Adjuvant therapy and role of radiation therapy in advanced endometrial cancers

The treatment of patients with endometrial cancer is rapidly evolving. Literature data give more information on prognostic factors, allowing treatment stratification. If treatment has become less heavy in early-stage disease, therapeutic approaches have become more aggressive in more advanced disease. In this situation, treatment combines external irradiation and chemotherapy. Despite these advances, numerous questions remain on the best therapeutic sequence. Optimal chemotherapy regimens remain to be determined. On-going randomized trials will help to answer these questions.     

Adjuvant therapy for sarcomas.

Adjuvant therapy is currently established in the treatment of osteosarcoma, Ewing's sarcoma and rhabdomyosarcoma. Of the 12 reported randomized studies of adjuvant chemotherapy for soft tissue sarcoma, only 2 show a significant overall survival advantage for chemotherapy (the most important endpoint). In three randomized trials, the survival of the observation arm exceeds that of the chemotherapy arm. In two additional studies, subset analyses currently indicate a significant DFS advantage for adjuvant chemotherapy in extremity lesions, but no significant improvement in survival. Although initial NCI reports showed significantly prolonged survival for the subset of chemotherapy-treated extremity primaries, survival on longer follow-up is no longer significantly different. In the subset analysis of retroperitoneal sarcomas in the same NCI study, the survival of the control group is superior to the treatment group. Doxorubicin associated cardiotoxicity has occurred in about 10% of treated patients, occasionally contributing to treatment-related deaths. Based on these data, adjuvant chemotherapy should be considered investigational for adult soft-tissue sarcomas of any primary site. Future randomized trials should include patients at high risk for metastases (large, high-grade lesions) with a reasonable likelihood of local control by radical resection, or resection with uninvolved margins and subsequent radiotherapy. Low-grade sarcomas are currently cured by surgical resection in 80% of cases, and thus should not be included in adjuvant trials.     

Adjuvant chemo-radiotherapy in ampullary cancers.

PURPOSE: Patterns of failure following surgical treatment of ampullary cancers indicate that up to 45% of patients develop loco-regional recurrence. The effect of adjuvant chemo-radiotherapy on survival and loco-regional control is not yet established in this malignancy. PATIENTS AND METHODS: From January 1989 to December 2000, 113 patients underwent pancreatico-duodenectomy for ampullary cancer. One hundred and four patients who survived the operation were available for analysis to study the effect of adjuvant chemo-radiotherapy on survival and loco-regional control. Forty-nine patients received adjuvant chemo-radiotherapy (median dose 50.4 Gy with concurrent 5-Flurouracil) and long-term outcome in these patients was compared with those 55 who did not receive adjuvant therapy. RESULTS: The overall median survival was 30.1 (range 1.6-140.0) months with actuarial 1, 3 and 5-year survival rates of 79, 43 and 33%, respectively. No significant difference in median survival (34.6 vs 24.5 months; P=0.3) and actuarial 5-year survival rates (38 vs 28%) was seen between those who received and those who did not receive adjuvant therapy. Adjuvant chemo-radiotherapy did not influence the survival in high-risk patients (P=0.84), in various T and N stages and had no impact on loco-regional recurrence (P=0.6). CONCLUSIONS: Adjuvant chemo-radiotherapy did not improve the long-term survival or decrease recurrence rates in patients with ampullary cancers who had undergone pancreatico-duodenectomy.     

Adjuvant therapy for breast cancer.

Different aspects of adjuvant therapy in breast cancer have been noteworthy in the past year. Evaluation of long-term results with nonspecific immunostimulatory agents in conjunction with adjuvant chemotherapy or tamoxifen have failed to show therapeutic benefit. Studies have also focused on whether tamoxifen represents an alternative to chemotherapy alone, or is more effective in combination with chemotherapy or radiation therapy.     

Adjuvant immunotherapy for melanoma and colorectal cancers

Immune approaches to the therapy of colorectal cancer and melanoma have substantially evolved over the past years, from treating patients with nonspecific immune stimulants to a focus on the use of tumor-associated antigens (TAAs) either by passive immune therapy with antibodies targeted directly to tumor cells or by active immune therapy via vaccination with tumor cells, tumor cell lysates, peptides, carbohydrates, gene constructs encoding proteins, or anti-idiotype antibodies that mimic TAAs. We review the different immunotherapeutic approaches to the treatment of melanoma and colorectal cancers, and summarize relevant clinical trials.     

Adjuvant therapy for melanoma

Patients with deep primaries (> or = 4 mm) or regional lymph node involvement often require adjuvant therapy in addition to surgery to successfully treat melanoma. Various adjuvant strategies are reviewed. Randomized trials of IFN-alpha adjuvant therapy have demonstrated statistically significant improvements in disease-free and overall survival rates, leading to approval by the United States Food and Drug Administration of the use of 1 year of intensive IFN-alpha2b following surgical resection of high-risk disease. A study comparing high-dose IFN with the ganglioside vaccine GMK was terminated early when the Data Safety Monitoring Committee concluded that the high-dose IFN treatment arm was associated with highly significantly improved relapse-free and overall survival. Studies of IFN-alpha in stage I and II melanoma are reviewed. Dose and schedule issues in the use of IFN-alpha are addressed. In addition to adjuvant therapy with IFN-alpha, various other treatment strategies appear promising. Adjuvant vaccine therapy may be useful for treatment of cutaneous melanoma. Polyvalent melanoma vaccines are discussed as a potential adjuvant therapy. Finally, nonrandomized preliminary studies suggest that postoperative radiation to the neck or axilla after radical lymph node dissection may decrease regional recurrence rates in node-positive patients, supporting the selective use of radiation therapy for melanoma.     

Adjuvant therapy for melanoma

Estimates from the U.S. Surveillance, Epidemiology, and End Results registry suggest that melanoma incidence will reach 70,230 cases in 2011, of whom 8790 will die. The rising incidence and predilection for young individuals makes this tumor a leading source of lost productive years in the society.High-dose interferon-α-2b is the only agent approved for adjuvant therapy for melanoma; the improvement in relapse-free survival has been observed across nearly all published studies and meta-analyses. However, toxicity affects compliance, and current research is focusing on biomarkers that may allow selection of patients with greater likelihood of response and exploring new agents either singly or in combination that may improve on the benefit of interferon.In this article, we review the data for the adjuvant therapy for malignant melanoma--focusing on the results obtained with various regimens testing the several formulations of interferon-α2 and the adjuvant studies of vaccines and radiotherapy. Recent advances in the treatment of metastatic disease have established a role for CTLA-4 blockade and BRAF-inhibition, raising hopes that these agents may have a role in the adjuvant setting. At present, several trials investigating combinations of novel agents with existing immunomodulators are underway.     

Adjuvant systemic therapy for early breast cancer.

Systemic therapy (chemotherapy or hormonal therapy) as an adjuvant to modalities of local control is now an integral part of the management of almost all patients with primary breast cancer metastatic to axillary lymph nodes. In addition, recent data suggest an expanding role for such treatments in patients without axillary involvement. Although some node-negative patients should probably not receive adjuvant therapy, the precise criteria to be used for selection are still under active discussion in the literature. Of the two types of systemic treatment, it is generally accepted that chemotherapy is indicated for premenopausal patients and that tamoxifen is useful for postmenopausal patients whose tumors contain estrogen or progesterone receptors. The recent analysis of several studies has suggested that chemotherapy may add to the benefits of tamoxifen in some postmenopausal patients as well. A possible role for tamoxifen in younger patients is being evaluated. For patients at relatively low risk of systemic relapse (i.e., those with zero to three involved axillary lymph nodes), no chemotherapy regimen has yet shown an advantage over 6 months of cyclophosphamide, methotrexate and 5-fluorouracil. For patients at high risk, however, doxorubicin-based regimens have demonstrated benefits. High-dose chemotherapies, some involving autologous bone marrow support, are being investigated for patients with ten or more involved nodes who are at very high risk of the eventual development of stage IV disease.     

Adjuvant postoperative radiation therapy for rectal adenocarcinoma.

From October 1975 to August 1988, 261 patients at high risk for local recurrence after curative resection of rectal carcinoma underwent high-dose postoperative irradiation. Patients received 45 Gy by a 4-field box usually followed by a boost to 50.4 Gy or higher when small bowel could be excluded from the reduced field. Since January 1986, patients also received 5-fluorouracil (5-FU) for 3 consecutive days during the first and last week of radiotherapy. Five-year actuarial local control and disease-free survival decreased with increasing stage of disease; patients with Stage B2 and B3 disease had local control rates of 83% and 87% and disease-free survivals of 55% and 74%, respectively. In patients with Stage C1 through C3 tumors, local control rates ranged from 76% to 23%, and disease-free survivals ranged from 62% to 10%, respectively. For patients with Stage C disease, disease-free survival decreased progressively with increasing lymph node involvement, but local control was independent of the extent of lymph node involvement. For each stage of disease, local control and disease-free survival did not correlate with the dose of pelvic irradiation. Preliminary data from this study suggest a trend toward improved local control for patients with Stage B2, C1, and C2 tumors who receive 5-FU for 3 consecutive days during the first and last weeks of irradiation compared with patients who do not receive 5-FU. Current prospective randomized studies are addressing questions regarding the optimum administration of chemotherapy with pelvic irradiation for patients following resection of rectal carcinoma.     

Adjuvant therapy for colon cancer

Colon cancer is a leading cause of cancer and cancer deaths in Western countries. Although 5-fluorouracil is still the basis of adjuvant therapy, advances in drug development have led to increased efficacy with the addition of oxaliplatin and options for oral therapy with capecitabine. The benefit of adjuvant therapy for stage II disease is consistently small and not statistically signifi-cant. Future studies will evaluate the role of the biologic agents that have proved to be effective in metastatic disease and better delineate the population at risk by identifying prognostic and predictive markers.     

Adjuvant therapy for colon cancer

As there have been advances in the treatment of metastatic colorectal cancer, exciting developments have also been achieved in the adjuvant treatment of colon cancer. At the same time, more questions have been raised, and some controversies remain. The results of the MOSAIC trial demonstrated the benefit of adding oxaliplatin to 5-fluorouracil (5-FU) and leucovorin (FOLFOX) in adjuvant therapy for stage II and III disease, but the optimal duration of therapy and the management of toxicities remain to be resolved. Capecitabine is at least equivalent to the Mayo Clinic bolus 5-FU and leucovorin regimen in the adjuvant treatment of stage III colon cancer with a lower incidence profile of adverse events, allowing additional options for patients and physicians. Routine adjuvant systemic therapy in all patients with stage II colon cancer is still debatable. Although a statistically significant advantage for adjuvant treatment in stage II disease was shown for the first time from a large randomized study (QUASAR), the subsets of patients who truly benefit from therapy need to be identified. The application of pharmacogenetics and pharmacogenomics in adjuvant therapy for colorectal cancer will help to distinguish those patients with risk factors and to guide individualized therapy.     

胰腺癌的辅助治疗

对于胰腺癌术后状态,研究表明进行吉西他滨全身化疗能够显著提高无瘤生存期和总生存期,而辅助放化疗则存在较大争议;局部介入化疗在小样本的研究中获得肯定,但仍缺乏大样本随机对照研究予以证实;新辅助治疗对于评价为可能切除的胰腺癌病灶提供了外科切除的可能.     

胰腺癌的辅助治疗

对于胰腺癌术后状态,研究表明进行吉西他滨全身化疗能够显著提高无瘤生存期和总生存期,而辅助放化疗则存在较大争议;局部介入化疗在小样本的研究中获得肯定,但仍缺乏大样本随机对照研究予以证实;新辅助治疗对于评价为可能切除的胰腺癌病灶提供了外科切除的可能.     

胃癌的辅助治疗

辅助化疗可改善日本胃癌患者的生存期;围手术期化疗给欧洲患者带来生存获益;辅助放化疗因其有效性和可行性成为美国胃癌根治术后患者的标准治疗方法;腹腔化疗亦在减少复发转移、延长生存期等方面起到了一定的作用,多在亚洲使用.     

Adjuvant therapy for malignant melanoma

Malignant melanoma is increasing in incidence worldwide, and many patients remain at a significant risk of recurrence following surgical resection. Over the past 30 years, interferon-alpha has been the only agent approved for adjuvant therapy of melanoma. This review summarizes the rationale for adjuvant therapy, and discusses the roles of interferon, immunotherapy, chemotherapy and radiation therapy in the adjuvant setting. New approaches and novel combinations that appear promising for the adjuvant therapy of malignant melanoma are also outlined.     

胰腺癌的辅助治疗

对于胰腺癌术后状态,研究表明进行吉西他滨全身化疗能够显著提高无瘤生存期和总生存期,而辅助放化疗则存在较大争议;局部介入化疗在小样本的研究中获得肯定,但仍缺乏大样本随机对照研究予以证实;新辅助治疗对于评价为可能切除的胰腺癌病灶提供了外科切除的可能.