Current Cancer Therapy Reviews (v.12, #1)

Editorial by Kurt S. Zaenker (1-1).

With advances in diagnosis and treatment, breast cancer has become an increasingly survivable disease with a growing population of long-term survivors. As an essential component of breast conservation therapy, radiotherapy is a standard treatment for many women with stage I/II breast cancer. Cardiac radiation exposure has been associated with an increased risk of cardiovascular diseases. Among these are coronary artery disease, cardiomyopathy, valvular heart disease, and pericardial disease. Microvascular changes and accelerated atherosclerosis are likely the primary underlying mechanisms of radiation induced cardiovascular damage. A simple and highly effective technique, deep inspiration breath-hold (DIBH), has been shown to decrease cardiac radiation exposure without compromising target coverage. This brief review focuses on the effects of radiation therapy on the heart, radiation-induced cardiovascular diseases in breast cancer survivors, and the DIBH technique as a means for reducing cardiac radiation exposure.

Merkel Cell Carcinoma: Epidemiology, Clinical Presentations, Histology, Polyomavirus Involvement, and Management by Bahar Bahrani, Hannah Liu, Elizabeth M Marchionne, Amor Khachemoune (15-22).
Merkel cell carcinoma (MCC) is an aggressive cutaneous malignancy with neuroendocrine origin. The rarity of the tumor and variable clinical presentation make the diagnosis especially challenging. The tumor grows rapidly and lymph node metastasis occurs early in the disease course. The etiology is related to prior UV exposure, immunosuppression, and polyomavirus infection. The 2008 discovery of an infectious cause for the majority of Merkel cell carcinoma cases sparked more research into the pathogenesis of the tumor and possible therapeutic options. Although there has been recent improvement, there is a lack of uniform consensus or well-established guidelines on the management of MCC. These difficulties in identifying and treating the disease, as well as the overall poor prognosis, highlight the importance of further research into the area, and the requirement for physicians to stay up to date with the most recent research findings.

Overcoming Chemotherapy Resistance in High Grade Serous Ovarian Cancer by Raghav Sundar, David Tan, Lim S. Lei, Whay-Kuang Chia (23-36).
High grade serous (HGS) cancer of the ovary (OC) is a lethal malignancy with advanced stage disease remaining incurable. HGS OC is sensitive to platinum based chemotherapy with complete responses being frequent, but relapses are inevitable, with resistance invariably emerging. Deeper understanding of the pathogenesis of HGS OC with new sequencing techniques shows that aberrations in the BRCA pathway may play a major role. Changes in the homologous recombination pathway and DNA repair may play a role in platinum resistance. This review article describes various approaches that have been studied in the management of chemotherapy resistance in HGS OC including Poly ADPribose polymerase (PARP) inhibition, Wee1 inhibition, epigenetic agents, immunotherapy and angiogenesis targeting agents.

Emerging Endocrine Therapies in the Treatment of HR-Positive Metastatic Breast Cancer by Diego Touya, Kathrin Strasser-Weippl, Ann Whalen, Jessica St. Louis, Paul Goss (37-53).
Breast cancer is the most common malignancy in women worldwide and the most common cause of cancer mortality in women. Seventy percent of breast cancers overexpress the estrogen (ER) and/or the progesterone receptor (PgR) making anti-endocrine therapies the most commonly used worldwide for this disease. These therapies are of low toxicity and low cost since most of them are off-patent and therefore very valuable in the armamentarium against this common form of breast cancer. Selective estrogen receptor modulators (SERMS), selective estrogen receptor down-regulators (SERDS), and aromatase inhibitors (estrogen synthetase) inhibitors (AIs) have been the backbone of recent endocrine treatment of breast cancer. These agents are reviewed here. More recently, combinations of evidence - based targeted therapies with these traditional endocrine therapies have further improved clinical outcomes. In the future, additional agents targeting pathways of resistance to endocrine therapy are likely to be developed.

Therapeutic Immunoconjugates. Which Cytotoxic Payload: Chemotherapeutic Drug (ADC) or Radionuclide (ARC) ? by Jean-François Chatal, Françoise Kraeber-Bodéré, Caroline Bodet-Milin, Caroline Rousseau (54-65).
Over the last decade, Antibody Drug Conjugates (ADCs) have gained a great success due to their documented clinical efficacy and manageable toxicity. Generally the word “drug” is associated with a chemotherapeutic drug, however “drug” can also be associated with other cytotoxic payloads such as radionuclides, termed more specifically, Antibody Radionuclide Conjugates (ARCs) for radioimmunotherapy (RIT).
A large number of clinical studies have evaluated both ADCs and ARCs in varied indications. This review collected the clinical results of 11 studies including 598 patients treated with 6 ADCs and 9 studies including 377 patients treated with 5 ARCs. Toxicity was generally less frequent with ADCs than with ARCs but often led to more uncomfortable side effects. Hematological toxicity was higher with ARCs than with ADCs regardless of the radionuclide used (90Y, 131I or 177Lu).
For radiosensitive hematological malignancies overall response rates varied from 7 to 86% (median: 50%) with ADCs and from 31 to 95% (median: 83%) with ARCs. Two studies including 135 patients were performed with ARCs in the most favorable situation of frontline therapy which can favor global efficacy. Median progression free survival (PFS) varied between 5.6 and 13.3 months (median: 7.8) with ADCs and between 6 and 25.9 months (median: 9.4) with ARCs, once again focusing on the most favorable situation of ARCs in frontline therapy. For solid tumors overall response rates varied from 6 to 34.5% (median: 15%) with ADCs and from 8 to 15% (median: 7.5%) with ARCs.
Both ADCs and ARCs have shown clinical efficacy with acceptable and manageable toxicity.

Anti-cancer Potential of Phyto-alkaloids: A Prospective Review by Sumaira Khattak, Haroon Khan (66-75).
Cancer is characterized as the second leading cause of death worldwide despite several therapies. In this regard, numerous researchers around the world are working on synthetic and natural products for the discovery of novel effective anticancer agents. Plants have been used in the treatment of various diseases and they have also shown tremendous potential in the treatment of cancer. This mini review has focused on the plant-based alkaloids, isolated from various parts of plants. These anticancer compounds have been found to be active against various types of cancer cells. Further research in this area may lead to better and effective anticancer agents.