclude that three courses of PVP16B is the preferred regimen for favorable-prognosis germ cell tumors.
Chronic daily administration of oral etoposide--a phase I trial.
Authors: Hainsworth J D , Johnson D H , Frazier S R , Greco F A
Published: February 2017

In this phase I study, we administered etoposide (VP-16) orally for 21 consecutive days to patients with advanced refractory cancers. All patients had received previous chemotherapy, and 50% of patients had received more than one combination regimen. When given for 21 consecutive days, the maximum-tolerated dose of oral VP-16 was 50 mg/m2/d. Myelosuppression was the dose-limiting toxicity, and occurred between days 21 and 28. In most patients, blood counts had recovered sufficiently by day 35 to begin another 3-week course. WBC count nadirs of less than 1,000/microL occurred in four of 20 courses at this dose, and three patients required hospitalization for treatment of neutropenia and fever. Alopecia occurred in most patients; gastrointestinal (GI) and other toxicities were uncommon. Five of 16 patients with measurable tumor had partial responses of 3 to 4 months duration. Four of these five patients had malignancies that are usually unresponsive to VP-16 when administered by previously investigated schedules. This method of VP-16 administration is well tolerated, convenient, and may optimize antitumor efficacy by exploiting the schedule dependency of this drug. Phase II studies are necessary to define the level of activity of this schedule of VP-16.
A prospective randomized comparison of continuous infusion fluorouracil with a conventional bolus schedule in metastatic colorectal carcinoma: a Mid-Atlantic Oncology Program Study.
Authors: Lokich J J , Ahlgren J D , Gullo J J , Philips J A , Fryer J G
Published: February 2017

One hundred seventy-nine patients with advanced measurable colorectal cancer not previously treated with chemotherapy were entered into a prospective randomized clinical trial by the Mid-Atlantic Oncology Program (MAOP) to compare two schedules of delivery for single-agent fluorouracil (5-FU). The "standard" treatment was a schedule commonly employed in clinical practice, namely, a daily bolus dose administered intravenously (IV) for five consecutive days and repeated at 5-week intervals. The investigational treatment was a continuous infusion of 5-FU administered 24 hours a day for a protracted time (10 weeks or more). Both treatments were continued until the development of disease progression or unless interrupted for toxicity. Using stringent objective criteria requiring independent confirmation of x-ray or scan-documented response, the tumor response rate reached 7% (six of 87) for the bolus arm and 30% (26 of 87) for the infusion arms (P less than .001). Toxicity was substantially different for the two arms with major leukopenia observed only on the bolus arm, 22% developing grade 3 (severe) or grade 4 (life-threatening) leukopenia with four sepsis-related deaths. Hand-foot syndrome was observed only in the infusional arm, requiring treatment interruptions and dose reductions in 24% of patients, but with little impact on quality of life. In spite of the major difference in objective response rate, overall survival for the two groups was comparable. Administration of 5-FU as a continuous infusion for protracted periods clearly improves the therapeutic index for this agent in patients with advanced colon cancer with respect to response rate and reduced toxicity. This schedule appears workable in the community setting and yields response rates similar to those reported for 5-FU with high-dose leucovorin, but without the gastroin testinal toxicity profile of the latter combination.
The fate of bone marrow micrometastases in patients with primary breast cancer.
Authors: Mansi J L , Berger U , McDonnell T , Pople A , Rayter Z , Gazet J C , Coombes R C
Published: February 2017

Using an immunocytochemical technique, micrometastases have been found in the bone marrow of approximately 26% of patients with primary breast cancer at the time of initial surgery. To determine the fate of these cells, both in patients receiving and not receiving adjuvant therapy, multiple bone marrow aspirates were repeated in 82 patients at a median time of 18 months after surgery but prior to overt relapse. In both treated and untreated patients micrometastases were only found in one of 45 (2%) and one of 37 (3%) patients, respectively. However, when multiple marrow aspirates were taken from patients with local recurrence the incidence of micrometastases was 19% (three of 16), and this increased to 30% (three of ten) in patients with disease at distant sites other than bone, and 100% (ten of ten) in patients with radiologically proven bony disease. Three of 11 (27%) patients in whom the primary tumor remained in situ while receiving adjuvant therapy before definitive surgery had micrometastases at the time of diagnosis and at follow-up 3 months later. These results suggest that many of the micrometastases from breast cancer patients are the result of "shedding" of cells from the primary carcinoma and that a proportion are not viable. The technique is currently insufficiently sensitive to accurately monitor adjuvant therapy in breast cancer patients.
Randomized trial of cyclophosphamide plus cisplatin with or without doxorubicin in ovarian carcinoma: a Gynecologic Oncology Group Study.
Authors: Omura G A , Bundy B N , Berek J S , Curry S , Delgado G , Mortel R
Published: February 2017

A randomized clinical trial was conducted in women with stage III ovarian carcinoma (less than or equal to 1 cm residual lesions), using cyclophosphamide plus cisplatin (CP) with or without doxorubicin. There were 349 evaluable patients, of whom 176 received CP while 173 patients received CP plus doxorubicin (CAP). Hematologic toxicity was almost identical. There was no significant difference in progression-free interval (PFI) (median, 22.7 months and 24.6 months), frequency of negative second-look laparotomy (30.2% and 32.8%), or survival (median, 31.2 months and 38.9 months) between CP and CAP, respectively. Thus, doxorubicin in the dose schedule employed does not improve combination chemotherapy of optimal stage III ovarian carcinoma. Several other findings, independent of treatment arm, were of interest. There was a significant difference in PFI and survival by residual disease category (yes v no) and by grade of differentiation (1 v 2 + 3). In multivariate analysis, age, residual disease at entry, cell type (clear cell carcinoma), and time from surgery to initiation of chemotherapy were significant predictors of survival. There was no difference in outcome comparing those who refused second-look with those who had a second-look.
A phase II study of interleukin-2 and lymphokine-activated killer cells in patients with metastatic malignant melanoma.
Authors: Dutcher J P , Creekmore S , Weiss G R , Margolin K , Markowitz A B , Roper M , Parkinson D , Ciobanu N , Fisher R I , Boldt D H
Published: February 2017

Thirty-six patients with metastatic melanoma were entered into a study of the therapeutic efficacy of adoptive immunotherapy with high-dose interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cells. Thirty-two patients who received all components of the therapy are evaluable for response, and all patients are evaluable for toxicity. Sites of disease included lung, liver, subcutaneous nodules, and intra-abdominal metastases. One complete response (CR) and five partial responses (PRs) resulted from treatment (19% response rate). The median response duration was 5 months, with the durable CR continuing at 31+ months and one durable PR continuing for 13 months. Sites of response included lung, liver, subcutaneous nodules, and lymph nodes. Response, response duration, or site of response did not correlate with the total dose of IL-2 administered, rebound lymphocytosis, or the number of LAK cells infused. Toxicity included hypotension, fluid retention with a "capillary leak syndrome" in most patients, and transient multiorgan dysfunction that resolved promptly after the completion of therapy. Adverse cardiac events occurred in 16% of patients, with one myocardial infarction leading to a death. This study confirms the activity of the initial IL-2/LAK cell regimen in metastatic melanoma reported by Rosenberg et al, supporting the concept of adoptive immunotherapy as an important new treatment approach for this disease.
Telling the diagnosis of cancer.
Authors: Lind S E , DelVecchio Good M J , Seidel S , Csordas T , Good B J
Published: February 2017

Although a concensus has emerged in this country that patients should be told when cancer is discovered, no data is available to indicate how and where patients are currently told that they have cancer. Fifty-five patients undergoing anticancer therapy were therefore interviewed to learn how this process occurs. The majority of patients were told by surgeons (74%) and only a minority by primary care physicians (11%). Most were told in a traditional medical setting (42% in the doctor's office, 17% in a hospital room), but 23% were told over the telephone and 19% in the recovery room. Two indicators of patient satisfaction with the telling process suggested that different sites of telling were not equivalent. Patients told over the telephone or in the recovery room were more likely to describe the telling in negative terms and less likely to describe their doctors as being helpful in understanding their illness than those told in a doctor's office or in their hospital bed. This pilot study indicates considerable variation in this aspect of patient care and suggests directions for future research. To determine whether interviews that explore these issues with cancer patients are unpleasant or stressful, patients' reactions to being subjects in this study were sought. Patients asked directly at the completion of the interview or surveyed 2 to 4 months later said the interview had been helpful and/or a positive experience. None expressed negative feelings about participating. Concerns about the psychological harm resulting from such study of this patient group do not appear to be warranted and should not impede future research.
Subcutaneous granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects.
Authors: Thompson J A , Lee D J , Kidd P , Rubin E , Kaufmann J , Bonnem E M , Fefer A
Published: February 2017

The toxicity, pharmacokinetics, and hematologic effects of granulocyte-macrophage colony-stimulating (GM-CSF) were studied in a phase I/II trial of 16 patients with myelodysplastic syndrome (MDS). The GM-CSF was administered subcutaneously (SC) daily so as to achieve prolonged blood levels and to establish an outpatient treatment regimen. Four dose levels were administered for ten days: 0.3 microgram/kg/d (three patients), 1.0 microgram/kg/d (three), 3.0 micrograms/kg/d (four), and 10.0 micrograms/kg/d (six). The most common toxicities were fever and a flu-like syndrome, which were dose-dependent. The maximum-tolerated dose was 10.0 micrograms/kg/d, which induced severe rigors (two patients), fever greater than 40 degrees C (one), severe bronchospasm (one), and WBC 60,000 (one). In one patient, refractory anemia with excess blasts in transformation (RAEB-T) progressed to acute nonlymphocytic leukemia after two doses of GM-CSF, and the patient died of leukemia that did not respond to chemotherapy. After doses of 3.0 and 10.0 micrograms/kg, serum GM-CSF levels peaked at 3.8 to 6.3 hours, and persisted for 14 and 24 hours, respectively. Circulating granulocytes (neutrophils and bands) increased in a dose-dependent manner, as 11 of 13 patients who received greater than or equal to 1.0 microgram/kg/d responded with a two- to 194-fold increase. Although the neutrophils usually returned to pretreatment levels shortly after stopping GM-CSF, two patients continue to exhibit an elevation of neutrophils for 6 months. Dose-related increases in circulating monocytes and eosinophils were also noted. Transient increases in platelet and reticulocyte counts were observed in two and three patients, respectively. Five of the 16 patients later received maintenance GM-CSF at 3 micrograms/kg/d for 2 to 9 weeks. All showed a dramatic increase in neutrophils after 2 weeks. Thereafter, despite continued therapy, the neutrophil count in four patients declined markedly. In conclusion, GM-CSF is well tolerated by the SC route and induces striking, but usually temporary, improvement in the neutropenia of MDS. Larger prospective phase III trials will determine the duration of hematologic responses and the impact on infection, morbidity, and mortality.
A phase I clinical and pharmacokinetic study of carboplatin and autologous bone marrow support.
Authors: Shea T C , Flaherty M , Elias A , Eder J P , Antman K , Begg C , Schnipper L , Frei E , Henner W D
Published: February 2017

A series of 33 patients were treated with a four-day continuous infusion of carboplatin in a phase I study to determine the maximum-tolerated dose (MTD) of this agent when used with autologous bone marrow reinfusion. Doses were escalated from 375 to 2,400 mg/m2; autologous bone marrow reinfusion was added to the regimen at doses of 1,600 mg/m2 and above. The MTD was determined to be 2,000 mg/m2. Dose-limiting toxicity consisting of reversible hepatotoxicity, renal dysfunction, and moderate to severe ototoxicity was observed with a dose of 2,400 mg/m2. There were ten responses in 31 heavily pretreated patients, including six responses in 11 patients with recurrent ovarian cancer. Pharmacokinetic studies revealed a systemic clearance (Clss) of 4.5 L/m2/h. This value is consistent with clearances reported for carboplatin administered at lower doses and by different schedules. No evidence for saturation of systemic clearance at higher doses was observed. Carboplatin appears to be an active drug that can undergo considerable dose escalation when used in conjunction with autologous bone marrow support.
Long-term follow-up of testicular function following radiation therapy for early-stage Hodgkin's disease.
Authors: Kinsella T J , Trivette G , Rowland J , Sorace R , Miller R , Fraass B , Steinberg S M , Glatstein E , Sherins R J
Published: February 2017

Seventeen male patients with pathological staged I-IIIA1 Hodgkin's disease were followed prospectively for radiation damage to the testes from low-dose scattered irradiation. During conventionally fractionated radiation therapy, the testicular dose ranged from 6 to 70 cGy. Testicular function was measured in a prospective fashion by repeated analyses (every 6 to 12 months) of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone. Patients were also followed by serial semen analyses and by a questionnaire on fertility. The follow-up period ranged from 3 to 7 years after completion of radiation therapy. In patients receiving greater than or equal to 20 cGy, there was a dose-dependent increase in serum FSH values following irradiation, with the maximum difference at 6 months compared with pretreatment levels. All patients showed a return to normal FSH values within 12 to 24 months following irradiation. No significant changes in LH and testosterone were observed in this patient group. Eight patients with a normal pretreatment semen analysis provided serial semen samples and two patients showed transient oligospermia with complete recovery by 18 months following treatment. Four patients have fathered normal offspring following radiation therapy. We conclude that low doses (greater than 20 cGy) of scatter irradiation during treatment for Hodgkin's disease can result in transient injury to the seminiferous tubule as manifested by elevations of FSH for 6 to 24 months following treatment. Below 20 cGy, FSH values remained in the normal range. No evidence of Leydig cell injury (using LH and testosterone) was seen in this dose range (up to 70 cGy). Thus, patients with early-stage Hodgkin's disease can be treated with radiation therapy with little to no risk of irreversible testicular injury. Radiation treatment techniques to shield the testes are discussed.
Hearing loss in children and young adults receiving cisplatin with or without prior cranial irradiation.
Authors: Schell M J , McHaney V A , Green A A , Kun L E , Hayes F A , Horowitz M , Meyer W H
Published: February 2017

One hundred seventy-seven children and young adults with various malignant neoplasms were prospectively tested for hearing loss after they had received cisplatin (n = 146), cranial irradiation (n = 18), or both (n = 13). Adequate renal function, no history of treatment with ototoxic drugs other than cisplatin, and availability for repeated audiometric testing were requirements for enrollment. Substantial hearing loss, defined as a hearing threshold of 50 dB or greater, was noted in only 11% of the cohort on tests conducted at the common speech frequencies (500 to 3,000 Hz). About half the patients had substantial deficits at higher frequencies (4,000 to 8,000 Hz). The probability of substantial hearing loss was directly related to the cumulative dose of cisplatin. In nonirradiated patients tested at the speech frequencies, there was a negligible risk of substantial deficits over the dose range of 90 to 360 mg/m2. As the dose increased to 720 mg/m2, the risk increased to 22%. In irradiated patients who later received cisplatin, cumulative drug doses as low as 270 mg/m2 were associated with a high probability of substantial hearing loss, suggesting potentiation of ototoxicity when these therapies are used together. Hearing acuity was either not affected or only minimally decreased in the irradiation-only group. Younger age, prior irradiation, and the presence of a CNS tumor each contributed significantly to the severity of hearing deficits at given cisplatin dose levels. We conclude that early increases in hearing threshold at a stimulus frequency of 4,000 Hz indicate probable subsequent deficits at lower frequencies, especially in young children with CNS tumors who have received cranial irradiation. The probability charts derived from this analysis should provide a useful tool for predicting hearing loss in the speech frequencies.