Lara Maria Pasetto

Complete Pathologic Response Following Preoperative Chemoradiation Therapy for Middle to Lower Rectal Cancer Is Not a Prognostic Factor for a Better Outcome

PURPOSEThe aim of this study was to evaluate factors associated with pathologic tumor response following preoperative chemoradiation therapy, and the prognostic impact of pathologic response on overall and disease-free survival.METHODSBetween 1994 and 2002, 132 patients underwent chemoradiation therapy followed by surgery for middle to lower rectal cancer. After excluding 26 cases (metastatic cancer, n = 13; nonradical surgery, n = 6; local excision procedure, n = 4; non-5-fluorouracil-based chemotherapy, n = 2; incomplete data on preoperative chemoradiation therapy regimen used, n = 1), the remaining 106 patients were included in the study. Variables considered were the following: age, gender, tumor location, pretreatment T and N stage, modality of 5-fluorouracil administration, total radiotherapy dose delivered, chemoradiation therapy regimen used (Regimen A: chemotherapy (bolus of 5-fluorouracil and leucovorin, days 1–5 and 29–33) + radiotherapy (45 Gy/25 F/1.8 Gy/F); Regimen B: chemotherapy (5-fluorouracil continuous venous infusion ± weekly bolus of carboplatin or oxaliplatin) + radiotherapy (50.4 Gy/28 F/1.8 Gy/F)), time interval between completion of chemoradiation therapy and surgery, postoperative chemotherapy administration, surgical procedures, pT, pN, and pTNM stage, and response to chemoradiation therapy defined as tumor regression grade, scored from 1 (no tumor on surgical specimen) to 5 (absence of regressive changes). Statistical analysis was performed by means of logistic regression analysis (Cox’s model for overall and disease-free survival).RESULTSMedian age of the 106 patients was 60 (range, 31–79) years and the male:female ratio, 66:40. Median distance of tumor from the anal verge was 6 (range, 1–11) cm. Pretreatment TNM stage, available in 104 patients, was cT3–T4N0, n = 41; cT2N1, n = 9; cT3N1, n = 39; and cT4N1, n = 17. The median radiotherapy dose delivered was 50.4 (range, 40–56) Gy; 58 patients received 5-fluorouracil by continuous venous infusion, and carboplatin with oxaliplatin was added to the chemotherapy schedule in 71 cases. Patients were given Regimen A in 47 cases and Regimen B in 59. The median interval between chemoradiation therapy and surgery was 42.5 (range, 19–136) days, and 94 patients underwent a sphincter-saving procedure. Tumor regression grade, available in 104 cases, was 1, n = 19; 2, n = 18; 3, n = 15; 4, n = 13; and 5, n = 39. At a median follow-up of 42 (range, 1–110) months, 11 patients had died, and 95 were alive. None of the patients had local recurrences, but 13 had distant recurrences. At logistic regression analysis, the chemoradiation therapy regimen used was the only independent predictor of tumor response following preoperative chemoradiation therapy (odds ratio = 0.29, 95% confidence interval = 0.13–0.67, P = 0.003). At Cox’s regression analysis, pretreatment T stage was the only independent prognostic factor for both disease-free survival (relative risk = 7.13, 95% confidence interval = 2.3–21.8, P = 0.001) and overall survival (relative risk = 4.83, 95% confidence interval = 1.1–19.9, P = 0.029).CONCLUSIONSTumor response following preoperative chemoradiation therapy is mainly related to the preoperative regimen used. For patients receiving preoperative chemoradiation therapy, pretreatment T stage, but not tumor response to preoperative chemoradiation therapy, is prognostic for outcome (both disease-free and overall survival).

Temozolomide in patients with high grade gliomas.

The incidence of central nervous system neoplasias ranges from 3.8 to 5.1 cases per 100,000 inhabitants. First-line treatment of brain tumors consists of surgery associated with radiotherapy, and followed or not by chemotherapy. When used as an adjuvant therapy after surgery and radiotherapy, chemotherapy prolongs the time to progression and the median survival time. At relapse, chemotherapy is the common therapeutic approach. In recent years, new drugs for the treatment of brain tumors have been tested, and some of them, such as temozolomide, are very promising.

Vulnerable and frail elderly: An approach to the management of the main tumour types

In dealing with older cancer patients undergoing chemotherapy, some form of geriatric evaluation is needed to distinguish those which can be treated as adults from those - the vulnerable ones - who need a modified approach and also from those who are frail or too sick to receive an active treatment. Only scarce data are available to guide treatment of vulnerable or frail patients, the neglected majority of older cancer patients. In most of these cases they receive an adapted approach which does not derive from the results of clinical trials, but from an enlightened empiricism. In this article we summarise and discuss available data for management of the main tumour types in frail and vulnerable patients, and call for further research in this field.

Old and new drugs in systemic therapy of pancreatic cancer

BACKGROUND The incidence of pancreatic cancer nearly equals its death rate (97%). Two-year survival is about 10%. Chemotherapy treatment is problematic because of the palliative and limited duration of response. MATERIAL AND METHODS The article analyzes the objective response and median survival time (MST) for old and new drugs in the treatment of pancreatic cancer. RESULTS The most encouraging results to date come from studies of 5-fluorouracil (5FU) as an adjuvant therapy and of gemcitabine in the advanced disease, which is one of the most active and best tolerated drugs in recent years. However, with the introduction of new drugs or with different old drug associations, interesting results are also becoming evident. CONCLUSIONS New approaches to CT treatment are necessary. Patient enrollment into rigorous and well conducted clinical trials, either at tumor diagnosis or after tumor recurrence, will generate new information regarding investigational therapies and it will offer improved therapies for patients with this disease.

High-dose chemotherapy with bone marrow rescue for high-grade gliomas in adults.

High-grade malignant gliomas are inevitably fatal, despite every effort to improve this prognosis, including various radiotherapeutic modalities, radio- and chemotherapeutic associations, and combinations of several drugs. High-dose chemotherapy and autologous bone-marrow transplantation (ABMT) have been increasingly used in the last 10 years for solid tumors, and several phase II studies in high-grade glioma patients have been conducted in the setting of both adjuvant treatment and recurrent disease. The most frequently used drug in the conditioning regimens is BCNU at doses higher than that employed by other regimens in other pathologies (800–1000 mg/m2). These dosages involve a high toxicity that is not balanced by a significant improvement in survival. New drugs and/or regimens must be tested in randomized trials.

Changing boundaries in the treatment of malignant gliomas

Malignant gliomas are still among the most lethal and difficult tumors to treat; even the most intensive combinations of radio- and chemotherapy are not curative and yield only a modest impact on survival for most of these patients, as long-term survivors are less than 10%. There is a major need for new chemotherapeutic drugs and alternative therapeutic modalities. This review aims to define the best standard treatment in the common clinical practice and also summarizes the most promising lines of investigational research in the field of neuro-oncology, which will probably offer new and long-awaited valid therapy options for brain tumor patients.

Determining Therapeutic Approaches in the Elderly with Rectal Cancer

BackgroundTo evaluate the toxicity and feasibility of pelvic radiotherapy (RT) and/or surgery in elderly patients with locally advanced low-lying rectal cancer.Patients and methodsFrom November 1999 to November 2005, 51 patients aged ≥70 years who underwent RT for locally advanced low-lying rectal cancer were retrospectively examined. Variables considered were age, co-morbidities (evaluated according to the Charlson score and the Cumulative Illness Rating Scale-Geriatric [CIRS-G] score) and surgery versus no surgery.ResultsThe median age was 80 years (range 70–94 years) and the male: female ratio was 33: 18. A total of 5.9% of patients were considered ‘fit’, 72.5% had one or more CIRS-G grade 1 or 2 co-morbidities and 21.6% had one or more CIRS-G grade 3 co-morbidities. 54.9% of patients underwent surgery and 45.1% underwent RT. Only 9 of 21 (42.8%) patients who underwent radical resection received the full course of adjuvant RT and only seven (50%) of all patients treated with RT alone received the full dose of therapy. Patients with one or more CIRS-G grade 3 co-morbidities reported similar numbers of grade 1–2 toxicities as patients with one or more CIRS-G grade 2 co-morbidities.ConclusionNotwithstanding the small number of patients analysed, the findings of this study indicate that elderly patients with rectal cancer and mild comorbidities could probably receive the same treatment as fit elderly patients, given that tolerability appeared to be similar in both categories of patients. Neither age nor co-morbidities should be considered reasons to deny the patient the possible benefits of receiving complete treatment. Moreover, Multidimensional Geriatric Assessment should always be undertaken to help clinicians make better decisions about treatment. Further prospective trials are needed to confirm these results.

Glutathione S-Transferase P1 Ile105Val Polymorphism is Associated with Haematological Toxicity in Elderly Rectal Cancer Patients Receiving Preoperative Chemoradiotherapy

AbstractBackground: Increasing evidence suggests that common gene polymorphisms may influence the toxicity of various cytotoxic agents used in the treatment of cancer. Objective: To evaluate the predictive value of acute toxicity of methylenetetrahydrofolate reductase 677T polymorphism, glutathione S-transferase P1 (GSTP1) substitution of isoleucine with valine at codon 105 (Ile105Val) polymorphism and the tandem repeat polymorphism in the thymidylate synthase gene promoter in elderly patients with rectal cancer receiving preoperative chemoradiotherapy (CRT). Method: From 1994 to 2002, 166 Caucasian patients underwent surgery following CRT for mid-low rectal cancer at a single institution, 42 (male-to-female ratio, 25:17) of whom were aged ≥65 years (median age 70 years, range 65–79). The pre-treatment clinical stage was tumour (T) stage 3–4 in 38 patients and node (N)-positive in 29 patients. Patients received external-beam radiotherapy with conventional fractionation and fluorouracil-based chemotherapy. Blood samples were used to extract and amplify DNA. Gene polymorphisms were determined by polymerase chain reaction and restriction enzyme digestion. Acute toxicity to preoperative therapy was reported according to the National Cancer Institute Common Toxicity Criteria, version 2. Univariate and multivariate analyses were performed using one-way analysis of variance and linear regression, respectively. Results: Haematological toxicity (grade 1–2) was observed in 15 of 40 patients for whom toxicity data were available and gastrointestinal toxicity (grade 1–4) in 24 of these same 40 patients. At univariate analysis, female sex (p = 0.036) and GSTP1 Ile105Val (p = 0.0376) were associated with haematological toxicity. At multivariate analysis, GSTP1 Ile105Val polymorphism (p = 0.041) was the only factor found to be associated with haematological toxicity. Patients carrying the Val/Val genotype in the GSTP1 gene had a lower risk of haematological toxicity (odds ratio = 0.322, 95% CI 0.101, 0.957) than patients with the Ile/Ile genotype. Conclusion: GSTP1 Ile105Val polymorphism is a promising marker of potential haematological toxicity in elderly patients with rectal cancer receiving preoperative CRT.

Endocrine dysfunctions in patients treated for brain tumors: incidence and guidelines for management.

Endocrine alterations are frequently found in patients undergoing treatment for CNS tumors. Careful follow-up aimed at the early detection of recurrences, with life-long monitor of hypothalamus–pituitary (HP) function, will also reveal any endocrine dysfunctions; indeed, their appropriate diagnosis and treatment may determine a significant improvement in the quality of life of these patients.

Improved tolerability of chemotherapy in soft tissue sarcomas: old and new strategies

Anthracyclines and alkylating agents (ifosfamide, Mitoxana®) are the mainstays of chemotherapy for soft tissue sarcoma and as there is a close correlation between dose- intensity and response, methods should be developed to ameliorate the clinical tolerability of these agents. Improvements in the efficacy of medical treatments for soft tissue sarcomas may derive from old strategies by aiming to counteract the side effects of standard chemotherapy regimes and from new, less toxic, anticancer drugs. This paper reviews the currently available options for reducing the cardiotoxicity of anthracyclines, the role of growth factors and autologous stem cell transplantation in dose-intensification of chemotherapy and also examines the clinical impact of the more promising new agents.