Phase I study of concurrent and consolidation cisplatin and docetaxel chemotherapy with thoracic radiotherapy in non-small cell lung cancer.

BACKGROUND: We designed a phase i study of concurrent chemoradiotherapy (ccrt) with docetaxel (D) and cisplatin (C), followed by consolidation dc, for unresectable stage iii non-small cell lung cancer (nsclc). METHODS: Patients with histologically proven and unresectable stage iii nsclc were eligible. During ccrt, C was given every 3 weeks (75 mg/m2) and D given weekly. The starting dose of D was 20 mg/m2, escalated in cohorts of 3 to define the maximum tolerated dose (mtd). Radiotherapy was prescribed to a dose of 60 Gy in 30 fractions. This was followed by 2 cycles of consolidation dc, which were dose escalated if ccrt was tolerated. RESULTS: Twenty-six patients were enrolled, with 1 excluded following evidence of metastatic disease. Nineteen patients completed both phases of treatment. There were 7 grade 3 events during ccrt (5 esophagitis, 2 nausea), and 8 grade 3 events during consolidation (2 neutropenia, 2 leukopenia, 1 esophagitis, 2 nausea, and 1 pneumonitis). Three patients had grade 4 neutropenia. No patients died due to toxicities. The mtd of concurrent weekly D was 20 mg/m2. Consolidation D and C were each dose escalated to 75 mg/m2 in 8 patients. The median overall survival (os) and progression-free survival (pfs) of all patients were 33.6 months and 17.2 months, respectively, with median follow-up of 26.6 months (range 0.43-110.8). CONCLUSIONS: The use of docetaxel 20 mg/m2 weekly and cisplatin 75 mg/m2 every 3 weeks concurrent with thoracic radiotherapy, followed by consolidation docetaxel and cisplatin, both given at 75 mg/m2 every 3 weeks, appears to be safe in this phase i trial.

What are the factors that predict outcome at relapse after previous esophagectomy and adjuvant therapy in high-risk esophageal cancer?

OBJECTIVES: The present study investigated factors affecting outcome at relapse after previous surgery and adjuvant chemoradiation (crt) in high-risk esophageal cancer patients. PATIENTS AND METHODS: From 1989 to 1999, we followed high-risk resected esophageal cancer patients who had completed postoperative crt therapy. Patients who relapsed with a disease-free interval of less than 3 months were treated with palliative crt when appropriate. Patients with a disease-free interval of 3 months or more were treated with best supportive care. Post-recurrence survival was estimated using the Kaplan-Meier technique, and statistical comparisons were made using log-rank chi-square tests and Cox regression. RESULTS: Of the 69 patients treated with adjuvant crt after esophagectomy, 46 experienced recurrence. Median time to relapse was 28 months (range: 0.1-40 months). Among the 46 relapsed patients, median age was 61 years (range: 37-82 years), and 42 were men. At the initial staging, 44 of 46 were node-positive; 31 of 46 had adenocarcinoma. In 33 of 46, post-esophagectomy resection margins were clear. Median follow-up after recurrence was 30.5 months (range: 1.3-100 months). Median overall survival after recurrence was 5.8 months, and the 12-month, 24-month, and 36-month survival rates were 20%, 10%, and 5% respectively. Of the prognostic factors analyzed, only resection margin status and interval to recurrence were statistically significant for patient outcome in univariate and multivariate analysis. Patients who had positive resection margins and who relapsed 12 or fewer months after surgery and adjuvant crt had a median post-recurrence overall survival of 0.85 months as compared with 6.0 months in other patients (more than 12 months to relapse, or negative resection margins, or both; log-rank p = 0.003). CONCLUSIONS: Resection margin status and interval to disease relapse are significant independent prognostic factors for patient outcome after adjuvant crt therapy.

Sunitinib malate for gastrointestinal stromal tumour in imatinib mesylate-resistant patients: recommendations and evidence.

QUESTION: Is sunitinib malate-marketed as Sutent (Pfizer Canada, Kirkland, QC)-superior to placebo or other interventions for primary outcomes of interest in adult patients with gastrointestinal stromal tumour (GIST) who have developed resistance or who exhibit intolerance to imatinib mesylate (IM)? BACKGROUND: In patients with resectable disease, surgery is the mainstay of treatment for GIST; in patients with unresectable or metastatic disease, the tyrosine kinase inhibitor IM is the therapy of choice. However, some patients have primary resistance or intolerance to IM, or they progress after optimal exposure (including an escalated dose). Here, we review the evidence for treating IM-resistant GIST with sunitinib malate. METHODS: Studies of sunitinib malate were identified through MEDLINE, EMBASE, the Cochrane Library databases, and Web sites of guideline organizations. Outcomes of interest included time to progression, progression-free survival, overall survival, and toxicity. RESULTS: One phase III randomized controlled trial, and one abstract and presentation describing that trial, served as the evidentiary base for this clinical practice guideline. Trial data confidently show that both time to progression and progression-free survival are highly statistically significant (p < 0.0001) in favour of sunitinib malate over placebo. Overall survival was improved with sunitinib malate (hazard ratio: 0.49; 95% confidence interval: 0.29 to 0.83; p = 0.007; absolute difference in weeks not reported). The most frequent of all adverse effects (experienced in greater proportion by patients on sunitinib malate) were grades 1 and 2 leucopenia (52% vs. 5% with placebo), neutropenia (43% vs. 4%), and thrombocytopenia (36% vs. 4%). Grade 3 hematologic adverse events were also reported more frequently in the sunitinib malate group, including leucopenia (4% vs. 0%), neutropenia (8% vs. 4%), lymphopenia (9% vs. 2%), and thrombocytopenia (4% vs. 0%). Toxicity comparisons did not include p values. The incidence of grades 1-3 fatigue was greater for the sunitinib malate group (34% vs. 22% with placebo). Other grade 3 nonhematologic treatment-related adverse events that occurred more frequently on sunitinib malate included hand-foot syndrome (4% vs. 0%), diarrhea (3% vs. 0%), and hypertension (3% vs. 0%). No grade 4 adverse events were observed. CONCLUSIONS: In the target population, sunitinib malate is the recommended option for second-line therapy of metastatic GIST.

Management of hot flashes in women with breast cancer.

Hormone-suppression therapies are used for the treatment of breast cancer in the adjuvant and metastatic settings alike. However, side effects-including hot flashes-are frequently reported by patients as a cause of therapy discontinuation. This paper presents an overview of hormonal therapies and the evidence-based management options for hot flashes, summarized in a treatment algorithm.

Management of aromatase inhibitor-induced arthralgia.

Aromatase inhibitors (AIs) are commonly used as adjuvant treatment in postmenopausal women with hormone receptor-positive early breast cancer. With both steroidal and nonsteroidal AIs, AI-induced arthralgia is frequently observed. The mechanism of AI-induced arthralgia remains unknown, and the data available from clinical trails using AIs are limited. We review the pertinent information from a clinical perspective, including an algorithm to treat AI-induced arthralgia.

Relative dose intensity delivered to patients with early breast cancer: Canadian experience.

Adjuvant chemotherapy for early breast cancer improves disease-free and overall survival in pre- and postmenopausal women. The importance of maintaining relative dose intensity (RDI) is well-known; however, little information is available from routine clinical practice regarding how well dose intensity is maintained with modern chemotherapy regimens.In a retrospective review of patients undergoing chemotherapy for early breast cancer at a single institution in Canada from January 2006 to November 2007, a total of 263 patients received one of the following regimens:AC-T [doxorubicin (Adriamycin: Pharmacia, Kalamazoo, MI, U.S.A.)-cyclophosphamide, paclitaxel (Taxol: Bristol-Myers Squibb, Princeton, NJ, U.S.A.)]FEC-100 (5-fluorouracil-epirubicin-cyclophosphamide)FEC-D (5-fluorouracil-epirubicin-cyclophosphamide, docetaxel)Overall, only 14.4% of patients had a RDI less than 85%. Dose delay or reduction (or both) occurred in 46%, 37%, and 20% of patients receiving fec-100, ac-t, and fec-d respectively. Optimal RDI was delivered to 96%, 95%, and 70.7% of patients for ac-t, fec-d and fec-100 regimens respectively. Patients over 65 years of age accounted for 14% of the total cohort and were more likely to receive a suboptimal RDI than were patients younger than 65 years of age (35% vs. 6.6%).Optimal chemotherapy RDI (>85%) for early breast cancer can be achieved at an academic cancer centre. This goal is less often accomplished in elderly patients, and thus a proactive approach is required for managing toxicity in that population.

An updated review on the efficacy of adjuvant endocrine therapies in hormone receptor-positive early breast cancer.

The third-generation aromatase inhibitors (AIS) are largely replacing tamoxifen in the adjuvant treatment of early-stage breast cancer in postmenopausal women with hormone receptor-positive tumours. To date, multiple trials have been conducted comparing tamoxifen treatment with an AI, and all have demonstrated improved disease-free survival with AI treatment. Trials have included direct 5-year comparisons between tamoxifen and an AI, switching to an AI within 5 years after initial tamoxifen treatment, or extending treatment with an AI after 5 years of completed tamoxifen treatment. Some of these trials have been completed; others are ongoing; and head-to-head trial comparisons of individual AIS are also in progress. The present article summarizes the data obtained from various clinical trials of hormonal therapy for early breast cancer. It also reviews recent data so as to shed light on the current status of these therapies. The focus is on the efficacy of treatment with an AI. Toxicity is discussed in the second article in this supplement.

Postoperative extended-volume external-beam radiation therapy in high-risk esophageal cancer patients: a prospective experience.

BACKGROUND AND PURPOSE: Extended-volume external-beam radiation therapy (RT) following esophagectomy is controversial. The present prospective study evaluates the feasibility of extended-volume RT treatment in high-risk esophagectomy patients with a cervical anastomosis receiving postoperative combined chemoradiation therapy. PATIENTS AND METHODS: From 2001 to 2006, 15 patients with resected esophageal cancer were prospectively accrued to this pilot study to evaluate the adverse effects of extended-volume RT. Postoperative management was carried out at London Regional Cancer Program. Eligibility criteria were pathology-proven esophageal malignancy (T3-4, N0-1), disease amenable to surgical resection, and esophagectomy with or without resection margin involvement. Patients with distant metastases (M1) and patients treated with previous RT were excluded. All 15 study patients received 4 cycles of 5-fluorouracil-based chemotherapy. External-beam RT was conducted using conformal computed tomography planning, with multi-field arrangement tailored to the pathology findings, with coverage of a clinical target volume encompassing the primary tumour bed and the anastomotic site in the neck. The radiation therapy dose was 50.40 Gy at 1.8 Gy per fraction. The RT was delivered concurrently with the third cycle of chemotherapy. The study outcomes-disease-free survival (DFS) and overall survival (OS)-were calculated by the Kaplan-Meier method. Treatment-related toxicities were assessed using the U.S. National Cancer Institute's Common Toxicity Criteria. RESULTS: The study accrued 10 men and 5 women of median age 64 years (range: 48-80 years) and TNM stages T3N0 (n = 1), T2N1 (n = 2), T3N1 (n = 11), and T4N1 (n = 1). Histopathology included 5 adenocarcinomas and 10 squamous-cell carcinomas. Resection margins were clear in 10 patients. The median follow-up time was 19 months (range: 3.5-53.4 months). Before radiation therapy commenced, delay in chemotherapy occurred in 20% of patients, and dose reduction was required in 13.3%. During the concurrent chemoradiation therapy phase, 20% of the patients experienced chemotherapy delay, and 6.6% experienced dose reduction. No patient experienced treatment-related acute and chronic esophagitis above grade 2. Disease recurred in 40% of the patients (6/15), and median time to relapse was 24 months. No tumour recurred at the anastomotic site. The median DFS was 23 months, and the median OS was 21 months. CONCLUSIONS: Extended-volume external-beam RT encompassing the tumour bed and the anastomotic site is feasible and safe for high-risk T3-4, N0-1 esophageal cancer patients after esophagectomy.

Dose-intensive chemotherapy with growth factor or autologous bone marrow or stem-cell transplant support in first-line treatment of advanced or metastatic adult soft tissue sarcoma: a clinical practice guideline.

QUESTIONS: In patients with inoperable locally advanced or metastatic soft tissue sarcoma, does first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem-cell transplantation improve response rate, time to disease progression, or survival as compared with standard-dose chemotherapy? What are the effects of first-line dose-intensive chemotherapy supported by growth factor or autologous bone marrow or stem-cell transplantation on toxicity and quality of life? PERSPECTIVES: Because therapeutic options for adult patients with advanced or metastatic soft tissue sarcoma are scarce and the possibility of cure for these patients is extremely limited, the Sarcoma Disease Site Group (dsg) felt that a review of the available literature on dose-intensive chemotherapy for adult patients with locally advanced or metastatic soft tissue sarcoma and subsequent development of a clinical practice guideline based on the evidence were important. METHODOLOGY: A systematic review was developed and clinical recommendations relevant to patients in Ontario were drafted. The practice guideline report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, a pathologist, a methodologist, and community representatives. External review by Ontario practitioners was obtained through a mailed survey, the results of which were incorporated into the practice guideline. Final review and approval of the practice guideline was obtained from the Report Approval Panel. PRACTICE GUIDELINE: Based on the systematic review, consensus, and external review, the Sarcoma dsg makes these recommendations: Dose-intensive chemotherapy with growth factor support is not recommended in the first-line treatment of patients with inoperable locally advanced or metastatic soft tissue sarcoma. The data are insufficient to support the use of high-dose chemotherapy with autologous bone marrow or stem-cell transplantation as first-line treatment in this group of patients. Eligible patients should be encouraged to enter clinical trials assessing novel approaches or compounds. QUALIFYING STATEMENTS: High-dose chemotherapy with growth factor or autologous bone marrow or stem-cell transplantation has adverse effects similar to those seen with standard-dose chemotherapy. With high-dose regimens, the incidence of grades 3 and 4 thrombocytopenia is significantly higher, and neutropenic fever and febrile neutropenia occur more frequently. Compared with standard treatment, the rate of treatment-related death is also higher with high-dose regimens.

Ifosfamide-based combination chemotherapy in advanced soft-tissue sarcoma: a practice guideline.

QUESTIONS: In adult patients with inoperable locally advanced or metastatic soft-tissue sarcoma, do combination chemotherapy regimens containing ifosfamide have an advantage in terms of response rate, time to progression, or survival, as compared with similar regimens without ifosfamide when used as first-line therapy? What are the adverse effects and effects on quality of life of ifosfamide-containing combination chemotherapy as compared with similar regimens without ifosfamide? PERSPECTIVES: The prognosis for patients with inoperable or meta-static soft-tissue sarcoma (sts) remains grim. Although the surgical resection of pulmonary metastases may be curative in 15%-30% of patients with isolated slow-growing metastases, most patients receive chemotherapy for palliative purposes. Ifosfamide has documented activity in patients who have received prior treatment with, or who have progressed on, doxorubicin. A number of studies have suggested a schedule and a dose-response relationship for ifosfamide in metastatic sts. Ifosfamide has also been assessed in combination with other drugs such as doxorubicin and dacarbazine (dtic); results of such studies have led some authors to suggest that polychemotherapy using "appropriate doses" of ifosfamide and doxorubicin may represent the "most effective systemic treatment" in this population. Given the limited effective therapeutic options available for patients with metastatic sts, the Sarcoma Disease Site Group (dsg) felt that a need existed to more specifically evaluate the potential benefits of ifosfamide-containing combination chemotherapy in that setting. The Sarcoma dsg developed an evidence-based series report through systematic review, evidence synthesis, and input from practitioners across Ontario. OUTCOMES: Outcomes of interest included survival, response rate, adverse events, and quality of life. METHODOLOGY: A systematic review and meta-analysis served as the evidentiary base for this clinical practice guideline. The report was reviewed and approved by the Sarcoma dsg, which comprises medical oncologists, radiation oncologists, surgeons, methodologists, and patient representatives. The results of an external review by Ontario practitioners, obtained through a mailed survey, were incorporated into this report. Final approval of the evidence-based series report was obtained from the Report Approval Panel of Cancer Care Ontario's Program in Evidence-Based Care (pebc). RESULTS: The current practice guideline reflects a combination of the draft recommendations (based on the evidence identified in a systematic review and meta-analysis) and the external feedback from Ontario practitioners and the pebc's Report Approval Panel. PRACTICE GUIDELINE: In patients with metastatic sts, the addition of ifosfamide to standard first-line doxorubicin-containing regimens is not recommended over single-agent doxorubicin. However, in patients with symptomatic, locally advanced, or inoperable sts, in whom tumour response might potentially result in reduced symptomatology or render a tumour resectable, use of ifosfamide in combination with doxorubicin is reasonable. QUALIFYING STATEMENT: In combination with a doxorubicin-containing regimen, the dose of ifosfamide should not exceed 7.5 g/m(2), given as either a split bolus or a continuous infusion.

Modulation of mRNA levels during human keratinocyte differentiation.

Cultures of human keratinocytes provide an excellent model system in which to study differentiation. Using the phorbol ester 12-O-tetradecanoyl-phorbol 13-acetate (TPA) and calcium, two agents known to induce keratinocyte differentiation in vitro, we examined the expression of the genes encoding c-fos, c-myc, and c-jun; involucrin, a protein precursor of the keratinocyte cornified envelope; and L-7, a ribosomal protein. Overall, at the doses studied, TPA induced a more rapid and profound differentiation than did calcium, as evaluated by culture morphology and northern blot analysis. Our studies showed a constant low level of c-fos and c-jun expression in unstimulated cells with no significant change after addition of either TPA or calcium except when transcript breakdown was inhibited by cycloheximide. The c-myc proto-oncogene, known to have a high constitutive expression in actively proliferating cells, was strongly downregulated by TPA, but calcium had no effect over a 32 hour period, consistent with the greater growth inhibition of TPA in this system. Involucrin was induced about ninefold by both TPA and calcium as early as 8 hours after stimulation, suggesting transcriptional regulation of this gene during differentiation. L-7, recently demonstrated to be downregulated in late passage human fibroblasts in an in vitro model of senescence, was also strongly downregulated by either TPA or calcium, consistent with an interrelationship between the basic cellular processes of aging and differentiation. These finding expand our knowledge of the differentiation process in human keratinocytes.

Autoimmunity and malignancy.

In patients with autoimmune diseases malignancy is observed more frequently than in an age-matched control group. In strains of mice susceptible to autoimmune diseases, the incidence of lymphoreticular malignancies is increased. Although viruses have not been directly implicated in their pathogenesis or etiology, there are suggestions that slow viruses may be involved. Viruses have been found to be important in the development of lymphomas. Hence in genetically susceptible animals, viruses can initiate the autoimmune process. Prolonged stimulation of the autoimmune process or a prolonged state of immunodeficiency could trigger or activate genes or their products, which could result in the development of malignancy.

The relationship of pemphigus to neoplasia.

A statistically increased incidence of malignancy has been observed in patients with pemphigus. A review of the literature reveals 42 cases of nonthymic malignancies and 18 cases of thymic malignancies. A significant predominance of men, with mean age at onset of 50 years, was observed. Pemphigus vulgaris is more common in patients with nonthymic neoplasms, whereas pemphigus foliaceus or pemphigus erythematosus and pemphigus vulgaris are equally common in patients with thymic neoplasms. Lymphoreticular malignancies, especially Kaposi's sarcoma, are most frequently observed. The majority of patients with nonthymic neoplasms have pemphigus before the detection of the malignancy and have a favorable 5-year survival rate after tumor resection. The majority of the patients with thymic neoplasms have a thymoma before the development of pemphigus. In some patients pemphigus develops after thymectomy and myasthenia gravis is often associated. Overall, 37 of the 60 patients, or 61%, had a neoplasm of the immune system.