bluuebunny/crossref_metadata_2025 huggingface dataset:
Palliative effect of metaiodobenzylguanidine in metastatic carcinoid tumors.
Authors: Taal B G , Hoefnagel C A , Valdes Olmos R A , Boot H , Beijnen J H
Published: February 2017

PURPOSE

To evaluate the therapeutic effect of iodine-131-labeled metaiodobenzylguanidine (131I-MIBG) and unlabeled MIBG in patients with carcinoid tumor.

MATERIALS AND METHODS

A therapeutic dose of 7.4 GBq (200 mCi) 131I-MIBG infused over 4 hours was administered to 30 patients with either carcinoid syndrome (n = 20) or tumor symptoms such as pain and fever due to carcinoid tumor (n = 10). In general, two courses were given, 6 weeks apart. Due to radioactivity, patients had to be isolated for 5 to 7 days. Subsequently, we studied the effect of unlabeled MIBG based on the possible pharmaceutic activity of MIBG and to avoid the isolation procedure. A doseescalation study of 8.5, 17, and 34 mg/m2 MIBG infused over 4 hours at 4-week intervals was performed in 20 patients with carcinoid syndrome who were not suitable for treatment with the radioactive compound.

RESULTS

Following 131I-MIBG treatment, symptomatic responses were observed in 60% of patients (median duration, 8 months; maximum, 2 years). Side effects were mild and rapidly reversible in 16 patients, and were related to the isolation procedure in seven of these patients. Unlabeled MIBG resulted in symptomatic improvement in 60% of patients (median duration, 4.5 months). Side effects, which included changes in blood pressure, were mild and transient. Symptomatic responses were not accompanied by biochemical responses.

CONCLUSION

Both MIBG treatment regimens were equally effective in the palliation of symptoms, but duration of response tended to be much longer with the radioactive compound. However, the unlabeled compound provided a simpler treatment, eg, in elderly patients and those in poor condition, without the need for isolation.
Amifostine, cisplatin, and vinblastine in metastatic non-small-cell lung cancer: a report of high response rates and prolonged survival.
Authors: Schiller J H , Storer B , Berlin J , Wittenkeller J , Larson M , Pharo L , Larson M , Berry W
Published: February 2017

PURPOSE

Based on preclinical and clinical studies that suggested amifostine may potentiate the effects of cytotoxic drugs, we conducted a phase II trial of amifostine, cisplatin, and vinblastine (ACV) in patients with metastatic non-small-cell lung cancer (NSCLC).

PATIENTS AND METHODS

Twenty-five patients with metastatic NSCLC received amifostine (740 or 910 mg/m2) before 120 mg/m2 of cisplatin on day 1, plus weekly 5 mg/m2 of vinblastine without amifostine. Cycles were repeated every 4 weeks. Patients were required to have good performance status, no prior chemotherapy or biologic therapy, adequate organ function, and measurable disease.

RESULTS

Sixteen of 25 assessable patients had an objective response documented by computed tomographic (CT) scan (64%; 95% confidence interval, 45% to 85%). With a median duration of follow-up of 19.2 months, the estimated median survival is 17 months and 1-year survival is 64% (+/- 10%). Toxicities included grades 3 and 4 neutropenia (8% and 92%, respectively) and nausea and vomiting (32% and 4%, respectively). Reversible grade 3 nephrotoxicity occurred in 12% of patients, although only one of 13 patients (7%) who received > or = four cycles of therapy had > or = 40% reduction in creatinine clearance. Grade 3 neuropathy was observed in seven patients at cumulative cisplatin doses that ranged from 324 to 660 mg/m2; grade 3 ototoxicity occurred in three patients at cumulative cisplatin doses that ranged from 390 to 450 mg/m2. Four patients (16%) required early stopping of an amifostine infusion due to hypotension.

CONCLUSION

ACV appears to be a highly active regimen in metastatic NSCLC. Acute toxicities were generally reversible and the data suggest that amifostine may protect against long-term renal insufficiency from cumulative doses of cisplatin. Although the sample size of this trial is small, the results are significantly encouraging to warrant confirmation in randomized multiinstitutional trials.
Port site recurrences after laparoscopic and thoracoscopic procedures in malignancy.
Authors: Johnstone P A , Rohde D C , Swartz S E , Fetter J E , Wexner S D
Published: February 2017

PURPOSE AND METHODS

A review of the literature was performed to determine the number of cases of port site recurrences (PSR) after laparoscopy or thoracoscopy. CANCERLINE and MEDLINE were searched, as were citings from retrieved and related papers.

RESULTS

There have been 35 reported cases of PSR after laparoscopic colectomy for colorectal carcinoma, and 23 cases after thoracoscopic procedures for lung neoplasms. All of these have been reported since 1993. Since 1991, 12 cases have been described after laparoscopic cholecystectomy of unsuspected gallbladder carcinoma, and another case after biopsy of a known gallbladder carcinoma. Ten cases of PSR have been reported after laparoscopic procedures for ovarian lesions, often in the presence of peritoneal seeding at diagnosis. Other rare PSRs have been documented after several procedures in various malignancies.

CONCLUSION

Enrollment of patients onto the ongoing intergroup study evaluating open versus laparoscopic resection of colon cancer should be encouraged. Until valid prospective data on PSR frequency are available, laparoscopic or thoracoscopic resection of malignancy off-protocol should be undertaken with circumspection.
Phase II trial of paclitaxel and cisplatin in women with advanced breast cancer: an active regimen with limiting neurotoxicity.
Authors: Wasserheit C , Frazein A , Oratz R , Sorich J , Downey A , Hochster H , Chachoua A , Wernz J , Zeleniuch-Jacquotte A , Blum R , Speyer J
Published: February 2017

PURPOSE

A phase II study of paclitaxel and cisplatin in patients with advanced breast cancer was performed to determine the objective response rate and make further observations about the toxicity of this regimen.

PATIENTS AND METHODS

Patients were required to have histologically proven adenocarcinoma of the breast with no more than one chemotherapeutic treatment for advanced disease. Treatment consisted of paclitaxel 200 mg/m2 administered as a 24-hour intravenous (i.v.) infusion followed by cisplatin 75 mg/m2 i.v. Patients received granulocyte colony-stimulating factor (G-CSF) 5 micrograms/kg subcutaneously on day 3 until WBC recovery. Cycles were repeated every 21 days. Patients continued to receive therapy until disease progression or unacceptable toxicity.

RESULTS

Forty-four patients entered the trial. Forty-two patients were assessable for response. Nineteen patients (43%) had no prior chemotherapy and 41 had no chemotherapy for metastatic disease. The median number of cycles administered per patient was five (range, one to seven). There were five complete responses (CRs) (11.9%) and 17 partial responses (PRs) (40.5%), with an overall response rate of 52.4% (95% confidence interval [CI], 36.4% to 68.0%). Nine patients had stage III disease. The response rate for this group was 66.7% (95% CI, 33.0% to 92.5%), with three CRs and three PRs. Among 35 patients with stage IV disease, there were two CRs and 14 PRs, with an overall response rate of 48.5% (95% CI, 30.8% to 66.5%). Overall, the median response duration was 10.6 months. Thirty patients (68%) developed transient grade 4 neutropenia. Cumulative neuropathy was the major dose-limiting toxicity. After five cycles of chemotherapy, 96% of patients had at least grade 1 neurotoxicity and 52% had at least grade 2 neurotoxicity. One patient had a toxic death after cycle 1 of therapy.

CONCLUSION

The combination of paclitaxel and cisplatin as first-line chemotherapy for women with advanced breast cancer is an active regimen. However, the cumulative neurotoxicity was significant and dose-limiting in the majority of patients.
Influence of inflammatory bowel disease on the ability of patients to tolerate systemic fluorouracil-based chemotherapy.
Authors: Tiersten A , Saltz L B
Published: February 2017

PURPOSE

To evaluate the safety of administering fluorouracil (5FU)-based chemotherapy to cancer patients with inflammatory bowel disease (IBD).

PATIENTS AND METHODS

We retrospectively reviewed all patients entered into the Memorial Sloan-Kettering Cancer Center clinical data base from 1985 through 1995 who had a diagnosis of IBD, had a gastrointestinal malignancy, and were treated with systemic 5FU-based chemotherapy. A total of 19 patient charts were identified and reviewed.

RESULTS

Fifty-three percent of patients reviewed experienced severe (grade III/IV) diarrhea on treatment. Sixty percent of patients with a history of active IBD and 40% of patients with a history of inactive IBD experienced severe diarrhea on treatment. The incidence of severe diarrhea did not appear to be substantially influenced by age, schedule of 5FU administration, concurrent radiation, or type of IBD.

CONCLUSION

While there does appear to be an increased risk of diarrhea exacerbation in IBD patients treated with 5FU, a substantial number of patients tolerate chemotherapy without increased difficulty. The degree of IBD activity or other clinical parameters can not be used to predict accurately the likelihood of toxicity.
Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.
Authors: Kaye S B , Paul J , Cassidy J , Lewis C R , Duncan I D , Gordon H K , Kitchener H C , Cruickshank D J , Atkinson R J , Soukop M , Rankin E M , Davis J A , Reed N S , Crawford S M , MacLean A , Parkin D , Sarkar T K , Kennedy J , Symonds R P
Published: February 2017

PURPOSE

In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial.

PATIENTS AND METHODS

After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died.

RESULTS

The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD).

CONCLUSION

Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.
Randomized trial assessing the addition of interferon alpha-2a to fluorouracil and leucovorin in advanced colorectal cancer. Colorectal Cancer Working Party of the United Kingdom Medical Research Council.
Authors: Seymour M T , Slevin M L , Kerr D J , Cunningham D , James R D , Ledermann J A , Perren T J , McAdam W A , Harper P G , Neoptolemos J P , Nicholson M , Duffy A M , Stephens R J , Stenning S P , Taylor I
Published: February 2017

PURPOSE

To determine the effects of interferon alpha-2a (IFN alpha) on the efficacy and toxicity of fluorouracil (FUra) and leucovorin (LV) in patients with advanced colorectal cancer.

PATIENTS AND METHODS

Two hundred sixty chemotherapy-naive patients were randomized to FUra/LV alone or FUra/LV plus IFN alpha. All patients received: LV 200 mg/m2 intravenous (IV) infusion over 2 hours, then FUra 400 mg/m2 i.v. bolus plus 400 mg/m2 i.v. infusion over 22 hours, all repeated on day 2. Treatment was every 2 weeks for up to 12 cycles. Patients randomized to IFN alpha received 6 x 10(6) IU subcutaneously every 48 hours throughout. Objective response (OR) and toxicity were assessed conventionally; in addition, palliative benefit and adverse effects were assessed using quality-of-life (QoL) questionnaires.

RESULTS

There were no differences in OR rate, progression-free survival, or overall survival. OR rates in assessable patients were as follows: FUra/LV alone (n = 104), complete or partial response (OR) = 27%, no change (NC) = 34%; FUra/LV/IFN alpha (n = 101), OR = 28%, NC = 30%. Median survival was 10 months in both arms. Dose-limiting FUra toxicities were not significantly increased by co-administration of IFN alpha, and the delivered FUra dose-intensity was not significantly reduced. However, QoL was adversely affected: patients on IFN alpha were less likely to report improvement in pretreatment physical and psychologic symptoms, and more likely to report new or worsening symptoms.

CONCLUSION

IFN alpha, at a dose that impaired QoL, did not improve the efficacy of FUra/LV. The power of this trial is sufficient to exclude with 95% confidence a benefit of 15% in OR or 10 weeks in median survival. Accordingly, we cannot recommend the use of IFN alpha as a clinical modulator of FUra/LV in the treatment of advanced colorectal cancer.
Chemotherapy followed by accelerated fractionated radiation for larynx preservation in patients with advanced laryngeal cancer.
Authors: Eisbruch A , Thornton A F , Urba S , Esclamado R M , Carroll W R , Bradford C R , Hazuka M B , Littles F J , Strawderman M , Wolf G T
Published: February 2017

PURPOSE

Larynx preservation in advanced, resectable laryngeal cancer may be achieved using induction chemotherapy (CT) followed in responding patients by definitive radiation (RT). To address potential accelerated repopulation of clonogenic tumor cells during the prolonged total treatment time, we studied the feasibility of accelerated fractionated RT after CT.

METHODS

Patients with advanced laryngeal cancer received two cycles of cisplatin 100 mg/m2 and fluorouracil (5-Fu) 1,000 mg/m2/d for 5 days. Responding patients received a third cycle after which those who had complete response or tumor down-staging to T1 proceeded with accelerated RT: 70.4 Gy delivered over 5.5 weeks. Patients who achieved a lesser response to CT underwent total laryngectomy and postoperative RT.

RESULTS

Thirty-three patients were accrued. Three died during the course of CT and two declined definitive treatment after CT. Twenty-one patients had a major response to CT, 20 of whom received accelerated RT. Median weight loss during RT was 11%. Late severe morbidity was observed in five patients (25%). All four patients who underwent salvage laryngectomy after accelerated RT experienced major postoperative complications. The locoregional failure rate was 25%. The larynx was preserved in 48% of the total study population and in 80% of the patients irradiated according to the study protocol.

CONCLUSION

Accelerated RT after CT as delivered in this study may increase both acute and long-term morbidity rates compared with studies using standard RT after CT. It did not seem to improve local/regional tumor control or survival despite stringent patient selection criteria.
Cisplatin-fluorouracil exclusive chemotherapy for T1-T3N0 glottic squamous cell carcinoma complete clinical responders: five-year results.
Authors: Laccourreye O , Brasnu D , Bassot V , Ménard M , Khayat D , Laccourreye H
Published: February 2017

PURPOSE

To evaluate cisplatin-fluorouracil exclusive chemotherapy (EC) for T1-T3N0 glottic squamous cell carcinoma complete clinical responders (CCR) after cisplatin-fluorouracil induction chemotherapy (IC).

PATIENTS AND METHODS

A retrospective analysis was performed of 58 patients with T1-T3N0 glottic squamous cell carcinoma CCR after IC consecutively managed at our department between 1985 and 1992. Twenty-one CCR were managed with EC. Thirty-seven CCR were managed with IC and a conventional laryngeal-preservation modality. Analyses of survival, local control, nodal recurrence, distant metastasis, and metachronous second primary tumor were performed using the Kaplan-Meier actuarial life-table method. In CCR managed with EC, the independent factors of age, tumor classification, exact tumor location, true vocal cord motion, arytenoid cartilage motion, total dosage of drugs delivered, and number of courses received were tested for potential correlation with survival, local recurrence, nodal recurence, and distant metastasis.

RESULTS

The 5-year survival, local control, nodal recurrence, distant metastasis, and metachronous second primary tumor rates in CCR managed with EC were 95.2%, 70.7%, 0%, 0%, and 14.3%, respectively. The 5-year rates of survival, local control, nodal recurrence, distant metastasis, and metachronous second primary tumor in CCR managed with IC and a conventional laryngeal-preservation modality were 86.1%, 97%, 2.7%, 6%, and 14.5%, respectively. Local recurrence was statistically more likely in CCR managed with EC (P = .002). Local recurrence in CCR managed with EC was always salvaged with partial laryngectomy or radiation therapy, which resulted in an overall 100% local control and laryngeal-preservation rate within this group. In CCR managed with EC, none of the variables analyzed was statistically related to survival, local recurrence, nodal recurrence, or distant metastasis.

CONCLUSION

The present retrospective studies demonstrated that within T1-T3N0 glottic squamous cell carcinoma CCR, there is clearly a significant subset of patients with chemocurable tumors who achieved both perfect preservation of structure-supporting voice and long-term survival after EC. Careful monthly follow-up evaluation allowed for timely successful salvage of local recurrence after EC without the need for total laryngectomy. Such management did not appear to increase the risk for subsequent nodal failure, subsequent distant metastasis, or reduced survival.
Phase I trial and pharmacologic trial of sequences of paclitaxel and topotecan in previously treated ovarian epithelial malignancies: a Gynecologic Oncology Group study.
Authors: O'Reilly S , Fleming G F , Barker S D , Walczak J R , Bookman M A , McGuire W P , Schilder R J , Alvarez R D , Armstrong D K , Horowitz I R , Ozols R F , Rowinsky E K
Published: February 2017

PURPOSE

A phase I and pharmacologic study to evaluate the feasibility of administering paclitaxel (PTX) in combination with topotecan (TPT) without and with granulocyte colony-stimulating factor (G-CSF) in women with recurrent or refractory ovarian cancer.

PATIENTS AND METHODS

TPT was administered as a 30-minute infusion daily for 5 days and PTX was given as a 24-hour infusion (PTX-24) either before TPT on day 1 or after TPT on day 5. Each patient received both schedules on an alternating basis every 3 weeks. Sequential dose escalation of TPT or PTX-24 without and with G-CSF resulted in five dosage permutations of TPT/PTX (mg/ m2): 0.75/135 without G-CSF and 0.75/135, 1.25/135, 1.50/135, and 1.25/170 with G-CSF.

RESULTS

Twenty-two patients received 109 courses of therapy. Dose-limiting myelosuppression consistently occurred at the first TPT/PTX-24 dose level (0.75/135 mg/m2) in the absence of G-CSF support. Although the addition of G-CSF resulted in reduced rates of complicated neutropenia, the incidences of dose-limiting neutropenia and thrombocytopenia were unacceptably high after the doses of either TPT or PTX-24 were increased. Paired analysis showed similar hematologic toxicities between the two sequences of drug administration. The pharmacologic behavior of both TPT and PTX-24 was not altered by drug sequencing. Major antitumor responses occurred in 40% of patients with measurable and assessable disease, including 45% and 9% of patients with potentially cisplatin-sensitive and -resistant tumors, respectively.

CONCLUSION

The recommended doses of TPT on a daily times-five schedule combined with PTX-24 in these patients were 0.75 mg/m2/d and 135 mg/m2, respectively, with G-CSF support. Although this dose of PTX has significant single-agent activity in ovarian cancer, the dose of TPT is much lower than the TPT dose at which single-agent activity has been observed. Due to the inability to administer near relevant single-agent doses of both drugs in combination, as well as the requirement for G-CSF support, further evaluations of this regimen in women with refractory or recurrent ovarian cancer are necessary before it can be recommended for previously treated patients in this setting.
Dose-effect study of carboplatin in ovarian cancer: a Danish Ovarian Cancer Group study.
Authors: Jakobsen A , Bertelsen K , Andersen J E , Havsteen H , Jakobsen P , Moeller K A , Nielsen K , Sandberg E , Stroeyer I
Published: February 2017

PURPOSE

To elucidate the effect of a doubled carboplatin dose-intensity in epithelial ovarian cancer in combination with a fixed dose of cyclophosphamide.

PATIENTS AND METHODS

A total of 222 patients with epithelial ovarian cancer stages II to IV were included in the study. Following surgery, patients were randomly assigned to receive carboplatin at an area under the concentration-versus-time curve (AUC) of 4 (AUC4) or carboplatin at an AUC of 8 (AUC8) and cyclophosphamide 500 mg/m2 given every 4 weeks for six courses. The AUC was calculated according to Calvert's formula. In 123 patients, the carboplatin AUC was also measured based on a single-sample method and the results were compared with the calculated AUC. The end points of the trial were complete pathologic remission (CPR) and crude survival.

RESULTS

Approximately 50% of patients in both arms underwent second-look surgery. The frequency of CPR was 32% and 30%, respectively. The survival curves showed no significant difference (P = .84). The dose-intensity of cyclophosphamide was almost identical in the two arms, whereas that of carboplatin was different. In the AUC8 arm, the dose-intensity was 1.86 times that of the AUC4 arm. The results also demonstrated good agreement between the calculated and the measured AUC in most patients. Bone marrow toxicity was significantly higher in the AUC8 arm.

CONCLUSION

A doubling of the carboplatin dose-intensity did not result in any significant improvement of pathologic remission or survival. Calvert's formula can be used to give a fairly accurate estimate of the carboplatin AUC. Bone marrow toxicity increased with higher dose-intensity, and a further increase of dose is only feasible with growth-factor or stem-cell support.
Complications after treatment with external-beam irradiation in early-stage prostate cancer patients: a prospective multiinstitutional outcomes study.
Authors: Beard C J , Propert K J , Rieker P P , Clark J A , Kaplan I , Kantoff P W , Talcott J A
Published: February 2017

PURPOSE

To use data from a prospective quality-of-life study to assess differences in disease-specific and general health-related quality-of-life changes after treatment with different external-beam irradiation techniques for prostate cancer.

PATIENTS AND METHODS

Patients were divided into three groups based on their pretreatment field size and planning technique: whole pelvis, small field, or conformal. Measures of bowel, urinary, and sexual function and of global health-related quality-of-life parameters (from the Health Survey Short Form [SF-36] and the Profile of Mood States [POMS]) were obtained from self-report questionnaires completed before initiation of therapy and at 3 and 12 months after therapy.

RESULTS

Irritative gastrointestinal and genitourinary side effects were frequent 3 months after treatment, but were substantially improved at 12 months. Sexual dysfunction increased steadily over the study period. The POMS and the SF-36 did not demonstrate significant changes over time. Despite small patient numbers, we found trends in favor of conformal therapy across several symptom measures, including sexual function. In the fatigue, energy, and vigor subscales, patients who received whole-pelvis treatment fared significantly worse than those in the other two groups.

CONCLUSION

Prospective, detailed data from a feasibility study allowed us to assess the effect of technique on quality of life following external-beam irradiation. Although limited by the small planned sample size, these results suggest that smaller radiation fields limit treatment-related complications, including, unexpectedly, sexual dysfunction. However, confirmation in a larger study is necessary.
Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.
Authors: Rougier P , Bugat R , Douillard J Y , Culine S , Suc E , Brunet P , Becouarn Y , Ychou M , Marty M , Extra J M , Bonneterre J , Adenis A , Seitz J F , Ganem G , Namer M , Conroy T , Negrier S , Merrouche Y , Burki F , Mousseau M , Herait P , Mahjoubi M
Published: February 2017

PURPOSE

To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients.

PATIENTS AND METHODS

Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function.

RESULTS

Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern.

CONCLUSION

CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.
Randomized trial comparing epirubicin, cisplatin, and fluorouracil versus fluorouracil, doxorubicin, and methotrexate in advanced esophagogastric cancer.
Authors: Webb A , Cunningham D , Scarffe J H , Harper P , Norman A , Joffe J K , Hughes M , Mansi J , Findlay M , Hill A , Oates J , Nicolson M , Hickish T , O'Brien M , Iveson T , Watson M , Underhill C , Wardley A , Meehan M
Published: February 2017

PURPOSE

We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous infusion fluorouracil (5-FU) (ECF regimen) with the standard combination of 5-FU, doxorubicin, and methotrexate (FAMTX) in previously untreated patients with advanced esophagogastric cancer.

PATIENTS AND METHODS

Two hundred seventy-four patients with adenocarcinoma or undifferentiated carcinoma were randomized and analyzed for survival, tumor response, toxicity, and quality of life (QL).

RESULTS

The overall response rate was 45% (95% confidence interval [CI], 36% to 54%) with ECF and 21% (95% CI, 13% to 29%) with FAMTX (P = .0002). Toxicity was tolerable and there were only three toxic deaths. The FAMTX regimen caused more hematologic toxicity and serious infections, but ECF caused more emesis and alopecia. The median survival duration was 8.9 months with ECF and 5.7 months with FAMTX (P = .0009); at 1 year, 36% (95% CI, 27% to 45%) of ECF and 21% (95% CI, 14% to 29%) of FAMTX patients were alive. The median failure-free survival duration was 7.4 months with ECF and 3.4 months with FAMTX (P = .00006). The global QL scores were better for ECF at 24 weeks, but the remaining QL data showed no differences between either arm of the study. Hospital-based cost analysis on a subset of patients was similar for each arm and translated into an increment cost of $975 per life-year gained.

CONCLUSION

The ECF regimen results in a survival and response advantage, tolerable toxicity, better QL and cost-effectiveness compared with FAMTX chemotherapy. This regimen should now be considered the standard treatment for advanced esophagogastric cancer.
Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study.
Authors: al-Sarraf M , Martz K , Herskovic A , Leichman L , Brindle J S , Vaitkevicius V K , Cooper J , Byhardt R , Davis L , Emami B
Published: February 2017

PURPOSE

The present intergroup phase III randomized study compared combined chemotherapy (CT) plus radiotherapy (RT) treatment versus RT only in patients with locally advanced esophageal cancer.

MATERIALS AND METHODS

Two courses of chemotherapy during 50 Gy RT followed by additional two courses of the same CT, versus 64 Gy RT alone were investigated. CT consisted of cisplatin 75 mg/m2 on day 1 [corrected] and fluorouracil (5FU) 1,000 mg/m2/d on days 1 to 4 every 4 weeks with RT and every 3 weeks post-RT. The main objective of the study was to compare overall survival between the two randomized treatment groups. Patients were stratified by tumor size, histology, and degree of weight loss.

RESULTS

Sixty-two assessable patients were randomized to receive RT alone, and 61 to the combined arm. Patients characteristics were as follows: squamous cell cancer, 90% versus 85%; weight loss greater than 10 lb, 61% versus 69%; and tumor size, > or = 5 cm, 82% versus 80% on the RT and CT-RT arms, respectively. Systemic side effects, which consisted of nausea, vomiting, and renal and myelosuppression, occurred more frequently on the combined arm, while local side effects were similar in both groups. With a minimum follow-up time of 5 years for all patients, the median survival duration was 14.1 months and the 5-year survival rate was 27% in the combined treatment group, while the median survival duration was 9.3 months with no patients alive at 5 years in the RT-alone group (P < .0001). Additional patients (69) were treated with the same combined therapy and were analyzed. The results of the last group confirmed all of the results obtained with combined CT-RT in the randomized trial, with a median survival duration of 17.2 months and 3-year survival rate of 30%.

CONCLUSION

We conclude that cisplatin and 5FU infusion given during and post-RT of 50 Gy is statistically superior to standard 64-Gy RT alone in patients with locally advanced esophageal cancer.
Dose-intensive weekly chemotherapy for treatment of relapsed small-cell lung cancer.
Authors: Kubota K , Nishiwaki Y , Kakinuma R , Hojo F , Matsumoto T , Ohmatsu H , Sekine I , Yokozaki M , Goto K , Ebi N , Kodama T
Published: February 2017

PURPOSE

This study was undertaken to determine the activity and toxicity of dose-intensive weekly chemotherapy (cisplatin, vincristine, doxorubicin, and etoposide [CODE] regimen) for previous treated, recurrent small-cell lung cancer (SCLC).

PATIENTS AND METHODS

The 17 patients with relapsed SCLC entered onto the study were to receive intensive weekly chemotherapy with the CODE regimen. All 17 patients had been heavily pretreated with some form of cisplatin-based combination chemotherapy. Six patients had received previous chemotherapy with CODE and one patient with cisplatin and etoposide (PE) as induction therapy. Nine patients had been treated with concurrent or sequential PE plus thoracic irradiation (TRT). The median time off chemotherapy was 6.7 months (range, 3.3 to 72). Patients were treated with 9 weeks of the CODE regimen. Response, survival, and toxicity data were noted.

RESULTS

All 17 patients were assessable for response, survival, and toxicity. Fifteen of 17 patients (88.2%) had an objective response, with five complete responses (CRs; 29%) and 10 partial responses (PRs; 58.8%). The median durations of response and survival were 156 days and 245 days, respectively. Myelosuppression was significant, with 76% of patients developing grade 4 leukopenia. No treatment-related death was observed.

CONCLUSION

The CODE regimen is highly active in the treatment of relapsed SCLC with an encouraging survival outcome.
Maximum-tolerated dose defined for single-agent gemcitabine: a phase I dose-escalation study in chemotherapy-naive patients with advanced non-small-cell lung cancer.
Authors: Fossella F V , Lippman S M , Shin D M , Tarassoff P , Calayag-Jung M , Perez-Soler R , Lee J S , Murphy W K , Glisson B , Rivera E , Hong W K
Published: February 2017

PURPOSE

We conducted a phase I trial of the novel nucleoside analog, gemcitabine, in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) to determine the maximum-tolerated dose and efficacy in this population.

PATIENT AND METHODS

Eligibility requirements included stage III or IV NSCLC, performance status < or = 1, and no prior chemotherapy. Gemcitabine was administered as a 30-minute intravenous infusion weekly for 3 weeks every 4 weeks. We enrolled patients at doses that ranged from 1,000 to 2,800 mg/m2/wk (three patients per cohort). Responses were assessed after every two courses (8 weeks).

RESULTS

We treated 33 chemotherapy-naive patients with stage III (n = 5) or IV (n = 28) NSCLC. Most had performance status 1, and 67% had adenocarcinoma. Eight of 32 assessable patients (25%) achieved a partial response. The projected median survival duration (all patients) is 49 weeks. The maximum-tolerated dose was 2,200 mg/m2/wk for 3 weeks every 4 weeks; dose-limiting toxicity was myelosuppression and reversible transaminase elevation. Other side effects were consistently mild. The maximum dose-intensity achieved with the first two cycles was 2,362 mg/m2/wk for 3 weeks every 4 weeks, which is a feasible phase II starting dose.

CONCLUSION

This study estimates a phase II starting dose of gemcitabine in chemotherapy-naive patients to be 2,400 mg/m2/wk for 3 consecutive weeks every 4 weeks; this is much higher than that previously reported in heavily pretreated patients. Twenty-five percent of patients with advanced NSCLC achieved a partial response to gemcitabine. This significant activity in conjunction with a very favorable toxicity profile supports the further evaluation of gemcitabine in combination with other active agents.
Thymidylate synthase inhibitors in cancer therapy: direct and indirect inhibitors.
Authors: Rustum Y M , Harstrick A , Cao S , Vanhoefer U , Yin M B , Wilke H , Seeber S
Published: February 2017

PURPOSE AND METHODS

Although fluoropyrimidines, in particular, fluorouracil (5-FU) and fluorodeoxyuridine (FdUrd), are active alone and in combination with other agents in a variety of human malignancies, therapeutic selectivity, resistance, and efficacy have been a major limitation in cancer therapy. Preclinical and clinical results in advanced and adjuvant colorectal cancers confirmed that the therapeutic efficacy of fluoropyrimidines, with thymidylate synthase (TS) as a primary target, can be improved significantly with leucovorin (LV) modulation. With the recognition that TS is an important therapeutic target, direct and specific inhibitors have been developed and are under intensive preclinical and clinical evaluation, primarily in patients with colorectal cancer, with demonstrable activity. The direct TS inhibitors have been shown to be potent, with a high level of specificity under therapeutic conditions for TS. This includes ZD1694, AG337, and LY231514. To date, although the therapeutic activity of both direct and indirect inhibitors of TS is similar, differences in the magnitude and profile of toxicity have been observed. A phase III comparative evaluation of a direct inhibitor of TS (ZD1694) with an indirect inhibitor (5-FU/LV) has been completed and showed similar activity but reduced toxicity in favor of ZD1694.

RESULTS

Recognition that greater than 95% of the injected dose of 5-FU is rapidly inactivated by dihydropyrimidine dehydrogenase (DPD) to therapeutically inactive products, but with toxicity to normal tissues, led to the development of inhibitors of this enzyme with the aim to modify the therapeutic index of 5-FU. Several inhibitors in combination with 5-FU are under preclinical and clinical evaluation, including uracil and 5-chloro-2,4-dihydroxy pyridine, as modulators of 5-FU derived from its prodrug tegafur and 5-ethynyluracil as a modulator of 5-FU.

CONCLUSION

In this review, an update of the present status of direct and indirect inhibitors of TS is discussed, as well as the future prospect for new drugs alone and in combination.
Fifteen-year survival and recurrence rates after radiotherapy for localized prostate cancer.
Authors: Eastham J A , Kattan M W , Groshen S , Scardino P T , Rogers E , Carlton C E , Lerner S P
Published: February 2017

PURPOSE

To determine 15-year survival and recurrence rates after radiotherapy for localized prostate cancer.

METHODS

One hundred thirty-six patients with clinically localized prostate cancer treated from 1966 to 1974 with interstitial gold seed and external-beam irradiation were evaluated to determine the probability of recurrence and survival > or = 15 years after therapy. All patients were surgically staged with pelvic lymphadenectomy and none received hormonal therapy before relapse.

RESULTS

Overall, 60 patients (44%) have never recurred, although 57% (34 of 60) of these same patients have died of causes other than prostate cancer. Local progression developed in 39% of patients and distant metastases in 42%. At 15 years, the probability of dying of prostate cancer was 33%+/-8% (% +/- 2SE) and of all causes was 72%+/-8%. In clinical stage A2 and B, 29%+/-9% of patients died of their cancer within 15 years, compared with 57%+/-21% in stage C1, while only 18%+/-8% with clinical stage A2 and B and negative lymph nodes died of cancer within this period. In contrast, the prostate cancer mortality rate at 15 years was high for patients with positive nodes regardless of the stage of the primary tumor (73% for A2 and B; 71% for C1). Patients with nodal metastases, poorly differentiated tumors, and advanced local disease all had a significantly (P < .0001) increased risk of cancer death.

CONCLUSION

The cancer-specific mortality rate for patients with stage A2 and B tumors and negative nodes compares favorably with other series of patients treated with radiation therapy and > or = 15 years' follow-up evaluation. While local progression rates are high and associated with a substantial risk of prostate cancer death, many patients live with the disease and ultimately die of causes other than prostate cancer.
Quantitation of intratumoral thymidylate synthase expression predicts for disseminated colorectal cancer response and resistance to protracted-infusion fluorouracil and weekly leucovorin.
Authors: Leichman C G , Lenz H J , Leichman L , Danenberg K , Baranda J , Groshen S , Boswell W , Metzger R , Tan M , Danenberg P V
Published: February 2017

PURPOSE

Response rates to fluorouracil (5-FU)-based therapy remain low. As new, active agents are being tested, information regarding specific intratumoral genetic determinants of chemotherapy sensitivity or resistance can be used to plan therapy rationally. Intratumoral thymidylate synthase (TS) quantitation may be among the most important determinants of sensitivity or resistance to 5-FU.

MATERIALS AND METHODS

Forty-six disseminated colorectal cancer patients had measurable tumor biopsies for polymerase chain reaction (PCR)-based determination of TS mRNA pretreatment. Protracted infusion of 5-FU 200 mg/m2/d for 21 days with weekly intravenous leucovorin 20 mg/m2 each cycle was given. After two cycles, responses were evaluated. Response data were correlated with independently determined intratumoral ratios of TS/beta-actin mRNA for each patient.

RESULTS

TS/beta-actin ratios were successfully obtained for 42 patients (91%). TS/beta-actin ratios ranged from 0.3 x 10(-3) to 18.2 x 10(-3) (median, 3.5 x 10[-3]). Twelve patients (26%) responded to treatment (median TS/beta-actin ratio, 1.7 x 10[+3]). Thirty-four patients did not respond (median TS/beta-actin ratio, 5.6 x 10[-3]). No patient with a TS mRNA level greater than 4.1 x 10(-3) responded. The median TS/beta-actin ratio (3.5 x 10[-3]) significantly segregated responders from nonresponders (P = .001). Median survival for patients with TS/beta-actin ratios < or = 3.5 x 10(-3) was 13.6 months; for patients with TS/beta-actin ratios greater than 3.5 x 10(-3), it was 8.2 months (P = .02).

CONCLUSION

For this cohort, the intratumoral TS/beta-actin ratio had a statistically significant association with response and survival. This relationship for other 5-FU schedules remains unknown. Confirmation of these data in a larger patient population could lead to determination of therapy for disseminated colorectal cancer based on a specific intratumoral molecular parameter.
High-dose cyclophosphamide for poor-prognosis and recurrent pediatric brain tumors: a dose-escalation study.
Authors: Yule S M , Foreman N K , Mitchell C , Gouldon N , May P , McDowell H P
Published: February 2017

PURPOSE

To determine the maximum-tolerated dose (MTD) of cyclophosphamide (CTX) when administered over 2 consecutive days followed by hematopoetic stem-cell rescue given as two sequential courses to children with glioblastoma multiforme, poor-prognosis pontine gliomas, and other recurrent CNS tumors.

PATIENTS AND METHODS

Two identical doses of CTX were administered 24 hours apart to 14 children and followed by hematopoetic stem-cell rescue. This treatment was repeated immediately following hematologic recovery. The starting dose of CTX was 2.5 g/m2/d with increments of 0.5 g/m2/d. CTX pharmacokinetics and metabolism were measured during 22 courses of treatment. Toxicity and tumor response were recorded.

RESULTS

There were two toxic deaths at the dose level of 4 g/m2/d. These were not clearly related to cardiac toxicity and may have been due to generalized capillary leak syndrome. Thus, the MTD of CTX was 3.5 g/m2/ d. There were six complete responses (CRs) (46%; (95% confidence interval [CI], 19% to 73%) and four partial responses (PRs) (31%; 95% CI, 6% to 56%), and one patient achieved stable disease. All children with intracranial primitive neuroectodermal tumors (PNETs) improved following CTX. The median duration of tumor response was 6 months (range, 4 to 29) and only one patient remains disease-free following CTX alone. Overall survival is 21% (95% CI, 13% to 29%) at a median follow-up time of 27 months (range, 12 to 34).

CONCLUSION

The MTD of CTX when followed by hematopoetic stem-cell rescue is 3.5 g/m2 administered on each of 2 consecutive days. This treatment was tolerable in children with poor-prognosis brain tumors and produced complete responses in children with recurrent PNETs.
Phase II trial of docetaxel in non-Hodgkin's lymphomas: a study of the Cancer and Leukemia Group B.
Authors: Budman D R , Petroni G R , Johnson J L , Cooper M R , Schlossman D M , Barcos M , Peterson B A
Published: February 2017

PURPOSE

To evaluate the new anticancer agent, docetaxel, with a novel mechanism of action in patients with non-Hodgkin's lymphoma International Working Formulation (IWF) A through H, to determine the response rate by histologic group and the toxicities of this agent in this population.

PATIENTS AND METHODS

Sixty-eight patients previously treated for non-Hodgkin's lymphoma with two prior cytotoxic regimens for low-grade and one prior regimen for intermediate-grade lymphoma were entered onto this phase II trial. Central pathologic review was required. Twenty-four IWF A to C and 31 IWF D to H patients with normal hepatic and renal function, performance status (PS) 0 to 2, and adequate hematologic function were eligible. Patients received docetaxel 100 mg/m2 intravenously over 1 hour without corticosteroid premedications every 3 weeks with weekly hematologic monitoring, and tumor assessment every 3 weeks. For grade 3 or 4 hematologic toxicity, the docetaxel dosage was lowered to 75 mg/m2. Patients received a maximum of six cycles of therapy.

RESULTS

The major response rate was 13% (95% confidence limits, 3% to 32%) for IWF A to C and 16% (95% confidence limits, 5% to 34%) for IWF D to H; response durations ranged from 1.4 to 20 months. Time to response ranged from 1.3 to 2.8 months. Patients refractory to previous chemotherapy were less apt to respond to docetaxel, but the differences were not statistically different in this small sample size. Twelve percent of IWF A to C and 6% of IWF D to H patients discontinued treatment because of toxicity. The major toxicity was granulocytopenia (grade 3 to 4), which occurred in virtually all patients during the first course of therapy.

CONCLUSION

This study confirms that docetaxel has limited but definite activity in patients with non-Hodgkin's lymphoma and suggests that the previously reported responses with taxanes can not be attributed solely to the use of corticosteroid premedications.
Intensive weekly chemotherapy for advanced gastric cancer using fluorouracil, cisplatin, epi-doxorubicin, 6S-leucovorin, glutathione, and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer.
Authors: Cascinu S , Labianca R , Alessandroni P , Marcellini M , Silva R R , Pancera G , Testa E , Martignoni G , Barni S , Frontini L , Zaniboni A , Luporini G , Cellerino R , Catalano G
Published: February 2017

PURPOSE

A multiinstitutional trial was performed to confirm the clinical activity, in terms of response rate and toxicity (primary objectives) and duration of responses and survival (secondary objectives), of an intensive weekly regimen in advanced gastric cancer.

PATIENTS AND METHODS

Patients with measurable unresectable and/or metastatic gastric carcinoma received 1-day per week administration of cisplatin (CDDP) 40 mg/m2, fluorouracil (5FU) 500 mg/m2, epi-doxorubicin (epi-ADR) 35 mg/m2, 6S-stereoisomer of leucovorin 250 mg/m2, and glutathione 1.5 g/m2. On the other days, filgrastim was administered by subcutaneous injection at a dose of 5 mg/kg. One cycle of therapy consisted of eight 1-week treatments. Patients who showed a response or stable disease received a further 6 weeks of therapy.

RESULTS

Of 105 enrolled patients, 11 had locally advanced unresectable disease only; 33 had primary nonresected and metastatic disease; 48 had metastatic disease and primary tumor resected; 10 had locoregional recurrence and metastatic disease; and three had locoregional recurrence only. After one cycle, 18 complete responses (CRs) and 47 partial responses (PRs) were achieved, for an overall response rate of 62% (95% confidence interval [CI], 53% to 71%). Twenty patients had stable disease and 20 progressed on therapy. The median survival duration of all 105 patients was 11 months, with 1- and 2-year survival rates of 42% and 5%, respectively. World Health Organization (WHO) grade III to IV toxicity, in terms of anemia, neutropenia, thrombocytopenia, and mucositis, was experienced by 40 patients (38%). There were no treatment-related deaths.

CONCLUSION

These data support the results of the pilot study and confirmed the high activity of the regimen, with acceptable toxicity. This schedule deserves evaluation in the adjuvant setting.