Chemotherapy and survival

Cristofanilli M, Gonzalez-Angulo A, Sneige N, et al. Invasive lobular carcinoma classic type Response to primary chemotherapy and survival outcomes. J Clin Oncol. 2005 23 41-48. 

Modem cancer therapy has been primarily dependent upon surgery, radiotherapy, chemotherapy, and hormonal therapy (72) (see Chemotherapeutics,anticancer Hormones Radiopharmaceuticals). Chemotherapeutic agents maybe able to retard the rate of growth, but are unable to eradicate the entire population of neoplastic cells without significant destmction of normal host tissue. This serious side effect limits general use. More recentiy, the immunotherapeutic approach to cancer has involved modification and exploitation of the cellular and molecular mechanisms in host defense, regulation of tissue proliferation, tissue differentiation, and tissue survival. The results have been more than encouraging. 

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

Small cell lung cancer typically presents as extensive disease (approximately 60% to 70% of new cases) and progresses very quickly. Small cell carcinomas are very responsive to chemotherapy and radiation. Radiotherapy became the standard in 1969, when a randomized trial showed that it offered the potential for cure, whereas surgery did not.20 For the vast majority of patients, chemotherapy with or without radiotherapy is the treatment of choice. Even after a complete response to therapy, the cancer usually recurs within 6 to 8 months, and survival time following recurrence is typically short ( 4 months). This yields a typical survival rate of 14 to 20 months for limited disease and 8 to 13 months for extensive disease.33 Table 87-6 illustrates the general treatment path of SCLC. 

Kerr C. Bevacizumab and chemotherapy improve survival in NSCLC. Lancet Oncol 2005 6(5) 266. 

The histology of the disease is a prognostic factor. For instance, clear-cell and undifferentiated tumors do not respond as well to chemotherapy.2 The extent of residual disease and tumor grade are also predictive of response to chemotherapy and overall survival.2 There are other prognostic factors that may predict how well a patient will respond to adjuvant chemotherapy. 

Chronic lymphocytic leukemia (CLL) patients who receive fludarabine-based combination chemotherapy and rituximab may have long-term disease-free survival. 

The primary goal in the treatment of multiple myeloma is to decrease tumor burden and minimize complications associated with the disease. A watch and wait approach is an option for asymptomatic patients who have no lytic lesions in the bone. Once symptoms occur, treatment is required. Chemotherapy can be used to reduce tumor burden in patients with symptomatic disease, but increasingly, immunomodula-tors such as thalidomide and dexamethasone are initial therapy. Almost all patients will become refractory to initial treatment and will require the use of salvage therapies such as bortezomib. Autologous stem cell transplantation prolongs overall survival in patients who can tolerate high-dose chemotherapy and may be the treatment of choice for many patients. 

Clinical trials combining chemotherapy and immunotherapy are based on the observations of independent clinical activity of each of these treatment modalities in treating metastatic MM. This combination is known as biochemotherapy. Only one phase III clinical trial showed significant improvement in response rate, time to progression, and median survival favoring the biochemotherapy arm versus the combination-chemotherapy arm.59 Currently, the use of biochemotherapy is not justified outside a clinical trial in patients with stage IV MM.53,58,60... 

Brognard, J., Clark, A.S., Ni, Y., and Dennis. P.A. 2001. Akt/protein kinase b is constitutively active in nonsmall cell lung cancer cells and promotes cellular survival and resistance to chemotherapy and radiation. 

In vitro studies have shown that increasing the number of repeats leads to stepwise increases of TS gene expression with the presence of a triple repeat resulting in a 2.6-fold greater TS expression than a double repeat [70, 80]. In vivo studies in human gastrointestinal tumors have shown a significant increase in TS protein levels and functional activity in patients with TSER 3 compared to individuals with TSER 2 [81]. As TS tumor levels are important for resistance and survival prediction, this may have important implications for TS-based chemotherapy. 

Malignant mesothelioma, described more than 100 years ago, is a comparatively rare tumor that occurs in the pleura and peritoneum, membranes that surround the lungs, line the thoracic cavity, surround the gut, and line the abdominal cavity. The survival time of mesothelioma patients is often less than a year, in spite of chemotherapy and radiotherapy. Combined therapy and surgical resection in cases of early diagnosis, a treatment currently being tested, has produced a few long-term (more than five years) survivors (Ant-man, et ah, 1980 Antman et ah, 1983), usually in cases with peritoneal rather than pleural involvement. 

This pediatric cancer stands as an example of how cooperative group studies (NWTS and SIOP) have been able to integrate both chemotherapy and radiation into standard therapy while minimizing side-effects and dramatically improving cure rates as seen in the improvement of the 5-yr relative survival rates from 74% in 1974-1976 to 93% in 1989-1996 (60). The fifth NWTS trial began in 1995 and is expected to continue until 2003 (see Table 5) (60). This study will search for biological prognostic factors and examine the rates of cancer and birth defects in children born to survivors of Wilms tumor. 

We are currently on the cusp of a new era in the treatment of cancers whereby we will learn to incorporate new drugs that are likely not cytotoxic on their own but when used in combination with standard chemotherapy and radiation hold the promise of superior tumor responses that will hopefully translate into improved local control and improved survival. At the same time it is reasonable to expect an increased selectivity for malignant cells compared to normal tissues given that many of these targets are either not altered in normal cells or their expression is not usually increased in normal tissues. This leads to the anticipation of no increase in normal tissue toxicities when these novel targeted agents are used to treat patients. 

The earliest combination chemotherapy and radiation trials in nonsmall-cell lung cancer included cisplatin and 5-fluorouracil and concurrent radiation therapy and found survival results comparable to those for sequential chemotherapy and radiation or to daily cisplatin and radiation therapy without surgery (119,121). Phase II studies of stage Ilia and Illb nonsmall-cell lung cancer patients treated with the combination of cisplatin with etoposide and 5 -fluorouracil and either single daily radiation fractionation or twice daily radiation fractionation prior to surgery produced similar clinical results (119,121). Complete surgical resection was accomplished in 70% of the patients, the median survival was 22 mo and the 2-yr survival rate was 45%. 

Suntharalingam M, Haas ML, Van Echo DA, et al. Predictors of response and survival after concurrent chemotherapy and radiation for locally advanced squamous cell carcinomas of the head and neck. Cancer 2001 91(3) 548-554. 

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