Adaptive radiotherapy for head and neck cancers: Fact or fallacy to improve therapeutic ratio?

Modern standards of precision radiotherapy, primarily driven by the technological advances of intensity modulation and image guidance, have led to increased versatility in radiotherapy planning and delivery. The ability to shape doses around critical normal organs, while simultaneously “painting” boost doses to the tumor have translated to substantial therapeutic gains in head and neck cancer patients. Recently, dose adaptation (or adaptive radiotherapy) has been proposed as a novel concept to enhance the therapeutic ratio of head and neck radiotherapy, facilitated in part by the onset of molecular and functional imaging. These contemporary imaging techniques have enabled visualisation of the spatial molecular architecture of the tumor. Daily cone-beam imaging, besides improving treatment accuracy, offers another unique angle to explore radiomics – a novel high throughput feature extraction and selection workflow, for adapting radiotherapy based on real-time tumor changes. Here, we review the existing evidence of molecular and functional imaging in head and neck cancers, as well as the current application of adaptive radiotherapy in the treatment of this tumor type. We propose that adaptive radiotherapy can be further exploited through a systematic application of molecular and functional imaging, including radiomics, at the different phases of planning and treatment.     

Anal cancer: is neoadjuvant cisplatin chemotherapy or chemoradiotherapy friend or foe?

This Practice Point commentary discusses the findings of the Intergroup RTOG 98-11 trial, which aimed to investigate both the potential role of cisplatin as neoadjuvant chemotherapy, and also its role concurrently in combination with radiotherapy, for anal-canal carcinoma. Although chemoradiotherapy has had an important effect on the treatment of anal cancer, and allows preservation of anorectal function with survival rates similar to or better than those of surgical treatment, overall survival rates for advanced tumors are still in the region of 50-60% at 5 years. A strong theoretical rationale for cisplatin-based treatment in anal cancer exists; several phase II trials have demonstrated a high response rate with reduced colostomy rates. The Intergroup results are disappointing in that neoadjuvant chemotherapy with cisplatin and 5-fluorouracil, followed by cisplatin-based chemoradiotherapy did not improve overall survival, disease-free survival and locoregional control when compared with the standard treatment of combined 5-fluorouracil and mitomycin chemoradiotherapy.     

Antiangiogenic therapy, hypoxia, and metastasis: risky liaisons, or not?

All human cells, including cancer cells, need oxygen and nutrients to survive. A widely used strategy to combat cancer is therefore the starvation of tumor cells by cutting off the blood supply of tumors. Clinical experience indeed shows that tumor progression can be delayed by anti-angiogenic agents. However, emerging evidence indicates that in certain experimental conditions, hypoxia as a result of pruning of the tumor microvasculature can promote tumor invasion and metastasis, although these findings are contextual and debated. Genetic studies in mice unveiled that vascular-targeting strategies that avoid aggravation of tumor hypoxia or even promote tumor oxygenation might prevent such an invasive metastatic switch. In this article, we will discuss the emerging link between hypoxia signaling and the various steps of metastasis.     

The Benefit of the Neutropenic Diet: Fact or Fiction?

There really should not be a debate about the use of neutropenic diet for cancer patients. Its usefulness has never been scientifically proven. However, neutropenic diets remain in place in many institutions even though their usefulness is controversial. Neutropenic diets were once thought to be important in protecting patients from having to succumb to infection from neutropenia while undergoing chemotherapy. Although food may contain harmful organisms and research has shown that bacterial translocation is possible, recent studies have been unable to obtain significant differences between placebo and intervention groups. The dietetic challenges neutropenic patients struggle with include decreased quality of life, malnutrition, gastrointestinal side effects, food aversion, and impaired cell-mediated immunity from vitamin deficiency. Unanswered questions in regard to the neutropenic diet include the following: (a) which food should be included; (b) which food preparation techniques improve patient compliance; (c) which patient populations benefit most; and (d) when should such a diet be initiated. Without scientific evidence, the best advice for neutropenic patients is to follow food safety guidelines as indicated by government entities.     

Prognostic outcomes and decision-making for local-regional therapy after neoadjuvant chemotherapy: Pretreatment clinical staging or posttreatment pathologic staging?

Presurgical chemotherapy is increasingly implemented as it improves breast conservation rates and may reveal novel information about therapeutic response. However, neoadjuvant therapy raises questions about prognosis and decision making for adjuvant local-regional therapy. Current prognostic information and therapeutic treatment planning is typically based on American Joint Committee on Cancer staging information for patients treated with adjuvant therapy. This information is not readily applicable to patients treated with neoadjuvant chemotherapy, however, as neither pretreatment clinical staging data nor post-treatment pathologic data alone accurately reflect disease status. This review summarizes the implementation of a new staging system for patients receiving neoadjuvant therapy. This system combines clinical and pathologic staging factors with biologic markers to refine the prognostic assessment of patients treated with neoadjuvant therapy. Controversies related to neoadjuvant therapy and sentinel lymph node biopsy, postmastectomy radiation therapy, and breast conservation are also discussed.     

Concurrent oxaliplatin,capecitabine, and radiation therapy in the neoadjuvant therapy of rectal adenocarcinoma: can we get the right dose first?

In the December 2005 issue of Annals of Oncology, Machiels etal. reported on a phase II study of weekly oxaliplatin, dailycapecitabine Mondays through Fridays, and radiation therapyin the neoadjuvant therapy of patients with T3 or T4 or anynodally positive adenocarcinoma of the rectum [1].     

Using aromatase inhibitors in the neoadjuvant setting: evolution or revolution?

Despite improvements in the management of patients with early breast cancer, the prognosis for women with locally advanced breast cancer (LABC) remains poor. The potential goals of neoadjuvant treatment for this disease include down-sizing tumours to allow breast conservation as well as the possibility of improving survival rates. Neoadjuvant treatment was initially dominated by chemotherapy, which increased rates of breast conserving surgery, but to date has demonstrated no survival benefit over standard adjuvant chemotherapy. With recent advances in endocrine therapy, and rapid and routine assessment of predictive factors of response such as estrogen (ER), progesterone (PR) and Her2 nu receptor status, endocrine therapy has come to the forefront of research investigating a neoadjuvant alternative to chemotherapy. Early studies of neoadjuvant endocrine therapy mainly evaluated the role of tamoxifen in the treatment of elderly postmenopausal women with LABC who were unselected for ER/PR status and were unsuitable for either surgery or chemotherapy. Response rates in these patients were found to be inferior to those traditionally obtained from trials with neoadjuvant chemotherapy. Paralleling the superiority that third-generation aromatase inhibitors have shown over tamoxifen in the metastatic and adjuvant settings however, AIs have also demonstrated superiority in the neoadjuvant setting. Recent studies have shown response rates for neoadjuvant treatment with aromatase inhibitors in carefully selected hormone receptor positive patients to be comparable to those seen with neoadjuvant chemotherapy. This is particularly important as hormone receptor positive tumours have repeatedly been shown to have lower response rates to neoadjuvant chemotherapy than hormone receptor negative tumours. Neoadjuvant endocrine treatment with aromatase inhibitors has therefore evolved from being an experimental effort to palliate women with LABC unsuitable for surgery or chemotherapy, to representing a viable and possibly preferred alternative for postmenopausal women with hormone receptor positive large tumours or LABC. Further benefits of neoadjuvant trials include allowing the study of predictive biomarkers of disease in order to provide insight into therapy resistance and sensitivity, and identifying promising systemic therapies for additional testing in larger adjuvant trials.     

Cancer gene therapy: fringe or cutting edge?

Direct targeting of cancer cells with gene therapy has the potential to treat cancer on the basis of its molecular characteristics. But although laboratory results have been extremely encouraging, many practical obstacles need to be overcome before gene therapy can fulfil its goals in the clinic. These issues are not trivial, but seem less formidable than the challenge of killing cancers selectively and rationally--a challenge that has been successfully addressed.