Combination of anti-estrogenic therapy with radiation in breast cancer: simultaneous or sequential treatment?

Adjuvant radiotherapy and adjuvant endocrine therapy are commonly given to patients with invasive breast cancer or with ductal carcinoma in situ (DCIS). Although both therapies have been well established through a number of randomized studies, little is known about a possible interaction of both treatment modalities if they are given simultaneously. A number of in vitro studies indicated that tamoxifen treatment might reduce the intrinsic radiosensitivity of MCF-7 breast cancer cells. Conversely, estradiol treatment increased the intrinsic radiosensitivity of MCF-7 cells. This phenomenon has not been found in clinical studies. Retrospective analyses of prospectively randomized clinical studies did not indicate an antagonistic effect of tamoxifen on the effectiveness of ionizing radiation (XRT), since local control has been consistently higher when XRT was combined with tamoxifen, compared to treatment with XRT alone, regardless of whether tamoxifen was started simultaneously with radiotherapy or after completion of radiotherapy. Currently there are no clinical data available that would suggest an adverse effect of adjuvant tamoxifen treatment started prior to or simultaneously with radiotherapy in breast cancer or DCIS. However, since an antagonistic effect of tamoxifen and simultaneous chemotherapy has been reported recently, the issue of simultaneous.     

IMRT or conformal radiotherapy for adjuvant treatment of retroperitoneal sarcoma?

Purpose

To compare the dose distribution between three-dimensional conformal radiotherapy (3DCRT), intensity modulated radiotherapy (IMRT) with six coplanar beams (6b-IMRT) and IMRT with nine coplanar beams (9b-IMRT) during adjuvant radiotherapy for retroperitoneal sarcoma.

Methods and materials

The 10 most recent patients who had received adjuvant radiotherapy were reviewed. Three different treatment plans were generated (3DCRT, 6b-IMRT and 9b-IMRT) to deliver 50.4 Gy in 28 fractions. The dose delivered to the organs at risk (intestinal cavity (IC), contra- and ipsilateral kidney, liver, stomach and whole body), and the conformity index (CI) were compared.

Results

The integral dose to the intestinal cavity was similar with the three modalities but the dose distribution was different, with a change-over around 25 Gy: the V50 and the V40 were reduced five- and twofold, respectively, with IMRT compared to 3DCRT, and the V20 was increased by about 25% with IMRT.A similar integral dose was delivered to the whole body with the three modalities. The treated volume (V95 body) was approximately halved with IMRT compared to 3DCRT, and the CI was twice as good with IMRT than with 3DCRT. As expected, the V5 (body) was higher with IMRT compared to 3DCRT (p < 0.0001) (a 12% increase with 6b-IMRT and a 21% increase with 9b-IMRT).Compared to 3DCRT, the mean dose delivered to the contralateral kidney increased from 1.5 to 4-4.4 Gy with IMRT.The number of monitor units was increased with IMRT, especially when nine beams were used instead of six.

Conclusions

As expected, IMRT greatly reduced the high-dose irradiated volume and increased the low-dose exposure of the intestinal cavity, with a change-over around 25 Gy, compared to 3DCRT. The conformity index was compellingly better with IMRT. The integral dose delivered to the whole body was conserved with both 3DCRT and IMRT.Longer follow-up is needed to assess late toxicities to the small bowel, contralateral kidney and the risk of second cancers.     

The FACE trial: letrozole or anastrozole as initial adjuvant therapy?

The adjuvant Femara versus Anastrozole Clinical Evaluation (FACE) trial compares upfront therapy letrozole 2.5 mg with anastrozole 1 mg daily for up to 5 years in postmenopausal, hormone receptor-positive, node-positive breast cancer patients.

This phase III b open label, randomized, multicenter study will include 4000. patients from up to 250 international sites. Patients will be stratified by degree of lymph node involvement and HER-2 status. Any efficacy and safety difference of the two drugs will be reported. Primary objective is DFS, secondary objectives are safety, OS, time to distant metastases, time to contralateral breast cancer and breast cancer specific survival.     

Neoadjuvant or adjuvant chemotherapy: what is the best treatment of muscle invasive bladder cancer?

Bladder cancer is the fourth most common cancer for men and the eighth most common cancer for women. Transitional cell carcinoma is the most predominant histological type. Bladder cancer is highly chemosensitive. In metastatic setting the treatment is based on cisplatin chemotherapy regimens type MVAC, MVAC-HD or gemcitabine plus cisplatin. The standard treatment of muscle invasive operable bladder cancer (T2–T4) used widely was radical cystectomy with pelvic lymph nodes dissection; the anatomical extent of pelvic lymphadenectomy has not accurately been defined so far. However, in the last decade, the treatment of tumors was improved by the introduction of chemotherapy as part of the management of the disease. Neoadjuvant chemotherapy should be considered at first, as standard treatment of choice, before local treatment for patients with good performance status (0–1) and good renal function–glomerular filtration rate (GFR) >60 mL/min. For patients treated with primary surgery, adjuvant chemotherapy is a valuable option in the case of lymph nodes involvement. This brief review would provide the evidence of the role of neoadjuvant chemotherapy in the management of operable muscle invasive (T2–T4) bladder cancer.     

Leiomyosarcoma of the rectum: What role does adjuvant therapy play?

Leiomyosarcoma of the rectum is an exceedingly rare malignancy and for this reason the literature fails to provide definitive management guidelines with regard to the place of adjuvant therapies. The role of radiotherapy (RT) is often downplayed on the basis of articles written at a time when state-of-the art RT equipment was unavailable. A case of leiomyosarcoma of the rectum is presented and the literature is reviewed. Because the rarity of this tumour type virtually precludes a prospective randomized trial of adjuvant therapies, the authors recommend (in otherwise fit patients) postoperative pelvic RT because its morbidity is minimal. Smaller tumours may benefit to a greater extent than those lesions that are large at presentation and thereby run a worse clinical course.     

Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy?

Aspirin inhibits the enzyme cyclooxygenase (Cox), and there is a significant body of epidemiological evidence demonstrating that regular aspirin use is associated with a decreased incidence of developing cancer. Interest focussed on selective Cox-2 inhibitors both as cancer prevention agents and as therapeutic agents in patients with proven malignancy until concerns were raised about their toxicity profile. Aspirin has several additional mechanisms of action that may contribute to its anti-cancer effect. It also influences cellular processes such as apoptosis and angiogenesis that are crucial for the development and growth of malignancies. Evidence suggests that these effects can occur through Cox-independent pathways questioning the rationale of focussing on Cox-2 inhibition alone as an anti-cancer strategy. Randomised studies with aspirin primarily designed to prevent cardiovascular disease have demonstrated a reduction in cancer deaths with long-term follow-up. Concerns about toxicity, particularly serious haemorrhage, have limited the use of aspirin as a cancer prevention agent, but recent epidemiological evidence demonstrating regular aspirin use after a diagnosis of cancer improves outcomes suggests that it may have a role in the adjuvant setting where the risk:benefit ratio will be different.     

Rectal cancer adjuvant therapy controversies: When? What? Why?

Although the need for adjuvant therapy in high-risk rectal cancer is widely accepted, controversies continue regarding timing, mode, and agents employed. The current recommended practice and its scientific basis are reviewed. Studies of induction therapy are discussed. Evidence of efficacy of new anticancer agents and modes of drug delivery are presented.     

Taxanes in the adjuvant treatment of breast cancer: why not yet?

The taxanes paclitaxel and docetaxel represent the most active chemotherapeutic agents developed for the treatment of advanced breast cancer in the last decade, and they are now being incorporated into adjuvant chemotherapy trials for lymph node-positive breast cancer with the hope of improving on the results achieved with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) or anthracycline-based regimens. So far, three randomized paclitaxel-based adjuvant clinical trials enrolling 3170 women (Cancer and Leukemia Group B [CALGB] 9344), 3060 women (National Surgical Adjuvant Project for Breast and Bowel Cancers [NSABP]-B28), and 524 women (M. D. Anderson), respectively, have been reported with respective median follow-up times of 52, 34, and 43 months. This article critically reviews these three studies and gives an overview of the many other randomized clinical trials, due to accrue more than 17 000 women, which are investigating the potential of taxanes in adjuvant breast cancer therapy. Given that the early promise of taxanes suggested by CALGB 9344 is not yet confirmed by the two other trials, only level 2 evidence has been reached to date in regard to a positive contribution of these agents to breast cancer outcome in the adjuvant setting. It is argued that level 1 evidence is highly desirable before adopting taxane-based regimens in standard practice. It is anticipated that a meta-analysis will be needed to comprehensively define the value of taxanes in early breast cancer, and a new model of international collaboration is proposed to find a balance between the need to offer new, more effective therapies to patients as soon as possible and the danger of drawing wrong, premature conclusions regarding the magnitude of benefit of a new regimen.     

Does use of the adjuvant! model influence use of adjuvant therapy through better risk communication?

Adjuvant! is a model that provides recurrence and mortality risk predictions for patients with breast cancer considering adjuvant therapies. Although low-risk patients who saw Adjuvant! chose adjuvant therapy less frequently, whether this was because of educational or other aspects of the decision aid is unknown. The authors explored whether Adjuvant! affects choice of therapy through increased patient knowledge. A subset of data were analyzed from a cluster randomized trial in which oncology practices in 2 major United States cities were randomly assigned to use either Adjuvant! or an informational pamphlet to educate patients. Of 405 patients, 48 were low-risk, with 28 assigned to the decision aid and 20 to the pamphlet. Among the low-risk patients, using frequency tables and Fisher exact tests, the authors explored whether Adjuvant! was associated with more accurate patient estimates of survival; whether accuracy was associated with treatment choice; and whether, after controlling for accuracy, any remaining association was seen between Adjuvant! and treatment choice. Adjuvant! was associated with more accurate estimates of baseline prognosis compared with the pamphlet (57% vs. 25%; P = .04). Patients who had more accurate estimates of baseline prognosis were less likely to choose adjuvant therapy (62% vs. 89%; P = .04). After controlling for accuracy, no statistically significant association was found between the use of Adjuvant! and adjuvant therapy (P = .59 and P = .11 for inaccurate and accurate patients, respectively). Adjuvant! seems to influence patient choice through educational rather than other means of persuasion. However, many patients held inaccurate risk perceptions after viewing Adjuvant!.     

Metronomic scheduling of anticancer treatment: the next generation of multitarget therapy?

Metronomic scheduling of anticancer treatment (MSAT) is progressively gaining interest after the antiangiogenic properties of metronomic chemotherapy and its potential to overcome drug resistance was initially described in 2000. MSAT has now grown beyond the anticipated scope of antiangiogenic chemotherapy, with accumulating evidence demonstrating that these treatments may also act by stimulating an antitumor immune response and could ultimately lead to reinduction of tumor dormancy. An increasing number of drugs, not initially developed as anticancer agents, are currently being used in metronomic protocols in order to increase treatment efficacy. Interestingly, these 'repositioned' agents can target cancer cells, the tumor vasculature or, more broadly, the tumor microenvironment. Malignant tumors are no longer regarded as simple congregations of cancer cells but as genuine tissues with various components such as blood vessels, fibroblasts, inflammatory cells and an extracellular matrix. These different components and their multiple interactions play a crucial role in tumor development and response to treatment. Therefore, future anticancer treatments will have to take into account the tumor microenvironment and aim to target the different cellular and molecular participants encompassed in a tumor, as well as their specific interactions. In this article, we explain why MSAT represents a very attractive strategy for developing next-generation multitarget therapies.     

What is the optimal treatment volume in Hodgkin's disease patients undergoing high-dose chemotherapy and adjuvant radiation therapy?

To determine the optimal treatment volume in Hodgkin's disease patients undergoing high-dose chemotherapy (HDCT) and radiation therapy (RT), failure sites were reviewed in 56 patients. Twenty-one (38%) received involved-field RT (IFRT) before or after HDCT encompassing sites of prior disease. Failure sites were designated as previously involved (old) or uninvolved (new) sites. Seven patients (12%) died in the immediate post-HDCT period, leaving 49 evaluable (median follow-up, 41 months). Twenty-five patients (51%) relapsed (14 HDCT, 11 HDCT + IFRT): seven (28%) in old, eight (32%) in new, and ten (40%) in old and new sites. Six of the seven who relapsed in old sites received HDCT alone, whereas seven of the eight who relapsed in new sites received IFRT. Relapse in old sites was particularly common in patients failing to achieve a complete response. The most common new failure site was nodal, occurring in 11 patients and was primarily (10/11) adjacent to an old site. Although it controls prior disease, IFRT is insufficient in Hodgkin's disease patients undergoing HDCT. Relapse is common in new nodal sites and is primarily adjacent to prior sites. These results suggest that extended-field RT encompassing old and adjacent uninvolved nodal sites may be the optimal treatment volume in these patients.     

Anthracyclines and taxanes in the neo/adjuvant treatment of breast cancer: does the sequence matter?

BackgroundIn early breast cancer, adjuvant chemotherapy decreases the risks of recurrence and breast cancer mortality, and neoadjuvant treatment leads to equivalent long-term outcomes. A large number of clinical trials have attempted to refine systemic therapeutic strategies in early breast cancer, but little attention has been paid to the sequence of anthracyclines and taxanes. Based on preclinical observations, there is limited rationale to administer the taxane before the anthracycline.MethodsWe searched PubMed, the American Society of Clinical Oncology website, and clinicaltrials.gov with the goal of identifying published or ongoing studies that aimed at comparing reverse sequences of anthracyclines and taxanes. Given the nature and the small number of studies identified, we did not attempt to quantitatively pool the study results.ResultsWe retrieved seven studies in the adjuvant setting and eight in the neoadjuvant setting: 10 randomized trials (only 2 were phase IIII), 3 retrospective studies, and 2 ongoing phase II trials. A total of nearly 5000 patients were included in such studies. None of the clinical trials has shown disadvantages in terms of efficacy or toxicity for sequences in which the taxane was administered first. In the neoadjuvant setting, studies have collectively shown similar or increased pathological complete response rates for sequences in which the taxane was administered first.ConclusionGiven the available information, there seems to be sufficient evidence to suggest that a taxane followed by an anthracycline is a sequence option that can be incorporated into daily clinical practice.     

Radiation therapy for older adults with glioblastoma: radical treatment,palliative treatment,or no treatment at all?

The incidence of glioblastoma in older adults has increased over the last few decades. Current treatment includes surgery, radiotherapy, and chemotherapy, but optimal disease management remains a matter of debate. Both standard (60 Gy in 30 daily fractions) and hypofractionated radiotherapy (30–40 Gy in 10–15 daily fractions) have been employed with a similar survival benefit. Recent randomized studies indicate that chemotherapy with the alkylating agent temozolomide is a safe and effective therapeutic option for patients aged 60 years or older with newly diagnosed glioblastoma, suggesting that it should be a sufficient treatment for patients presenting with a methylated O6-methylguanine-DNA methyltransferase (MGMT) promoter gene. The addition of concomitant temozolomide chemotherapy, adjuvant temozolomide chemotherapy, or both to postoperative radiotherapy, which is the standard treatment for adults with glioblastoma, has been associated with a survival benefit for older patients with a good performance status; however, aggressive treatment in this population may be associated with a high risk of neurological toxicity and deterioration of quality of life. Survival stratification according to age, MGMT promoter methylation status, and neurological status may be useful for clinical decision making and designing randomized trials for adequately evaluating the optimal combination of radiotherapy and chemotherapy for older patients with glioblastoma.