Locally advanced breast cancer

In vitro studies suggest p53 and bcl-2 may be important in the apoptotic response to irradiation, and that rapidly proliferating cells are more sensitive to radiotherapy. The clinical relevance of biological factors in predicting radiotherapy response was investigated in 62 patients with locally advanced breast cancer. Immunocytochemical staining for p53 protein, BCL-2 protein and MIB 1 antigen on the primary tumour, showed that none of these factors significantly predicted radiotherapy response (BCL-2 p=0.45, p53 p=1.0, MIB 1 p=0.92) and appear to be of no clinical value. A semi-quantitative assessment of MIB 1 staining showed a reduction in positive cells following radiotherapy (p=0.04), consistent with a reduced proliferation associated with response.     

Locally advanced esophageal cancer

Opinion statement Patients diagnosed with adenocarcinoma or squamous cell carcinoma of the esophagus should undergo computed tomography of the chest and abdomen and positron emission tomography to look for evidence of distant metastatic disease. In the absence of systemic metastases, locoregional staging should be performed with endoscopic ultrasonography and fine needle aspiration of accessible periesophageal lymph nodes and any detectable celiac lymph nodes. Patients found to have T3 tumors (transmural extension), T4 tumors (invasion of adjacent structures), or N1-M1a (lymph nodepositive) disease do poorly when treated with surgery alone; 5-year survival is less than 20%. These patients should be considered for combined modality therapy. Patients with T4 disease are generally not deemed candidates for surgical resection; they may be considered for definitive chemoradiotherapy. Patients with T3 disease or lymph node-positive disease may be treated with neoadjuvant chemoradiotherapy followed by surgery or definitive chemoradiotherapy alone. Patients considered for trimodality therapy should be fully restaged before surgery to assess their response to neoadjuvant treatment. This should include repeat endoscopic ultrasound and fine needle aspiration of lymph nodes. Patients whose lymph node metastases do not completely respond to neoadjuvant therapy are unlikely to benefit from the addition of surgery. Patients with persistently positive celiac lymph nodes have a very poor prognosis and should not undergo surgery. Patients with persistent nodal disease who have good performance status may be considered for additional chemotherapy. Patients with locally advanced esophageal cancer who have poor performance status are not good candidates for combined modality therapy. These individuals are best managed with palliative intent. Particular attention should be given to alleviating the common problem of dysphagia, which causes significant morbidity.     

Locally advanced nasopharyngeal cancer

Opinion statement The Head and Neck Cancer Intergroup phase III clinical trial (Int 0099) for patients with locally advanced, squamous cell carcinomas (SCC) of the nasopharynx (or NPC) has been recently completed in the United States. The results of this study have defined the new standard of treatment for the group of patients studied. Patients with untreated, locally advanced stages III and IV NPC were randomized to a conven-tional course of radiation, or to radiation given concurrently with chemotherapy followed by three courses of combination chemotherapy. The 3-year progression-free survival (PFS) and overall survival (OS) were 24% versus 69% (P < 0.001) and 46% versus 76% (P < 0.001) for the control and experimental groups, respectively. Recent updates of these survival figures show that they have not changed appreciably. The considerable improvement in OS versus PFS for the patient group receiving radiation alone is accounted for primarily by re-treatment with concurrent radiation-chemo-therapy, combination chemotherapy, and isolated salvage neck dissections. Highly significant differences in local control (41% vs 14%) and distant metastases (35% vs 13%) were demonstrated in favor of the chemoradiation treatment arm. The median age for these patients was 51 years, with a 2:1 male to female ratio. Although many patients had a significant history of tobacco exposure with or without alcohol use or abuse, only 24% had keratinizing or well-differentiated squamous (World Health Organization [WHO] I) type tumors. Whether these results can be extrapolated to the more common Asian variety (WHO II and III) of advanced NPC must be addressed in future clinical trials.     

Locally advanced breast cancer

Opinion statement Over the past 20 years, the prognosis for women diagnosed with locally advanced breast cancer (LABC; clinical stages IIB through IIIB) has improved significantly with recognition of the efficacy of multimodal therapy for reducing both local and distant recurrences, even in patients with inflammatory breast cancer (IBC). Most patients will respond to induction, or neoadjuvant, chemotherapy (NAC) with an anthracycline-based regimen, enabling many patients with large but operable tumors to undergo breast-conserving surgery (BCS) and enabling resection in most patients with inoperable disease. However, only a small percentage of patients achieve a pathologic complete response (CR) with this approach. Long-term disease-free survival (DFS) and overall survival (OS) correlate with the extent of residual disease in the breast and axillary nodes following NAC. The addition of paclitaxel or docetaxel, either in combination with an anthracycline or as a separate regimen administered before or after anthracycline-based therapy, increases clinical and pathologic response rates and may improve DFS. With the possible exception of patients with IBC, BCS does not compromise outcome. Partial mastectomy should be accompanied by standard nodal dissection in patients with clinically or radiographically positive axillae; in patients with negative axillae, sentinel lymph node (SLN) sampling, with subsequent axillary dissection reserved for patients with involved nodes, may reduce postoperative morbidity. Patients who received only anthracycline-based NAC who are found to have significant residual disease in the breast or involved axillary nodes at surgery should receive adjuvant chemotherapy with paclitaxel. Postoperative radiation to the residual breast or chest wall and regional nodal areas reduces locoregional recurrences, but its impact on OS remains controversial. Adjuvant hormonal therapy with tamoxifen improves DFS and OS in patients with hormone receptor (HR)-positive tumors, and ovarian ablation should be considered in premenopausal patients with HR-positive tumors and multiple involved nodes or stage IIIB disease. Neoadjuvant hormonal therapy with either tamoxifen or an aromatase inhibitor may benefit frail or elderly patients with HR-positive tumors for whom chemotherapy is not an option. No advantage has been demonstrated for highdose chemotherapy requiring hematopoietic stem-cell support as either NAC or adjuvant therapy in LABC. Newer treatment approaches, including trastuzumab (Herceptin, Genentech, Inc., South San Francisco, CA), in patients with Her-2-overexpressing tumors or other biologic agents, do not have a proven role in the management of LABC at this time.     

Locally advanced differentiated thyroid cancer

Although most patients with differentiated thyroid cancer (DTC) of follicular cell origin enjoy a relatively good prognosis, some patients unfortunately present with or develop locally advanced DTC which leads to significant local morbidity and mortality. DTC accounts for 54-94% of all locally advanced thyroid cancers. DTC invasion of the recurrent laryngeal nerve, strap muscles and trachea are the most common followed by invasion of the esophagus, internal jugular vein and carotid artery. Surgical resection is the primary treatment for locally advanced DTC. Although the optimal surgical approach (ranging from conservative shave excision to aggressive en bloc resection of tumor and vital structures) in patients with locally advanced DTC is controversial, a curative resection should be the goal unless complete tumor resection results in unwanted perioperative morbidity and mortality or widely metastatic disease is present. Postoperative radioiodine ablation with TSH suppression is imperative after surgical resection of locally advanced DTC. Patients with microscopic or small gross residual disease, after surgical resection, may benefit from postoperative external radiotherapy for local control of disease.     

Locally advanced pancreatic cancer.

Of the 32,180 patients diagnosed with pancreatic carcinoma in the United States this year, approximately 40% will present with locally advanced disease. Radiotherapeutic approaches are often employed because these patients have unresectable tumors by virtue of local invasion into the retroperitoneal vessels in the absence of clinically detectable metastases. These treatments include external-beam irradiation with and without fluorouracil-based chemotherapy, intraoperative irradiation, and, more recently, external-beam irradiation with new systemic targeted agents.     

Locally advanced prostate cancer: combination of high-dose high-precision radiotherapy and androgen deprivation therap

Locally advanced prostate cancer entails a risk of local, regional and systemic relapse requiring the combination of a loco-regional treatment, namely external beam radiotherapy(EBRT) to control the pelvic-confined disease, combined with a systemic therapy, namely androgen-deprivation therapy(ADT), to potentiate irradiation and to destroy the infra-clinical androgen-dependant disease outside the irradiated volume. Many phases III randomized trials have paved the way in establishing the indications of this combined approach, which requires a long term ADT(≥2 years) with LHRH agonists. The duration of ADT may be reduced to 6 months should there be a significant comorbidity, a reluctance from the patient or a poor tolerance. A multidisciplinary approach will enable physicians to tailor the treatment strategy and a close cooperation between the specialists and the general practitioners will be set up to prevent as much as possible the side-effects of ADT.     

Locally advanced non-small cell lung cancer

Opinion statement Locally advanced non-small cell lung cancer remains a paradoxical entity to manage. Although this type of cancer is confined to the thorax and is ostensibly curable, most patients presenting at this stage of disease eventually succumb to it. The accepted therapy presently includes chemotherapy and radiation. The exact agents, schedules, and combinations need to be defined further, although cisplatin has become the widely viewed standard cytotoxic drug in this setting. Notwithstanding, newer chemo-therapeutic and biologic agents are being extensively tested to find less toxic options with greater efficacy. Drugs that are gaining widespread approval include carboplatin, paclitaxel, gemcitabine, and vinorelbine. At the same time, advances in radiation therapy are triggering a revolution in dose intensity and scheduling that will one day offer superlative local control.     

Locally advanced head and neck cancer

Opinion statement The simultaneous administration of chemotherapy and radiation has produced a significant impact on the treatment of advanced squamous cell carcinomas of the head and neck. Although no single regimen has emerged as the “standard” approach, recent trials have consistently demonstrated the superiority of combined treatment programs over radiotherapy alone for local tumor control and overall survival. More-over, multimodal treatment has emerged with important ancillary goals of organ preservation, improved cosmesis, and enhancement of quality of life. With improving survival in all stages of disease, much attention can be given to identifying effective measures to reduce the risk of metachronous primary cancers in this high-risk group.     

Locally advanced and metastatic bladder cancer

Opinion statement Metastatic transitional cell carcinoma of the bladder is an aggressive neoplasm characterized by rapid growth and dissemination with a median survival of typically less than 1 year. Despite the availability of a myriad of antineoplastics with moderatesignificant anti-tumor activity yielding overall response rates in the 40% to 80% range, randomized trials continue to demonstrate median survival rates in the 13- to14-month range, with very limited long-term survival. Subsets of patients with advanced bladder cancer present additional management problems, including those with renal insufficiency or nontransitional-cell histology. Various observers have noted the similarity in treatment outcomes in advanced bladder cancer and extensive small cell lung cancer where chemotherapy produces relatively high response rates but with limited impact on survival. The optimal chemotherapy combination for patients with advanced bladder cancer remains undefined, however, there is increasing recognition that in order to achieve tangible improvements in complete response rates and survival in this disease will likely require a combination of chemotherapy and targeted molecular therapies and in some settings adjunctive surgery.     

Locally advanced breast cancer and postmastectomy radiotherapy

Most patients with locally advanced breast cancer should be treated with a combination of chemotherapy, mastectomy (with immediate reconstruction if the patient so desires), and radiotherapy. Nonetheless, it seems reasonable to offer breast-conserving treatment to selected individuals who respond well to neoadjuvant therapy. Postmastectomy radiotherapy clearly reduces the risk of local-regional and distant failure for patients with earlier-stage invasive breast cancer with involved axillary lymph nodes. Certain subgroups of patients, however, may have such low local-regional failure rates that patients will not routinely find the benefits of radiotherapy sufficient to undergo such treatment. Further investigation of this issue is needed.     

Locally advanced breast cancer in octogenarian women

Elderly patients are more likely to present with locally advanced breast cancer than younger patients. Furthermore, due to the accelerated aging of the western population, the incidence of breast cancer in this population is expected to steadily rise in the coming decades. So far, no guidelines are available for the management of octogenarian patients presenting with inoperable disease, what frequently results in a dilemma for the treating physician. For the time being, these patients should be ideally treated within the context of a clinical trial. In all other cases, the treatment has to be individualised, frequently based on data extrapolated from different population of patients, or retrospective series. This article reviews the current evidence, options, and most promising approaches for these patients.     

Locally advanced pancreatic cancer: a review

It is anticipated that there will be 37,170 new cases of pancreatic cancer diagnosed in the United States this year, resulting in approximately 33,370 deaths from the disease. Approximately 40% of these patients will present with locally advanced, non-metastatic disease. Treatment regimens that incorporate conventional radiation therapy for local tumor control, and chemotherapy to prevent distant failure in this metastasis-prone malignancy, are the current standard of care. A number of clinical studies have been undertaken to establish the optimal definitive chemoradiation treatment in this setting. Other potential treatment strategies include chemoradiation incorporating novel chemotherapeutic agents, intraoperative radiation therapy, brachytherapy, and the integration of combined therapies that utilize targeted molecular agents. This review summarizes the current status, controversies, and future prospects for the treatment of locally advanced pancreatic cancer.