胰腺癌:辅助治疗

Pancreatic cancer ranks tenth in terms of newly diagnosed cases, but just 10%-15% of these patients can undergo resection. Survival after curative surgery is dismal, as recurrences occur either locally or in the liver. Adjuvant treatment with either chemotherapy or chemoradiation （with or without maintenance chemotherapy） has been employed, to improve the poor prognosis. Justification for the use of chemoradiation, with follow on chemotherapy, is based on the results of an underpowered 1987 GITSG study, which closed prematurely and compared intervention to observation. There has been no survival advantage demonstrated in the one randomized controlled trial that examined chemoradiation compared to chemotherapy. There is a clear cut survival advantage however with chemotherapy compared to observation, based on the results from two large randomized controlled trials, and supported by an individual patient data meta-analysis. The standard of care for adjuvant therapy based on level I evidence （from the ESPAC-1 trial） is post operative chemotherapy using 5-Fluorouracil with folinic acid providing a best estimate of 29% five years survival.     

Practice guideline for the role of combination chemotherapy in the initial management of limited-stage small-cell lung cancer

An evidence-based practice guideline was developed to identify the optimal combination chemotherapy regimen, schedule of administration, and duration of therapy for the first-line treatment of adults with limited-stage small-cell lung cancer. The guideline is based on a systematic search and review of literature published between 1985 and December 2002. Three reviewers selected studies for inclusion in the guideline according to pre-defined criteria. Fifty randomized controlled trials, five in abstract form, were included in the review, and feedback on a draft version of the guideline was obtained from medical oncologists in the province of Ontario, Canada. The most commonly used regimens in clinical trials are cyclophosphamide-doxorubicin(Adriamycin)-vincristine, and etoposide-cisplatin. No combination chemotherapeutic regimen has been conclusively shown to be superior to either of these regimens. Most studies comparing chemoradiation regimens used sequential rather than concurrent thoracic radiotherapy. When treating for cure with chemoradiation, there is evidence from one randomized controlled trial to support the use of etoposide-cisplatin over an anthracycline-containing regimen. There is conflicting evidence concerning a survival advantage for a regimen that alternates cyclophosphamide-doxorubicin-vincristine with etoposide-cisplatin compared with either regimen alone. If bolus etoposide-cisplatin is the treatment of choice, evidence from one randomized trial suggests that the optimal sequence of administration is cisplatin followed by etoposide. The use of maintenance chemotherapy is not indicated. There is insufficient evidence to support the routine use of dose-intensive regimens outside a clinical trial, to determine the optimal duration of chemotherapy, or to support the routine substitution of carboplatin for cisplatin in combination chemotherapy regimens in this patient population. RECOMMENDATIONS: Etoposide-cisplatin is the preferred chemotherapy regimen for patients with limited-stage small-cell lung cancer when concurrent thoracic radiotherapy is used. It is reasonable to offer the alternation of etoposide-cisplatin with cyclophosphamide-doxorubicin-vincristine, provided the administration of radiotherapy concurrent with an anthracycline is avoided.     

Surgical treatment of pancreatic cancer: the role of adjuvant and multimodal therapies.

Surgical treatment in specialized referral centers has improved the prognosis of resectable pancreatic cancer considerably despite the generally aggressive behavior of this malignancy. At the same time, adjuvant therapy for pancreatic cancer has been shown to be effective in providing a survival benefit. However, some controversy remains over whether to use chemotherapy alone or combined chemoradiation. Few prospective randomized controlled clinical trials (RCTs) on the use of adjuvant chemotherapy and chemoradiation have demonstrated a distinct survival advantage of systemic chemotherapy (5-FU/FA or gemcitabine) following surgical resection. The most notable published trial is the European Study Group for Pancreatic Cancer (ESPAC)-1 trial. In addition, there are several retrospective analyses and two randomized studies on adjuvant radiation and chemoradiation. Some of these suggested increased survival rates using chemoradiation, which was subsequently widely introduced in clinical routine, especially in the United States. RCTs and a recent meta-analysis of these RCTs confirm, however, the superiority of chemotherapy over chemoradiation, except for a subgroup of patients with positive resection margins. Thus, curative surgery followed by adjuvant systemic chemotherapy should be the standard treatment for patients with resectable, locally confined pancreatic cancer. Further RCTs may clarify potential benefits of chemoradiation in the adjuvant treatment setting. Moreover, the best chemotherapy, or a combination thereof, remains to be determined in large-scale randomized trials.     

Systematic review, including meta-analyses, on the management of locally advanced pancreatic cancer using radiation/combined modality therapy

There is no consensus on the management of locally advanced pancreatic cancer, with either chemotherapy or combined modality approaches being employed (Maheshwari and Moser, 2005). No published meta-analysis (Fung et al, 2003; Banu et al, 2005; Liang, 2005; Bria et al, 2006; Milella et al, 2006) has included randomised controlled trials employing radiation therapy. The aim of this systematic review was to compare the following: (i) chemoradiation followed by chemotherapy (combined modality therapy) vs best supportive care (ii) radiotherapy vs chemoradiation (iii) radiotherapy vs combined modality therapy (iv) chemotherapy vs combined modality therapy (v) 5FU-based combined modality treatment vs another-agent-based combined modality therapy. Relevant randomised controlled trials were identified by searching databases, trial registers and conference proceedings. The primary end point was overall survival and secondary end points were progression-free survival/time-to-progression, response rate and adverse events. Survival data were summarised using hazard ratio (HR) and response-rate/adverse-event data with relative risk. Eleven trials involving 794 patients met the inclusion criteria. Length of survival with chemoradiation was increased compared with radiotherapy alone (two trials, 168 patients, HR 0.69; 95% confidence interval (CI) 0.51-0.94), but chemoradiation followed by chemotherapy did not lead to a survival advantage over chemotherapy alone (two trials, 134 patients, HR 0.79; CI 0.32-1.95). Meta-analyses could not be performed for the other comparisons. A survival benefit was demonstrated for chemoradiation over radiotherapy alone. Chemoradiation followed by chemotherapy did not demonstrate any survival advantage over chemotherapy alone, but important clinical differences cannot be ruled out due to the wide CI.     

Have the changes in treatment of rectal cancer made a significant difference to our patients?

The treatment for patients with locally advanced, resectable rectal cancer has evolved over the years. Various combinations and sequences of chemotherapy, radiation therapy, and total mesorectal excision (TME)-based surgery are the mainstay of current therapy. Preoperative combined chemoradiation, followed by surgery, is now the preferred treatment strategy, with the majority of patients receiving either infusion fluorouracil (5-FU) or capecitabine (Xeloda) with radiation. Clinical trials with oxaliplatin (Eloxatin)-based neoadjuvant chemoradiation have not shown improvement in the pathologic complete response rate (pCR) compared with 5-FU; however, final data addressing local recurrence rates and disease-free survival are pending.The use of adjuvant chemotherapy following preoperative chemoradiation and surgery has not been optimally defined. Some studies have shown that patients who obtained significant pathologic downstaging after chemoradiation and surgery have improved survival with the use of adjuvant chemotherapy. Since FOLFOX (folinic acid, 5-FU, and oxaliplatin) is the preferred adjuvant chemotherapy regimen for stage III colon cancer based on randomized clinical trial results, FOLFOX is also recommended for rectal cancer patients as an adjuvant therapy approach.     

Chemoradiation and adjuvant chemotherapy in cervical cancer.

PURPOSE: Radiotherapy is the standard treatment for locally advanced cervical cancer, but treatment results remain disappointing, particularly for women with bulky central disease. We investigated the role of concurrent chemoradiation and adjuvant chemotherapy in a randomized trial. PATIENTS AND METHODS: Two hundred twenty patients with bulky stage I, II, and III cervical cancer were randomized to receive either standard pelvic radiotherapy or chemoradiation (epirubicin 60 mg/m(2)) followed by adjuvant chemotherapy with epirubicin 90 mg/m(2) administered at 4-week intervals for five additional cycles. RESULTS: Fifty-nine patients have relapsed, with a median follow-up duration of 77 months. Patients who received epirubicin radiation therapy showed a significantly longer disease-free (P =.03) and cumulative survival (P =.04). Patients who received radiation alone had significantly more distant metastasis than those who received chemoradiation (P =.012). There was no difference in long-term local tumor control (P =.99). CONCLUSION: Survival benefit has been demonstrated in patients treated with chemoradiation followed by adjuvant chemotherapy with epirubicin as compared with patients treated with standard pelvic radiotherapy alone.     

Current state of adjuvant therapy in resected pancreatic adenocarcinoma

Pancreatic carcinoma cannot generally be cured by surgery alone. This review summarizes the development of adjuvant therapy over the past two decades. Four randomized controlled trials compare long-term survival of different treatments. The small GITSG-study supports combined chemoradiation, but the EORTC-study found no significant effect. A Norwegian study of adjuvant chemotherapy found an increased median survival, but no effect beyond two years. The large ESPAC-1 study shows a benefit for 5-FU based chemotherapy, while chemoradiation had a negative effect. Thus, evidence favours adjuvant therapy, but 5-FU may not be the ultimate drug. Support for gemcitabine is given by preliminary data from a German randomized trial, and further American and European studies are upcoming. However, postoperative therapy is problematic, as 20-30% of resected patients never undergo treatment because of slow recovery or other reasons. Preoperative therapy has some theoretical advantages, and moreover, patients with rapidly progressive disease may be spared surgery. Randomized controlled trials are lacking, but published results compare well with postoperative, adjuvant therapy. The value of locally targeted therapy is difficult to assess. Reasonable results have been obtained with regional chemotherapy, whereas intraoperative radiotherapy does not seem to increase survival despite reducing reducing local recurrences.     

Is Concurrent Chemoradiation the Standard of Care for Locally Advanced Non-small Cell Lung Cancer? A Review of Guidelines and Evidence

In the past 15 years, the treatment of locally advanced non-small cell lung cancer (NSCLC) has shifted from radiotherapy alone. There are now schedules using induction chemotherapy, concurrent chemoradiation using either radiosensitising doses of chemotherapy or full-dose chemotherapy, consolidation chemotherapy after radiation or combinations of these options. There is no consensus on the optimal chemotherapy regimen and its scheduling and the issue of radiation dose and optimal fractionation equally remains unresolved. This overview is in two sections. First, we have evaluated a selection of international guidelines on the management of locally advanced NSCLC. We assessed the methodology by which individual guidelines were produced and the levels of evidence quoted in support of the recommendations. Second, we have updated the literature search of the 2004 Cochrane review on concurrent chemoradiation. Trials were identified that compared sequential with concurrent chemoradiation using median survival as the primary outcome measure. Two-year survival and toxicity were evaluated as secondary outcome measures. Eleven trials were identified, of which six fulfilled criteria for inclusion. The median survival for concurrent treatment was 16–17 months compared with 13–15 months with sequential treatment. Treatment-related mortality was 3% for concurrent treatment and 1.7% for sequential treatment. The rate of grade 3 or worse oesophagitis was 19% in concurrent treatment compared with 3% for sequential treatment. In conclusion, chemotherapy adds benefit to radiotherapy treatment of locally advanced NSCLC. Concurrent chemoradiation is associated with significant toxicity. The evidence to support concurrent chemoradiation as the standard of care is not robust, in spite of its recommendation within a number of guidelines. Further trials should be supported.     

Induction chemotherapy in the management of squamous cell carcinoma of the head and neck

Platinum-based chemotherapy administered concurrently with radiation has been adopted as the standard treatment for locally advanced head and neck squamous cell carcinoma. Historically, randomized trials using induction chemotherapy prior to radiation therapy alone have failed to demonstrate a clear survival advantage, and concurrent chemoradiation has delivered better results than previously obtained with radiation therapy alone, establishing the benefit of adding chemotherapy. This method of treatment, together with new modalities of therapy and novel agents, has reintroduced the question of induction chemotherapy before definitive chemoradiation. Systemic chemotherapy offers a better possibility of reducing systemic metastasis and improving cosmetic appearance. This article reviews developing trends using induction chemotherapy followed by chemoradiation in patients with head and neck squamous cell carcinoma.     

Combined Treatment Modalities in Esophageal Cancer: Should chemotherapy be included?

The poor prognosis of esophageal carcinoma patients after treatment with local modalities (surgery/radiotherapy) is well known. The purpose of this review is to assess the question whether addition of chemotherapy to local treatment of squamous cell carcinoma of the esophagus has had any beneficial effect on treatment results. In the absence of a sufficient number of randomized trials addressing this issue, data mainly from single-arm studies are discussed. Compiled data from studies on preoperative chemotherapy, preoperative chemoradiation and chemoradiation without surgery suggest that addition of chemotherapy to local treatment (surgery/radiotherapy) might increase short-term survival (2 years) compared to local therapy alone. In the case of chemoradiation without surgery this conclusion is strengthened by results from randomized trials. In general lack of long-term follow-up data limits conclusion whether to recommend the inclusion of chemotherapy into treatment of esophageal cancer or not. Treatment results, however, from studies utilizing combination chemotherapy given concomitant with radiotherapy support the contention that well-designed randomized trials with long-term follow-up should be performed. Outside controlled trials, however, surgery or radiotherapy should still be regarded as standard treatment modalities.