bluuebunny/crossref_metadata_2025 huggingface dataset:
HER-2/neu oncogene protein and prognosis in breast cancer.
Authors: Tandon A K , Clark G M , Chamness G C , Ullrich A , McGuire W L
Published: February 2017

Amplification of the HER-2/neu oncogene was recently reported to predict poor clinical outcome in node-positive breast cancer patients. Since expression of the oncogene as its protein product might be even more closely related than gene amplification to disease progression, we have now examined levels of the HER-2/neu oncogene protein for its prognostic potential in both node-positive and node-negative breast cancer. Using Western blot analysis, levels of this protein were determined in 728 primary human breast tumor specimens. We examined relationships between this protein and other established markers of prognosis, as well as clinical outcome. In node-negative patients (n = 378), the HER-2/neu protein failed to predict disease outcome. However, in node-positive patients (n = 350), those patients with higher HER-2/neu protein had statistically shorter disease-free (P = .0014) and overall survival (P less than .0001) than patients with lower levels of the protein. Higher HER-2/neu protein was found in tumors without estrogen receptor (ER) (P = .02) or progesterone receptor (PgR) (P = .0003), and in patients with more than three positive lymph nodes (P = .04). A significant correlation between levels of the HER-2/neu gene protein and amplification of the gene itself was also found (n = 48, P less than .001). Multivariate analyses in these patients showed that the HER-2/neu protein is a significant independent predictor of both the disease-free and the overall survival in node-positive breast cancer, even when other prognostic factors are considered.
Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy.
Authors: Jones S E , Miller T P , Connors J M
Published: February 2017

In order to assess long-term outcome of patients with localized (stage I or II) diffuse large-cell lymphoma treated with initial combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without involved-field radiotherapy following chemotherapy, we combined data from two prospective trials in Tucson (64 patients) and Vancouver (78 patients). Follow-up on 142 patients was updated and a variety of potential pretreatment prognostic factors were analyzed for impact on outcome. One hundred forty patients (99%) achieved a complete remission and there were no differences in outcome between institutions. Twenty-three patients have relapsed and 22 have died from lymphoma at a median follow-up of 4.4 years, resulting in an overall relapse-free survival of 82% at 5 years. There was no treatment-related mortality and were no instances of late cardiac toxicity or leukemia. Of the following potential pretreatment prognostic factors (age, stage, "B" symptoms, extranodal disease, gastrointestinal tract involvement, bulky disease, or disease above or below the diaphragm), only stage affected relapse-free survival (RFS) (P = .16) and survival (.003). Among 34% of patients over age 65, outcome was similar to younger patients. RFS for 108 patients treated with CHOP plus radiotherapy was not significantly superior to the use of CHOP alone in 34 patients (P = .2).
Functional and psychosocial effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas.
Authors: Chang A E , Steinberg S M , Culnane M , Lampert M H , Reggia A J , Simpson C G , Hicks J E , White D E , Yang J J , Glatstein E
Published: February 2017

We have documented functional and psychosocial changes in patients with extremity soft tissue sarcomas who have undergone multimodality limb-sparing treatments. In 88 patients, parameters related to economic status, sexual activity, pain, limb function, and global quality of life (QOL) were recorded prior to surgery and every 6 months postoperatively. Changes from the preoperative assessment for every parameter were analyzed in each patient. Six months after surgery, there was a decrease in employment status, sexual activity, and in limb function in a significant number of patients. At 12 months, these decreases were still evident. Despite these changes, global QOL measured by a standardized test showed at least some improvement in a significant proportion of patients at 12 months. These findings highlight the difficulty in defining QOL. It could not be ascertained if radiation therapy and/or chemotherapy were causative factors in specific changes because of the small numbers of patients in each subgroup. However, among 60 patients with high-grade sarcomas, significant wound problems developed in 10 of 33 who received postoperative radiation therapy in combination with adjuvant doxorubicin and cyclophosphamide chemotherapy compared with one of 27 patients who received adjuvant chemotherapy alone (P = .016). Also, among high-grade sarcoma patients with 12-month follow-up, six of 19 patients who received radiation therapy and chemotherapy developed joint contractures compared with zero of 15 patients who received chemotherapy alone (P less than .04). The combination of postoperative radiation therapy and chemotherapy appeared to be associated with significantly more tissue-related injury in patients with high-grade sarcomas compared with chemotherapy alone.
High-dose cytarabine and daunorubicin as consolidation therapy for acute myeloid leukemia in first remission: long-term follow-up and results.
Authors: Wolff S N , Herzig R H , Fay J W , Phillips G L , Lazarus H M , Flexner J M , Stein R S , Greer J P , Cooper B , Herzig G P
Published: February 2017

In an effort to increase the proportion of patients with acute myeloid leukemia (AML) remaining in continued complete remission (CCR), we administered intensive postremission consolidation therapy with high-dose cytarabine (Ara-C) and daunorubicin. Eighty-seven patients, with a median age of 38 years (range, 7 to 71), received consolidation therapy after first complete remission was obtained with standard induction chemotherapy that included conventional doses of Ara-C. Consolidation therapy consisted of from one to three cycles of high-dose Ara-C (3 g/m2 intravenously [IV] over 1 hour every 12 hours for 12 doses) followed by daunorubicin (30 mg/m2/d IV bolus for 3 days). After completion of the high-dose Ara-C and daunorubicin, no further therapy was administered. Myelosuppression encountered with consolidation resulted in a median duration of neutropenia and thrombocytopenia of 3 weeks. Four patients (5%) died during consolidation due to infection and/or hemorrhage; 59% of patients experienced severe but nonfatal infectious or extramedullary organ toxicity. With a median follow-up of more than 3.5 years from diagnosis, the proportion of patients, by Kaplan-Meier product-limit estimate, remaining in CCR is 49% (95% confidence limits, 37% to 61%). In a Cox multivariate analysis, only age significantly (P less than .001) influenced the probability of remaining in CCR. The probability of remaining in CCR was 83%, 50%, and 23% for age groups of 25 or less, 26 to 45, and more than 45 years, respectively. These survival curves all have stable long-term plateaus, suggesting cure. In this study, the administration of brief, intensive nonmarrow ablative chemotherapy resulted in a large proportion of patients with AML remaining in CCR, results similar to those reported with allogeneic bone marrow transplantation. Relapse of acute leukemia was still the major reason for therapy failure, suggesting that more effective or additional postremission therapy will be required to further improve the likelihood of cure especially for older patients.
Regimen-related toxicity and early posttransplant survival in patients undergoing marrow transplantation for lymphoma.
Authors: Bearman S I , Appelbaum F R , Back A , Petersen F B , Buckner C D , Sullivan K M , Schoch H G , Fisher L D , Thomas E D
Published: February 2017

Ninety-five patients transplanted for malignant lymphoma were retrospectively evaluated for regimen-related toxicity (RRT) and early posttransplant survival. Nineteen patients developed life-threatening (grade 3) or fatal (grade 4) RRT in one or more organs. Grade 3 or 4 RRT was more common in patients with advanced disease versus those transplanted earlier in their course (P = .008), and was more common in patients with advanced disease conditioned with cytarabine (Ara-C)/total body irradiation (TBI) versus those prepared with cyclophosphamide (CY)/TBI (P = .033). There was no significant difference in the incidence of grade 3 or 4 toxicity in autologous, histocompatibility locus antigen (HLA)-identical, or HLA-mismatched marrow recipients. Grade 3 or 4 RRT tended to be more common and 100-day survival worse in patients with a Karnofsky performance status of less than 90 (P = .063 and .0002, respectively). Patients receiving 20 Gy or more of mediastinal irradiation before coming to transplant had more idiopathic or cytomegalovirus (CMV) interstitial pneumonitis than those who received less than 20 Gy (30% v 9%, P = .027). The probability of survival decreased with the number of organs in which toxicity was observed (P = .0001). Severe or fatal toxicities directly related to the preparative regimen are a significant problem in the treatment of patients with advanced malignant lymphoma and can be reduced by carrying out transplantation earlier in the course of the disease.
Phase II trial of intraperitoneal mitoxantrone in the management of refractory ovarian cancer.
Authors: Markman M , George M , Hakes T , Reichman B , Hoskins W , Rubin S , Jones W , Almadrones L , Lewis J L
Published: February 2017

To define both the toxicity and efficacy of intraperitoneal mitoxantrone in the treatment of refractory ovarian carcinoma, 31 patients were entered onto a phase II trial of this agent delivered in a 2 L treatment volume on a monthly basis. Due to excessive local pain at the initial dose level (30 mg/m2), the amount of drug delivered with each treatment course was reduced to 20 mg/m2. Despite this reduction, 74% of patients required narcotic analgesia during treatment. In addition, there were four episodes of bowel obstruction (one requiring surgical intervention) during therapy, and two patients developed bowel obstruction and intraabdominal abscesses following the completion of treatment. Six of 18 evaluable patients (33%) whose largest tumor diameter was less than or equal to 1 cm at protocol initiation experienced surgically documented responses, compared with one of 11 patients (9%) whose largest tumor was greater than 1 cm in diameter. If the two patients exhibiting what we called a mixed response to treatment are included, seven of 21 patients previously treated with intraperitoneal cisplatin responded to this treatment program, including four patients who had failed to respond to intraperitoneal cisplatin. No responding patient has demonstrated clinical evidence of relapse with a median follow-up of 7 months (range, 3+ to 13+ months) from response laparotomy. Intraperitoneal mitoxantrone is an active treatment program in patients with small-volume refractory ovarian carcinoma, but local toxicity can be severe. Due to the toxicity encountered with this specific program, its use cannot be recommended for standard clinical practice. However, in view of the activity observed in refractory ovarian carcinoma, including responses in patients who had previously failed intraperitoneal cisplatin, it is important to continue to explore alternative therapeutic regimens using intraperitoneal mitoxantrone to reduce local toxicity while maintaining or improving efficacy.
Risk-adapted treatment choice in stage I nonseminomatous testicular germ cell cancer by regarding vascular invasion in the primary tumor: a prospective trial.
Authors: Pont J , Höltl W , Kosak D , Machacek E , Kienzer H , Julcher H , Honetz N
Published: February 2017

Based on the results of a retrospective study, which found blood vessel invasion to be the most important prognostic factor in clinical stage I nonseminomatous testicular germ cell cancer (NSTGCC I), a prospective study was started in 1985 which assigned NSTGCC I patients without evidence of vascular invasion to surveillance and patients with vascular invasion to two cycles of adjuvant chemotherapy with cisplatin, etoposide, and bleomycin. Twenty-two patients entered the surveillance group and 18 patients received adjuvant chemotherapy. Median follow-up is 30 months (3 to 50 months). Relapses occurred in three patients (7.5%), one in the surveillance group (4.5%), two in the chemotherapy group (11%). Thirty-eight patients (95%) are alive and without evidence of disease. Two patients of the adjuvant-treated group died, one of progressive germ cell cancer and one of lung cancer. We conclude that low- and high-risk NSTGCC I patients can be identified by considering blood vessel invasion. The presence of embryonal carcinoma and vascular invasion seem to be interrelated prognostic factors, because in 94% of vessel invasion the invading element was embryonal carcinoma. The exclusion of patients with vascular invasion from surveillance decreases relapse rates remarkably. Adjuvant chemotherapy diminishes relapse rates in high-risk patients but does not entirely prevent relapse.
Therapy of renal cell carcinoma with interleukin-2 and lymphokine-activated killer cells: phase II experience with a hybrid bolus and continuous infusion interleukin-2 regimen.
Authors: Parkinson D R , Fisher R I , Rayner A A , Paietta E , Margolin K A , Weiss G R , Mier J W , Sznol M , Gaynor E R , Bar M H
Published: February 2017

Forty-seven patients with metastatic or unresectable renal cell carcinoma were treated with interleukin-2 (IL-2) and lymphokine-activated killer (LAK)-cell therapy, using a hybrid IL-2 regimen. IL-2 was administered initially by intravenous bolus (10(5) U/kg [Cetus Corp, Emeryville, CA] every 8 hours for 3 days) during the priming phase, and subsequently by continuous infusion (3 x 10(6) U/m2 for 6 days); during this second treatment period, in vitro-generated LAK cells were administered. Despite selection of patients for good performance status (PS) (29, PS 0; 18, PS 1) prior nephrectomy (43 of the 47 patients), and low tumor burden, the response rate was low (two complete [CRs] and two partial responses [PRs], for an overall objective response rate of 9%). Toxicity was comparable to that experienced with the high-dose bolus regimen. These results suggest that the dose and schedule of IL-2 administration may influence the likelihood of response to IL-2 in renal cell carcinoma.
Multimodal therapy for the management of primary, nonmetastatic Ewing's sarcoma of bone: a long-term follow-up of the First Intergroup study.
Authors: Nesbit M E , Gehan E A , Burgert E O , Vietti T J , Cangir A , Tefft M , Evans R , Thomas P , Askin F B , Kissane J M
Published: February 2017

A total of 342 previously untreated eligible children were entered into the first Intergroup Ewing's Sarcoma Study (IESS) between May 1973 and November 1978. In group I institutions, patients were randomized between treatment 1 (radiotherapy to primary lesion plus cyclophosphamide, vincristine, dactinomycin, and Adriamycin [doxorubicin; Adria Laboratories, Columbus, OH] [VAC plus ADR]) or treatment 2 (same as treatment 1 without ADR), and group II institutions randomized patients between treatment 2 or treatment 3 (same as treatment 2 plus bilateral pulmonary radiotherapy [VAC plus BPR]). The percentages of patients relapse-free and surviving (RFS) at 5 years for treatments 1, 2, and 3 were 60%, 24%, and 44%, respectively. There was strong statistical evidence of a significant advantage in RFS for treatment 1 (VAC plus ADR) versus 2 (VAC alone) (P less than .001) and 3 (P less than .05) and also of treatment 3 versus 2 (P less than .001). Similar significant results were observed with respect to overall survival. Patients with disease at pelvic sites have significantly poorer survival at 5 years than those with disease at nonpelvic sites (34% v 57%; P less than .001). Among pelvic cases, there was no evidence of differing survival by treatment (P = .81), but among nonpelvic cases, there was strong evidence of differing survival by treatment (P less than .001). The overall percentage of patients developing metastatic disease was 44%; the percentages by treatments 1, 2, and 3 were 30%, 72%, and 42%, respectively. The overall incidence of local recurrence was 15%, and there was no evidence that local recurrence rate differed by treatment. Patient characteristics related to prognosis, both with respect to RFS and overall survival experience, were primary site (nonpelvic patients were most favorable) and patient age (younger patients were more favorable).
Prognostic value of c-myc proto-oncogene overexpression in early invasive carcinoma of the cervix.
Authors: Bourhis J , Le M G , Barrois M , Gerbaulet A , Jeannel D , Duvillard P , Le Doussal V , Chassagne D , Riou G
Published: February 2017

The prognostic effect of c-myc oncogene overexpression was assessed in a multivariate analysis of 93 patients with invasive carcinoma of the cervix, stage Ib, IIa, and IIb proximal. The treatment was based on the association of brachytherapy-colpohysterectomy and lymphadenectomy. Analysis of c-myc gene expression was done using Northern and slot blot hybridization techniques. Overexpression of c-myc (ie, levels at least three times the mean observed in normal tissues) was present in 33% of the tumors. The proportion of carcinomas with c-myc overexpression significantly increased with the size of the primary tumor (P = .04). No relationship was found between c-myc overexpression and the other clinical and histologic parameters, including the nodal status. The relative risk of relapse (overall, pelvic failure, distant metastases) was analyzed in a Cox's proportional hazards model. Three factors were significantly related to the risk of overall relapse when the multivariate analysis was performed, namely, the tumor size, the nodal status, and c-myc expression. A combination of c-myc expression and the nodal status provided a very accurate indication of the risk of relapse. Indeed, patients with negative nodes had a 3-year disease-free survival rate of 93% (95% confidence interval [Cl], 79% to 98%) when c-myc was expressed at a normal level, whereas this rate was only 51% (95% Cl, 26% to 63%) when c-myc was overexpressed (log-rank test, P = .02). In addition, in the subgroup of patients with positive nodes, this rate was 44% (95% Cl, 25% to 77%) and 15% (95% Cl, 4% to 49%) when c-myc gene was expressed at normal level, or overexpressed, respectively. Finally, c-myc gene overexpression was, in the multivariate analysis, the first factor selected by the model regarding the risk of distant metastases.
Changes in the clearance of total and unbound etoposide in patients with liver dysfunction.
Authors: Stewart C F , Arbuck S G , Fleming R A , Evans W E
Published: February 2017

The disposition of total and non-protein-bound etoposide was investigated in 21 cancer patients receiving etoposide and cisplatin combination chemotherapy. Etoposide plasma concentrations were determined using a specific high-performance liquid chromatography (HPLC) method, and etoposide plasma protein binding was determined by equilibrium dialysis. The patients had a wide range of renal function (creatinine clearance, 32 to 159 mL/min/m2) and hepatic function (total bilirubin range, 0.3 to 21.5 mg/dL; aspartate aminotransferase [AST] range, 14 to 415 IU/L; serum albumin range, 2.7 to 4.1 g/dL). The mean etoposide total systemic clearance was not different in 15 patients with total bilirubin less than 1.0 mg/dL versus six patients with total bilirubin 1.1 to 21.5 mg/dL (18.7 +/- 5.9 mL/min/m2 v 26.4 +/- 10.7 mL/min/m2; t-test P = .06), with a trend toward higher total clearance in the patients with abnormal bilirubin values. However, the mean clearance of unbound etoposide was significantly lower in patients with increased total bilirubin (220 +/- 90 mL/min/m2 v 135 +/- 61 mL/min/m2; t-test P = .027). The fraction of etoposide unbound (fu) in plasma was significantly higher in patients with increased bilirubin (9% +/- 3% v 27% +/- 15%; t-test P = .002), explaining the trend toward higher total clearance in these patients. Etoposide clearance (total or unbound) in the 14 patients with measurable hepatic metastases was not different from the clearance in the seven patients without hepatic metastases. This study provides an explanation for why patients with increased bilirubin do not have lower total systemic clearance of etoposide, and indicates that such patients have a higher exposure to unbound etoposide. The results of ongoing pharmacodynamic studies of total and unbound etoposide in patients with increased bilirubin will determine the clinical relevance of altered etoposide protein binding.
Clinical evaluation of a side entry access port: a novel dual-lumen venous access device.
Authors: Ravikumar T S , Hollingshead J
Published: February 2017

The initial clinical experience with a low-profile side entry access (SEA) dual-lumen implantable venous access port for cancer chemotherapy administration is summarized in this report. The catheter material is polyurethane. The overall experience in 35 patients in this study was a total of 6,224 patient days, with a mean of 178 days per patient. A variety of chemotherapeutic agents, biologic response modifiers, and antibiotics were administered. In 26% of the patients, the device chambers were in simultaneous use during the treatment period. A 6% incidence of clinical subclavian vein thrombosis was noted. There was no infectious complications. Inconsistencies in blood withdrawal and temporary catheter dysfunction were comparable to other access ports in clinical use. The novel design of this side entry port and the catheter material of low thrombogenicity make this device a good option in patients requiring a low-profile system and dual access. Nursing staff should be made aware of the side entry design and that in-service training for accessing the septum is required in centers where such devices are not routinely used.
Gallium-67 imaging: a predictor of residual tumor viability and clinical outcome in patients with diffuse large-cell lymphoma.
Authors: Kaplan W D , Jochelson M S , Herman T S , Nadler L M , Stomper P C , Takvorian T , Andersen J W , Canellos G P
Published: February 2017

Durable complete remissions (CRs) can be achieved in patients with diffuse large-cell lymphoma (DLCL) with multidrug chemotherapy. The length of time to reach CR may be predictive of treatment outcome. However, defining CR by chest radiograph or computed tomography (CT) is often difficult since residual abnormalities do not always indicate residual disease. We have prospectively evaluated the ability of gallium-67 citrate (Ga-67) imaging to define residual disease and predict outcome in 37 consecutive patients with DLCL. Patients received 296 to 370 megabecquerels (MBq) Ga-67 and were imaged prior to, following cycles 4 to 6, and at completion of intensive chemotherapy. Ga-67 scan results were correlated with radiographic studies. Seventeen of 37 patients (46%) showed persistent, abnormal Ga-67 uptake halfway through chemotherapy. Of these, four were in CR, 11 were in partial remission (PR), and two showed no change in tumor size. At follow-up, 10 (59%) have died (three who were scored as CR and seven who were in PR halfway through therapy), two are alive with active tumor, one relapsed and survives following bone marrow transplant, and four (three in PR and one in CR at the therapeutic halfway point) are without disease at a median of 28 months from presentation. Of the 20 patients who were Ga-67-negative halfway through therapy, 11 were in CR and nine were in PR. Five of 20 patients (25%) have died. Three, in radiographic CR died at 11, 26, and 28 months, and two in radiographic PR died at 15 and 17 months. One patient is alive with active tumor, and 14 patients (70%) are alive without disease at a median of 34 months from presentation. Ga-67 imaging proved to be an excellent indicator of residual viable tumor; a positive scan halfway through therapy predicted for a poor outcome and may well justify a change in treatment.
Adjuvant cyclophosphamide, methotrexate, and fluorouracil in patients with axillary node-positive breast cancer: an update of the Guy's/Manchester trial.
Authors: Richards M A , O'Reilly S M , Howell A , George W D , Fentiman I S , Chaudary M A , Crowther D , Rubens R D
Published: February 2017

Between 1976 and 1985, 391 patients (202 premenopausal, 189 postmenopausal) with operable breast cancer and positive axillary lymph nodes were randomized after total mastectomy and axillary clearance to receive cyclophosphamide, methotrexate, and fluorouracil (CMF) (n = 193) or no adjuvant therapy (n = 198). After a median follow-up of 8 years, both relapse-free survival (RFS) and survival (S) were significantly prolonged in premenopausal patients receiving CMF (RFS, P less than .001; S, P = .003). Treatment with CMF resulted in a significant improvement in RFS in premenopausal patients both with steroid receptor-positive and steroid receptor-negative tumors and also in subgroups of premenopausal patients defined by the number of axillary nodes involved. Premenopausal patients who developed permanent amenorrhea following CMF had a significantly better RFS than those who continued to menstruate. Induction of amenorrhea following CMF was related to age, with almost all patients over 40 years becoming amenorrheic. For patients less than or equal to 40 years, development of amenorrhea following CMF did not influence outcome. No difference was detected between control and CMF groups (RFS, P = .9; S, P = .9) in postmenopausal patients nor in any subgroup of these patients. The results of this trial of the efficacy of CMF for improving RFS and S have strengthened with longer follow-up.
Phase I clinical and pharmacologic study of intraperitoneal cisplatin and fluorouracil in patients with advanced intraabdominal cancer.
Authors: Schilsky R L , Choi K E , Grayhack J , Grimmer D , Guarnieri C , Fullem L
Published: February 2017

Fluorouracil (5-FU) and cisplatin display marked therapeutic synergy in preclinical models and are effective in the treatment of a number of solid tumors when combined and administered intravenously (IV). Each drug has also been administered intraperitoneally (IP) and displays a favorable pharmacologic profile and acceptable clinical toxicity. We therefore undertook a phase I study to determine the feasibility and toxicity of combination IP chemotherapy with these agents. Thirty-one patients with histologically documented malignancy confined to the peritoneal space were treated with cisplatin 90 mg/m2 mixed with 5-FU in 2 L of lactated Ringer's solution and given IP for 4 hours every 28 days. Cohorts of at least three patients received starting 5-FU concentrations ranging from 5 mmol/L (1,300 mg in 2 L) to 20 mmol/L. The dose-limiting toxicity was neutropenia with a median granulocyte nadir of 156 cells per microliter occurring at a 5-FU dose of 20 mmol/L. Intrapatient escalation of the 5-FU dose was permitted and 15 cycles of chemotherapy were delivered at 5-FU concentrations greater than 20 mmol/L, the highest concentration being 30.7 mmol/L (8 g of 5-FU in 2L). Other toxicities included mild to moderate nausea during all cycles of therapy, vomiting in 54% of cycles, and diarrhea in 15% of cycles. Abdominal pain, renal dysfunction, peripheral neuropathy, and oral mucositis occurred infrequently and were not related to the 5-FU dose. Peritoneal fluid and plasma 5-FU concentrations were measured by high-performance liquid chromatography (HPLC) in selected patients. Mean peak plasma 5-FU concentrations ranged from 6.19 mumol/L to greater than 60 mumol/L, and peritoneal fluid to plasma 5-FU area under the curve (AUC) ratios ranged from 85 to 1,150. Nine of 15 patients with nonbulky disease had resolution of malignant ascites or at least a 50% reduction of peritoneal studding by tumor at repeat laparotomy. We conclude that combination IP chemotherapy with cisplatin and 5-FU is technically feasible and has acceptable clinical toxicity and a favorable pharmacologic profile. The recommended starting 5-FU dose for phase II trials is 3,900 mg mixed with 90 mg/m2 of cisplatin in 2 L of isotonic fluid.
Modulation of the antitumor effect of methotrexate by low-dose leucovorin in squamous cell head and neck cancer: a randomized placebo-controlled clinical trial.
Authors: Browman G P , Goodyear M D , Levine M N , Russell R , Archibald S D , Young J E
Published: February 2017

Randomized trials comparing high-dose methotrexate (HDMTX) plus leucovorin (LV) with standard-dose methotrexate (SDMTX) have not detected a therapeutic advantage for the HDMTX arm despite compelling evidence from experimental systems. We hypothesized that these negative trials might reflect modulation of the antitumor effect of methotrexate (MTX) by LV. To test this we randomized 61 patients with locally advanced and recurrent squamous cell head and neck cancer to receive SDMTX (40 mg/m2 weekly for 8 weeks) and either LV or placebo "rescue" starting 24 hours later. Of the 61 randomized patients, there were protocol violations in two cases, leaving 59 patients evaluable for response using standard criteria, and for toxicity using the Eastern Cooperative Oncology Group (ECOG) scale. Of the 29 patients randomized to MTX plus LV, there were five responders (17.2%) compared with 11 of 30 (36.7%) patients randomized to MTX plus placebo (P = .047). Response was influenced independently by age, gender, and by previous treatment. Toxicity overall was more severe in patients randomized to MTX plus placebo (P = .016). This was accounted for primarily by differences in toxicities related to bone marrow function (neutrophil and platelet counts), stomatitis, and elevations of liver function tests. MTX therapy was more often interrupted for toxicity in the placebo group (P = .007) and discontinued for progressive disease in the LV group (P = .07). These results indicate that at the doses of MTX and LV used, LV modulates the antitumor effect as well as the toxicity of MTX in patients with head and neck cancer.
Induction chemotherapy with cisplatin, fluorouracil, and high-dose leucovorin for locally advanced head and neck cancer: a clinical and pharmacologic analysis.
Authors: Vokes E E , Schilsky R L , Weichselbaum R R , Kozloff M F , Panje W R
Published: February 2017

Both cisplatin and leucovorin (LV) interact with fluorouracil (5-FU) by increasing intracellular reduced folate levels and thereby the inhibition of thymidylate synthase. Therefore, the addition of LV to cisplatin and 5-FU (PFL) may increase the activity of that combination in head and neck cancer. We treated 31 patients with locally advanced head and neck cancer with two cycles of neoadjuvant PFL consisting of 100 mg/m2 of cisplatin on day 1 followed by a 5-day continuous infusion of 5-FU at 1,000 mg/m2/day and oral LV at 100 mg administered every 4 hours during the entire duration of chemotherapy infusion. Two patients died during neoadjuvant chemotherapy of sudden death and sepsis, respectively, and were not evaluated for response. Of 29 evaluable patients, nine had a complete response (CR), 17 had a partial response (PR), and three had stable disease. Toxicities consisted of mild to moderate myelosuppression and moderate to severe mucositis, necessitating reduction of 5-FU on cycle 2 to less than or equal to 80% of the intended dose in 22 of 29 patients. Administration of LV by repeated oral dosing resulted in total reduced folate plasma concentrations of 5.3 (+/- 2.9) and 6.7 (+/- 3.4) mumol on days 2 and 4 of the 5-FU infusion. The sum of 1-LV and its metabolite 5-CH3-tetrahydrofolate exceeded the concentration of d-LV, consistent with selective absorption of the biologically active 1-stereoisomer from the gastrointestinal tract.
Allogeneic bone marrow transplantation in a program of intensive sequential chemotherapy for children and young adults with acute nonlymphocytic leukemia in first remission.
Authors: Dahl G V , Kalwinsky D K , Mirro J , Look A T , Pui C H , Murphy S B , Mason C , Ruggiero M , Schell M , Johnson F L
Published: February 2017

Eighty-seven consecutive children and young adults with acute nonlymphocytic leukemia (ANLL) were treated uniformly with induction chemotherapy based on daunorubicin and cytarabine (ara-C), with the addition of etoposide (VP-16) and azacytidine (5-Az) for refractory patients. Of the 65 patients who entered complete remission, 42 were eligible for assessment of response to intensive chemotherapy consisting of four pairs of drugs administered in sequential fashion. Nineteen others with available histocompatibility locus antigen (HLA)-compatible donors were assigned to receive allogeneic bone marrow transplants within 16 weeks from their dates of complete remission. Durations of continuous complete remission (CCR) in the two groups were not significantly different at a median follow-up time of 6 years (P = .30 by log-rank analysis). Kaplan-Meier estimates of CCR probabilities (+/- SE) at 6 years were 43% +/- 13% (transplantation) and 31% +/- 7% (sequential chemotherapy). Postremission failures in the sequential chemotherapy group resulted from bone marrow relapse in 23 of 29 patients (79%), whereas in the transplantation group, failures were equally divided between marrow relapse and transplantation-related complications of graft-versus-host disease (GVHD) or infection due to the immunosuppressive effects of ablative chemotherapy. Comparison of hematologic remission curves indicated a significant advantage for marrow transplantation in terms of systemic leukemia control (P = .06). Thus, in programs of intensive chemotherapy of the type described here, allogeneic marrow transplantation should be seriously considered as alternative therapy for patients in first remission who have an HLA-matched sibling donor, provided that effective methods for control of transplant-related complications are available.
Stature loss following skeletal irradiation for childhood cancer.
Authors: Silber J H , Littman P S , Meadows A T
Published: February 2017

A model is presented to predict adult stature in children treated successfully for cancer outside the CNS. The model is based on radiation dose in Gray adjusted for location of therapy and attained stature (GALA); ideal adult stature (IAS), assuming the patient had not developed cancer, calculated by the Roche-Wainer-Thissen (RWT) method (which uses patient stature and weight before developing cancer, and parent stature data); a femur correction if both the acetabula or heads of both femurs were irradiated (FEMUR); and sex. The model was constructed using data from 49 patients with a mean time from completion of therapy to follow-up of 8.9 years (range, 3.3 to 15.4 years). Thirteen patients received no radiotherapy. All model coefficients were highly significant (P less than .001), and the model appears to be an excellent predictor of adult stature, with a multiple correlation coefficient of 0.84 (R2 = .74) between corrected adult stature (CAS) based on the most recent follow-up stature available for the patient projected to final adult stature, compared with the model's predicted adult stature (MPAS), based only on initial data at presentation and subsequent radiation treatment. Patients who did not receive radiotherapy did not have loss of stature, ie, there was no significant difference between IAS and CAS, (P less than .71; n = 13), but patients who received radiotherapy had shorter statures than would be expected from the healthy population model (P less than .0004; n = 36). The magnitude of the loss in stature appears to be well explained by the dose and location of radiation, the stature already achieved at the time of radiotherapy, along with IAS, FEMUR, and sex. We believe this model will help clinicians to predict the growth effects of radiotherapy in children with cancer not involving the CNS.
Ten-year survival of patients with small-cell lung cancer treated with combination chemotherapy with or without irradiation.
Authors: Johnson B E , Grayson J , Makuch R W , Linnoila R I , Anderson M J , Cohen M H , Glatstein E , Minna J D , Ihde D C
Published: February 2017

We evaluated the 10- to 15-year outcome of 252 patients with small-cell lung cancer entered into therapeutic clinical trials with or without chest and cranial irradiation. Thirty-two patients (13%) survived free of cancer for 2 or more years. Twelve patients (5%) survived at least 10 years free of cancer, and 10 patients are currently alive and free of cancer beyond 10 years. Six of these 10 patients currently function at a level comparable with that before diagnosis. The other 22 patients who were cancer-free at 2 years have died. Nine patients died from recurrent small-cell lung cancer 2 to 6.2 years after initiation of chemotherapy. Five died from non-small-cell lung cancer, three died of other malignancies, and five died of causes other than cancer. A small fraction of patients with small-cell lung cancer are cured of their original malignancy, but these patients remain at high risk for second cancers and death from other causes.
The clinical significance of variant-morphology small-cell carcinoma of the lung.
Authors: Aisner S C , Finkelstein D M , Ettinger D S , Abeloff M D , Ruckdeschel J C , Eggleston J C
Published: February 2017

Past attempts to subclassify small-cell lung cancer (SCCL) histology (oat cell, fusiform, polygonal, intermediate, etc) have not been useful because of interrater variability and a lack of clinical significance. A review of outcome in a previous series suggested that a different histologic subtype, small-cell/large-cell (SC/LC) conferred an inferior response and survival analogous to the relative chemotherapy and radiation resistance seen in the variant-morphology (SC/LC) cultured cell lines. To evaluate the clinical impact of SC/LC we applied the proposed International Association for the study of Lung Cancer (IASLC) histology subclassification that incorporates the SC/LC category for patients with extensive-disease SCCL entering Eastern Cooperative Oncology Group (ECOG) protocol 1582. All cases were reviewed for eligibility by one pathologist, and all possible SC/LC (variant) plus 10% of all cases were reviewed together with a second pathologist; 577 of the 628 patients who entered were eligible, of whom 550 had histologic material submitted for review and are considered for this analysis. Initial review disclosed 24 cases with SC/LC (4.4%) and 526 with "classic" histology. The second review showed 100% agreement for classic form, but only 11 SC/LC cases with concordance between the reviewing pathologists. Eight of 24 (33%) cases from first review and three of 11 (27%) with concordance on second review achieved complete response (CR) compared with 101 of 526 (19%) for "classic" SCCL (P = .11 and .45, respectively, for the first and second review groups).(ABSTRACT TRUNCATED AT 250 WORDS)
Adjuvant trial of 12 cycles of CMFPT followed by observation or continuous tamoxifen versus four cycles of CMFPT in postmenopausal women with breast cancer: an Eastern Cooperative Oncology Group phase III study.
Authors: Falkson H C , Gray R , Wolberg W H , Gillchrist K W , Harris J E , Tormey D C , Falkson G
Published: February 2017

A prospectively controlled randomized trial to compare the adjuvant efficacy of 12 cycles of cyclophosphamide, methotrexate, fluorouracil, prednisone, and tamoxifen (CMFPT) followed by observation or a total of 5 years of continuous tamoxifen versus four cycles of CMFPT followed by observation in postmenopausal women with operable node-positive breast cancer was started by the Eastern Cooperative Oncology Group (ECOG) in 1982. In 1986 the study was modified to allow patients on CMFPT X 12 plus continuous tamoxifen to be rerandomized after completing 5 years of tamoxifen to either continue for life or to stop therapy. Patients were stratified for number of involved nodes and estrogen-receptor (ER) status and randomized to receive one of three treatments: CMFPT X 4, CMFPT X 12, or CMFPT X 12 plus continuous tamoxifen. Of 962 patients entered on the study, 803 were eligible. Life-threatening toxicity occurred in 75 and lethal toxicity in seven patients. Median follow-up is 4.1 years; 279 patients had recurrent disease. Time to relapse (TTR) is significantly longer for patients on CMFPT X 12 plus continuous tamoxifen than for CMFPT X 4 (P = .002), or CMFPT X 12 (P = 0.05). Differences between four or 12 cycles of CMFPT are not significant; relapse-free rates at 5 years are 61% for CMFPT X 12 plus continuous tamoxifen, 51% on CMFPT X 12, and 52% on CMFPT X 4. Treatment differences in overall survival are not significant. Hormone receptor status and number of involved nodes were found to be significant prognostic parameters.
Adjuvant bacillus Calmette-Guérin therapy in non-Hodgkin's malignant lymphomas: long-term results of a randomized trial in a single institution.
Authors: Ravaud A , Eghbali H , Trojani M , Hoerni-Simon G , Soubeyran P , Hoerni B
Published: February 2017

Between 1973 and 1977, 48 patients less than 65 years old with non-Hodgkin's malignant lymphoma (NHML) of poor prognosis (+/- high grade malignancy, +/- clinical stages III or IV, +/- first or repeated relapse) were included in a prospective clinical trial. After complete remission (CR), obtained with chemotherapy and radiotherapy, patients were randomized to receive bacillus Calmette-Guérin (BCG) or no further therapy. BCG was administered in weekly scarifications up to 3 years. Forty-three patients are assessable. Twenty-four patients have relapsed: nine out of 21 in the BCG group, and 15 out of 22 in the control group. There is a significant difference in favor of the BCG group in disease-free survival (P = .03). Twenty-one patients have died, 18 from NHML: seven in the BCG group, and 11 in the control group. There is a significant difference in favor of the BCG group for overall survival at 10 years (P = .05). A multivariate analysis points out BCG as a significant prognostic factor. Adjuvant BCG may improve particularly disease-free survival and overall survival for patients with clinical stages I and II or intermediate- and high-grade malignancy. These results suggest that in patients less than 65 years old with NHML of poor prognosis, BCG may significantly increase disease-free survival and overall survival.
Cyclophosphamide, carmustine, and etoposide with autologous bone marrow transplantation in refractory Hodgkin's disease and non-Hodgkin's lymphoma: a dose-finding study.
Authors: Wheeler C , Antin J H , Churchill W H , Come S E , Smith B R , Bubley G J , Rosenthal D S , Rappaport J M , Ault K A , Schnipper L E
Published: February 2017

Cyclophosphamide, carmustine (BCNU), and etoposide (VP-16) (CBV) is a widely used conditioning regimen in autologous bone marrow transplantation (ABMT) of patients with refractory and relapsed lymphoma. However, the maximum-tolerated dose (MTD) of these agents when used in combination has not been systematically explored. We treated 58 patients (28 with non-Hodgkin's lymphoma [NHL], 30 with Hodgkin's disease [HD]) at seven dose levels of CBV. Doses were cyclophosphamide 4,500 to 7,200 mg/m2, BCNU 450 to 600 g/m2, and VP-16 1,200 to 2,000 mg/m2. The MTD was cyclophosphamide 7,200 mg/m2, BCNU 450 mg/m2, and VP-16 2,000 mg/m2. Six hundred milligrams per square meter of BCNU was associated with five of 18 cases of interstitial pneumonitis versus two of 40 at 450 mg/m2 (P = .02). Treatment-related mortality was 5% at dose levels less than or equal to the MTD and 22% at the highest dose. In this heavily pretreated patient population, most of whom had high volume residual disease, complete responses (CRs) to CBV and ABMT occurred in 25% of assessable patients with NHL and 43% of patients with HD. Thirteen of 28 patients with NHL and 14 of 30 with HD remain free from disease progression with median follow-up of 212 and 215 days, respectively. CBV can be administered with acceptable toxicity over a wide range of doses to patients with refractory and relapsed lymphoma.
A new treatment protocol for childhood non-Hodgkin's lymphoma: preliminary evaluation.
Authors: de Andrea M L , de Camargo B , Melaragno R
Published: February 2017

Between November 1986 and July 1988, 21 consecutively diagnosed children with nonlocalized abdominal lymphoma (Murphy's stage III and IV without CNS disease) were eligible for treatment with a multidrug chemotherapy schedule. The induction phase was the same for all (fractionated cyclophosphamide, intermedian-dose methotrexate [Mtx], vincristine [Vcr], and prednisone). After that the children were randomized to repeat the same scheme or intercalate teniposide (VM26) plus cytarabine (AraC) with the induction-phase scheme. All of them were treated for only 6 months. The protocol approved to be very effective with 85% remission in all the children and 94% survival in patients surviving the induction phase. The toxicity was acceptable, also considering the characteristics of our population (malnourished children). The group VM26 and AraC had few hospital admissions in spite of the small number of children because they received VM26 and AraC as outpatients. The sale purpose of the present study is to report that with a few simple procedures such as hydration, alkalinization, and drug fractionation, the chemotherapy schemes used can bring about a dramatic improvement in short-term survival.
Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood.
Authors: Chan H S , Thorner P S , Haddad G , Ling V
Published: February 2017

Increased expression of P-glycoprotein is associated with multidrug resistance (MDR) in many cell lines. Significant levels of P-glycoprotein have been detected in a number of human tumors. The purpose of this study was to determine whether P-glycoprotein expression correlates with both response to chemotherapy and prognosis in soft tissue sarcoma of childhood. In a retrospective study, biopsy samples from 30 cases of rhabdomyosarcoma (RMS) and undifferentiated sarcoma (US) treated at The Hospital for Sick Children in Toronto were analyzed using a semiquantitative immunohistochemical procedure. P-glycoprotein was detected in nine patients, four at diagnosis, and five at subsequent biopsy. All nine patients relapsed after a clinical response (complete [CR] 55%, partial [PR] 45%) to chemotherapy. Twenty of 21 patients with consistently P-glycoprotein-negative tumors received chemotherapy and they all responded clinically (CR 80%, PR 20%). Only one of these 20 patients has relapsed. The probability of relapse-free survival was significantly different (P less than .000000012) in chemotherapy-treated patients whose tumors contained detectable levels of P-glycoprotein (n = 9), compared with those whose tumors contained no detectable P-glycoprotein (n = 20). The overall probability of survival was also significantly different in these two groups (P less than .0000267). Both relapse-free and overall survivals remained statistically different in the two groups of patients when analyzed by the log-rank method, after adjustment for differences in stages and sites. The incidence of other adverse prognostic factors in the two groups, for example, younger and older ages, low pretreatment lymphocyte counts, large tumors, and unfavorable histology were not significantly different. Thus, detectable P-glycoprotein appears to be an important adverse prognostic factor in children with soft tissue sarcoma, and consistent absence of the protein is associated with a favorable prognosis.