bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of cyclophosphamide on relationships between carboplatin exposure and response or toxicity when used in the treatment of advanced ovarian cancer.
Authors: Reyno L M , Egorin M J , Canetta R M , Jodrell D I , Swenerton K D , Pater J L , Burroughs J N , Novak M J , Sridhara R
Published: February 2017

PURPOSE

To determine (1) the impact of cyclophosphamide 600 mg/m2 on previously defined relationships between carboplatin area under the plasma concentration versus time curve (AUC) and indices of toxicity and response in women with advanced ovarian cancer; and (2) the relationships between indices of cumulative drug exposure and clinical outcomes.

METHODS

Carboplatin AUC = dose/(creatinine clearance [CCr] + 25) and was calculated in 224 women who received carboplatin 300 mg/m2 and cyclophosphamide 600 mg/m2. The likelihood of grade 3 or greater myelotoxicity at any carboplatin AUC was compared with the likelihood of myelotoxicity at the same single-agent carboplatin AUC. The nadir count predicted using the University of Maryland single-agent carboplatin dosing formula was compared with the nadir count observed. Received and relative-received dose-intensity were calculated. Carboplatin exposure-intensity was defined by substituting cumulative carboplatin exposure for total dose. Relationships were sought between these indices and therapeutic outcomes.

RESULTS

The incidence of leukopenia and thrombocytopenia at any carboplatin AUC was greater for the two-drug combination than for single-agent carboplatin. The platelet nadir in 83% of patients was less than or equal to the nadir predicted for the same single-agent carboplatin AUC. Despite a narrow range of received dose-intensities, carboplatin exposure-intensity was distributed over a twofold range. There were no relationships between received and relative-received dose-intensity or carboplatin exposure-intensity and time to progression or survival.

CONCLUSION

Any carboplatin AUC when administered with cyclophosphamide 600 mg/m2 produces greater myelotoxicity than the same AUC of single-agent carboplatin. Received carboplatin dose-intensity underestimates the range of plasma drug exposure resulting from a fixed carboplatin dosing regimen. Whether higher carboplatin exposures can improve outcome requires prospective validation.
Pharmacodynamics of prolonged oral etoposide in patients with advanced non-small-cell lung cancer.
Authors: Miller A A , Tolley E A , Niell H B , Griffin J P , Mauer A M
Published: February 2017

PURPOSE

This study was undertaken to investigate the pharmacodynamic relationship between etoposide drug levels on 21-day oral treatment courses and hematologic toxicities in patients with advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Thirty-two patients with stage IIIB or IV NSCLC were treated with oral etoposide 50 mg/m2/d for 21 consecutive days in combination with cisplatin 100 mg/m2 on day 1. Treatment was repeated every 28 days for up to six courses. Patients had not received previous chemotherapy and had a performance status of 0 to 2. Patients were monitored weekly while on treatment for compliance with oral etoposide and toxicity, including complete blood cell counts, and a blood sample before the daily etoposide dose (drug trough levels). Etoposide concentrations were measured in the plasma by high-performance liquid chromatography (HPLC).

RESULTS

Three patients achieved a complete response (CR) and 10 patients a partial response for an objective response rate of 41% (95% confidence interval, 24% to 58%). The median survival was 4 months (range, 1 to 23). Neutropenia was dose-limiting, and two patients died of neutropenic sepsis. Pharmacodynamic correlations for drug concentrations and hematologic toxicities were available for 27 patients and a total of 76 treatment courses, and correlations were significant for graded hematologic toxicity and nadir counts of leukocytes, neutrophils, hemoglobin, and platelets. The grade of infection (77 courses) was also related to drug levels. Using data from 27 initial courses, a pharmacodynamic model was developed to estimate the nadir leukocyte or neutrophil count (WBCn, ANCn) based on the pretreatment count (WBCp, ANCp) and the etoposide concentration (Ec) as follows: WBCn = 0.35 (1 + WBCp x e-1.12 x Ec) and ANCn = 0.32 (1 + ANCp x e-2.47 x Ec).

CONCLUSION

Etoposide concentrations are related to the resulting hematologic toxicities. It is possible to predict nadir counts in the first course by a pharmacodynamic model. The above equations need to be validated prospectively and may be useful in future studies of prolonged oral etoposide.
Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.
Authors: Vandenberg T A , Pritchard K I , Eisenhauer E A , Trudeau M E , Norris B D , Lopez P , Verma S S , Buckman R A , Muldal A
Published: February 2017

PURPOSE

The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer.

PATIENTS AND METHODS

The planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence.

RESULTS

Mucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive.

CONCLUSION

Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.
Treatment of primary hepatobiliary cancers with conformal radiation therapy and regional chemotherapy.
Authors: Robertson J M , Lawrence T S , Dworzanin L M , Andrews J C , Walker S , Kessler M L , DuRoss D J , Ensminger W D
Published: February 2017

PURPOSE

To develop more effective regional therapy for patients with unresectable primary hepatobiliary cancer using concurrent conformal radiation therapy and intraarterial hepatic (IAH) fluorodeoxyuridine (FdUrd).

PATIENTS AND METHODS

Twenty-six patients with unresectable, nonmetastatic primary hepatobiliary cancer were treated with concurrent IAH FdUrd (0.2 mg/kg/d) and conformal hepatic radiation therapy (1.5 to 1.65 Gy per fraction twice per day). The total dose of radiation administered to the tumor depended on the fraction of normal liver excluded from the high-dose volume. All patients were assessed for toxicity, hepatobiliary relapse, and survival; 17 patients were assessable for response (eight had cholangiocarcinoma not assessable by computed tomographic [CT] scan and one progressed distantly during treatment). The median potential follow-up duration was 27 months.

RESULTS

Whole-liver radiation was administered to six patients with diffuse hepatocellular carcinoma (HCC). Eleven patients with localized HCC and nine with cholangiocarcinoma received focal radiation to a dose of 48 to 72.6 Gy. An objective response for assessable patients was observed in 11 of 11 patients treated with focal radiation, but only one of six patients treated with whole-liver radiation. Whole-liver radiation accounted for five of seven patients with > or = grade 3 toxicity and four of six local treatment failures. Two patients had nonfatal radiation hepatitis. The median survival duration for patients with localized hepatobiliary cancer was 19 months, while patients with diffuse HCC had a median survival duration of 4 months. The rate of actuarial freedom from hepatobiliary progression in patients with localized disease was 72% at 24 months.

CONCLUSION

These findings suggest that three-dimensional planned focal liver radiation and IAH FdUrd can produce a high, durable response rate and an encouraging median survival duration in patients with nondiffuse, unresectable primary hepatobiliary cancer.
Circadian cancer therapy.
Authors: Hrushesky W J , Bjarnason G A
Published: February 2017

PURPOSE AND DESIGN: To review briefly the growing body of published data about circadian variation in cytotoxic drug metabolism and tissue sensitivity to chemotherapeutic agents. The suggestion that toxicity may be reduced and anticancer efficacy improved by administering antineoplastic agents at carefully selected times of the day was assessed. RESULTS AND CONCLUSION: The medical literature describing molecular, cellular, and organismic time-keeping mechanisms, as well as circadian rhythms, in cytokinetic, pharmacokinetic, and pharmacodynamic parameters relevant to cancer chemotherapy, which support the predictable rhythmic relationship between dose and effect that occurs during each day, were reviewed. Advantages for optimal circadian scheduling have been demonstrated for diminishing side effects and increasing maximal safe dose-intensity of drugs of diverse class. The use of the predictable circadian relationship of dose and response provides another increment of progress in the treatment of cancer patients.
Phase II study of goserelin for patients with postmenopausal metastatic breast cancer.
Authors: Saphner T , Troxel A B , Tormey D C , Neuberg D , Robert N J , Pandya K J , Edmonson J H , Rosenbluth R J , Abeloff M D
Published: February 2017

PURPOSE

To determine the response rate of postmenopausal breast cancer patients to the gonadotropin-releasing hormone (GN-RH) agonist, Zoladex (goserelin; ICI Pharma, Wilmington, DE).

PATIENTS AND METHODS

A multi-institutional single-agent trial in postmenopausal patients was conducted. Serum levels of follicle-stimulating hormone (FSH), testosterone, and estradiol were requested before and after Zoladex treatment.

RESULTS

For estrogen receptor-positive (ER+) patients, the response rate was 11%, with one complete response (CR) and three partial responses (PRs) among 36 eligible patients. Responses were of short duration. There were no responses among 16 estrogen receptor-negative (ER-) patients.

CONCLUSION

GN-RH agonists have activity in ER+ postmenopausal patients, but response rates are not as high as with other available endocrine therapies and the duration of response is short.
Phase I clinical and pharmacokinetic study of a 14-day infusion of etoposide in patients with lung cancer.
Authors: Minami H , Shimokata K , Saka H , Saito H , Ando Y , Senda K , Nomura F , Sakai S
Published: February 2017

PURPOSE

A phase I study was conducted to determine the maximum-tolerated dose (MTD) of a 14-day continuous infusion of etoposide, and to evaluate the pharmacokinetics in patients with lung cancer.

PATIENTS AND METHODS

Etoposide was administered continuously through a central venous catheter using a pump. The starting dose level was 300 mg/m2 over 14 days, with dose escalations of 100 mg/m2 over 14 days until unacceptable toxicities occurred. Pharmacokinetic studies were performed in all patients.

RESULTS

Twenty-one patients, 20 with non-small-cell lung cancer and one with refractory small-cell lung cancer, received 37 courses. No World Health Organization (WHO) grade III or greater toxicity occurred at doses up to 400 mg/m2 over 14 days. At 700 mg/m2 over 14 days, all four patients experienced grade III or IV leukocytopenia, and two developed grade III stomatitis. No cumulative toxicity was observed. A steady concentration of etoposide was achieved 24 hours after the start of chemotherapy, and it was significantly correlated with surviving fractions of leukocytes (r = -.64, P = .001) and platelets (r = -.68, P < .001). The leukocyte count at the termination of chemotherapy predicted the nadir count (r = .93, P < .001).

CONCLUSION

Steady blood levels of etoposide were maintained for prolonged periods, during 14-day continuous infusions. Leukocytopenia and stomatitis were dose-limiting. Nadir counts and surviving fractions of leukocytes were predicted by the leukocyte count at the end of chemotherapy and the concentration of etoposide, respectively. The recommended dose for phase II trials is 600 mg/m2 over 14 days.
Assessment of estrogenic recruitment before chemotherapy in advanced breast cancer: a double-blind randomized study. European Organization for Research and Treatment of Cancer Breast Cancer Cooperative Group.
Authors: Paridaens R , Heuson J C , Julien J P , Veyret C , Van Zyl J , Klijn J G , Sylvester R , Mignolet F
Published: February 2017

PURPOSE

In the present phase III study, the specific effect of estrogenic recruitment was assessed by comparing two groups of patients with advanced breast cancer receiving either ethinylestradiol (EE2) or placebo (PL) before chemotherapy (CT).

PATIENTS AND METHODS

The therapeutic regimen consisted of (1) estrogen suppression by aminoglutethimide (AGL) 1 g/d plus hydrocortisone (HC) 40 mg/d, with surgical castration performed on premenopausal patients; (2) fluorouracil (5-FU) 500 mg/m2, doxorubicin 50 mg/m2, and cyclophosphamide (CPA) 500 mg/m2 (FAC) intravenously (IV) every 3 weeks; (3) following randomization, patients were double-blinded to receive either PL or EE2 50 micrograms exactly 24 hours before receiving FAC. All patients had advanced breast cancer presumably sensitive to endocrine therapy (estrogen receptor-positive [ER+] and/or progesterone receptor-positive [PgR+] status) with measurable lesions; none had received prior systemic antineoplastic therapy for metastatic disease; prior adjuvant hormonal therapy (HT) or CT (without anthracyclines) was allowed if interval since completion was longer than 1 year.

RESULTS

Among 154 patients treated according to the protocol, tolerance, response rates, time to progression, and median survival duration were identical in the PL and EE2 groups. Only performance status, dominant metastatic site, and menopausal status seemed to influence response (overall response, 64%), with the highest levels of partial remission (PR) and complete remission (CR) being achieved in premenopausal women (CR plus PR, 26% plus 55%) and in those with dominant soft tissue lesions (CR plus PR, 45% plus 28%).

CONCLUSION

We conclude that the validity of the hormonal recruitment concept has not yet been established in clinical practice so that this approach remains experimental. The results achieved by combining (near) complete estrogenic suppression and cyclical FAC chemotherapy are not significantly different from those to be expected with the more conventional use of HT followed by CT in presumably hormone-responsive (ER+) patients.
Intraoperative lymphatic mapping and selective cervical lymphadenectomy for early-stage melanomas of the head and neck.
Authors: Morton D L , Wen D R , Foshag L J , Essner R , Cochran A
Published: February 2017

PURPOSE

We developed intraoperative lymphatic mapping with selective lymphadenectomy (SLND) to identify micrometastatic spread of cutaneous melanoma to regional lymph nodes. This study was undertaken to assess the sensitivity and specificity of our technique in patients with clinical stage I (CS-I) melanoma of the head or neck.

PATIENTS AND METHODS

Seventy-two CS-I melanoma patients underwent intraoperative lymphatic mapping of primary cutaneous melanomas located on the head, neck, or upper chest/back draining to the neck. Key (sentinel) cervical lymph nodes in the regional lymphatic drainage basin were identified, selectively excised during SLND, and examined for microscopic evidence of tumor cells. If these sentinel nodes were tumor-negative, the surgery was concluded; if the sentinel nodes were tumor-positive, all nodes in the drainage basin were removed during en bloc lymphadenectomy (LND).

RESULTS

Intraoperative lymphatic mapping identified sentinel nodes in 90% of the regional drainage basins. Fifteen percent of these nodes were tumor-positive, indicating the need for LND. There were no false-negative sentinel nodes, and extended follow-up showed no local nodal recurrences in patients whose sentinel-node histology did not indicate the need for LND.

CONCLUSION

Intraoperative lymphatic mapping and SLND is a minimally invasive and highly accurate screening technique for determining which patients with CS-I head and neck melanomas have subclinical node metastases and therefore might benefit from cervical LND.
Intravenous mercaptopurine: life begins at 40.
Authors: Pinkel D
Published: February 2017

PURPOSE

This review is intended to provide a concise portrayal of the background, rationale, and current use of intravenous infusions of mercaptopurine (6MP) in patients with acute leukemia.

DESIGN

After a brief description of the mode of action of 6MP and the formulation, pharmacokinetics, and history of its intravenous administration, the rationale for current use of intravenous 6MP infusion is explained. Subsequently, the review summarizes and discusses clinical experience with intravenous 6MP alone and in combination with intravenous methotrexate (Mtx) and cytarabine (Ara-C).

RESULTS

Although still an investigative drug, intravenous 6MP has been used for 40 years and currently is being administered extensively to children with previously untreated acute lymphoid leukemia (ALL) in frontline protocol studies. The reasons are the better and more consistent bioavailability of intravenous versus oral MP, higher blood and CSF levels, compliance, and preliminary evidence suggesting superior remission experience for intravenous Mtx and 6MP than for Mtx alone. The apparent lack of late adverse sequelae with 6MP as compared with other antileukemia drugs adds to this interest.

CONCLUSION

The new life of intravenous 6MP at age 40 years illustrates the need for continued investigation of significant anticancer drugs as insights and technology progress.
Erratum
Authors: Gray James R. , Bridges James D. , Sobczak Mark L.
Published: February 2017

Response Migration: Area Versus Volume for Tumor Response Assessment

To the Editor: A correction is necessary regarding the method of assessing tumor response as put forward by Drs Clamon and Clamon. They stated that tumor volume is a stricter criterion than tumor area in determining a partial response (PR, 50% reduction) for use in clinical trials. In fact, just the opposite is true. A PR by measuring tumor area is a more dramatic reduction in tumor bulk than a PR or 50% reduction by measuring tumor volume. Let us demonstrate by example.

If a spherical tumor mass originally measures 8 cm across, its initial area calculation is (π)*(r)2 = 50.26 cm2. To be scored as a PR, the area must decrease to 25.13 cm2. This corresponds to a mass measuring 5.6 cm across (note, not 4 cm). However, the initial volume of this mass is (4/3)*(π)*(r) = 268.08 cm3. To be scored as a PR by the volume criterion the volume must decrease to 134.04 cm3. This corresponds to a mass measuring 6.3 cm across. A mere loss of 1.7 cm from the original tumor dimension results in a PR! If area of the tumor is used, the measurement must decrease by 2.4 cm, obviously a more stringent criterion.

Trials that require a 50% reduction in tumor area for a PR have in essence demanded a 65% reduction in volume, not a 35% reduction as stated by Clamon and Clamon. If future clinical trials are to use computed tomography or magnetic resonance imaging data to calculate tumor volumes as a measurement of response, and the definition of a PR becomes a 50% reduction in volume, treatment regimens may seemingly become more effective with a higher overall response rate. The corresponding required area reduction in this case would be only 38%, not 50%.

Just as more complete staging information can lead to stage migration with fewer malignancies labeled as early stage (the Will Rogers phenomenon2), a change to volume determination for response assessment could lead investigators to conclude erroneously that newer therapies are more successful than those in the past. We must be careful to judge all therapeutic maneuvers on an even playing field to determine truly what is best for our patients.
Successful Pneumocystis carinii pneumonia prophylaxis using aerosolized pentamidine in children with acute leukemia.
Authors: Weinthal J , Frost J D , Briones G , Cairo M S
Published: February 2017

PURPOSE

We report our experience replacing trimethoprim-sulfamethoxazole (TMP/SMX) with aerosolized pentamidine (AP) in 22 children with acute leukemia who could not tolerate TMP/SMX.

PATIENTS AND METHODS

Children (age 1 to 15 years) with acute leukemia during maintenance chemotherapy or post-bone marrow transplantation (BMT) receiving prophylaxis for Pneumocystis carinii pneumonia (PCP) with TMP/SMX received AP following prolonged neutropenia or allergy to TMP/SMX. Patients received 300 mg of AP monthly (children < 4 years received 150 mg) dissolved in 5 mL of distilled water over 20 to 30 minutes.

RESULTS

Over a 3-year period, 358 courses of AP were administered over 10,124 observable days. AP was adequately tolerated on a monthly basis for prophylaxis against PCP in 22 children with acute leukemia. AP was demonstrated to be effective in preventing PCP. There were minimal side effects observed during this trial. The majority of children with acute lymphoblastic leukemia (ALL; 12 of 14 [86%]) undergoing maintenance chemotherapy were able to resume full-dose therapy.

CONCLUSION

AP in children is well tolerated and shows high efficacy for PCP prophylaxis in children with leukemia. We conclude that AP should be considered as second-line PCP prophylactic therapy for children with acute leukemia in instances in which TMP/SMX cannot be tolerated. Phase III trials are required to determine its effect on dose intensification and event-free survival.
Bioequivalence of 20-mg once-daily tamoxifen relative to 10-mg twice-daily tamoxifen regimens for breast cancer.
Authors: Buzdar A U , Hortobagyi G N , Frye D , Ho D , Booser D J , Valero V , Holmes F A , Birmingham B K , Bui K , Yeh C
Published: February 2017

PURPOSE

We studied the bioequivalence of a new once-daily regimen of tamoxifen citrate relative to the standard twice-daily regimen of tamoxifen citrate, an established antiestrogenic treatment for breast cancer.

PATIENTS AND METHODS

Of 30 women with breast cancer, 27 completed this open, two-period, crossover randomized trial. During one 3-month period, patients took one standard 10-mg tamoxifen tablet twice daily; during the preceding or following 3-month period, patients took one of the new 20-mg tablets once daily. Pharmacokinetic profiles and safety parameters were assessed at the end of each 3-month treatment period.

RESULTS

Overall, measured concentrations of tamoxifen and its principal active metabolite, N-desmethyltamoxifen, remained relatively constant over the 24-hour sampling periods at the end of each treatment sequence. For both compounds, the percentage differences of the geometric means for all pharmacokinetic parameters indicated bioequivalence of the once-daily regimen of tamoxifen relative to the standard twice-daily regimen. Both treatment sequences were well tolerated; reported adverse events occurred at similar frequencies with the two treatment regimens.

CONCLUSION

The 20-mg tamoxifen tablet taken once daily was bioequivalent to the 10-mg tamoxifen tablet taken twice daily, with no difference in relative risk. The once-daily treatment is a simpler regimen and may facilitate compliance, which may enhance therapeutic outcomes during long-term treatment of breast cancer.
Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.
Authors: Bukowski R M , Budd G T , Gibbons J A , Bauer R J , Childs A , Antal J , Finke J , Tuason L , Lorenzi V , McLain D
Published: February 2017

PURPOSE

Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated.

PATIENTS AND METHODS

rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy.

RESULTS

The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy.

CONCLUSION

rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.
Long-term follow-up of the first randomized study of cisplatin versus carboplatin for advanced epithelial ovarian cancer.
Authors: Taylor A E , Wiltshaw E , Gore M E , Fryatt I , Fisher C
Published: February 2017

PURPOSE

A phase III trial was performed between October 1981 and June 1984 to compare the efficacy of single-agent cisplatin and single-agent carboplatin in previously untreated patients with International Federation of Gynecology and Obstetrics stage III or IV carcinoma of the ovary following surgery. This report describes the survival rates of patients in this study after a minimum follow-up duration of 8 years.

PATIENTS AND METHODS

Sixty-four patients were randomized to receive cisplatin and 67 patients to receive carboplatin. Cisplatin was administered every 4 weeks for a total of 10 courses, courses 1 to 5 at a dosage of 100 mg/m2 and courses 6 to 10 at 30 mg/m2. Carboplatin was administered at a dosage of 400 mg/m2 every 4 weeks for 10 courses. Patients who had clinical or radiologic evidence of response after five courses of chemotherapy underwent second-look surgery. The study was designed to allow crossover between the two arms. Thirteen patients were excluded from response analyses because they were incorrectly randomized. Patients were crossed over to the other arm of the study because of progressive disease (PD), nonresponse, or toxicity.

RESULTS

The overall response rate for patients randomized to the cisplatin arm was 53.8% (28 of 52; 95% confidence interval [CI], 39% to 68%) and for those randomized to the carboplatin arm, 38.4% (20 of 52; 95% CI, 25% to 53%). There were 16 (30.8%) and 14 (26.9%) complete remissions (CRs) in the cisplatin and carboplatin arms, respectively. None of these differences were statistically significant. The median duration of response for the cisplatin and carboplatin arms was 21 months and 17 months, and the 5-year relapse-free survival rates were 22% and 25%, respectively. The median survival durations for the cisplatin and carboplatin arms were 19.5 and 13 months, and the 5-year survival rates were 15% (95% CI, 8% to 26%) and 19% (95% CI, 11% to 30%), respectively. None of these differences was statistically significant. The median follow-up duration of patients is 9 years. Crossover due to toxicity was more frequent in the cisplatin than the carboplatin arm, occurring in 50% and 3.3% of patients, respectively.

CONCLUSION

The mature data from this study of patients with advanced ovarian cancer show that cisplatin and carboplatin have similar long-term survival results.
Vinorelbine is an active antiproliferative agent in pretreated advanced breast cancer patients: a phase II study.
Authors: Gasparini G , Caffo O , Barni S , Frontini L , Testolin A , Guglielmi R B , Ambrosini G
Published: February 2017

PURPOSE

To evaluate the efficacy and toxicity of single-agent vinorelbine (VNB), a semisynthetic vinca alkaloid, in patients with breast cancer previously treated with other chemotherapeutic regimens for metastatic disease.

PATIENTS AND METHODS

Sixty-seven of 70 patients with assessable disease entered onto the study were assessable. The main characteristics were as follows: median age, 60 years (range, 41 to 77); median performance status (PS; Karnofsky score), 90 (range, 60 to 100); and number of previous chemotherapeutic regimens given--one in 17, two in 27, three in eight, four in two, and five in one patient. The dominant sites of metastasis were viscera in 40, bone in 16, and soft tissues in 11 patients. VNB was administered beginning with the dose of 20 mg/m2 by 60-minute intravenous (iv) infusion weekly, with a dose escalation up to 25 mg/m2 if the first four courses were well tolerated. The treatment was continued until disease progression.

RESULTS

Overall, 845 courses of VNB were given (median, 10; range, eight to 33). Objective responses were as follows: complete response (CR) in three (4.5%), partial response (PR) in 21 (31.2%), stable disease (SD) in 20 (30%), and progressive disease (PD) in 23 patients (34.3%). Twenty-four of 67 assessable patients obtained a major objective response (CR or PR, 36%; 95% confidence interval [Cl], 24% to 47%). Thirty-three percent of patients had a > or = 33% reduction of dose-intensity (DI). The median time to progression was 18 weeks. The drug was active in patients pretreated with either cyclophosphamide, methotrexate, and fluorouracil (CMF) or anthracyclines. The most relevant toxicity observed was myelosuppression: 17 (25%) and 19 patients (28%) had World Health Organization grade III, and six (9%) and six patients (9%) had grade IV leukopenia and granulocytopenia, respectively; two (3%) and two patients (3%) had grade III and IV anemia, respectively. Nonhematologic toxicities were phlebitis (grade II or III in 15 patients), alopecia (grade I or II in 16), nausea and vomiting (grade II or III in 15), diarrhea (grade II in two), constipation (grade II or III in 16), stomatitis (grade II or III in 13), peripheral neuropathy (grade II in seven), and asthenia (grade II in five).

CONCLUSION

This study shows that VNB is an effective and well-tolerated agent in pretreated patients with advanced breast cancer. This drug does not seem to present cross-resistance with previous CMF or anthracycline regimens. Future clinical trials should be designed to prove whether the inclusion of VNB in combination chemotherapy regimens, or whether an enhancement of its dose-intensity using bone marrow growth factors, is able to improve further the efficacy of this drug in breast carcinoma.
Childhood acute myeloid leukemia: outcome in a single center using chemotherapy and consolidation with busulfan/cyclophosphamide for bone marrow transplantation.
Authors: Shaw P J , Bergin M E , Burgess M A , Dalla Pozza L , Kellie S J , Rowell G , Stevens M M , Webster B H , Bradstock K F
Published: February 2017

PURPOSE

To report the impact of bone marrow transplantation (BMT) with busulfan/cyclophosphamide (BuCy) as end consolidation in a cohort of consecutively diagnosed children with acute myeloid leukemia (AML).

PATIENTS AND METHODS

Between May 1987 and November 1992, 43 patients were diagnosed with AML. Tissue typing at diagnosis determined whether patients would proceed to autologous or allogeneic BMT as end consolidation after six cycles of chemotherapy. Conditioning for BMT was with BuCy, followed by allogeneic or unpurged autologous marrow infusion.

RESULTS

Of 37 patients who received chemotherapy, 35 achieved remission (95%) after one to six courses of treatment and 34 (92%) were transplanted. Five relapsed before BMT, four were subsequently transplanted in second complete remission (CR2) (n = 3) or untreated first relapse (n = 1), and one failed to respond to further therapy. All other patients proceeded to BMT in first complete remission (CR1). Eleven patients received allografts: one relapsed and one died of graft-versus-host disease (GvHD), for a leukemia-free survival rate of 90% at a median of 41 months after BMT (range, 3 to 60). For 23 autografts, there were two toxic deaths and eight relapses, with a leukemia-free survival rate of 61% at a median of 11 months after BMT (range, 0 to 66). The high relapse rate following autologous BMT led us to escalate the dose of Bu from 16 mg/kg to 600 mg/m2 using a single daily dose of Bu.

CONCLUSION

With modern supportive therapy, most newly diagnosed children with AML will enter remission and are eligible for intensification therapy. BuCy is well tolerated in children, which allowed us to escalate the dose of Bu in recent patients. Further follow-up is needed to determine whether this has an impact on the relapse rate following autologous BMT.
Phase II trial of vinblastine, ifosfamide, and gallium combination chemotherapy in metastatic urothelial carcinoma.
Authors: Einhorn L H , Roth B J , Ansari R , Dreicer R , Gonin R , Loehrer P J
Published: February 2017

PURPOSE

Phase II trial in metastatic urothelial carcinoma using a novel combination chemotherapy regimen consisting of vinblastine, ifosfamide, and gallium nitrate (VIG).

PATIENTS AND METHODS

Twenty-seven patients were entered onto this phase II study. Dosages were vinblastine 0.11 mg/kg days 1 and 2, ifosfamide 1.2 gm/m2 days 1 through 5 (with mesna), and gallium 300 mg/m2 as a 24-hour infusion days 1 through 5, with calcitriol (1,25-dihydroxycholecalciferol) 0.5 microgram/d orally starting 3 days before each course (except the first) and continuing throughout gallium administration, plus recombinant human granulocyte colony-stimulating factor (rhG-CSF) (filgrastim) 5 micrograms/kg/d days 7 through 16. Courses were repeated every 21 days for a maximum of six cycles.

RESULTS

The major toxicity was granulocytopenia. Fifteen patients (55.6%) had grade 3 or 4 granulocytopenia, including eight patients with granulocytopenic fevers. Eleven patients had grade 3 or 4 anemia and four had grade 3 or 4 nephrotoxicity, which was reversible. Other grade 3 to 4 toxicities included hypocalcemia (three patients), thrombocytopenia (two), encephalopathy (one), and temporary blindness (one). There was one treatment-related mortality. Toxicity was more severe in patients older than 70 years and those with prior pelvic irradiation, prior cisplatin adjuvant therapy, or prior nephrectomy. We now decrease VIG by 20% in this patient population. Eighteen patients (67%) achieved an objective response, including 11 (41%) who attained a disease-free status (five with VIG alone and six with subsequent surgery). Median duration of remission was 20 weeks, with five patients still in remission at 22+ to 56+ weeks.

CONCLUSION

VIG combination chemotherapy is very active in patients with metastatic urothelial carcinoma. Toxicity was significant but manageable.
Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin's lymphoma.
Authors: Stone R M , Neuberg D , Soiffer R , Takvorian T , Whelan M , Rabinowe S N , Aster J C , Leavitt P , Mauch P , Freedman A S
Published: February 2017

PURPOSE

To determine the incidence, natural history, and risk factors associated with myelodysplastic syndrome (MDS) occurring as a late complication following autologous bone marrow transplantation for patients with non-Hodgkin's lymphoma.

METHODS

We retrospectively reviewed the charts of all 262 patients who underwent autologous bone marrow transplantation for non-Hodgkin's lymphoma at the Dana-Farber Cancer Institute from 1982 through 1991. Although patients received a variety of treatments before they were eligible for transplant, identical myeloablative therapy (cyclophosphamide 60 mg/kg/d for 2 days plus total-body irradiation twice daily for 3 days) was administered in each case. By collecting data on pretransplant and early posttransplant variables, we attempted to identify risk factors for the development of MDS.

RESULTS

The crude overall incidence of posttransplant MDS or acute myeloid leukemia (AML) was 7.6%. The actuarial risk at 6 years was 18% +/- 9%. The median time of onset was 31 months (range, 10 to 101) after transplant or 69 months (range, 27 to 141) after initial treatment for lymphoma. Pretreatment variables predictive for the development of MDS (univariate analysis) included prolonged interval between initial treatment and the transplant procedure (P = .003), increased duration of exposure to chemotherapy (P = .019) or to alkylating agents (P = .045), and use of radiation therapy (P = .032) or pelvic radiation (P = .003) before transplant.

CONCLUSION

MDS is a potential complication of autologous bone marrow transplantation for non-Hodgkin's lymphoma; bone marrow stem-cell damage sustained before the transplant may be the most important risk factor.
Immunologic, cytogenetic, and clinical characterization of childhood acute lymphoblastic leukemia with the t(1;19) (q23; p13) or its derivative.
Authors: Pui C H , Raimondi S C , Hancock M L , Rivera G K , Ribeiro R C , Mahmoud H H , Sandlund J T , Crist W M , Behm F G
Published: February 2017

PURPOSE

To evaluate the immunophenotypes, karyotypes, and clinical features, including treatment responses, of patients with childhood acute lymphoblastic leukemia (ALL) and either a t(1;19)(q23;p13) or a der(19)t(1;19)(q23;p13) translocation.

PATIENTS AND METHODS

The lymphoblasts of 45 patients with a balanced translocation, t(1;19) or its derivative form, der(19)t(1;19), were analyzed by cytogenetic and immunologic methods for differences that might suggest distinct subtypes of ALL. This cohort was treated in four consecutive clinical trials with a median overall follow-up duration of 7 years.

RESULTS

A pre-B immunophenotype was found in 10 cases with the balanced t(1;19) and 31 with the unbalanced der(19)t(1;19). The four remaining cases, each with a derivative t(1;19), were classified as early pre-B ALL. The characteristic surface antigen profile of the 41 pre-B cases was CD19+/CD10+/CD22+/CD34-/CD20+/-, whether the translocation was balanced or derivative. In contrast to the four early pre-B cases, which had hyperdiploid karyotypes (> 50 chromosomes), the pre-B cases were primarily pseudodiploid. Comparison of presenting clinical and laboratory features, as well as event-free survival, failed to disclose any differences that would warrant separation of pre-B cases with a balanced or derivative translocation. However, neither subgroup responded to therapy as well as patients with early pre-B ALL, each of whom remains in complete remission for > or = 3 years.

CONCLUSION

The t(1;19) and the der(19)t(1;19) identify a relatively homogeneous group of patients with pre-B ALL, who can be expected to respond similarly to intensive chemotherapy. The exceptional cases have an early pre-B phenotype with hyperdiploid karyotypes and appear to have favorable prognosis.
The role of thymidylate synthase expression in prognosis and outcome of adjuvant chemotherapy in patients with rectal cancer.
Authors: Johnston P G , Fisher E R , Rockette H E , Fisher B , Wolmark N , Drake J C , Chabner B A , Allegra C J
Published: February 2017

PURPOSE

We assessed the prognostic importance of the level of thymidylate synthase (TS) expression in patients with primary rectal cancer and whether, for Dukes' B and C cancer patients, the benefit of chemotherapy was associated with TS expression.

PATIENTS AND METHODS

The level of TS expression in the primary rectal cancers of 294 of 801 patients enrolled on protocol R-01 of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was immunohistochemically assessed with the monoclonal antibody TS 106.

RESULTS

Forty-nine percent of patients whose tumors had low TS levels (n = 91) were disease free at 5 years compared with 27% of patients with high levels of TS (n = 203; P < .01). Moreover, 60% of patients with low TS levels were alive after 5 years compared with 40% of patients with high TS levels (P < .01). The level of TS protein was significantly associated with Dukes' stage (P < .01); patients with a more advanced Dukes' stage had a significantly higher level of TS. The level of TS expression remained prognostic for both disease-free survival (P < .01) and survival (P < .05) independent of Dukes' stage and other pathologic characteristics evaluated. Thirty-eight percent and 54% of patients with high TS levels (n = 71) were disease free and alive, respectively, after 5 years when treated with chemotherapy, compared with 17% and 31%, respectively, of similar patients when treated with surgery alone (n = 64) (P < .01). No difference was noted in disease-free survival (P = .46) or survival (P = .43) in patients with low TS levels.

CONCLUSION

The expression of TS is an important independent prognosticator of disease-free survival and survival in patients with rectal cancer. Adjuvant fluorouracil (5-FU)-based chemotherapy demonstrated significant improvement in disease-free and overall survival for patients with high TS levels. Prospective studies measuring TS levels will be needed to understand further the role of TS as a prognosticator of survival and chemotherapeutic benefit.
Phase I trial of outpatient weekly paclitaxel and concurrent radiation therapy for advanced non-small-cell lung cancer.
Authors: Choy H , Akerley W , Safran H , Clark J , Rege V , Papa A , Glantz M , Puthawala Y , Soderberg C , Leone L
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD) and dose-limiting toxicities of paclitaxel administered weekly on an outpatient basis with concurrent thoracic radiation to patients with advanced non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

In this phase I clinical trial, paclitaxel was administered as a 3-hour intravenous (IV) infusion, repeated every week for 6 weeks. The starting dose of paclitaxel was 10 mg/m2. Doses were escalated at 10-mg/m2 increments in successive cohorts of three new patients if tolerated. Unacceptable toxicity was defined as grade 3 nonhematologic toxicity, excluding nausea and vomiting, and grade 4 hematologic toxicity according to Cancer and Leukemia Group B expanded common toxicity criteria. Radiation was administered to the primary tumor and regional lymph nodes (40 Gy) followed by a boost to the tumor (20 Gy).

RESULTS

Twenty-seven patients were entered onto this study through seven dose escalations (from 10 mg/m2/wk to 70 mg/m2/wk for 6 weeks). Severe esophagitis occurred at 70 mg/m2 (two patients with grade 4 disease and one patient with grade 2). One of six patients at 60 mg/m2 developed grade 3 esophagitis and three of seven patients had grade 2 esophagitis. One of 27 patients developed a hypersensitivity reaction. One of 27 patients developed grade 3 neutropenia.

CONCLUSION

Esophagitis is the principle dose-limiting toxicity of weekly paclitaxel and thoracic radiation in the outpatient setting. A phase II trial using concurrent radiation and paclitaxel at the MTD of 60 mg/m2/wk is underway.
A randomized study in stage IIIB and IV Hodgkin's disease comparing eight courses of MOPP versus an alteration of MOPP with ABVD: a European Organization for Research and Treatment of Cancer Lymphoma Cooperative Group and Groupe Pierre-et-Marie-Curie controlled clinical trial.
Authors: Somers R , Carde P , Henry-Amar M , Tarayre M , Thomas J , Hagenbeek A , Monconduit M , de Pauw B E , Breed W P , Verdonck L
Published: February 2017

PURPOSE

We report a prospective randomized study comparing the relative efficacy of alternating chemotherapy mechlorethamine, vincristine, procarbazine, and prednisone/doxorubicin, bleomycin, vinblastine, and dacarbazine (MOPP/ABVD) with the standard MOPP chemotherapy in patients with stage IIIB and IV Hodgkin's disease (HD). The purpose is to study the influence of time of remission on clinical outcome.

PATIENTS AND METHODS

After two courses of MOPP, patients were randomized to receive six further courses of MOPP, or two courses of ABVD followed by two courses of MOPP and two courses of ABVD. Radiotherapy was given to areas presenting with masses > or = 5 cm and to residual masses after course no. 4. Evaluation of response (complete remission [CR]) took place after two courses (CR2), after four courses (CR4), at the end of chemotherapy (CR8), and after additional radiotherapy (CR(CT + RT)). Logistic regression analysis was used to study prognostic factors for response at the end of chemotherapy. Cox analysis was used to study prognostic factors for survival. Two hundred seven patients were registered, 192 (93%) of whom were randomized.

RESULTS

The CR rate at the end of chemotherapy (CR8) was similar in both arms (57% v 59%). However, there were more progressions in the MOPP arm compared with the MOPP/ABVD arm (23% v 8%, P = .014). A significantly higher failure-free survival (FFS) rate was found in the MOPP/ABVD arm (60% v 43% at 6 years, P = .025). There was no difference in the relapse-free survival (RFS) or survival rate. Of patients not in CR4, only 28% still reached a CR8. RFS at 6 years of patients with CR4 (69%) was not different from that of patients with CR8 (68%); patients with a CR(CT + RT)) had a lower RFS rate (48%). CR4 (P < .001) predicted strongly for final remission at the end of chemotherapy. Cox analysis showed that age more than 50 years, six or more involved lymph node areas, no CR by the fourth cycle, chemotherapy with MOPP alone, and no radiotherapy were unfavorable factors for survival.

CONCLUSION

MOPP/ABVD chemotherapy significantly improved response and FFS rates, but had no influence on RFS and survival rates. Early CR (CR4) is an important factor for final remission and might be used to select a group of patients with a good prognosis.
Cathepsin D by western blotting and immunohistochemistry: failure to confirm correlations with prognosis in node-negative breast cancer.
Authors: Ravdin P M , Tandon A K , Allred D C , Clark G M , Fuqua S A , Hilsenbeck S H , Chamness G C , Osborne C K
Published: February 2017

PURPOSE

We attempted to replicate and improve on our previous study (N Engl J Med 322:297-302, 1990) that showed that 34-kd cathepsin D levels as determined by Western blotting strongly correlated with disease-free survival (DFS) and overall survival (OS) of axillary node-negative (N-) breast cancer patients. We also examined the prognostic significance of cathepsin D measured by immunohistochemistry (IHC) in these patients.

PATIENTS AND METHODS

Western blotting was performed on cytosols from frozen tumor specimens of 927 N- breast cancer patients in the San Antonio Breast Tumor Bank. The monoclonal antibody M1G8 was used to detect cathepsin D (in previous study, a polyclonal antiserum had been used). The same monoclonal antibody was also used for frozen-section IHC staining of tumor specimens from 562 N- patients from the same tumor bank. Levels of cathepsin D expression were then correlated with DFS and OS.

RESULTS

Although the levels of cathepsin D expression as measured by Western blotting and IHC correlated with each other and with levels of cathepsin D measured in previous work using Western blotting with the polyclonal antiserum, in this present study, using the monoclonal antibody M1G8, we were unable to demonstrate that cathepsin D expression (measured by either Western blotting or by IHC) correlates with DFS or OS.

CONCLUSION

In this study, cathepsin D expression as determined by either Western blotting or IHC using the monoclonal antibody M1G8 failed to improve the prognostic evaluation of N- breast cancer patients. The role of cathepsin D expression as a prognostic factor is still not precisely defined, raising questions about its use in the routine evaluation of N- breast cancer patients.