Prognostic and predictive factors in early-stage breast cancer

Breast cancer is the most common malignancy among American women. Due to increased screening, the majority of patients present with early-stage breast cancer. The Oxford Overview Analysis demonstrates that adjuvant hormonal therapy and polychemotherapy reduce the risk of recurrence and death from breast cancer. Adjuvant systemic therapy, however, has associated risks and it would be useful to be able to optimally select patients most likely to benefit. The purpose of adjuvant systemic therapy is to eradicate distant micrometastatic deposits. It is essential therefore to be able to estimate an individual patient's risk of harboring clinically silent micrometastatic disease using established prognostic factors. It is also beneficial to be able to select the optimal adjuvant therapy for an individual patient based on established predictive factors. It is standard practice to administer systemic therapy to all patients with lymph node-positive disease. However, there are clearly differences among node-positive women that may warrant a more aggressive therapeutic approach. Furthermore, there are many node-negative women who would also benefit from adjuvant systemic therapy. Prognostic factors therefore must be differentiated from predictive factors. A prognostic factor is any measurement available at the time of surgery that correlates with disease-free or overall survival in the absence of systemic adjuvant therapy and, as a result, is able to correlate with the natural history of the disease. In contrast, a predictive factor is any measurement associated with response to a given therapy. Some factors, such as hormone receptors and HER2/neu overexpression, are both prognostic and predictive.     

Retrospective analysis of prognosis for scirrhous-type gastric cancer: one institution's experience

Background Scirrhous gastric cancer is biologically aggressive, and the prognosis is poor even with curative surgery. We compared outcomes with different therapies in order to identify prognostic factors. Methods Records for 83 patients, who were treated between 1991 and 2004, were evaluated for survival and stage, treatment, and clinicopathological factors. Results Cumulative 5-year overall survival was 10.2% for all 83 patients, including 27 (32.5%) patients with stage II/III disease and 56 (67.4%) with stage IV disease. The 5-year overall survival rate and median survival time for patients with stage II/III disease after curative surgery were 24.3% and 1150 days. For patients with stage IV disease, 2-year and 5-year survival rates after initial surgery were 13.7% and 0% and median survival was 250 days. In contrast, preoperative chemotherapy for advanced, unresectable disease produced 2-year and 3-year overall survival rates of 53.6% and 26.8% and medican survival was 910 days. Conclusion Aggressive surgery alone does not seem to improve outcome, but preoperative chemotherapy might be beneficial and should be investigated further.     

Do we really need prognostic factors for breast cancer?

Summary The role of prognostic factors in optimizing treatment for breast cancer patients has clearly changed with the trend toward general use of adjuvant therapy. Nevertheless, there are at least three situations in which prognostic factors could be helpful. The first is to identify patients whose prognosis is so good that adjuvant therapy after local surgery would not be cost-beneficial. The second is to identify patients whose prognosis is so poor that a more aggressive adjuvant approach would be warranted. The third is to identify patients likely to be responsive or resistant to particular forms of therapy. Here we will discuss all of these situations, together with the appropriate cutpoint analyses and validation of individual prognostic factors and their combination into prognostic indexes which may make the discrimination of patient subsets more reliable.     

Prognosis of T4 gastric carcinoma patients: an appraisal of aggressive surgical treatment

BACKGROUND AND OBJECTIVES: Despite precipitous drop in the incidence of gastric carcinoma in Japan, it is still one of the leading causes of death associated with malignant disease. Once the contiguous organs are involved the prognosis becomes dismal. Prognostic factors governing the survival of patients with T4 gastric carcinoma remain unclear. METHODS: Between 1980 and 1998, 150 patients were treated for T4 gastric carcinoma. Results and prognostic factors were evaluated by univariate and multivariate analyses. RESULTS: With a 73% resectability, patients with tumor resection had a significantly (P < 0.0001) improved survival rate. Within an acceptable operative mortality (2.6%), apparently curative cases had survival benefit (P < 0.0001) over noncurative cases. In the multivariate analysis, the death risk increased by 2.18 (relative risk) when splenectomy was spared from the operative procedure (P < 0.0071). Presence of esophageal invasion was the other independent prognostic factor in T4 gastric carcinoma patients (relative risk 2.11). Conventional prognostic factors along with the type of organs invaded by the carcinoma had no impact on prognosis. CONCLUSIONS: Patients with T4 gastric carcinoma might be benefited from aggressive surgery with a curative intent. Whenever possible, splenectomy should be done along with invaded organ resection.     

Anaplastic thyroid cancer

Anaplastic thyroid carcinoma is one of the most aggressive malignancies, with a poor prognosis. Although rare, representing only 2% of clinically recognized thyroid cancers, the overall median survival is limited to months. Most patients are elderly and seek treatment with a rapidly growing mass. Almost half the patients seek treatment with distant metastases, with as many as 75% developing distant disease during their illness. In most the patients, complete surgical resection is not possible. There are, however, a few patients with resectable disease reported in the literature who have demonstrated long-term survival with aggressive multimodal therapy that included surgery, radiation, and chemotherapy. Preclinical studies in human anaplastic thyroid carcinoma cell lines show promise that new approaches to the management of this disease will be found in the future. Until such time when an effective regimen is found, all patients with anaplastic thyroid carcinoma should be evaluated for multimodal therapy in the setting of a clinical trial.     

Prognostic factors in squamous cell carcinoma of the head and neck

Therapy for squamous cell carcinoma of head and neck relies on surgery, radiotherapy and chemotherapy, mostly a combination thereof. In patients treated with curative intent, the intensity of therapy is adapted to the supposed prognosis and should be defined upon prognostic factors. Besides classical prognostic parameters, T, N and M stage, the presence of extranodal growth (extracapsular spread, ECS), tumor volume, lymph node burden, extent of tumor necrosis, histologic grading, but also type of treatment were determined in consideration of prognosis. The p53 status does not correlate with prognosis in most investigations. The tumor hypoxia seems to be of prognostic value, and strategies to overcome the adverse effect are currently investigated. Not all factors are relevant for all types of treatment. Besides ECS, these new factors so far have rarely been used to stratify prospective combined modality treatment according to the risk of locoregional and distant failure.     

Management of early breast cancer in the elderly

Breast cancer is the most common malignancy in women with an age related increase in incidence ranging from 1 in 50 at age 50 to 1 in 10 at age 80. This is particularly significant in view of the changing demographics in the western population, characterised by an aging population and increased life expectancy. However in spite of favourable prognostic factors and less aggressive biological behaviour, elderly breast cancer patients receive less aggressive treatment when compared with their younger counterparts. Appropriate treatment should be offered depending on physiological reserve and comorbidities. Primary endocrine treatment has been shown to be associated with significant morbidity in terms of disease progression. Prompt surgery and adjuvant treatment can decrease relapse and improve survival. Radiation therapy is shown to decrease local relapse and chemotherapy may have a role in a select group of patients with adverse prognostic factors. With incidence of breast cancer bound to increase in the elderly population, it is essential to establish optimum therapy in this cohort of patients as studies reveal good outcome from standard treatment.     

Treatment selection in metastatic renal cell carcinoma: expert consensus

In metastatic renal cell carcinoma (mRCC), many factors influence clinical decisions, including histology, tumour burden, prognostic factors, comorbidities, and the ability of the patient to tolerate treatment. Progression-free survival (PFS) durations reported from randomized trials of targeted therapies vary considerably, in part because of differences in patient characteristics. For first-line therapy, an estimate of PFS with sunitinib, bevacizumab plus interferon, or sorafenib in a 'general' population is 8-9 months, but each regimen is suitable for different patient categories. For example, sunitinib is suitable for all-prognosis groups, particularly younger, fitter patients; pazopanib for patients with a good or intermediate prognosis; bevacizumab plus interferon for good-prognosis patients or those with indolent disease; and sorafenib for patients at all prognostic risk levels, particularly the elderly and those with comorbidities. Sequential therapy with targeted agents provides significant benefit, and should be considered in all patients who can tolerate such treatment. Level 1 evidence supports sequential use of tyrosine kinase inhibitors, as well as these agents followed by everolimus. We consider how patient characteristics have influenced the results of studies of first-line therapy, and we provide expert opinion on the most appropriate treatment choices for particular patient groups receiving first-line and second-line therapy.     

The management of borderline tumours of the ovary

PURPOSE OF REVIEW: The treatment of borderline ovarian tumours has been similar to that for their invasive counterparts for a long time. However, in view of the good prognosis for borderline ovarian tumours, their occurrence in a younger age group and the development of less invasive techniques, the question can be asked as to whether a more conservative treatment is warranted. RECENT FINDINGS: Recent articles discuss the mode of surgery (laparotomy or laparoscopy), the possibility of fertility-sparing surgery, the need for restaging procedures and adjuvant therapy. SUMMARY: The ultimate goal in treating patients with borderline ovarian cancer is defining those patients with bad prognostic factors and risk for recurrence and who consequently require more aggressive therapy. A proper staging procedure is crucial to estimate the risk. Translational research might help identify borderline tumours with poor prognosis. Fertility-sparing surgery is often a good option in young patients with Fédération International de Gynécologie et Obstétrie (FIGO) stage I disease or in selected cases with noninvasive implants, since long-term survival does not seem to be negatively influenced by conservative surgery.     

Acute Myeloid Leukemia in the Elderly: A Critical Review of Therapeutic Approaches and Appraisal of Results of Therapy

In the elderly, acute myeloid leukemia (AML) is characterized by a poorer prognosis than in younger patients, due to either host related factors (poor performance status, co-morbid diseases, organ function impairment) or the biology of leukemia itself (high incidence of adverse cytogenetic abnormalities, high frequency of preceding myelodysplastic syndromes, intrinsic resistance to cytotoxic drugs). Current therapeutic results are mostly unsatisfactory and studies reporting high rates of complete remission are probably influenced by selection biases as suggested by the low rate of elderly patients inclusion into cooperative trials. Availability of intensive support including hematopoietic growth factors could stimulate clinicians to manage an increasing number of elderly patients with AML with aggressive programs. However, chemotherapy in the elderly is difficult, costly and usually associated with high morbidity and mortality rate. Therefore, all efforts should be made to identify those subset of elderly patients in whom aggressive treatment may result in a true improvement of disease free and overall survival. The critical analysis of our five years experience, as reported here, seems to suggest that older AML patients displaying unfavourable prognostic factors at diagnosis (i.e., adverse karyotype and high serum LDH levels), but clinically eligible for intensive chemotherapy, do not actually benefit from an aggressive approach. A blind attempt to treat these patients aggressively may be associated with a life threatening toxicity not counterbalanced by an actual survival advantage. We suggest therefore that aggressive treatment should be reserved for elderly AML cases in whom the presence of good prognostic factors at diagnosis predicts that the loss of some patients due to toxicity may be balanced by the achievement of a substantial proportion of long term survivors. Finally, given the biological and clinical heterogeneity of elderly AML patients, a more precise prognostic categorization of these patients would be particularly useful in interpreting future therapeutic results.     

Medical management of early-stage breast cancer

With improved screening and education, a greater proportion of breast cancer is detected at an early stage. Although the prognosis for many of these patients is excellent following definitive local therapy alone, some subsets of node-negative patients have a 30% chance of eventually developing metastatic disease that will be incurable with current therapy. Thus, an increasing proportion of early-stage patients are being offered some form of adjuvant therapy, with the expectation of improved relapse-free survival, and possibly improved overall survival. Efforts have been made to base the selection of patients for adjuvant therapy on specific prognostic factors. Meanwhile, the scope and complexity of putative prognostic factors continues to widen, and now includes such items as the presence of occult microscopic metastases, DNA ploidy and proliferative fraction, cytogenetic abnormalities, oncogene expression, growth factor receptors, and expression of hormonally regulated proteins. In addition, there is now a considerable range of options with regard to the composition, dose intensity, and sequence of multimodality therapy. Data regarding the classification, significance, and interpretation of prognostic factors is reviewed together with the development, current status, and recommendations regarding adjuvant therapy for patients with early-stage breast cancer. For 1991, the National Cancer Institute (NCI) has estimated that 175,000 new cases of breast cancer will be diagnosed in American women. It is also estimated that 44,500 women will die of breast cancer. Unfortunately, the age-adjusted death rate from breast cancer has shown no overall change from 1930 through 1987. However, effective screening techniques continue to identify an increasing percentage of early-stage tumors, which should exceed 50% of all new tumors in 1991. Ultimately, our understanding of environmental and genetic risk factors may identify new ways to reduce the impact of this disease. In the interim, development and application of effective systemic adjuvant chemotherapy and hormonal therapy has become increasingly important. There is no question that a greater proportion of patients with less extensive disease are now being offered some form of adjuvant therapy. Meanwhile, selection of patients for adjuvant therapy, and choice among specific adjuvant regimens, has remained controversial. Analysis of multiple prognostic factors is performed not only in the context of cooperative investigational trials, but more often in the offices of individual physicians caring for individual patients. Tumor biopsies can now be routinely sent to specialized laboratories for performance of complex assays with potential prognostic information, although interpretation of these results with reference to a specific patient is often uncertain.(ABSTRACT TRUNCATED AT 400 WORDS)     

Incorporating prognostic information into treatment decisions in chronic lymphocytic leukemia

Most patients with chronic lymphocytic leukemia are diagnosed at an early stage, when traditional staging systems fail to distinguish those with an aggressive disease course from those with an excellent prognosis. This failure underscores the need for better prognostic markers. Although many markers have been explored, this review focuses on the newer and most clinically relevant markers: cytogenetic aberrations, zeta-associated protein 70, immunoglobulin mutational status, and CD38 expression. Although these markers have been shown to predict outcomes for groups of patients, individual patients may have a variable course; therefore, the outcome for any one patient remains hard to predict. To date, no study has shown a benefit from early cytotoxic therapy for any subgroup of patients with chronic lymphocytic leukemia.     

Treatment of thoracic esophageal carcinoma invading adjacent structures

T4 esophageal cancer is defined as the tumor invading adjacent structures, using tumor-node-metastasis (TNM) staging. For clinically T4 thoracic esophageal carcinoma, multimodality therapy, that is, neoadjuvant chemoradiotherapy (CRT) followed by surgery or definitive CRT, has generally been performed. However, the prognosis of patients with these tumors remains poor. Another strategy is needed to achieve curative treatment. In the present article, the treatment strategies employed to date are reviewed. Furthermore, the strategies for these malignancies are reassessed, based on our experiences. R1/2 and R0 resections are regarded as those with residual and no tumor after surgery. The present data show that patients who underwent R1/2 resection after neoadjuvant CRT experienced little survival benefit, while complete response (CR) cases after definitive CRT had comparatively better results. Therefore, curative surgery should not be attempted without down-staging, and definitive CRT should be the initial treatment. Then surgery is indicated for the eradication of residual cancer cells. Close surveillance is essential for early detection of relapse even after CR, because the operation will gradually become increasingly difficult due to post-CRT fibrosis. In conclusion, multimodality therapy consists of definitive CRT followed by R0 resection, which can be the treatment of choice for T4 esophageal carcinoma. These challenging treatments have the potential to constitute the most effective therapeutic strategy.     

Surgical strategies in patients with gallbladder cancer: nihilism to optimism

INTRODUCTION: Gallbladder cancer is an aggressive disease with dismal results of surgical treatment and a poor prognosis. However, over the last few decades selected groups have reported improved results with aggressive surgery for gallbladder cancer. METHODS: Review of recent world literature was done to provide an update on the current concepts of surgical treatment of this disease. RESULTS: Long-term survival is possible in early stage gallbladder carcinoma. Tis and T1a gallbladder carcinoma can be treated with simple cholecystectomy only. However, in T1b and beyond cancers, aggressive surgery (extended cholecystectomy) is important in improving the long-term prognosis. Laparoscopic cholecystectomy should not be performed where there is a high index of suspicion of malignancy due to the frequent association with factors (such as gallbladder perforation and bile spill) which may lead to implantation of cancer cells and dissemination. Surgical resection for advanced carcinoma gallbladder is recommended only if a potentially curative R0 resection is possible. Aggressive surgery with vascular and multivisceral resection has been shown to be feasible albeit with an increase in mortality and morbidity. However, the true benefit of these radical resections is yet to be realized, as the actual number of long-term survivors of advanced gallbladder carcinoma is few. CONCLUSIONS: Surgery for gallbladder carcinoma, like other malignancies, has the potential to be curative only in local or regional disease. Pattern of loco-regional spread of disease dictates the surgical procedure. Radical surgery improves survival in early gallbladder carcinoma. The long-term benefit of aggressive surgery for advanced disease is unclear and may be offset by the high mortality and morbidity.     

Isolated paraaortic lymph-node recurrence after the curative resection of colorectal carcinoma

BACKGROUND AND OBJECTIVES: Isolated paraaortic lymph-node recurrence (IPLR) after curative surgery for colorectal carcinoma is rare and no previous report has specifically addressed this type of recurrence. We investigated the clinical features of IPLR and analyzed prognostic factors. METHODS: Of 2,916 patients who underwent curative surgery for colorectal carcinoma, IPLR was identified in 38 patients (1.3%). The clinical features and prognostic factors of these patients were analyzed. RESULTS: IPLR was first detected by increased serum carcinoembryonic antigen (CEA) levels (63.2%) or by routine follow-up computed tomography (CT) (36.8%). Curative resection of IPLR was performed in six patients (15.8%). A total of 19 patients (50.0%) received chemoradiation therapy and 13 patients (34.2%) received chemotherapy only. The median survival from IPLR was 13 months (range: 5-60 months). The median survival time from IPLR for the resected patients was 34 months, whereas it was 12 months for those who did not undergo resection (P = 0.034). The factors associated with the prognosis were histological grade (P = 0.003), location (P = 0.032), and resection of IPLR (P = 0.034). CONCLUSIONS: IPLR after curative surgery for colorectal carcinoma is rare. Although it is generally associated with poor prognosis, better survival might be achieved through curative resection in selected cases.     

Surgical Salvage of Recurrent Cancer of the Head and Neck

The therapeutic options and prognosis for recurrent squamous cell carcinoma of the upper aerodigestive tract vary greatly depending on site, extent of disease, and previous treatment. Surgical salvage represents the primary curative option when recurrent disease is resectable. Common factors associated with poor salvage surgery outcomes include positive surgical margins, lack of disease-free interval following previous definitive radiation therapy, advanced initial and recurrent tumor stage, and presence of concomitant recurrent neck disease. Surgical salvage of oropharyngeal and hypopharyngeal recurrences after primary chemoradiation therapy is associated with significant patient morbidity and poor long-term survival. Patients with laryngeal recurrences generally have the best comparative survival and functional outcomes, while patients with oral cavity recurrences have a relatively intermediate prognosis. Nasopharyngeal recurrences have often been treated with reirradiation, but surgical salvage represents the best option for small recurrences confined to the nasopharynx. Most patients with recurrent upper aerodigestive tract squamous cell carcinoma after previous aggressive therapy are not curable, and clinical judgment in determining which patients are appropriate candidates for salvage surgery is paramount.     

Prognostic factors in colorectal cancer

Prognosis of patients after colorectal cancer resection is predominantly influenced by the extent of local tumour growth and the presence or absence of nodal or distant metastasis. However, many factors have been used to generate numerous classification systems, leading to some debate and confusion. The effects on survival of 7 clinical and pathological parameters were reviewed in 801 consecutive patients operated upon with locally curative intent for colorectal cancer over a ten-year period. Age less than 50 or more than 70 years, poor cellular differentiation, high mucous secretion by tumour cells and Dukes' staging were the parameters significantly correlated to poor overall survival (p<0.001 for each). The Cox's regression analysis identified the same parameters as independent prognostic factors. The value of age as a prognostic factor remains debatable, but the other three parameters must be considered when evaluating prognosis after curative surgery for colorectal cancer and when considering adjuvant therapy.     

Potentially curable metastatic colorectal cancer

Although patients with metastatic colorectal cancer have historically had a uniformly dismal prognosis, recent advances in chemotherapeutics and surgical techniques allow many patients to be treated with the potential for long-term survival and cure. Patients with potentially curable disease are those in whom multidisciplinary strategies including surgery can result in safe resection of all metastatic disease with negative margins. Although favorable outcomes using such strategies can increasingly be predicted, the presence of poor prognostic factors does not necessarily represent a contraindication to the use of a potentially curative strategy as long as a margin-negative resection can ultimately be obtained. Further analysis of the innovative strategies and techniques described in this article are needed to maximize cure rates in patients with this disease.     

Result of 11,946 gastric cancer treatment with immunochemosurgery

Although the therapeutic results of gastric cancer have markedly improved, it still remains the most common of cancer deaths in Korea. Annually more than 700, and all together 11,946, gastric cancer patients were surgically treated from 1970 to 1998 at Seoul National University Hospital. Stage III gastric cancer is already a systemic disease, Radical surgery alone cannot cure the patient, and about 35% recurred within 2-3 years. To improve the prognosis of advanced gastric cancer, systemic treatment such as immunotherapy and chemotherapy is required in the early postoperative period to kill the micrometastatic or remaining cancer cells after curative resection. We evaluated the survival rate and prognostic factors for 9,262 consecutive patients from 1981 to 1996. The clinicopathologic variables used for evaluating prognostic values were classified into patient, -tumor- and treatment-related factors. The prognostic significance of treatment modality was evaluated in stage III gastric cancer. The five-year survival rates were 55.9% for overall patients and 64.8% for patients who received curative resection. Radical lymph node dissection was found to produce survival gains in patients with stage II and IIIa. For postoperative adjuvant therapy, immunochemotherapy was most effective in patients with stage III. In multivariate analysis, curability of operation, depth of invasion, and ratio of involved-to-resected lymph nodes were the significant prognostic factors. Consequently, early detection and real curative resection with radical lymph node dissection, followed by immunochemotherapy (particularly in patients with stage III gastric cancer) should be recommended as a standard treatment principle for patients with gastric cancer.     

Intensive weekly chemotherapy for locally advanced gastric cancer using 5-fluorouracil, cisplatin, epidoxorubicin, 6S-leucovorin, glutathione and filgrastim: a report from the Italian Group for the Study of Digestive Tract Cancer (GISCAD).

Local extension prevents curative resection in more than two-thirds of gastric cancer patients. Unfortunately, resectability is one of the main prognostic factors in these patients, and survival is longer when tumours are completely removed. Preoperative chemotherapy is an attractive concept for obtaining curative resection. Thirty-two locally advanced unresectable gastric cancer patients were enrolled in five Italian Group for the Study of Digestive Tract Cancer (GISCAD) centres. For 16 patients, surgical unresectability was based on computerized tomography scan evaluation of tumour size (four patients) and invasion of adjacent structures (12 patients), whereas in another 16 patients locally advanced disease was confirmed by laparotomy. They received weekly administration of cisplatin 40 mg m(-2), 5-fluorouracil 500 mg m(-2), epidoxorubicin 35 mg m(-2), 6S-stereoisomer of leucovorin 250 mg m(-2) and glutathione 1.5 g m(-2). From the day after to the day before each chemotherapy administration, filgrastim was administered by subcutaneous injection at a dose of 5 microg kg(-1). One cycle of therapy consisted of eight weekly treatments. Fifteen of 32 patients (47%) responded to chemotherapy, whereas 13 (41 %) had stable disease and four (12%) progressed on therapy. Of the 15 responding patients, 13 were completely resected after chemotherapy and two of them had a complete pathological response. Two clinically responding patients were found unresectable at operation because of peritoneal seeding. At a median follow-up from the start of treatment of 24 months (range 11-39 months), 10 of 13 resected patients are alive and eight are relapse free. Three patients died after 11, 12, and 14 months respectively. Toxicity was acceptable: side-effects consisted mainly of grade II National Cancer Institute common toxicity criteria (NCICTC) leucopenia and thrombocytopenia in ten patients. Neither treatment-related death nor surgical complications in patients undergoing surgery were observed. This weekly intensive regimen enabled resection in half of previously inoperable tumours with a moderate toxicity. It can be offered to patients with locally advanced unresectable gastric cancer to obtain curative resection.