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.

The development of dose-dense adjuvant chemotherapy.

Dose-dense chemotherapy has made a significant contribution to the adjuvant treatment of breast cancer. One way of achieving dose-density is through the use of sequential therapy with noncross resistant therapies to cause cell kill in tumors composed of heterogeneous cells. Another way to achieve this is to shorten the inter-treatment interval to minimize the re-growth of tumor cells, thus allowing for more effective cell killing. Several trials have tested this concept with the majority demonstrating improved efficacy with a dose-density when compared with the traditional schedule. One such notable trial was CALGB 9741 that showed that when dose size and cycle numbers were kept constant, shortening the interval between each chemotherapy dose, with granulocyte-colony stimulating factor support, significantly improved disease-free and overall survival. This important and practice-changing trial led to the wide adoption of dose-dense chemotherapy and formed the basis of many subsequent studies, including allowing for the addition of biologic and targeted agents with excellent safety profile.

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.

Adjuvant therapy for colorectal cancer: yesterday, today, and tomorrow.

During the 1980s, the only drug routinely used to treat colorectal carcinoma was single-agent fluorouracil (5-FU), a drug that had shown no proven benefit in the adjuvant setting. Since then, significant improvements in the overall management of colorectal cancer have been made. This review will compare today's standard of care for adjuvant colorectal carcinoma to that practiced 20 years ago. The authors examine key questions asked about adjuvant therapy and the answers that ultimately changed clinical practice standards and improved overall survival for patients diagnosed with this disease. In addition, this review explores whether 5-FU should be given as part of a multidrug regimen and which route of administration is best when this drug is given. Further, the authors delve into both the use of locally directed therapies to the liver or peritoneum to improve outcomes and the selection of patients to receive adjuvant chemotherapy. Finally, a look to the future shows monoclonal antibodies to be an avenue of great promise infighting colorectal cancer.

Adjuvant therapy for colon cancer 2005: new options in the twenty-first century.

The most effective current regimen for adjuvant treatment of surgically resected stage III colon cancer is the FOLFOX regimen of oxaliplatin, 5-FU and LV for 12 weeks, with a proportional risk reduction of 45% compared with approximately 36% for 5-FU/LV regimens. Infusion regimens of 5-FU with and without LV have been shown to confer equivalent benefit to bolus regimens in reducing the risk of cancer recurrence, but with lesser toxicity profiles. Oral 5-FU prodrug regimens have similarly shown equivalent benefit to bolus regimens, and toxicity comparable to infusional regimens, but with the added convenience over 5-FU infusion therapy. The addition of irinotecan to 5-FU and LV regimens has not demonstrated an advantage compared with 5-FU/LV treatments in the adjuvant setting.

Adjuvant chemotherapy for stage II colorectal cancer: the time is right!

Colorectal cancer is the second most common cause of cancer death in much of the developed world. Cancer-related mortality is slowly decreasing as a result of better detection and improved surgery. Adjuvant chemotherapy is now considered the standard treatment for stage III colon cancer, and has evolved recently with the introduction of infusional, combination chemotherapy. Adjuvant therapy for stage II colon cancer has been more controversial. Recent trial data suggest, however, that there is a legitimate case for discussing the advantages and limitations with individual patients.

[40 years of progress in chemotherapy]. / Quarante ans de progrès en chimiothérapie.

The history of medical oncology's history is exemplary for the rapidity of its evolution and its therapeutic acquisitions; Chemotherapy contributes to modify the natural history of the majority of cancers. The development of clinical research in medical oncology has entered a conflict phase, where patients have become an economical stake. The necessary co-operation between oncologists, other medical specialists, the basic scientists and competent regulatory authorities should be treated as a trump card in the attempt to exit from the current mid-life crisis of our specialty.

Tamoxifen: a personal retrospective.

Tamoxifen, originally described as an anti-oestrogen and antifertility agent in the rat, is now a pioneering medicine for the treatment and prevention of breast cancer. Its success is the result of an effective collaboration between laboratory research and clinical trial processes. However, this drug is more than just an anti-oestrogen to treat breast cancer. Laboratory and clinical research defined the concept of selective oestrogen receptor modulation in the 1980s. Non-steroidal anti-oestrogens show oestrogen-like activity in bones and lower cholesterol, but block oestrogen action in the breast and uterus. This realisation led to the development of chemical cousins, known as selective oestrogen receptor modulators. One of these compounds, raloxifene, is used for the prevention of osteoporosis, but is currently being tested as a preventive for breast cancer.