Biology of esophageal cancer and the role of combined modality therapy

1. The biology of esophageal cancer involves multifactorial environmental and genetic events. 2. The understanding of the clinical significance of molecular markers is rapidly evolving. 3. Combined-modality approaches should still include surgery in good performance status (ECOG scale < or = 2) patients. 4. Neoadjuvant chemoradiation is probably better than surgical resection alone for patients with potentially curable disease, but only validation of this approach by CALGB-9781 can justify this as a new "proven" standard-of-care in the United States. 5. A pathologic complete response to neoadjuvant therapy is the strongest predictor of long-term survival. 6. 5-FU, by either short course or protracted continuous infusion, comprises the backbone of combination chemotherapy in combined-modality design. 7. Radiation therapy should be given at standard 1.8 to 2 Gy/fraction without a scheduled break. 8. Only by enrolling sufficient numbers of patients in prospective clinical trials will clinicians be able to further define the optimal sequencing and actual necessity of each individual component of combined-modality therapy.     

Endoscopic therapy of esophageal cancer

In the management of esophageal cancer, endoscopy has evolved from a tool used to provide biopsy confirmation of suspected tumor to an integral part of the staging and ongoing treatment of patients. Endoscopic ultrasound is currently the most accurate means for T and N staging. Improved endoscopic techniques like dye staining and aggressive biopsy protocols can identify very early stage tumors in high-risk groups and allow curative surgery. Patients with early-stage tumors who are not surgical candidates can also be treated with endoscopic mucosectomy, photodynamic therapy, or Nd:YAG laser and still have a chance of long-term cure. Palliation of advanced tumors remains the major role of endoscopy in patients with esophageal cancer. A variety of techniques have proven effective over the years, including dilatation, laser, and rigid prostheses. Newer developments like bipolar probes, injection therapy, photodynamic therapy, and brachytherapy offer potential applications. The development and continuing improvements in both coated and uncoated expandable metal stents have been perhaps the greatest recent advance in endoscopic palliation of malignant dysphagia and esophagorespiratory fistulas. With the increasing array of endoscopic treatments and palliative techniques, emphasis must be placed on considering functional status; tumor characteristics like stage, location, and shape; patient wishes; and local expertise in tailoring treatment plans for each situation.     

Should adjuvant or neoadjuvant treatment be administered in esophageal cancer?

The Nissen fundoplication is not the proper antireflux procedure for patients with poor esophageal peristalsis as it does not strengthen impaired esophageal peristalsis. The aim of this study was to investigate if tailoring of antireflux surgery according to esophageal contractility is an effective treatment of gastroesophageal reflux disease (GERD) with a low incidence of postoperative dysphagia. The Toupet fundoplication was laparoscopically performed on 32 patients with poor esophageal peristalsis and the Nissen fundoplication on 17 patients with normal peristalsis. After a median follow-up of 15 months, only 1 of the 49 patients (2.04%) complained of heartburn. Acute esophagitis was found in none of them on endoscopy. Of 40 patients tested postoperatively, 2 (5%) underwent pathologic esophageal pH monitoring. Postoperative dysphagia was found in two patients (4.1%) compared with 25 (51%) preoperatively (p < 0.05). There was a significant reduction of dysphagia following the Toupet fundoplication. Both procedures increased the resting pressure of the lower esophageal sphincter (LES) significantly, which was more pronounced following the Nissen fundoplication. Relaxation of the LES was significantly better following the Toupet than after the Nissen fundoplication. There was significant improvement of esophageal peristalsis following the Toupet fundoplication. Tailored antireflux surgery is an effective strategy for treatment of GERD. The incidence of postoperative dysphagia is low owing to improvement of impaired esophageal peristalsis following the Toupet fundoplication. It may be due to the fact that the Toupet fundoplication causes less esophageal outflow resistance than the Nissen fundoplication.     

The emerging role of paclitaxel in breast cancer therapy

Bradykinin and thrombin caused a time- and dose-dependent stimulation of prostanoid biosynthesis in human dental-pulp fibroblasts, as assessed by the release of prostaglandin E2 (PGE2) and 6-keto-prostaglandin F1 alpha (the stable breakdown product of prostacyclin). The stimulatory effect of bradykinin and thrombin on PGE2 biosynthesis was maximal within 5-10 min. The concentration of bradykinin producing half-maximal stimulation (EC50) of PGE2 and prostacyclin formation was 10 nM. EC50 for thrombin-induced formation of PGE2 and prostacyclin were 0.05 and 0.2 U/ml, respectively. Bradykinin analogues with affinity to the bradykinin B2 receptor, but not those with affinity to the B1 receptor, caused a burst of PGE2 formation. The stimulatory action of bradykinin and thrombin on PGE2 biosynthesis was abolished by two structurally different cyclo-oxygenase inhibitors and significantly reduced by two corticosteroids. Thrombin dose-dependently enhanced the incorporation of [3H]-thymidine into DNA in pulpal fibroblasts by a mechanism that was unrelated to the effect on prostanoid biosynthesis. Bradykinin did not affect thymidine incorporation. Thrombin, but not bradykinin, stimulated the biosynthesis of type 1 collagen in the pulpal fibroblasts. The stimulatory effect of thrombin on collagen biosynthesis was not affected by cyclo-oxygenase inhibitors. These data show that human dental-pulp fibroblasts are equipped with receptors for bradykinin and thrombin linked to enhanced prostanoid biosynthesis. Occupancy of the thrombin receptors also leads to a prostaglandin-independent stimulation of cell proliferation and collagen biosynthesis.     

Radiation therapy with neoadjuvant hormonal therapy for prostate cancer confined to pelvis

Neoadjuvant endocrine treatment prior to radical prostatectomy for prostate cancer confined to pelvis has of some value to prevent progression although there are many controversies. In order to improve the prognosis of locally advanced prostate cancer (stage B2 and C), definitive radiotherapy with neoadjuvant endocrine therapy has been investigated. Endocrine therapy reduces the volume of prostate, thus reduces the amount of side effect via reducing the area of irradiated normal tissue. Effect of radiation and that of endocrine therapy to induce apoptosis might be synergistic. The result is favorable although the follow-up period is too short. Further studies are needed to make conclusion.     

Application and limitation of neoadjuvant hormonal therapy for prostate cancer

Of 156 patients, 111 (clinical stage T1a-b; 21, T1c; 17, T2a-b; 36, T2c; 27, T3; 10) immediately underwent radical prostatectomy (surgery group), and 45 (clinical stage T1a-b; 8, T1c; 4, T2a-b; 10, T2c; 9, T3; 14) received neoadjuvant hormonal therapy (NHT group). NHT offered probability of increasing organ-confined cancer(OCC; pathological stage pT2 or lower N0M0) in the following group, which contains (a) patients who had moderately differentiated adenocarcinoma in the biopsy specimen and T2b or lower diseases, and (b) those who had well differentiated adenocarcinoma, T2c diseases and PSA levels of 10 ng/ml or higher, referred to as "OCC suitable criteria". Of 156 patients, 51 (33%) met OCC suitable criteria. In those cases, the proportion of OCC in NHT group was significantly higher than that in surgery group (11/12 (92%) vs. 16/39 (41%), p = 0.002). NHT is useful for increasing OCC in patients who meet OCC suitable criteria.     

The etiopathogenesis of esophageal cancer

Cancer of the oesophagus is a challenging clinical problem. Overall survival is poor, but patients who present early are eminently curable. Most cancers of the middle and upper oesophagus are squamous cell carcinoma. Adenocarcinoma is the most common cancer of the third of the oesophagus; this is not surprising when the usual distribution of Barrett's mucosa is considered. The geographical variation in the prevalence of oesophagus cancer is important. In most parts of the world, alcohol consumption and tobacco usage are the principal risk factors. Other risk factors have been identified in "the high-risk areas": a diet high in nitrosamines, deficient in trace elements, in vitamins (C.A, E) and the hereditary conditions like: Barrett's oesophagus, achalasia, caustic strictures.     

The role of adjuvant radiation therapy in the treatment of colorectal cancer

The hypercatabolic response to trauma, extensive surgery and sepsis is characterized by an increased metabolic rate, severe muscle wasting and a negative nitrogen balance. This process of 'autocannibalism' may be in part a consequence of a disordered growth hormone (GH)/insulin-like growth factor (IGF) axis. In this chapter the normal physiology of the GH/IGF axis is first briefly reviewed. This is followed by a discussion of the changes that accompany fasting and catabolic illness, the effects of IGF-1 administration in health and disease and a comparison of the effects of IGF-1, GH and insulin on catabolism. Although initial investigations of IGF-1 administration in animals and human volunteers have often been encouraging, studies in catabolic patients have so far proved disappointing. Combined treatment with GH, IGF-1 (and insulin) or with IGF-1 and its major binding protein, may prove more effective, especially when used in conjunction with nutritional supplements such as glutamine.     

The role of staging laparoscopy for multimodal therapy of gastrointestinal cancer

BACKGROUND: This prospective study was conducted to evaluate the accuracy and the therapeutic relevance of staging laparoscopy. METHODS: Between June 1993 and February 1997 staging laparoscopy was performed in 389 patients with various neoplasms. Additionally, 144 selected patients of this group were examined with laparoscopic ultrasound using a semiflexible ultrasound probe (7.5 MHz). RESULTS: Compared to conventional imaging methods, laparoscopy and laparoscopic ultrasound improved the accuracy of staging in 158 of 389 patients (41%). Statistical subgroup analysis of 131 patients with gastric cancer showed that the accuracy of staging laparoscopy in the detection of distant metastases (68%) was significantly higher (p < 0.01) than that of ultrasound (63%) or computed tomography (58%). In the whole group, laparoscopy alone disclosed intraabdominal tumor dissemination or nonresectable disease in 111 patients. Laparoscopic ultrasound displayed additional metastases-i. e., liver metastases (n = 9), M1 lymph nodes (n = 15), or nonresectable tumors (n = 6) in 30 patients. Although metastastic disease was suggested by preoperative imaging, benign lesions were found in five patients with laparoscopy and in a further 12 patients with ultrasonography. The findings of staging laparoscopy changed the treatment strategy in 45% of the patients. Conversion to open surgery was necessary in 5% of the cases, and complications related to laparoscopy occured in 4% of the patients. CONCLUSIONS: Laparoscopy with laparoscopic ultrasound improves the staging of gastrointestinal tumors and has a significant impact on a stage-adapted surgical therapy.     

Adjuvant radiation therapy in resectable rectal cancer: should local recurrence rates affect the decision?

Adjuvant external beam pelvic radiotherapy (XRT) for resectable rectal cancer has been mandated by the National Cancer Institute because of reported 20 to 50 per cent reductions in local recurrence rates. However, these series' reported local recurrence rates are 18 to 39 per cent in the nonradiated patients, which seems extraordinarily high compared to the 3 to 5 per cent rates reported by surgeons advocating proctectomy with complete mesorectal excision. This fact, coupled with the high cost of XRT ($11,000-$14,000), the risk of radiation injury to small bowel and the neo-rectum, and the failure of XRT to provide any survival advantage, raises questions as to the precise role of XRT for rectal cancer. The purpose of this study was to perform a review of 212 consecutive patients undergoing curative resection via low anterior resection (LAR) or abdominoperineal resection (APR) for rectal cancer between 1989 and 1993, focusing on local and distant recurrence rates and survival. The choice of surgery alone (SUR), preoperative radiation (PRE) (45 Gy), or postoperative radiation (POST) (45-50 Gy) was at the surgeon's discretion. There were no significant differences in male:female ratio (SUR, 83:60; PRE, 14:8; POST, 34:13) or type of procedure (SUR-LAR, 112:APR, 31; PRE-LAR, 5:APR, 17; POST-LAR, 30:APR, 17) between the groups. There were no significant differences in age between the preoperative and postoperative radiation groups (PRE, 64.0 +/- 2.4; POST, 59.2 +/- 1.7); however, age was significantly different (P < 0.05) between the surgery-alone and the postoperative radiation groups (SUR, 68.5 +/- 0.8; POST, 59.2 +/- 1.7). With a median follow-up of 49 months, there were no significant differences in local recurrence (SUR, 4.2%; PRE, 4.5%; POST, 2.1%); however, there was a significantly longer survival for the SUR group compared to the other groups (SUR, 45.9 months; PRE, 36.4 months; POST, 39.3 months; P < 0.05 least significant difference). The PRE group also had shorter survival compared to the other groups when only Stage II and III lesions were studied (S, 40.0 months; PRE, 28.3 months; POST, 39.3 months). Local recurrences based on TNM stage were: T1N0 (S, 0 of 27; PRE, 0 of 3); T2N0 (S, 4 of 4S; PRE, 0 of 7); T2N1 (S, 0 of 9; POST, 1 of 5); T3,4N0 (S, 2 of 37; PRE, 1 of 9; POST, 0 of 10); and T3,4N1,2 (S, 0 of 21; PRE, 0 of 3; POST, 0 of 30). The results of this series support the contention that proctectomy with complete mesorectal excision yields a 4.2 per cent local recurrence rate without the need for adjuvant XRT. In this series, if all the patients had received adjuvant radiation, an additional $2.2 million would have been added to the costs of medical care. Therefore, the potential risks, costs, and benefits of adjuvant pelvic XRT for rectal cancer must be weighed against optimal benchmarks for local recurrence rate for surgery alone.     

The role of video-assisted thoracic surgery in esophageal disease

Numerous applications of video-assisted thoracic surgery (VATS) in the management of diseases of the esophagus for structural, functional, benign, and malignant conditions have been reported. Indications and techniques for the use of VATS in the assessment and treatment of esophageal disease are discussed in this article. The need for careful evaluation of the safety, efficacy, and cost-effectiveness of these techniques is emphasized.     

Breast-preserving operations in surgically treatable breast cancer

Since 1980, based on international experience, breast conserving operations have been introduced at the Surgical Department, in the National Oncological Institute, Budapest. In 12 years, out of 4622 primary breast cancer operations, 1055 breast preserving interventions were carried out. For all patients adjuvant radiotherapy was indicated. In lymph node positive premenopausal cases chemo-radio-chemotherapy, for postmenopausal patients radiotherapy with tamoxifen has been provided. The first 604 patients (10 years) have been evaluated and 489 of them could be followed. The mean follow-up time was 49 months. During this period of time metastases have developed in 61 patients (12.5%); 26 (5.3%) of them died with the disease. Local recurrences occurred in 29 patients (5.9%). For small recurrences reexcision, for the others mastectomy or/and radiotherapy was carried out. Critical evaluation of the local recurrences was done.     

The role of esophagectomy in the management of esophageal perforations

BACKGROUND: Despite the many advancements made in thoracic surgery, the management of patients with esophageal perforation remains problematic and controversial. METHODS: Between 1985 and 1995, 27 esophagectomies were performed for perforation of the thoracic esophagus. A retrospective review of the records of these patients was carried out, and a scoring scale developed by Elebute and Stoner to grade the severity of sepsis was applied. RESULTS: Among the 27 patients undergoing esophagectomy for a perforation, the interval between rupture and esophagectomy was less than 24 hours in only 11 patients (40.7%). Postoperative surgical complications occurred in 4 patients (14.8%) and nonsurgical complications, in 7 (25.9%). The hospital mortality rate was 3.7% (1/27). In 14 patients, primary reconstruction was performed in the bed of the excised esophagus. There were no anastomotic leaks in this subgroup. This suggests that an anastomosis between viable, well-vascularized tissues is more important for successful healing than avoidance of some degree of contamination of the adjacent mediastinum. On follow-up, which averages 41 months, 73% of patients (16/22) have neither symptoms nor complaints. CONCLUSIONS: Esophageal resection definitively eliminates the source of intrathoracic sepsis, the perforation, and the affected esophagus. Reconstruction carried out in one stage does not increase operative morbidity. Esophageal resection and reconstruction is a valid approach even in cases of spontaneous perforation in which the diagnosis is markedly delayed.     

Prevalence of hot flushes during and after neoadjuvant hormonal therapy for localized prostate cancer

OBJECTIVES: We sought to determine the prevalence of hot flushes after neoadjuvant hormonal therapy. METHODS: Forty-three patients who received neoadjuvant hormonal therapy before radical prostatectomy were asked to complete a questionnaire regarding hot flushes. RESULTS: Complete information was available for 35 of the 43 patients. No hot flushes were noted in 20%; in 69%, hot flushes were noted during treatment but resolved after termination of treatment; and in 11%, hot flushes continued for at least 3 months after cessation of hormonal therapy. Analyzing the data with respect to duration of hormonal therapy showed that patients receiving neoadjuvant hormonal therapy for more than 4 months had the highest incidence of persistent hot flushes. CONCLUSIONS: Hot flushes will be noted in 80% of patients who receive neoadjuvant hormonal therapy. In approximately 10%, hot flushes will continue for a significant period after hormonal therapy is terminated. Patients should be apprised of this potential side effect.     

Adjuvant and neoadjuvant therapy of rectal carcinoma. The current status

BACKGROUND: The Consensus Conference of the German Cancer Society (CAO/AIO/ARO, 1.7.1998) has recently updated recommendations for patients with rectal cancer. Instead of a former reservation regarding the indication of adjuvant therapy for rectal cancer the actual version of the consensus particularly emphasizes the role of postoperative radiochemotherapy for stage-II/III tumors. This article reviews the most recent and ongoing trials of adjuvant and neoadjuvant therapy of rectal cancer. RESULTS: To avoid local recurrence is the most important aspect in the primary treatment of rectal cancer. In some series, e.g. the results of the Surgical Department of the University of Erlangen, a significant correlation between local control and survival was noted. The final results of the Swedish Rectal Cancer Trial with 1168 randomized patients not only confirmed the potential of radiotherapy to reduce local recurrence rate, but also demonstrated a significant survival advantage for patients receiving short-course preoperative radiation therapy. Postoperative combination therapy is usual in the United States and in most European countries since the publication of two randomized trials of the Gastrointestinal Tumor Study Group (GITSG) and the North Central Cancer Treatment Group (NCCTG). The survival advantage resulting from an adjuvant radiotherapy with conventional doses and concurrent fluorouracil-based chemotherapy as compared to surgery alone was recently confirmed in a Norwegian trial. Protracted venous 5-fluorouracil infusion should further improve treatment results. Numerous phase-II studies have demonstrated the efficacy of preoperative radiochemotherapy with high rates of pathological response. Thus, neoadjuvant radiochemotherapy is recommended for patients with locally advanced tumor primarily not amenable to curative surgery. Prospective randomized trials are ongoing to clarify the role of preoperative versus postoperative combined treatment for patients with resectable rectal cancer. CONCLUSION: Radiochemotherapy for rectal cancer is recommended as standard treatment outside clinical trials for stage II/III patients after curative treatment and for patients with T4-tumor prior to surgery. The optimal use of chemotherapy and the sequence of treatment modalities remains to be elucidated.     

Neoadjuvant therapy for surgically staged IIIA N2 non-small cell lung cancer (NSCLC)

INTRODUCTION: Neoadjuvant therapy in patients with Stage IIIA NSCLC is associated with a 50-70% resection rate and a 3-5 year survival of 20-32%, but few trials have required meticulous staging of the mediastinum to ensure homogeneity of the study population. Continuous infusion cisplatin 25 mg/m2/day 1-5, 5-fluorouracil 800 mg/m2/day 2-5, and high-dose leukovorin 500 mg/m2/day 1-5 (PFL) given every 4 weeks achieved a 41% response rate in metastatic NSCLC (Lynch TJ, Kalish LA, Kass F, Strauss G, Elias A, Skarin A, Shulman L, Sugarbaker D, Frei E. Continuous infusion cisplatin, 5-fluorouracil, and leukovorin for advanced non-small cell lung cancer. Cancer 1994; 73: 1171-1176). The regimen was therefore evaluated in 34 patients with pathologic Stage IIIA N2 disease between 3/91 and 10/92. METHODS: Staging consisted of chest, liver, brain computerized tomography and bone scan, bronchoscopy and surgical mediastinal node mapping. Patients received PFL for 3 cycles, followed by thoracotomy and thoracic radiotherapy (TRT) to 54-60 Gy. RESULTS: Median age was 57 (42-68) years. Demographic factors included: male 56%; adenocarcinoma 59%, squamous cell carcinoma 24%; Stage T3N2 26%, T2N2 56%, and T1N2 18%. No treatment related deaths occurred. Radiographically defined response to PFL was 65% (6% complete). Thoracotomy was performed in 28 patients (82%) (6 had no attempt due to disease progression). Complete resection was achieved in 21 (75%) and seven were unresectable. Pathologic complete response was observed in five patients (15%) and an additional unresectable patient had fibrosis-only documented at thoracotomy for an overall clinicopathologic response rate of 76% (18% pathologic CR). Another ten patients had residual primary with or without hilar disease with resolution of previously documented mediastinal involvement. Six (18%) patients remain alive and disease-free with a median follow-up of 46 (33-50) months, four of whom had achieved pathologic complete response at time of surgery. CONCLUSIONS: Long-term event-free survival was associated with complete surgical resection which in turn was associated with clinical response to chemotherapy. There was a possible trend associating pathologic downstaging (absent residual disease in mediastinal nodes), particularly pathologic complete response observed in patients with non-bulky mediastinal disease, with improved event-free survival. Pathologic downstaging might therefore be a useful surrogate endpoint in trials evaluating the preoperative activity of new chemotherapy regimens. While radiographic response generally correlated with findings at surgery, response as determined by histologic examination of resected tissue was generally more extensive and may more accurately reflect the systemic impact of the chemotherapy regimen.     

The role of resistance in sex therapy

Resistance, the sum of forces opposing the treatment process, is particularly manifest in conjoint sex therapy and may well threaten the successful conduct of treatment unless recognized promptly and dealt with appropriately. A classification of resistant behaviour most common in sex therapy is proposed and illustrated with clinical vignettes. Treatment strategies are discussed as well as indications for referral to longer term therapy.