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Approximately 30-50% of advanced HER2-positive breast cancer patients will develop central nervous system (CNS) metastases, with an annual risk of around 10%, and a half of them will die from brain progression. An increased risk of brain metastases is also seen in patients with early HER2-positive breast cancer administered curative therapy. Brain metastases in HER2-positive breast cancer patients usually constitute the first site of recurrence. The administration of anti-HER2 monoclonal antibodies, trastuzumab and pertuzumab, considerably delays the onset of symptomatic brain disease: however, the limited penetration of these compounds into the CNS hinders their efficacy. The small-molecule tyrosine kinase inhibitors of epidermal growth factor receptors family have established activity in HER2-positive breast cancer in both advanced disease and neoadjuvant setting. Favorable physico-chemical properties of these compounds allow them for a more efficient penetration through the blood-brain barrier, and hold the promise for more effective prevention and treatment of brain metastases. In this article we review the role of currently available or investigational HER2 tyrosine kinase inhibitors: lapatinib, neratinib, afatinib and tucatinib in the treatment of brain metastases in HER2-positive breast cancer patients.

Lung cancer represents the most common cause of brain dissemination. Oncogene-addicted (EGFR- and ALK-positive) non-small cell lung cancers (NSCLCs) are characterized by a unique metastatic neurotropism resulting in a particularly high incidence of brain metastases. The goal of optimal brain metastases management is to improve both overall survival and quality of life, with the focus on neurocognitive function preservation. Neurosurgery is offered to patients presenting with limited intracranial tumor burden located in surgically accessible un-eloquent regions of the brain, whereas stereotactic radiosurgery represents the preferred radiotherapy option for patients not amenable to surgery. Whole brain radiotherapy, owing to its neurocognitive sequelae, should be reserved for patients with multiple lesions. EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression-free survival compared to standard chemotherapy in the molecularly defined NSCLC subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies. The aim of this review is to summarize the current therapeutic landscape of brain metastases management in NSCLC, with a particular focus on EGFR-mutated and ALK-rearranged NSCLC subtypes.

Background Health-related quality of life (HRQOL) is often used as an endpoint in cancer clinical trials. We assessed the frequency and correlates of HRQOL use in phase III trials in advanced colorectal cancer. Methods We searched PubMed for phase III trials published between January 1998 and December 2014, as well as for companion papers reporting on HRQOL separately. We excluded papers reporting on correlative biology or prognostic factors in isolation from the main trial results, as well as trials on supportive care and on local therapy. Results We retrieved 111 trials that enrolled a total of 61,531 patients in 241 trial arms. HRQOL was reportedly used as an endpoint in 40 trials (36%), in all but two as a secondary endpoint. There was a significant decrease in the use of HRQOL, with frequencies of 46% in trials published between 1998 and 2006, and 27% between 2007 and 2014 ( P =0.04). Trials with HRQOL as endpoint were significantly larger than trials without such endpoint. Formal statistical comparisons involving HRQOL parameters were reported in 36 of 40 trials (90%) with HRQOL assessment, with a significant difference between arms found in 14 (39%), six of which favoring the experimental arm. HRQOL gains were usually accompanied by improvements in efficacy endpoints, but were not related to the number of patients or chemotherapy line. Conclusions HRQOL has been formally assessed in about one-third of recent phase III trials in advanced colorectal cancer, with a significant gain in HRQOL in about 40% of cases. It is questionable whether HRQOL results may largely help select between competing treatments. This assumption may be one of the reasons for the apparent decreased use of HRQOL as an endpoint in phase III trials in this disease.

Background Health-related quality of life (HRQOL) parameters are often used as secondary endpoints in advanced non-small-cell lung cancer (NSCLC). We assessed the frequency and correlates of both usage and gain in HRQOL endpoints in NSCLC phase III trials. Methods We searched PubMed for phase III trials on systemic anticancer therapies for NSCLC published between 1/98 and 12/09 in 13 leading journals. Results The search yielded 122 trials that enrolled a total of 56,031 patients in 273 trial arms. HRQOL was reportedly used as an endpoint in 72 trials (59%). HRQOL parameters were used as primary or co-primary endpoints in nine trials, whereas overall survival (OS) was the primary endpoint or one of the co-primary endpoints in 90 trials. There was no temporal trend for usage of HRQOL parameters as endpoints. Formal statistical comparisons involving HRQOL were reported in 68/72 cases, and a significant difference was found in 37/68 trials (54.4%), 24 of which favored the experimental arm. In many cases, such differences were restricted to specific symptoms or even favored more than one regimen according to symptoms analyzed. We found no significant association between gain in HRQOL and gain in OS or any other trial feature. Conclusions HRQOL has been assessed formally in nearly 60% of contemporary phase III trials in advanced NSCLC, and a significant gain in HRQOL has been found in almost one-half of cases. It is questionable, however, whether HRQOL results may help select between treatments with no differential impact on OS.

Many methods of systemic anticancer treatment have detrimental effects on the cardiovascular system, thus limiting the possibility of further therapy, worsening patients' quality of life and increasing mortality. The best recognized and most clinically relevant is the cardiotoxicity of anthracyclines. Other cytotoxic drugs associated with significant risk of cardiovascular complications include alkylating agents, 5-fluorouracil and paclitaxel. Cardiovascular adverse effects are also associated with the use of targeted therapies, such as trastuzumab, bevacizumab and tyrosine kinase inhibitors, and some of the drugs used in the treatment of hematological malignancies, such as all-trans-retinoic acid and arsenic trioxide. The most serious cardiac complication of anticancer therapy is congestive heart failure, associated predominantly with the use of anthracyclines, trastuzumab and high-dose cyclophosphamide. Myocardial ischemia is mainly caused by antimetabolite and interferon alpha treatment. Other adverse effects may include hypotension, hypertension, arrhythmias and conduction disorders, edema, pericarditis and thrombo-embolic complications. The aim of this review is to summarize and critically analyze the available evidence on the cardiovascular toxicity of systemic anticancer therapies, with particular attention to the recently recognized adverse effects of targeted therapies.

Radiotherapy is associated with several toxicities affecting healthy tissues. One of the strategies aimed at decreasing radiation toxicity is the use of radioprotective agents, such as amifostine and palifermin, or factors stimulating hemopoetic stem cells (colony stimulating factors, CSFs): granulocyte-CSF, granulocyte macrophage-CSF and recombinant erythropoetins. The potential beneficial effect of these substances demonstrated in preclinical in vitro and in vivo studies led to numerous clinical trials. This review addresses the current experience on the use of cytoprotective agents in combination with radiotherapy, with particular focus on the safety of these approaches. Despite a relatively large body of literature data, the role of cytoprotective agents combined with radiotherapy remains controversial. Overall, their use in this application is still limited due to modest radioprotective effect for normal tissues, potential risk of tumor protection and increased treatment toxicity. The use of erythropoetins in combination with radiotherapy should generally be discouraged, whereas the safe and effective application of other agents warrants further investigations.

Over the last years, significant survival benefits for breast cancer were derived from the use of postoperative systemic therapies and radiotherapy. Although these two modalities have been extensively used, the optimal strategies of their combining remain debatable. There have been few randomized studies addressing this issue and their results are generally inconclusive. This article reviews combining systemic therapies (chemotherapy, hormonotherapy and trastuzumab) with radiation in breast cancer patients. In clinical practice, chemotherapy and radiotherapy are most commonly used sequentially but this strategy is not based on level 1 evidence. Increased cardiotoxicity and skin reactions preclude the concomitant radiotherapy and anthracycline-based chemotherapy. Further investigations are warranted to determine the safety of taxane-based schedules used concomitantly with radiotherapy, particularly with regard to pneumotoxicity. Concurrent chemo-radiotherapy with the use of selected schemes may be considered in patients with locally advanced cancer but this strategy still needs to be verified in large randomized studies. The optimal combination of tamoxifen and aromatase inhibitors with radiotherapy has also not been determined in randomized trials and the results of retrospective studies are inconsistent. Finally, the data on combining targeted therapies with radiation are still scarce and do not allow for meaningful conclusions.

Due to increasing indications for postmastectomy radiotherapy and a growing demand for breast reconstruction or augmentation, increasing numbers of patients are currently being exposed to both these treatments. In view of the wide range of available techniques for breast reconstruction, either prosthetic or autologous, and their various sequencing in relation to radiotherapy, physicians can be faced with numerous clinical situations requiring comprehensive knowledge of the topic. This review discusses physical, radiobiological and clinical aspects of combining breast reconstruction and radiotherapy. The available data indicate the feasibility of such combinations, although at the expense of increased risk of complications and less satisfactory cosmesis. Of the two methods of breast reconstruction: using autologous tissue or prosthesis, the former seems to provide better cosmesis and a lower risk of complications in conjunction with radiotherapy. To minimize the risk of unfavourable outcome, the techniques and timing of both breast reconstruction and radiotherapy should be given meticulous attention.

Despite their specific functional consequences, radiotherapy-induced thyroid abnormalities remain under-estimated and underreported. These sequelae may include primary or central hypothyroidism, thyroiditis, Graves' disease, euthyroid Graves' ophthalmopathy, benign adenomas, multinodular goitre and radiation-induced thyroid carcinoma. Primary hypothyroidism, the most common radiation-induced thyroid dysfunction, affects 20-30% of patients administered following curative radiotherapy to the neck region, with approximately half of the events occurring within the first 5 years after therapy. The relative risk of radiation-induced cancer (mainly well-differentiated tumours) is 15-53-fold higher than in non-irradiated population. The aetiology of radiation-induced thyroid injury includes vascular damage, parenchymal cell damage and auto-immune reactions. Total radiotherapy dose, irradiated volume of the thyroid gland, and the extent of prior thyroid resection are among the most important factors associated with the risk of hypothyroidism. The contribution of other treatment modalities (chemotherapy, endocrine therapy) as well as patient- and tumour-related factors is less clear. Reduction in radiation dose to the thyroid gland and hypothalamic/pituitary complex should be attempted whenever possible. New radiotherapy techniques, such as stereotactic radiosurgery, three-dimensional conformal irradiation, intensity modulated radiotherapy and proton therapy allow generally better dose distribution with lower dose to the non-target organs. The diagnostic approach to thyroid radiation injury includes baseline thyroid function assays in all patients undergoing thyroid or parasellar irradiation. Recommended follow-up procedures include at least annual evaluation with a history for symptoms of thyroid dysfunction, clinical examination, and measurement of thyroid hormones and thyrotropin. Management of overt hypothyroidism is based on hormone replacement therapy. Thyroid hormone therapy is also recommended in cases of subclinical hypothyroidism. Treatment of other radiation-induced thyroid disorders (thyroiditis, Graves' disease, thyroid cancer) is similar to that employed in spontaneously occurring conditions. Further improvements in radiotherapy techniques and progress in endocrine diagnostics and therapy may allow better prevention and management of radiation-related thyroid injury.

For many years hormonal replacement therapy (HRT) has been considered to offer not only effective relief of climacteric symptoms but also a reduction in the risk of osteoporosis and cardiovascular disease, plus a possible prevention of cognitive decline. Randomised trials of HRT in women with preexisting coronary heart disease have not confirmed, however, cardiovascular benefits of HRT and have even suggested increased cardiac risk associated with this management. Numerous retrospective studies demonstrated that the risk of breast cancer is higher in HRT-users and is related to therapy duration. More recent studies suggested that breast cancer risk increases further if oestrogen is coupled with progestogen. On the other hand, some data show that breast cancers diagnosed in women during HRT administration may be less aggressive. Typically, tumours in these patients are smaller and better differentiated. HRT also increases the relative risk of endometrial cancer, particularly if oestrogen alone is administered. Currently, the indications for HRT in healthy subjects should include only reduction of menopausal symptoms and prevention of osteoporosis. The use of HRT in breast cancer survivors is controversial, and until the results from prospective randomised trials are available, cannot be recommended in this group as a standard care.

are detected in less than 10% of cases. Most of the patients with locally advanced tumours are managed with external beam irradiation with or without surgery. Despite the continued refinement of radiotherapy techniques, local tumour control remains a significant problem, with a recurrence rate of up to 60% (3,4). The majority of deaths from this malignancy are attributable to progressive locoregional disease. Many patients suffer significant morbidity both from the therapy and from cancer itself. In an attempt to improve the outcome, many alternative strategies have been tested within the last decades. Particular attention has focused on the possibility of adding chemotherapy to standard local treatment. Chemotherapy has traditionally been used in head and neck cancer as a palliative mode in patients with metastatic and recurrent tumour after surgery and radiotherapy. A response rate of approximately 70%, with 20% complete responses, suggested the potential usefulness of chemotherapy as an adjunct to standard primary treatment. The possible uses of chemotherapy in multidisciplinary approaches include its application before definite local therapy (induction, neoadjuvant), after local treatment (adjuvant) or concomitantly with radiotherapy. The major expectation from the addition of chemotherapy is to increase the cure rate by either improved locoregional tumour control or by elimination of micrometastases. Another

Background Health-related quality of life (HRQOL) parameters are often used as end points in phase III trials in advanced breast cancer. The frequency and correlates of significant gains in HRQOL have not been assessed. Methods To evaluate the contemporary role for HRQOL assessment in advanced breast cancer, we searched PubMed for the main and companion papers reporting the results of phase III trials on systemic antineoplastic therapies published between 1/98 and 7/09 in 11 leading journals. Results The search yielded 87 trials that enrolled a total of 33,669 patients. HRQOL was mentioned/reported in the main paper in 34 trials, reported in a companion paper in one (a total of 35/87 = 40%), and mentioned in the abstract of the main paper in 19/34 cases (56%). There was no temporal trend for reporting on HRQOL in the two 6-year periods. Although formal statistical comparisons were reported in 31/35 cases (89%), a significant difference was found in only 4/31 (13%) trials, always favoring the experimental arm. Given the small number of studies with a significant HRQOL finding, we could not assess correlates of gain in HRQOL. Conclusions HRQOL is one of the key indicators of treatment benefit in advanced breast cancer, but contemporary systemic therapies in this setting do not appear to affect HRQOL differentially.

The existence of branchiogenic carcinoma remains controversial. According to some authors, this malignancy is more conceptual than a true clinicopathologic entity. The originally proposed diagnostic criteria of branchiogenic carcinoma have been subsequently challenged. Many reports regarding primary branchiogenic carcinoma have failed to provide sufficient evidence to distinguish this entity from nodal metastases arising from unrecognized primary tumours. There is growing evidence that the majority of branchiogenic carcinomas are in fact cystic metastases from oropharyngeal carcinoma, most commonly originating in the tonsils, and not true carcinomas arising in a branchial cleft cyst. The missing link between branchial cyst and branchiogenic squamous cell carcinoma could be fulfilled by the occurrence of in situ branchial cyst carcinomas, yet such cases are extremely rare. Isolated cystic neck lesions, necessitate a thorough search for a primary tumour, similarly to other occult primaries presenting with cervical metastases. The treatment of cervical cyst with dysplasia or carcinoma in situ includes complete surgical excision. The true branchiogenic carcinomas should be approached with postoperative irradiation to the half neck. A cervical metastatic cystic squamous carcinoma of unknown origin should be treated as for other cases of occult primaries, i.e. with surgery and radiotherapy. The data on the prognosis of branchiogenic carcinoma are scarce, though long-term survival has been reported. Further histopathologic and clinical studies are warranted in order to better understand the biology and natural history of cervical cystic lesions. The existence of true branchiogenic carcinoma remains to be verified with new clinical and molecular criteria.

Tamoxifen is an effective and relatively non-toxic compound used in palliative and adjuvant treatment of breast cancer. More recently its preventive role in breast cancer has also been demonstrated. However, tamoxifen use is related to some increase in the risk of endometrial cancer and to a significant rise in the incidence of benign endometrial pathologies. The activity of tamoxifen against breast cancer is mainly achieved by blocking the oestrogen receptor, whereas the effect of this compound on the female genital tract is mostly related to its agonistic properties. Despite numerous studies no effective methods of tamoxifen-user surveillance have been developed and currently no active screening for endometrial cancer, apart from yearly gynaecological examination, is recommended in these patients. In other parts of the genital tract, tamoxifen increases the risk of some benign conditions and may cause difficulties in the interpretation of cervical smears. Further studies are warranted to develop more effective surveillance and methods decreasing the detrimental effects of tamoxifen on the female genital tract.

Cervical lymph node metastases of squamous cell carcinoma from occult primary constitute about 2-5% of all patients with carcinoma of unknown primary site (CUP). Metastases in the upper and middle neck are generally attributed to head and neck cancers, whereas the lower neck (supraclavicular area) involvement is often associated with primary malignancies below the clavicles. The diagnostic procedures include physical examination with thorough evaluation of the head and neck mucosa using fiber-optic endoscopy, biopsies from all suspicious sites or blindly from the sites of possible origin of the primary, computer tomography and/or magnetic resonance. A systematic tonsillectomy in the absence of suspicious lesions is often recommended since up to 25% of primary tumors can be detected in this site. The thoracic primary (tracheal, bronchial, lung, esophagus) has to be excluded, especially in the case of lower neck involvement. Positron emission tomography (PET) with fluoro-2-deoxy-D-glucose allows detection of primary tumor in about 25% of cases, but this procedure is still considered investigational. Therapeutic approaches include surgery (lymph node excision or neck dissection), with or without postoperative radiotherapy, radiotherapy alone and radiotherapy followed by surgery. In early stages (N1), neck dissection and radiotherapy seem to have similar efficacy, whereas more advanced cases (N2, N3) necessitate combined approaches. The extent of radiotherapy (irradiation of bilateral neck and mucosa versus ipsilateral neck radiotherapy) remains debatable. A potential benefit from extensive radiotherapy should be weighted against its acute and late morbidity and difficulties in re-irradiation in the case of subsequent primary emergence. The role of other methods, such as chemotherapy and hyperthermia, remains to be determined.