Neoadjuvant Therapy For Esophageal Cancer Research Articles

Personalized medicine – p53 gene analysis for prediction of response to neoadjuvant therapy in esophageal cancer

The present review introduces a protocol for a prospective randomized predictive marker clinical trial. The study evaluates the interaction between the proposed predictive marker p53 and response to neoadjuvant chemotherapy in patients with potentially resectable oesophageal cancer. This trial is designed to provide "level of evidence I" data, which are a prerequisite for the clinical implementation of a predictive marker. Despite curative resection, the 5-years survival rates of oesophageal cancer patients do not exceed 20%. Several phase II and III studies have shown that patients who responded to preoperative chemotherapy had a significantly better survival than patients treated with surgery alone. Up till now, it is not possible to identify the responders before commencing treatment. Eighty-four patients with measurable disease will be enrolled in the pANCHO trial. After testing the marker genotype (p53 normal versus p53 mutant), patients will be randomly assigned to receive two different chemotherapies −5FU/Cispaltin or Docetaxel. All patients will be rendered to subsequent surgery and as a primary endpoint response to neoadjuvant treatment will be evaluated. The pANCHO trial is a nationwide academic initiative. The 13 affiliated investigational centres recruited 70% of estimated patients within one year. Patients enrolled in the pANCHO trial benefit from the standardized diagnostic and therapeutic procedures. The study is supposed to identify the need for new guidelines for response assessment in neoadjuvant treated patients. Marker specific results are awaiting autumn 2009 and could be relevant to the choice of therapy in oesophageal cancer.

P53 adapted neoadjuvant therapy for esophageal cancer: Pilot study

4535 Background: Randomized trials could not yet prove clinical efficacy of neoadjuvant chemotherapy for esophageal cancer. A survival benefit could be shown for treatment responders only. Using platinum based regimen, yet about 20 % of patients can achieve pathological complete remission which translates in reported 3-year survival rates of 64% in this group. Factors identifying this subgroup of responders and selecting optimal drugs for non responders could dramatically enhance treatment efficacy. Several studies suggest that mutations in the p53 gene may induce drug resistance especially for agents whose effect is based on apoptosis induction, like Cisplatin. Methods: In order to test the hypothesis that the p53 genotype is predictive for chemotherapy response, a prospective study was conducted. Thirty-eight patients with potentially respectable esophageal cancer were evaluated for the relation between p53 genotype and response to two different neoadjuvant treatments. P53 gene mutations were assessed by complete direct sequencing of DNA extracted from diagnostic biopsies. Response to neoadjuvant chemotherapy was assessed pathohistologically in the surgical specimen. Results: 20 squamous cell carcinoma and 18 adenocarcinoma were included. Overall the p53 mutation rate was 58% (22/38), with 66 % for squamous cell and 53% for adenocarcinomas, respectively. 30 patients received CIS/5FU (cisplatin 80mg/m2 d1 5-FU 1,000mg/m2 d 1–5, q21,2 cycles), 8 received docetaxel (75mg/m2, q21,2 cycles). The overall response rate was 48% (18/38). Patients with p53 mutation did not respond to CIS/5-FU (0/16), while all mutant patients responded to docetaxel (6/6). The overall response to p53 adapted neoadjuvant therapy was 94%. P53 adapted treatment was associated with a significant survival advantage (p=0,042) after a median follow up of 15,4 months. Conclusions: A prospective randomized trial was initiated to test the interaction between the predictive marker p53 and response to CIS/5-FU and Docetaxel, respectively. [Table: see text] No significant financial relationships to disclose.

Prospective comparison of transthoracic versus transhiatal esophagectomy following neoadjuvant therapy for esophageal cancer

Transthoracic esophagectomy (TT) has been championed as a better cancer operation than transhiatal esophagectomy (TH) because the approach facilitates meticulous wide tumor excision and lymphadenectomy. However, neoadjuvant chemoradiotherapy (CRTS) and chemotherapy (CS) have been reported to improve outcomes, and we aimed to compare outcomes after multimodal therapy related to the operative approach. One hundred and fifty-one consecutive patients were studied prospectively. All patients were staged with computed tomography and endoluminal ultrasound, and treatment decisions were related to stage and performance status. One hundred and nineteen TT (median age 58 years, 92 male, 54 CRTS, 65 CS) were performed compared to 32 TH (median age 57 year, 27 male, 14 CRTS, 18 CS). Primary outcome measure was survival. Post-operative morbidity and mortality were 54% and 4%, respectively, after TT compared with 59% and 6% after TH (chi2 0.239 df 1, P=0.625). Recurrent cancer was no less frequent after TT (52%) than after TH (37.5%, chi2 2.151 df=1, P=0.142). Cumulative uncorrected 5-year survival was 34% after TT compared with 53% after TH (log rank 1.44, df=1, P=0.2298). Median survival was also similar in lymph node positive patients (TT vs. TH, 23 months vs. 22 months, respectively, log rank 0.25, df=1, P=0.6199). Despite the fact that patients receiving multimodal therapy and a TH esophagectomy were less fit, operative morbidity, mortality and recurrence were similar, and survival did not differ significantly when compared with multimodal TT esophagectomy.

Thoracotomy or not after neoadjuvant therapy for oesophageal cancer?

Morgan, Matthew A.; Lewis, Wyn G.; Hopper, Andrew N.; Escofet, Xavier; Harvard, Timothy J.; Brewster, Alison E.; Crosby, Tom D. L.; Ashley Roberts, S.; Clark, Geoffrey W. B. Author Information

Neoadjuvante Therapie des Ösophaguskarzinoms - Standortbestimmung 2005

Neoadjuvant therapy has been implemented to improve the prognosis of patients with oesophageal cancer. Operative therapy remains the therapy of choice for nonmetastatic disease in patients who can tolerate resection. Adjuvant therapy following resection is usually not indicated. For neoadjuvant therapy it seems to be confirmed that preoperative radiotherapy has only very little benefit and therefore, should not be recommended. Data for preoperative chemotherapy are conflicting. Following preoperative combined radio-chemotherapy a complete response of tumour can be expected in 20-25 % of treated patients with a marked advantage for these patients. However, there are still no markers available indicating tumour response before the start of perioperative radio-chemotherapy. Recently published meta-analyses confirm a small overall benefit for perioperative radio-chemotherapy. However, these data so far have not led to a broad agreement on the indication of neoadjuvant therapy in oesophageal cancer.

SENTINEL LYMPH NODE IN ESOPHAGEAL CANCER BEFORE NEOADJUVANT THERAPY

The technique of sentinel lymph node identification and biopsy has become a new popular technique for surgeon to improve staging of malignant diseases. It may also reduce the risk of complication related to standard lymphadenectomy. The method is still in experimental phase in case of esophageal cancer. A possible complication for employment of the method in this tumor is neoadjuvant therapy. The authors developed the technique for identifying and obtaining the sentinel lymph node in esophageal cancer using minimally invasive surgical technique before neoadjuvant therapy. The sentinel lymph node is detected using 99mTc-labelled nanocolloid. The authors report and discuss possible difficulties of the method in the case of a patient with detected sentinel lymph node in this way. It is possible to identify and obtain a sentinel lymph node before neoadjuvant therapy in esophageal cancer. On the other hand, the clinical significance and applicability of the method of sentinel lymph node still remains controversial in this kind of a tumor.

Immunohistochemistry analysis of micrometastasis in pretreatment lymph nodes from patients with esophageal cancer

Background With recent advances in neoadjuvant therapy in esophageal cancer, pretreatment lymph node staging has become increasingly important in stratifying patients to appropriate treatment regimens and for prognostication. Immunohistochemical analysis (IHC) using epithelial markers has been shown to identify micrometastases in histologically negative lymph nodes. We performed this study to evaluate if IHC analysis in thoracoscopic/laparoscopic (Ts/Ls) pretreatment staging lymph nodes can reveal additional diagnostic information to routine histopathology. Methods Specimens of 106 patients with esophageal cancer who had pretreatment Ts/Ls staging were retrospectively studied. Lymph node biopsies were obtained for IHC staining using cytokeratin (CK) of AE1/AE3. IHC staining for p53, an apoptosis protein associated with poor prognosis in esophageal cancer, was also performed. Results 331 Ts/Ls staging lymph node biopsies were collected from 106 patients. A total of 15.4% (51/331) of the lymph nodes or 34.9% (37/106) of patients were found to have metastatic deposits by routine histology. All the histologically positive lymph nodes were CK positive. Among the remaining 280 histologically negative lymph nodes, 11(3.9%) were found to have micrometastasis by CK staining. Three patients (4.3%, 3/69) were upstaged from N0 to N1. They died of early recurrences after treatment. A total of 67.6% (25/37) of the patients with histologically positive lymph node were p53 positive. No histologically negative lymph node was found to be p53 positive in this series. Conclusions Immunohistochemical analysis for CK can detect micrometastatic involvement of lymph nodes that are missed on routine pathologic examination, and, therefore, can improve lymph node staging. Its clinical significance in esophageal cancer warrants further study.

Predictive factors for success of neo-adjuvant therapy in upper gastrointestinal cancer.

Predicting response to treatment has long been the Holy Grail of clinicians treating patients with upper gastrointestinal malignancy. The widespread use of neoadjuvant therapy for esophageal cancer has provided an added urgency to the issue and at the same time brought success a step closer because accurate response can be determined from analysis of the resected specimen. A search was undertaken of the Medline database for text references to neoadjuvant therapy, esophagus, stomach and predicting response. The references of these publications were further scanned for appropriate references in the text and reference lists. Publications describing predictive markers to neoadjuvant therapy for esophageal cancer, which were most likely to be of clinical significance, were selected for inclusion in this report. The most reliable tissue markers of response based on analysis of pretreatment biopsy specimens include P53, Ki-67, EGFR and the most impressive serum marker for monitoring response are CYFRA 21-1 and CEA. The results, however, are inconsistent, and the markers of relatively low sensitivity and none reliably identifies individual patients who will respond.

Neoadjuvant Therapy for Esophageal Cancer: Standard of Care or Elusive Myth?

Although surgical resection as the sole treatment modality for esophageal carcinoma has historically been associated with poor survival rates, improvements have recently been reported using varied neoadjuvant chemo-radiation protocols. This study evaluates the outcome of patients undergoing surgery for esophageal carcinoma at the University of Miami/Jackson Memorial Hospital between July 1991 and June 1996. Seventy-two patients underwent esophageal resection; 51 males and 21 females with a median age of 62.5 years (range = 42-82). Histology was equally distributed between adenocarcinoma (36 patients; 50%) and squamous cell carcinoma (36 patients; 50%). Pathological stage distribution consisted of 6 stage 0 (8%), 10 stage I (14%), 23 stage II (32%), 31 stage III (43%), and 2 stage IV (3%) lesions. Patients were divided into three groups according to the type of preoperative treatment; Group 1 (n = 44); surgery alone; Group 2 (n = 18); neoadjuvant 5-fluorouracil based chemotherapy, and Group 3 (n = 9); neoadjuvant 5-fluorouracil based chemotherapy in conjunction with external beam radiation (XRT). One patient received preoperative XRT alone. All survivors were followed for a minimum of 1 year and statistical analysis was performed using Kaplan-Meier curves, log-rank, and chi-square tests. In the 28 patients receiving any form of neoadjuvant therapy only one patient had a pathological complete response (CR) (3.5%). The overall 5 year and median survival rates were 18 per cent and 20.5 months (range = 0-73), respectively. Individual treatment group survival rates at 5 years were 28% for Group 1; 21% for Group 2; and 0% for Group 3, showing no survival difference between Groups 1 and 2; Group 3 fared significantly worse than the other two, probably as a result of the high operative mortality in this group. These results indicate that surgical resection continues to be an important treatment modality for esophageal carcinoma. Neoadjuvant chemotherapy in our experience failed to improve these survival rates and pre-operative chemoradiation was associated with a high perioperative mortality rate. Chemotherapy regimens with higher CRs may further improve these survival rates.

Staging and neoadjuvant therapy of squamous cell carcinoma of esophagus

Once the diagnosis of esophageal cancer is established, the decision on treatment will depend on the stage of the disease. Since improvement of prognosis can only be expected in patients with complete removal of their tumor, preoperative staging plays a pivotal role in the decision-making process. Preoperative diagnostic procedures should define the tumor in its relation to the tracheal bifurcation (site), determine the depth of tumor invasion (T status), evaluate regional lymph node metastases (N1 disease) and exclude distant metastases (M1 disease). Endosonography represents currently the most accurate imaging technique for detecting the correct T stage over the correct N stage. A higher accuracy rate may be achieved by combining endosonography with other staging modalities such as computed tomography. Chest x-ray, and percutaneous ultrasonography (abdominal, neck) form the diagnostic basis in staging M1 disease. Computed tomography (neck, chest and abdomen) is currently the best method to detect metastases in the liver and in celiac nodes. Staging laparoscopy when combined with laparoscopic ultrasonography shows a higher sensitivity than ultrasonography and computed tomography in the diagnosis of smaller metastases and peritoneal seedings. En bloc esophagectomy together with the regional lymph nodes remains the treatment of choice in medically fit patients with localized esophageal carcinoma (Stage I-IIB, T1-T2/N0-N1/M0). Due to early involvement of mediastinal structures, curative resection is unlikely to be achieved in patients with locally advanced esophageal carcinoma (Stage III, T3-T4/N0-N1/M0). Most available data indicate that neoadjuvant radiochemotherapy leads in a significant number of patients to downstaging of the tumor, increases the rate of R0 resection, improves local tumor control, and prolongs the recurrence free interval. However, neoadjuvant radiochemotherapy resulted in a marked increase of morbidity and postoperative mortality without improvement of survival. At present, neoadjuvant therapy is still experimental and there is no consensus for an optimal treatment regimen. Its use outside of an investigational setting can not be recommended. Future research must focus on more effective and less toxic neoadjuvant modalities (e.g. new chemotherapy agents, hyperthermia).

Neoadjuvant Therapy for Cancer of the Esophagus.

BACKGROUND: The standard of care for esophageal cancer has historically been surgical resection. However, survival following surgical treatment of esophageal cancer remains poor. In inoperable patients, both radiation therapy and chemotherapy alone and in combination have been used with some success. Consequently, these therapies have been utilized in the neoadjuvant setting to improve palliation and prolong survival. METHODS: The author reviewed the literature regarding clinical trials that employed neoadjuvant chemotherapy and radiation therapy in the treatment of squamous cell carcinoma and adenocarcinoma of the esophagus. RESULTS: In most patients, surgery alone is noncurative therapy, even when performed with curative intent. Most phase III trials of neoadjuvant therapy have not been designed with adequate statistical power to detect clinically relevant improvement. The available data are insufficient to determine a benefit to preoperative radiation therapy alone. Preoperative chemotherapy with 5-FU plus cisplatin followed by surgery probably offers little or no improvement over surgery alone. Trials of combined preoperative chemoradiation therapy have yielded promising but not definitive results. CONCLUSIONS: Outside of a clinical trial, neoadjuvant therapy for esophageal cancer should be reserved for only a select group of patients. Future clinical trials may determine a role for neoadjuvant chemoradiation and identify more active chemotherapeutic agents and populations most likely to benefit.

Impact of Clinical Staging for Neoadjuvant Therapy of Esophageal Cancer

Survival of patients with esophageal carcinoma (EC) can be improved by preoperative neoadjuvant chemoradiation followed by esophageal resection. We introduced this treatment modality in 1994. Treatment results of 25 patients presenting with stage Ila/b or III EC (UICC 1987) were analyzed. After assessment of operability and clinical staging, all patients received radiation therapy (36 Gy, 1.8 Gy/day, days 1-5, weeks 1-4) and chemotherapy (cisplatin 20 mg/m2, days 1-5, weeks 1 and 4, and 5-fluorouracil 500 mg/m2, days 1-5, weeks 1-4). Patients were operated upon 8-10 weeks after treatment initiation and clinical restaging. In 3 patients thoracotomy demonstrated inoperability due to local tumor progression into the tracheobronchial tree. Major postoperative morbidity was observed in 72%, 2 patients died after resection while in hospital (8%). The comparison of pretreatment clinical staging with restaging after neoadjuvant therapy revealed tumor down-staging (UICC) in 12 patients, no change in 11 patients and up-staging in 2. Comparison of restaging after neoadjuvant therapy and pathohistological staging after resection demonstrated down-staging in 2 patients, no change in 8 patients and up-staging in 15 patients. Complete pathohistological remission was observed in 3 patients. Pathohistological findings revealed a different tumor stage (UICC) in 21 patients (11 × up-staging, 10 × down-staging) when compared with pretreatment clinical staging. Mean 2-year survival was 87.5% in patients with remission and 16.5 % in patients without remission or progress of disease. The data demonstrate the feasibility of neoadjuvant preoperative chemoradiation in EC. On the basis of staging results some patients benefit from neoadjuvant therapy while others show progress of disease. The impact of neoadjuvant therapy needs to be carefully evaluated to exclude pitfalls due to clinical misstaging.

Screening for cancer, 1995: An update

Summary Background This study was designed to evaluate the feasibility of a neo-adjuvant combined chemo-radiotherapy in patients with localized squamous cell carcinoma of the esophagus. Patients and methods Forty-two patients with squamous cell carcinoma of the esophagus, stages II and HI (or stage I if considered to be poor candidates for immediate curative surgery), age less than 70 years and WHO performance status 0 to 2, were enrolled in a study of radiotherapy combined with chemotherapy, consisting of 2 (operated patients) or 3 (non-operated patients) courses of cisplatin, vindesine, mitomy-cin-C or cisplatin, vinblastine. Surgery was routinely proposed to patients. Results Thirty-seven patients (88%) received full pre-operative therapy. Of 30 patients responding to this pre-operative therapy, 12 had a third cycle of treatment and 15 had esophagectomy. Three of the operated patients had no pathological evidence of residual tumour. Median survival of all 42 patients is 11 months and the 2-year survival rate is 29%. There is no difference in survival among responding operated or non-operated patients. Our group represents 95% of all eligible cases of squamous cell carcinoma of the esophagus occurring in Geneva during the study period. Conclusion Our series gives a realistic view of the median survival of a population of patients eligible for neo-adjuvant therapy of esophageal cancer, and suggests that secondary surgery might not improve the patient survival. Furthermore, non-selected patients are at high risk for therapy-related death.

Who benefits from neoadjuvant therapy of esophageal cancer?

Who benefits from neoadjuvant therapy of esophageal cancer?