Combined modality therapy for esophageal cancer

Whereas many patients with esophageal carcinoma present with what appears to be localized disease, cure rates with surgical resection alone remain low. Although surgical resection, where feasible, affords patients the best chance of cure, the primary tumor has often invaded local tissues or structures, and occult micrometastases often exist at the time of presentation. In an effort to improve treatment results, various combinations of surgery, radiotherapy, and chemotherapy have been used. The results of combined modality therapy are reviewed in this article. The importance of accurate pretreatment staging is discussed, and ongoing prospective randomized trials are reviewed.     

Combined modality therapy of esophageal cancer

Esophageal cancer is a deadly disease. Only one third of patients with localized disease experience long-term survival. Over the past 20 years, investigators have evaluated neoadjuvant strategies to improve the outcomes of surgical management. Chemotherapy and radiation have been evaluated individually and in combination for preoperative management of patients with localized esophageal cancer. This article provides a critical review of the data on multimodality approaches to the management of esophageal cancer.     

Patterns of failure following combined modality therapy for esophageal cancer, 1984-1990.

From 1984-1990, 143 patients with squamous cell or adenocarcinoma of the esophagus were enrolled in a Phase I/II study of neoadjuvant chemotherapy followed by concurrent chemotherapy plus radiotherapy with or without subsequent esophagectomy. Patients received one cycle of Cisplatin or Carboplatin plus Etoposide for squamous cell carcinoma, or Cisplatin or Carboplatin plus 5FU for adenocarcinoma, followed by two cycles of the same chemotherapy given concurrently with 44-46 Gy over 5 weeks. Operable patients then underwent esophagectomy. Inoperable patients and those with positive surgical margins received additional irradiation (16-18 Gy). Twelve percent of the surgical group received preoperative radiotherapy doses > or = 50 Gy. Seventy-two percent (103) had clinical Stage I-III tumors and 28% (40) were clinical Stage IV (1983 American Joint Committee on Cancer criteria). Only clinical Stage I-III patients were analyzed with respect to patterns of failure. Isolated local failure occurred in 19/103 (18%) of clinical Stage I-III patients. Both local and distant relapse occurred in 15/103 (15%), and distant metastases alone occurred in 25/103 (24%). The 3-year actuarial rates of local and distant failures were 45% and 60%, respectively. Among the clinical Stage I-III patients who underwent surgery (n = 58) versus those who did not (n = 45), the 3-year actuarial local and distant failure rates were 30% versus 60% and 45% versus 45%, respectively. Multivariate analysis was performed to identify significant predictors of local control. For all clinical Stage I-III patients, treatment with surgery (p = 0.001) and with three or more cycles of chemotherapy (p = 0.02) were significant predictors of improved local control. Patients who underwent surgery were significantly younger and had a better performance status than those who did not. The improvement in local control with surgery did not translate into better survival, likely on account of a high operative mortality rate in older patients and those receiving > or = 50 Gy preoperatively. We conclude that local control remains poor with concurrent chemotherapy + radiotherapy for esophageal cancer. The addition of surgery improved local control, but distant metastases remain a problem both in this group of patients as well as those treated without esophagectomy. Efforts to improve local control appear warranted, but it remains to be demonstrated that improved local control translates into improved survival in esophageal cancer because of a high rate of distant metastases in patients whose disease is controlled in the esophagus.     

Cervical cancer: combined modality therapy

Prospective, randomized studies conducted over the past 10 years have changed the management of patients with advanced cervical cancer. The reviewed studies evaluated the use of surgery, irradiation, and chemotherapy in patients with various stages of cervical carcinoma in the absence and presence of high-risk factors for recurrence. A study by the Radiation Therapy Oncology Group (RTOG) compared pelvic with pelvic plus prophylactic para-aortic irradiation in patients with stages IB (> 4 cm), IIA, and IIB cervical cancer. The 10-year survival advantage was 11% for patients treated with prophylactic para-aortic irradiation. A follow-up study compared pelvic plus prophylactic para-aortic irradiation and brachytherapy with pelvic irradiation, brachytherapy, and chemotherapy with cisplatin and 5-FU in patients with IB-to IVA-stage cervical cancer. Overall and disease-free survivals were significantly improved in patients receiving chemotherapy. In patients with a prevalence of stage IIB and III, the Gynecologic Oncology Group (GOG) demonstrated that treatment with hydroxyurea alone was inferior to cisplatin or cisplatin, 5-FU, and hydroxy-urea in patients treated concurrently with pelvic irradiation and brachytherapy, and the GOG adopted irradiation and weekly cisplatin as standard therapy. Further GOG studies suggest that irradiation and weekly cisplatin chemotherapy without hysterectomy is the optimal treatment for patients with stage IB cervical cancer. High-risk factors for recurrence include tumor size, depth of tumor invasion, lymphovascular space involvement, and lymph node involvement. Prospective, randomized studies conducted by the GOG evaluated the effectiveness of various treatments in patients with high-risk factors. In one study that did not use chemotherapy, the recurrence-free interval was about 10% better for stage IB patients receiving postoperative irradiation after radical hysterectomy and pelvic lymphadenectomy compared with those who received no further therapy. Patients with Stages IB and IIA disease who, following radical hysterectomy and lymph node dissection, are identified as having positive pelvic lymph nodes and positive parametrial involvement, are at higher risk for recurrence and death than the high-risk group described above. An intergroup study conducted by the GOG, RTOG, and Southwest Oncology Group compared postoperative pelvic irradiation alone with postoperative pelvic irradiation plus concurrent chemotherapy in this group of patients. Overall and progression-free survivals were superior for patients receiving chemotherapy, and their greatest survival occurred in patients who received 3 or 4 chemotherapy cycles compared with 1 or 2 cycles or no chemotherapy. These findings are summarized with respect to their implications fortreatment of patients with advanced cervical cancer.     

Progress of gene therapy for esophageal cancer in Japan

Retrovirally expressed interleukin-2 gene, granulocyte macrophage-colony stimulating factor gene, herpes simplex virus-thymidine kinase gene and p53 gene in human esophageal cancer cells showed antitumor effects in a nude mice xenotransplant model. We established a clinical protocol of gene therapy for advanced esophageal cancer using the wild type p53 gene with an adenovirus vector. In December of 2000, we began the first tumor suppressor gene therapy trial. Now, this trial, which has 9 patients. There have been no serious adverse event excluding fever and local pain. The feasibility of this treatment appears fairly good in these 9 cases. Furthermore, we developed a new method for transducing genes without a virus vector since a virus vector has several potentially unwanted properties. In vivo electroporation is a useful strategy for cancer gene therapy. Moreover, electric pulse to established solid tumors increases intracellular concentrations of chemotherapeutic agents. Transduction of the wild-type p53 gene by electroporation decreased the amount of nedaplatin required for tumor suppression. Electrochemo-gene therapy is a relatively simple method and can produce a better therapeutic effect.     

Bladder preserving combined modality therapy for invasive bladder cancer

The purpose of this paper is to increase the nurse's knowledge about invasive bladder cancer through discussion of a current protocol treatment using chemo and radiation therapy. Pathophysiology, clinical features, and current medical management are addressed along with appropriate nursing interventions, including symptom management and patient/family education. Research supports the observation that once patients complete the protocol regimen, the complete response rate is high and the need for radical surgery is low.     

胃癌综合治疗进展

手术被认为是可以彻底治愈胃癌的最有效的方法,但是术后仍有很多患者发生局部复发和远处转移,对此只能采用姑息性的治疗方法.放疗和化疗虽然可以提高局部控制率和生存率,但放化疗的价值以及模式仍存争论.     

Combined modality therapy in esophageal cancer: the Memorial experience

Over the past 20 years in the United States, esophageal cancer has shown the most rapid rate of increase of any solid tumor malignancy. Esophageal cancer is an aggressive disease, and poor survival is achieved with surgery or chemoradiation therapy alone. Ongoing trials are investigating the use of preoperative chemoradiation followed by surgical resection. Chemoradiation employing a combination of cisplatin and a continuous infusion of 5-fluorouracil (5-FU) is the most commonly used therapy. The significant gastrointestinal toxicity of traditional cisplatin/5-FU-based regimens has prompted the evaluation of new agents in combined-modality therapy. The Memorial Sloan-Kettering Cancer Center has conducted chemoradiation trials with weekly paclitaxel/cisplatin and irinotecan/cisplatin, and the results suggest that this regimen has the potential to improve the therapeutic index without compromising efficacy. Randomized trials are now being conducted to evaluate the tolerance and efficacy of paclitaxel/cisplatin in comparison with paclitaxel/5-FU combined with radiotherapy in locally advanced esophageal cancer. The incorporation of these non-5-FU-based therapies with novel biologic agents is planned.     

Multiple management modalities in esophageal cancer: combined modality management approaches

The overall success rate nationally in treating esophageal carcinomas remains poor, with over 90% of patients succumbing to the disease. In part I of this two-part series, we explored epidemiology, presentation and progression, work-up, and surgical approaches. In part II, we explore the promising suggestions of integrating chemotherapy and radiation therapy into the multimodal management of esophageal cancers. Alternative approaches to resection alone have been sought because of the overall poor survival rates of esophageal cancer patients, with failures occurring both local-regionally and distantly. Concomitant chemotherapy and radiation therapy (XRT) have been shown, by randomized trial, to be more effective than XRT alone in treating unresectable esophageal cancers and also have shown promise as a neoadjuvant treatment when combined with surgery in the multimodal treatment of this disease. Various studies have also addressed issues such as preoperative chemotherapy, radiation dose escalation, chemotherapy/XRT as a definitive treatment versus use as a surgical adjuvant, and alternative chemotherapy regimens. There are suggestions of some progress, but this remains a difficult problem area in which management is continuing to evolve.     

Ten-year outcome after combined modality therapy for inflammatory breast cancer

PURPOSE: To evaluate the long-term outcome of combined modality therapy for inflammatory breast cancer. METHODS AND MATERIALS: The data from 54 women treated between 1983 and 1996 for inflammatory breast cancer were analyzed. Patients with metastatic disease or disease progression on induction chemotherapy were excluded. Induction chemotherapy was given to 52 patients. Mastectomy was performed in 52 patients. Radiotherapy was delivered to the breast or chest wall and regional lymph nodes in all patients. The median follow-up for all patients was 5.1 years. RESULTS: The 5- and 10-year overall survival rate was 56% and 35%, respectively; the corresponding relapse-free survival rates were 49% and 34%. Patients with a pathologic complete response after chemotherapy with or without preoperative radiotherapy had better 5- and 10-year overall survival rates (65% and 46%, respectively) and 5- and 10-year relapse-free survival rates (59% and 50%, respectively) compared with patients without a pathologic complete response. Those patients had a 5- and 10-year relapse-free survival rate of 45% and 27%, respectively. Locoregional failure at 5 and 10 years was 8% and 19%, respectively. CONCLUSION: The outcomes for patients completing multimodality therapy compare favorably with published data; however, the exclusion of patients with progression during induction chemotherapy may account in part for these results. The pathologic complete response rate was found to be an important prognostic factor. Selected patients with inflammatory breast cancer have the potential for long-term survival.     

Combined modality therapy of esophageal carcinoma

One hundred ten patients with epidermoid carcinoma of the esophagus were treated at the Memorial Sloan-Kettering Cancer Center (MSKCC) with combined modality techniques involving preoperative irradiation (RT) and surgery, and with preoperative chemotherapy (CT), surgery, and irradiation. For the 76 patients receiving preoperative RT during the period 1965-1976, the overall resectability rate was 54% with an operative mortality of 12%; long-term survivors (greater than 3 years) were few (7%). For 34 patients receiving preoperative CT with cisplatin and bleomycin, major objective tumor regression (greater than 50%) was seen by day 18 in 20%, with an additional 44% having smaller but definite improvement in the barium esophagram and in swallowing function. Of those receiving preoperative CT, 76% had resectable lesions, with an operative mortality of 11%. The median follow-up for this group is 24 months; of the 30 patients followed for at least 12 months, 20% are alive without evidence of disease. Although the resection rate following preoperative chemotherapy seems to be higher, thus allowing better palliation, neither preoperative radiation nor chemotherapy with cisplatin and bleomycin have had a major impact on long-term survival.     

Sequential combined modality therapy for stage III non-small cell lung cancer

These pilot trials clearly demonstrate the feasibility of administering neoadjuvant chemotherapy to patients with stage III NSCLC. Response rates in most of these trials reach or exceed 50%, indicating increased activity of chemotherapy in NSCLC when used at an earlier time in the natural history of the disease, as has been shown in other diseases. In addition, histologic confirmation of complete response can occasionally be achieved. Most of the studies reviewed here have included patients with unresectable disease, who would now frequently be classified as stage IIIB. For these patient cohorts the survival data reported are frequently disappointing, suggesting that the high response rates to neoadjuvant chemotherapy do not necessarily translate into improved survival of the patients. On the other hand, where patients with stage IIIA disease were treated and surgery was included in the overall treatment plan, the survival data are more encouraging. Although most chemotherapy regimens have included cisplatin, it is not clear which combination of drugs and which schedules are superior. Clinical research, therefore, clearly needs to continue to focus on the development of innovative drug combinations and the evaluation of new drugs in NSCLC in an attempt to further increase overall and complete response rates to neoadjuvant chemotherapy. At the same time, randomized studies are needed to unequivocally establish whether the addition of neoadjuvant chemotherapy to standard therapy improves survival for stage IIIA and/or stage IIIB NSCLC as compared with standard therapy alone. Results from one such randomized study, which was conducted by the Cancer and Leukemia Group B (CALGB), have recently been reported. One-hundred and eighty patients with unresectable NSCLC were randomized to receive radiotherapy alone or two cycles of cisplatin and vinblastine followed by radiotherapy. One-hundred and fifty-five eligible patients were analyzed for response. Of 77 patients receiving radiotherapy alone, 43% responded, including 16% with a complete response. Of 78 patients receiving neoadjuvant chemotherapy, 56% responded to both treatment modalities, including 19% with complete response. With a median follow-up of 19 months, the median survival was 16.5 months for patients receiving combined modality therapy and 8.5 months for patients receiving radiotherapy alone. The pattern of relapse was identical in both study arms, showing a predominance of local recurrence or of combined local and distant recurrence, whereas few patients experienced distant disease progression alone.(ABSTRACT TRUNCATED AT 400 WORDS)     

Improved long-term survival with combined modality therapy for pediatric nasopharynx cancer

PURPOSE: Nasopharynx cancer is a rare malignancy in childhood. This study aims to determine the role of chemotherapy, the optimal dose of radiation, and the long-term outcome for children with locoregional disease. METHODS AND MATERIALS: Thirty-three patients [median age 14 (range: 12-20) years] were treated for Stage I-IVB nasopharynx cancer. Thirteen patients (39%) received radiotherapy alone and 20 patients (61%) had chemotherapy and radiotherapy. The median radiation dose to the primary tumor was 66 Gy (range: 54-72 Gy). The median follow-up time for surviving patients was 8.4 years (range: 0.5-23.6 years). RESUL TS: The actuarial 10-year locoregional relapse-free survival, distant metastases-free survival, and overall survival rates were 77%, 68%, and 58% , respectively. Locoregional control was improved for patients treated with radiation doses > 60 Gy compared to those receiving < or = 60 Gy (93% vs. 60%, p < 0.03). The addition of chemotherapy had no significant effect on locoregional control but did reduce the development of distant metastases (16% vs. 57%, p = 0.01). Combined modality therapy improved 10-year disease-free survival (84% vs. 35%, p < 0.01) and survival (78% vs. 33%, p < 0.05) over radiation alone. The 10-year actuarial rate of severe complications was 24%.60 Gy are used for gross disease. The addition of chemotherapy decreases the risk of distant metastases and increases survival.     

Combined modality therapy for esophageal squamous cell carcinoma

Of 55 patients with esophageal squamous cell carcinoma, 30 with localized disease were treated with a combined modality for curative intent. Treatment consisted of mitomycin C (10 mg/m2 day 1) and continuous infusion 5-FU (1000 mg/m2 day, days 1-4, 29-32) (CT), radiation (XRT) (3000 rad, days 1-21) with nutritional support, and surgery (days 49-64). Surgery consisted of celiotomy, esophagectomy and esophagogastrostomy +/- postoperative ventilatory support. Postoperative CT plus an additional 2000 rad XRT was restricted to patients with histologic positive tumor. Since five resected patients with subclinical metastatic tumor had an inferior survival equal to 25 patients treated essentially for palliation, pretreatment celiotomy seems warranted to identify patients with an inferior prognosis. Of 18 resected patients without disseminated tumor evaluable for this combined modality: six were tumor free, three had intramural and nine transmural tumor; the median survival is 76 weeks and five of six living patients are disease free at 95-190 weeks; and local recurrence occurred in two and in two of seven unresected patients. Since toxicity was minimal except for postoperative pneumonitis (13%) and local recurrence low (13%), two courses of chemotherapy and 5000 rad XRT perhaps obviates the need for resection.     

Topoisomerase I inhibitors in the combined modality therapy of lung cancer

Locally advanced non small-cell lung cancer (NSCLC) represents 30%-40% of all pulmonary malignancies. Despite the fact that the disease is confined to the chest, most patients will eventually succumb to their dis-ease. Therefore, the management of NSCLC is undergoing rapid evolution with hope of improving overall survival. The arrival of a new generation of chemotherapeutic agents, including the taxanes, gemcitabine, and topoisomerase inhibitors such as irinotecan and topotecan, offers the hope of real advances against this malignancy. Irinotecan and topotecan are camptothecin derivatives that are felt to exert their cytotoxic effects by targeting topoisomerase I. It is believed that topoisomerase I inhibitors stabilize a DNA-topoisomerase I cleavable complex, and interactions between this complex and the replication machinery may lead to cell death. There is a significant volume of in vitro and in vivo data demonstrating that these topoisomerase I inhibitors also act as radiosensitizers. Early clinical data with topotecan suggests that it is a more active agent in small-cell lung cancer than it is in NSCLC despite a common mechanism of action with irinotecan. With the increasing data that exist on the improved outcome with concurrent chemoradiation treatment for malignancies including lung cancer and head and neck cancers, there is an impetus to pursue the addition of other drugs that can radiosensitize tumors and further improve local control. Irinotecan is undergoing early clinical trials in the combined modality setting in several different disease sites. This paper will review the in vitro and in vivo data on the ability of irinotecan and topotecan to render tumors more susceptible to ionizing radiation. It will then focus on the experience with both drugs and thoracic radiation in the treatment of NSCLC, in which irinotecan has yielded acceptable toxicity results and response rates in excess of 60% in early trials. It is hoped that newer treatment strategies, such as the combination of radiation and topoisomerase I inhibitors in lung cancer, will have a significant impact on cure rates in the future.     

10 years' results of combined modality therapy of cervix cancer

The study was concerned with 5 and 10-year results of combination treatment (surgery + radiation) of 304 cases of cervical cancer. Recurrence and metastases developed in 32 patients (10.5%). The 5-year survival rate for cases with stage I tumor was 95.1% and stage II--90.5%. At 10 years, the said rates were 95.1 and 84.7%, respectively. Minimal effective dose was found to be 1,330 reu.