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.     

Why does cancer therapy lack effective anti-metastasis drugs?

The suppression of cancer metastasis is an urgent therapeutic need. Yet, most existing drugs inhibit only cancer cell proliferation. Historically, the reason is the much later elucidation of the molecular biology of metastasis versus that of the early steps in transformation. Because the molecules that drive the dissemination of malignant cells are shared among cancers, drugs that inhibit their functions will be broadly beneficial. There are two complementary anti-metastasis strategies, the prevention of cancer cell dissemination and the suppression of already existing metastases. To accelerate the availability of potentially life-saving anti-metastasis agents several adjustments must be made. The risk tolerance in drug trials needs to increase with a worsening prognosis. Clinical trials of drug molecules that prevent cancer dissemination need to be approved for use right after diagnosis, not after failure of standard-of-care therapies. For agents that treat existing metastases, the clinical trial system needs to be modernized. Because cancer metastasis is often fatal, improved and innovative approaches to anti-metastasis drugs are eminently suited to play a lead role in changing the standards of drug development.     

Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy?

Personalized medicine for oestrogen receptor-α (ERα)-positive breast cancer requires predictive biomarkers for broad endocrine resistance as well as biomarkers capable of predicting resistance to a specific agent. In addition, biomarkers could be used to select patients that might benefit from the addition of treatments that do not target ERα. However, biomarker identification studies seem to be far from consistent and identified biomarkers seldom face an introduction into clinical practice. Importantly, most of the studies that seek to identify biomarkers have been performed using material from consecutive series of patients treated with tamoxifen (the most commonly prescribed ERα antagonist). Consequently, the predictive value of any biomarker identified is confounded by its prognostic value. Another important issue is the lack of differentiation between premenopausal and postmenopausal patients with breast cancer. The hormonal environment of a tumour in patients who are premenopausal is intrinsically distinct from those arising in postmenopausal women. Biomarkers of different biological mechanisms might enable the prediction of either broad endocrine resistance or resistance to a specific agent in each of these patient subtypes. Ultimately, improvements to study design are needed to establish the clinical validity of the most promising biomarkers to predict benefit from endocrine therapy.     

Anti-VEGF therapy as adjuvant therapy: clouds on the horizon?

Anti-angiogenic therapies have demonstrated their value in the setting of advanced cancer, and are being explored for use in micrometastatic disease. Recent preclinical studies suggest that adjuvant anti-vascular endothelial growth factor (VEGF) therapies may increase the risk of metastasis. How concerning are these preclinical studies, and should they affect our willingness to explore anti-VEGF therapy in the adjuvant setting?     

Durable efficacy of adjuvant radiation therapy for prostate cancer: will the benefit last?

Radical prostatectomy can be an effective therapy for men with organ-confined disease. However, extension beyond the confines of the prostate (pT3) can be found in many men, and this is often associated with longterm prostate-specific antigen (PSA) failure. Not all patients will progress with pT3 disease. The identification of additional adverse prognostic features (high Gleason score, PSA greater than 10 ng/mL, and seminal vesical invasion) can help identify those men at highest risk of progression following definitive surgery. The role of postoperative therapy in patients with high-risk features is often controversial. The lack of long-term survival benefit, toxicity, and cost are often cited. We reviewed our experience with a unified approach to this patient population and performed matched-pair analysis of patients with similar adverse prognostic features treated with and without postoperative radiation therapy. For our series, the results indicate that the addition of adjuvant radiation therapy is associated with a significantly reduced risk of PSA recurrence. The 5-year bNED rate after adjuvant radiation therapy was 89% (95% CI: 76% to 100%) compared with 55% (95% CI: 34% to 79%) after surgery alone (P = .002). This benefit also appears to hold true for men with pathological involvement of their seminal vesicles. A dose-response curve was observed with improved disease control above a level of 61.2 Gy. Appropriate patient selection and delivery of an adequate dose of radiation can improve the PSA recurrence of most patients with pT3 disease.     

Lung cancer clinicians’ preferences for adjuvant chemotherapy in non-small-cell lung cancer: What makes it worthwhile?

Aims

We sought (i) lung cancer clinicians’ judgements about the smallest survival benefits that would make the harms of adjuvant chemotherapy for non-small-cell lung cancer (NSCLC) worthwhile, (ii) factors associated with their judgements, and (iii) comparisons with breast cancer and colon cancer clinicians surveyed similarly in 2002-2003.

Methods

Delegates at the Australian Lung Cancer Conference 2008 were invited to complete a validated, self-administered questionnaire that used the time trade-off method to determine the minimum survival benefits judged sufficient to make adjuvant chemotherapy worthwhile. The baseline survival times were 3 and 5 years, and the baseline 5-year survival rates were 50% and 65%. Chemotherapy was 4 cycles of cisplatin and vinorelbine.

Results

Characteristics of the 156 respondents were: median age 41 years (range 23-62), female 55%, married 83%, with dependent children 62%, respiratory physician 28%, nurse 24%, medical oncologist 14%, radiation oncologist 12%, trial nurse/coordinator 12%, thoracic surgeon 4%. Moderate survival benefits were judged sufficient to make chemotherapy worthwhile. The median benefit judged sufficient was an extra 9 months beyond a baseline survival time of 3 or 5 years. The median benefit judged sufficient was an extra 5% for a baseline survival rate of 65%, versus an extra 10% for a baseline survival rate of 50% (p < 0.001). Smaller benefits were judged sufficient by clinicians who were married (p = 0.02) or had dependants (p = 0.04). Lung cancer clinicians judged smaller benefits sufficient than breast cancer (n = 89) and colon cancer (n = 72) clinicians in similar prior studies (median required benefit of 9 months versus 12 months, p < 0.001).

Conclusion

Most lung cancer clinicians attending a national lung cancer conference judged moderate improvements in survival sufficient to make adjuvant chemotherapy worthwhile. Smaller benefits were judged sufficient by lung cancer clinicians in 2008 than by breast cancer and colon cancer clinicians 5-6 years earlier. Clinicians should be aware of their own preferences, and explore their patients’ preferences, when discussing adjuvant chemotherapy.     

What is the ideal duration of adjuvant therapy for primary breast cancer: are four cycles of cyclophosphamide and doxorubicin enough?

For 25 years we have known that adjuvant chemotherapy improves both disease-free and overall survival for many of our patients with primary breast cancer. We also know that these therapies have significant toxicities and are not always effective. We have therefore focused a great deal of effort into maximizing the effectiveness of adjuvant chemotherapy and defining just how much chemotherapy, with respect to both dose and duration, is necessary to achieve this maximum benefit. In our attempt to define these parameters through clinical trials, we have been faced with many options, and we may not yet have defined an optimal regimen of chemotherapy, or an optimal duration. Although many physicians in the United States consider four cycles of cyclophosphamide and doxorubicin as “standard of care” for patients with primary breast cancer, many feel that both choice of regimen and duration of treatment remain controversial. The reasons for this uncertainty and lack of clarity are complex, and they are addressed in this review.     

What is the Japanese consensus on adjuvant chemotherapy in breast cancer?

The international conference of adjuvant therapy for primary breast cancer in St. Gallen and the National Institute of Health Consensus Conference for Breast Cancer Treatment have recommended appropriate treatment for individual subgroups by recurrence risk. However, evidence provided by Japanese clinical trials did not contribute to the consensus recommendations. To compare the risk of recurrence in breast cancer patients between Japan and western countries, a database of Japanese breast cancer patients was analyzed. From 1991 to 2001, approximately 12100 articles listed on MEDLINE were reviewed by abstract, and articles were then selected and reviewed by the authors. According to the AHPC (Agency for Health Care Policy and Research), quality assessment and strength for recommendation of the evidence from clinical trials were classified. Even though there are likely some unknown ethnic differences, we should provide Japanese patients with state of the art treatment for breast cancer in accordance with global standard therapies, which have been evaluated by breast cancer specialists in western countries.     

Patients' preferences for adjuvant endocrine therapy in early breast cancer: what makes it worthwhile?

Adjuvant endocrine therapy improves recurrence and survival rates, but has side effects and is inconvenient. The aim of this study was to determine the preferences of premenopausal women who had adjuvant endocrine therapy in a randomised trial. In all, 85 (or eighty-five) women completed semistructured interviews 6-30 months after finishing adjuvant endocrine therapy. Hypothetical scenarios based on known potential survival times (5 or 15 years) and rates (60% or 80% at 5 years) without adjuvant endocrine therapy were used to determine the smallest gains women judged necessary to make their adjuvant endocrine therapy worthwhile. Although a third of the women considered gains of 1% in survival rates or 6 months in survival times sufficient to make their adjuvant endocrine therapy worthwhile, more than half the women required gains of at least 5% in survival rates or 3 years in survival time as necessary to make adjuvant endocrine therapy worthwhile. Larger benefits were required by women who had longer treatment, worse side effects, and by those who were treated with goserelin alone. The route of administration (tablet vs injection) did not affect preferences and some women judged small benefits sufficient to make their adjuvant endocrine therapy worthwhile, but many women required larger benefits than their counterparts in similar studies of preferences for adjuvant chemotherapy.     

Resected non-small-cell lung cancer stage I/II: indication for adjuvant/neoadjuvant therapy?

Complete surgical resection remains the current standard of care for operable patients with stage-I or stage-II non-small-cell lung cancer. However, there is a strong rationale that supports the concept of the addition of systemic therapy to surgery either preoperatively or postoperatively even in patients with early-stage disease, as distant relapse continues to be the dominant form of relapse after surgical resection of NSCLC. Earlier trials of adjuvant therapy have yielded mixed results and the survival gains demonstrated have been modest at best. However, recently presented data of randomised phase-III trials showed an absolute survival benefit of 12-15% for patients with completely resected stage-IB and stage-II NSCLC receiving adjuvant platinum-based chemotherapy compared with observation alone. These trials provide resounding approval for adjuvant chemotherapy being the new standard of care for patients with early-stage non-small-cell lung cancer who have undergone complete resection of the tumour.     

Why did p53 gene therapy fail in ovarian cancer?

Promising preclinical and clinical data led to the initiation of an international randomised phase II/III trial of p53 gene-therapy trial for first-line treatment of patients with ovarian cancer. In that trial, replication-deficient adenoviral vectors carrying wild-type p53 were given intraperitoneally in combination with standard chemotherapy to patients with ovarian cancers harbouring p53 mutations. The study was closed after the first interim analysis because an adequate therapeutic benefit was not shown. In this review, we discuss the possible reasons for failure of p53 gene therapy, which include the multiple genetic changes in cancer and epigenetic dysregulations leading to aberrant silencing of genes. These complex interactions lead us to conclude that repair of single genes might not be a suitable strategy for the treatment of cancer. Moreover, dominant negative cross talk between ectopic wild-type p53 and recently identified dominant p53 mutants and splice variants of p63 and p73--which are frequently overexpressed in ovarian cancers--could seriously compromise the effectiveness of p53 gene therapy. Other substantial problems in targeting tumour cells with adenoviral vectors are the heterogeneity or lack of expression of coxsackie-adenovirus receptors and integrin co-receptors in ovarian tumours and the presence of adenovirus-neutralising antibodies in ovarian cancer-related ascites.     

Rectal cancer staging: is there an optimal method?

The staging process in a newly diagnosed rectal cancer is divided into three parts. One essential part is the local staging, in which both endorectal ultrasound and MRI are used to disclose the size of the tumor and its correlation to the perirectal fascia, and to identify lymph node deposits and vascular invasion. This local staging process will guide clinicians to decide upon not only the type of surgery (local excision or radical surgery) but also whether or not some type of neoadjuvant treatment, such as radiotherapy and/or chemotherapy, is indicated. The second part is to evaluate whether or not the tumor has already metastasized at diagnosis. The most important organs to evaluate are the liver and lungs, and imaging techniques such as ultrasound, CT-scan, or sometimes PET-CT, and MRI can be used. The third important part is to investigate the rest of the large bowel for synchronous adenomas or cancers. This will preferably be done with colonoscopy or CT-colonography and sometimes barium enema. This article discusses the imaging techniques used for local staging and distant metastases.