Adjuvant and Neoadjuvant Chemotherapy for Osteosarcoma: A Historical Perspective.

Osteosarcoma was initially resistant to chemotherapy that worked for Ewing sarcoma and rhabdomyosarcoma as well as other chemotherapeutic agents available in the 1960s. In the early 1970s, responses of osteosarcoma to adriamycin were reported, and at about the same time, so were responses of osteosarcoma to high-dose methotrexate. These agents were introduced into adjuvant therapy due to the dire prognosis associated with apparently localized osteosarcoma. After initial questions regarding the role of chemotherapy delayed its uniform acceptance, there is now general agreement that chemotherapy is primarily responsible for the cure of patients with osteosarcoma when combined with surgical elimination of the primary tumor. Advances with combination chemotherapy later adding cisplatin and ifosfamide have improved ultimate survival. The history of the development of effective chemotherapy combinations at Memorial Sloan Kettering Cancer Center, UT MD Anderson Cancer Center, and the Rizzoli Institute are highlighted, and recent large cooperative group studies are reviewed in the context of those findings.

Frontline therapy of ovarian cancer: trials and tribulations.

PURPOSE OF REVIEW: The current article reviews the advances and challenges in the fight with cancer and the hope for cure, with a focus on clinical trials, at the one time with the best outcomes; first-line therapy. RECENT FINDINGS: To date there have been four great stories that bridge inception to development of new drugs in ovarian cancer: Serendipitous insight into the role of platinum, discovery of taxanes, understanding the microenvironment and angiogenesis, and following the science in the development of Poly (ADP-Ribose) Polymerase (PARP) inhibitors. There is a fundamental difference between overall survival (OS), simply living longer; and eradicating disease, cure. The scientific underpinning of both our understanding and the recent developments encourages an optimistic view of the remaining hurdles. SUMMARY: There has been an unprecedented explosion in the number of new drugs approved for the treatment of ovarian cancer with three new classes of agent, and five new drugs receiving food and drug administration approval in the last 3 years (Fig. 2). Getting the right drug truly transforms patients' experience with the seminal event being the development of imatinib in CML. In 1980, an average patient would have lived only 3 years, and now they only live 3 years less than a full lifespan [Bower et al. (2016). J Clin Oncol 34:2851].

The 21st century revolution in CLL: Why this matters to patients.

The 21st century has seen rapid, positive changes in the management of chronic lymphocytic leukaemia from the patient's perspective. New prognostic and predictive markers have ushered in the start of more precise and individualized therapy. For the first time, combined therapy [fludarabine, cyclophosphamide and rituximab] has been shown to prolong life significantly. Clinical trials have become more adaptive, faster and more patient friendly. Perhaps the greatest change of all is the development of novel oral agents (ibrutinib and idelalisib) and powerful monoclonal antibodies that offer robust and durable disease control. Finally, access to and understanding of these changes through an empowered and educated patient population has grown through live education forums and the Internet.

Combination chemotherapy of solid tumors: an American-Italian collaboration: a celebration of the work of Gianni Bonadonna.

This article highlights the important collaboration between the U.S. NCI in Bethesda, Maryland and the Istituto Tumori in Milan, Italy that had a major impact on the development of curative regimens for breast cancer, Hodgkin's disease and diffuse large B cell lymphoma.In addition to his contribution to developing new therapies, Gianni Bonadonna played an important role in bringing highly focused, disciplined, ethical clinical trials to the European continent.

Treatment evolution for metastatic castration-resistant prostate cancer with recent introduction of novel agents: retrospective analysis of real-world data.

Despite increasing drug treatment options for metastatic castration-resistant prostate cancer (mCRPC) patients, real-world treatment data are lacking. We conducted retrospective analyses of commercial claims and electronic medical record (EMR) databases to understand how treatment patterns for mCRPC have changed in a US-based real-world population. Truven Health Analytics MarketScan(®) (2000-2013) and EMR (2004-2013) databases were used to identify patients with an index prostate cancer diagnosis (ICD-9 codes 185X or 233.4X) and prescription claims for an mCRPC drug (mitoxantrone, estramustine, docetaxel, sipuleucel-T, cabazitaxel, abiraterone acetate, enzalutamide, or radium-223). Regimen analyses for first line of therapy (LOT1), second line of therapy, and beyond were performed among cohorts based on year of first mCRPC drug usage. mCRPC drug usage and treatment duration were compared across cohorts and age groups within each cohort. The commercial claims cohort yielded 3437 evaluable patients. Most men (91%) commencing mCRPC treatment had docetaxel as LOT1 in 2010; this number had declined to 15% in 2013. In 2013, 67% and 9% of patients used abiraterone acetate and enzalutamide, respectively, as LOT1. Among both commercial claims and EMR cohorts, treatment pattern changes were most pronounced in men aged >80 years, and median treatment duration for some mCRPC drugs was shorter than expected based on available clinical trial information. These results demonstrate a shift in mCRPC treatments during the past 5 years, with greater use of newer noncytotoxic treatments than docetaxel. These real-world data aid in understanding the changing role of chemotherapy in the management of mCRPC.

Radiotherapy in early stage classical Hodgkin lymphoma: past, present and future.

For early stage classical Hodgkin lymphoma (HL), extended field irradiation (EFRT) alone has shown excellent results in low relapse rate and high long-term survival rate. With the patients achieving long-term survival, the risk of the RT-related late complications was increased, such as secondary malignancies and heart infarctions. According to a series of studies, the combined modality therapy (CMT) as the first-line therapy has replaced the radiotherapy (RT) alone. The recommended regimens are 2 cycles of ABVD followed by involved field radiotherapy (IFRT) (20-30 Gy) for the favorable patients, and 4 cycles of ABVD followed by IFRT (30 Gy) for unfavorable patients. The involved nodular radiotherapy (INRT) has shown the potential to achieve satisfactory primary tumor control with lower RT-related toxicity than EFRT or IFRT in combined therapy. Some prospective randomized studies are going about chemotherapy (CT) plus INRT under the guidance of PET. It is not certain that whether CT alone has more benefits to cure limited HL. Appropriate application of new RT techniques can improve the radiation dose distribution in target fields and protect normal tissues from excess RT-related damage.

CCR 20th Anniversary commentary: in search of cetuximab's first indication-combination therapy with irinotecan in colorectal cancer.

The research article by Prewett and colleagues, published in the May 1, 2002, issue of Clinical Cancer Research, provided important translational data that extended earlier preclinical and clinical studies with the human-murine chimeric anti-EGFR monoclonal antibody C225. Subsequent clinical trials with C225 led to the demonstration of its efficacy in combination with irinotecan and regulatory approval for the treatment of metastatic colorectal cancer.

Historical perspective on the introduction and use of chemotherapy for the treatment of osteosarcoma.

Chemotherapy for treatment of osteosarcoma was demonstrated to be effective in eradicating primary tumor and pulmonary metastases in the mid-twentieth century. The first agents that held promise were doxorubicin and high-dose methotrexate with leucovorin (citrovorin factor) in the mid-1970s. Since then, other agents that can eliminate or cause regression of tumor have been discovered: cis-diamminedichloroplatinum II (cisplatin) and the oxazaphosphorines ifosfamide and cyclophosphamide. Additional agents await further study to define their potential. The effective agents have been utilized in various combination regimens and have escalated the survival rate from <10 to 75 %. They have also enabled pulmonary metastectomy in patients with persistent and/or recurrent pulmonary metastases and tumor ablation and limb salvage in 80 % of newly diagnosed patients. Unfortunately, however, despite these impressive advances no change in survival expectancy of patients with osteosarcoma during the past 40 years has occurred. There have been no new chemotherapeutic agents effective in addressing disease that is resistant to current agents; the few that have been introduced await further study to substantiate their efficacy. This also includes attempts at alternate administration of chemotherapy (intra-arterial and inhalation therapy.) In this chapter, we provide an account of the sequential introduction of the chemotherapeutic agents, review the results of their application in selected regimens, and discuss the role of neoadjuvant chemotherapy.

Where we were, where we are, where we are going: progress in multiple myeloma.

The celebration of the 50th anniversary of the founding of the American Society of Clinical Oncology provides the occasion to review the progress that has been made in the biology and treatment of multiple myeloma. With the advent of melphalan and cyclophosphamide in the early 1960s the median survival of patients with multiple myeloma more than doubled from 10 months to approximately 24 months. Throughout multiple clinical trials in the 1970s and 1980s, melphalan and prednisone remained the gold standard, with a 3-year survival of 42%. The use of high-dose melphalan with autologous hematopoietic stem cell support provided an incremental advance in the 1990s. The outlook for patients was dramatically improved in the 2000s with the introduction of thalidomide analogs and proteasome inhibitors, so that the 3-year survival of patients treated in 2008 with melphalan and prednisone had increased to 66%. The 2010s are dominated by studying the optimal combination, sequence, and duration of therapies. These clinical advances have occurred along with our evolving understanding of the molecular pathogenesis of myeloma. Myeloma can be divided into two main groups: hyperdiploid, with multiple trisomies of odd-numbered chromosomes, and nonhyperdiploid, with recurrent immunoglobulin heavy chain gene translocations. Disease progression is associated with rearrangements of MYC, the most common mutation in myeloma, present in nearly half of patients. Genomic studies have highlighted marked subclonal heterogeneity that poses one of the main challenges to successful control of the disease. This problem will be addressed in future studies in the 2020s, which will include a focus on immunologic approaches such as monoclonal antibodies, checkpoint inhibitors, engineered T-cells, and novel immunomodulators.

Ovarian cancer: a brief historical overview of intraperitoneal trials.

The standard platinum-based treatment of previously untreated advanced ovarian cancer continues to evolve because despite high response rates to such first-line treatment, a majority of patients will experience relapse. For many years, the optimal treatment for women with advanced ovarian cancer has been maximum cytoreductive surgery followed by intravenous (IV) platinum and taxane chemotherapy. Later, several randomized multicenter phase III clinical trials demonstrated that intraperitoneal (IP) chemotherapy was superior to standard IV chemotherapy when there was minimal residual disease after primary debulking surgery. The underlying rationale for use of IP therapy is based on the dose-effect relationship for platinum drugs in ovarian cancer. However, barriers to implementation of IP therapy in the routine clinical setting include concern for toxicity, tolerability of planned treatment, and catheter-related complications. In this article, we highlight the key trials and recent directions in IP therapy of ovarian cancer and briefly discuss another approach to the delivery of IP chemotherapy, known as hyperthermic intraperitoneal chemotherapy.

Important milestones in acute leukemia in 2013.

This year marked the occurrence of several important milestones in the treatment of acute leukemias. First, the standard 7 + 3 protocol for acute myeloid leukemia (AML) was developed 40 years ago, and with some adaptations, has stood the test of time. Second, the 1 millionth hematopoietic cell transplant was recorded this year. Stem cell transplant, the first reported by Dr E. Donnall Thomas in 1957, had been considered a rare procedure until about a decade ago. Today, it has become a proven and often life-saving therapy for patients with acute leukemia. Advances in the treatment of patients with AML continue to take place, many of which relate to an increased understanding of the clinical heterogeneity of known subtypes. Forty years ago, the regimen that has come to be known as 7+3 for acute myeloid leukemia (AML) was born [1,2]. Cytosine arabinoside, or arabinosylcytosine as it was then called, was given as a continuous intravenous infusion of 100 mg/m(2) for 7 days, and the anthracycline, daunorubicin, was administered at 45 mg/m(2) intravenously for 3 days. Sixteen patients were originally treated on this protocol, and 5 of 8 previously untreated and 2 of 8 previously treated patients achieved a complete response (CR). This regimen has withstood the test of time. Attempts to add or substitute other agents have not yielded superior results. The only major contemporary change is that a higher dose of daunorubicin is safe and has become the standard of care [3].

Uracil mustard and 5-fluorouracil combination chemotherapy: a historic record.

BACKGROUND: Uracil mustard and 5-fluorouracil (UM-FU) combination chemotherapy was used as one of the earliest combination chemotherapies in ovarian carcinoma from 1964 to 1971 at Yale New Haven Medical Center. METHODS: UM-FU was offered to patients with stage III and IV, histologically verified, ovarian carcinoma. Uracyl mustard was administered orally--1 mg/ kg, daily. 5-Fluorouracyl was administered every four weeks at 5 mg/kg for five days by intravenous infusion. RESULTS: Of a total 185 patients with ovarian cancer, 76 received UM-FU. Thirty-five patients had measurable disease. Fifteen (42%) showed objective response lasting three to 95 months, with decrease in size of masses and disappearance of ascites or hydrothorax. Their survival from diagnosis to death was 41 months. Twenty patients showed no response; their mean survival was 18 months. Three of the 76 patients who received UM-FU developed acute nonlymphocytic leukemia. CONCLUSION: UM-FU was effective in controlling ascites and hydrothorax and diminished intraabdominal masses. The discovery of adriamycin and then platinum led to more effective therapy and the use of uracil mustard was superseded. It is no longer available. The experience reported is of historic interest.

High-dose therapy with autologous stem cell support for lymphoma--from experimental to standard treatment.

High-dose therapy with autologous stem cell support (HDT) has been a therapeutic option for lymphomas in Norway since as far back as 1987. By restoring bone marrow function through reinfusion of the patient's own stem cells, it is possible to administer cancer treatment in higher and otherwise lethal doses, and thereby achieve better treatment results. Originally stem cells were harvested from bone marrow and the high-dose therapy included total body irradiation, but since the mid 1990s stem cells have been harvested by apheresis and the high-dose therapy has consisted of chemotherapy alone (BEAM chemotherapy). In 1995 the treatment was regionalised and since then it has been performed in all health regions. The HDT procedure was introduced as an experimental treatment in clinical studies with international collaboration. The indications have changed over time, and this is now established treatment for a number of types of lymphoma.