Adjuvant treatment of pancreatic cancer

The prognosis of pancreatic cancer is poor at any stage. The complete resection of the tumour offers the only chance of cure, but 10-25 % of the patients at most present with operable disease, and median survival following surgery with curative intention is 18 months. Local recurrence is often accompanied or rapidly followed by distant metastasis. Studies of postoperative (adjuvant) treatment have yielded contradictory results. Combined radiochemotherapy resulted in improved survival in a few studies while others failed to demonstrate any survival benefit. Intraoperative radiation therapy given in addition to percutaneous irradiation may improve local tumour control at best. At present only few data support the benefit of adjuvant systemic chemotherapy alone. Unfortunately, the recently completed ESPAC-1 study was not very helpful in settling this issue due to its problematic design. Therefore, the results of ongoing studies of adjuvant chemotherapy are eagerly awaited. These studies have also included arms with gemcitabine, the current standard for palliative treatment of pancreatic cancer, and will hopefully allow firm conclusions as to the role of postoperative chemotherapy.     

Strength of the Evidence: Adjuvant Therapy for Resected Pancreatic Cancer

Pancreatic cancer remains one of the greatest challenges within oncology. Among resected patients, 5-year survival is typically only 10–25%. Among eight major randomized trials for resected pancreas cancer, five (GITSG, EORTC, ESPAC-1, RTOG 9704, and CONKO-1), containing a total of over 1,200 patients, have shaped world opinion on this subject. These trials have many significant methodological differences. Major conclusions that can be drawn from these trials in composite are (1) adjuvant chemotherapy is superior to observation following pancreaticoduodenectomy for pancreatic cancer, (2) gemcitabine is superior to 5-FU as adjuvant chemotherapy, and (3) the benefit of adjuvant chemoradiation is uncertain. Additional randomized trials are needed to address significant areas of controversy within available data. Presented at the Postgraduate Course of the 48th Annual Meeting of the Society for Surgery of the Alimentary Tract, May 20, 2007, Washington, DC.     

Influence of Resection Margins on Survival for Patients With Pancreatic Cancer Treated by Adjuvant Chemoradiation and/or Chemotherapy in the ESPAC-1 Randomized Controlled Trial

OBJECTIVE: To assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study. SUMMARY BACKGROUND DATA: Pancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies. METHODS: ESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status. RESULTS: Of 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups. CONCLUSIONS: Resection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.     

Therapy of advanced stomach carcinoma. Current study concepts

Patients with gastric cancer have a poor prognosis. Only in early tumorstadium a tumor-free-resection is possible. Because curative surgery is often impossible or extremely difficult and the majority of patients undergoing curative resection relapse. To improve this situation adjuvant and neoadjuvant concepts necessary to check. Current adjuvant therapy regimes have a marginal importance. Only nodal positive patients (T3N2M0) may profit from an adjuvant therapy. Neoadjuvant concepts seem to be very effective. The activity is proving in two current studies. Several combination chemotherapy regimens have been developed with activity in locally advanced and metastatic disease. But only an overall survival in median of about 11 month could be reached and a standard protocol not exists. Therefore many studies are initiated. In the follow article three study concepts with new substances especially with Taxanes and with CPT-11 having a great potential to improve the prognosis of patients with advanced gastric cancer are explained.     

ROLE OF EARLY ADJUVANT HORMONAL THERAPY AFTER RADICAL PROSTATECTOMY FOR PROSTATE CANCER

PURPOSE: Recent prospective randomized studies have shown that adjuvant hormonal therapy combined with local treatment can significantly improve overall survival in patients with locally advanced disease. This finding challenges the previous belief that adjuvant hormonal therapy may not be beneficial for minimal stages TxN + M0 or less prostate cancer, particularly when combined with local treatment. We reviewed the benefits of adjuvant hormonal therapy in patients at risk for disease progression, especially when administered after radical prostatectomy. MATERIALS AND METHODS: We retrospectively reviewed the current literature and evaluated clinical information on stage pT3b cancer from a large single institution prostate cancer database to determine the current role of adjuvant hormonal therapy after radical prostatectomy for prostate cancer. RESULTS: Retrospective experimental and clinical studies have proved the impact of adjuvant hormonal therapy for decreasing prostate specific antigen (PSA) and clinical disease progression in patients with regionally limited prostatic cancer. This finding applies to stage pT3b as well as to lymph node positive cancer. Our literature review and current data from the Mayo Clinic database show that adjuvant hormonal therapy after prostatectomy has a significant impact on prostate specific antigen (PSA) progression but it also decreases systemic progression and cause specific death in patients with stage pT3b and lymph node positive disease. After adjusting for preoperative PSA, margins, grade, ploidy and patient age the risk ratio for stage pT3b disease in 707 cases was 0.3 (95% confidence interval 0.2 to 0.7). A recent prospective randomized trial showed a significant decrease in cancer death in N+ cases when adjuvant hormonal therapy was administered after radical prostatectomy, supporting previous Mayo Clinic data on N+ disease that favors combination therapy. In the PSA era, that is 1987 and after, our database data on stage pTxN+ cancer indicates that radical prostatectomy and hormonal therapy for single node positive disease resulted in 94% 10-year cause specific survival, which was not significantly different from the rate in patients with N0 disease after adjusting for local stage, Gleason grade, margins, ploidy, PSA and adjuvant hormonal therapy. CONCLUSIONS: Our literature review, including prospective randomized studies, and more recent results in the PSA era from our database indicate that early adjuvant hormonal therapy has a significant impact on time to progression and cause specific survival in patients with seminal vesicle invasion and limited lymph node disease who undergo radical prostatectomy, although in a retrospective nonrandomized study. Future prospective studies with longer followup are needed to evaluate the potential benefit of adjuvant treatment in regard to survival for stages pT2 and pT3a disease with unfavorable pathological variables.     

Is there an indication for adjuvant or neoadjuvant systemic therapy in prostate cancer?

In the meantime prostate cancer has become the most common malignancy in the male population. Due to the shift in age at the time of first diagnosis in favour of younger men with a high life expectancy and a maximum of physical and sexual activity it would be desirable to have neoadjuvant or adjuvant therapy concepts at hand which lead to an improvement of therapeutic success. So far the results of studies for adjuvant and neoadjuvant hormonal ablation therapy concepts have not led to a clear therapeutic reference. Only before radiation therapy is neoadjuvant hormonal ablation a standard part of therapy at most centres. Existing data for chemotherapeutic concepts are limited to androgen-independent advanced prostate cancer. An international study using docetaxel as an adjuvant drug is currently being performed, but the results are not yet available.     

Gibt es eine Indikation für eine adjuvante oder neoadjuvante Systemtherapie beim Prostatakarzinom?

In the meantime prostate cancer has become the most common malignancy in the male population. Due to the shift in age at the time of first diagnosis in favour of younger men with a high life expectancy and a maximum of physical and sexual activity it would be desirable to have neoadjuvant or adjuvant therapy concepts at hand which lead to an improvement of therapeutic success. So far the results of studies for adjuvant and neoadjuvant hormonal ablation therapy concepts have not led to a clear therapeutic reference. Only before radiation therapy is neoadjuvant hormonal ablation a standard part of therapy at most centres. Existing data for chemotherapeutic concepts are limited to androgen-independent advanced prostate cancer. An international study using docetaxel as an adjuvant drug is currently being performed, but the results are not yet available.     

Operative management in the treatment of pancreatic cancer

The carcinoma of the pancreas is one of the 10 leading causes of death in the Western countries. Because of the resistance of pancreatic cancer against radiation and/or chemotherapy surgery is still the only possibility for cure. However, about 80 % of patients with the diagnosis of pancreatic cancer are no more suitable for curative resection at the time of diagnosis because of local tumor infiltration or the presence of distant metastases. This is one reason for the unsatisfactory situation in terms of 5-year-survival rate of 3 to 24 %. In resectable tumors of the pancreas head the standard Whipple dominates still as the surgical method of choice. However, the pylorus preserving Whipple has been established as a surgical alternative to the classical Whipple. Other surgical procedures like extended or regional pancreatic resections, predominantly done by Japanese surgeons seem to fit the concept of radical resection. But compared to the classical Whipple or the pylorus preserving Whipple resection there is still no clear advantage in terms of long term survival. The prospective European multicenter study ESPAC-1 firstly demonstrated a survival advantage for adjuvant chemotherapy (5-FU and folic acid) but no gain for radiochemotherapy in the treatment of patients with R0 or R1 resected pancreatic cancer in terms of prolongation of mean survival (19.7 months vs. 14.0 months).     

Neoadjuvant and adjuvant therapy of ductal pancreatic carcinoma

The optimal oncological management of ductal pancreatic cancer remains undefined. More than 60% of these patients have disseminated disease at the time of presentation. Here radical surgery alone cannot guarantee a cure. Even in the best case of a R0-resection with extended lymph node dissection the reported 5-year survival rates of 20-30% are dissatisfying. This would suggest that neoadjuvant or adjuvant therapies may play an even greater role in improving the medium and long-term survival rates than in other tumor entities. Reports in the literature to date are from small randomised trials which do not elucidate the benefit of therapy. However, it does appear that neoadjuvant radiochemotherapy in combination with R0-resection will best improve patient outcome and mean survival rates. Therefore there is a need for large prospective randomized studies regarding (neo-)adjuvant therapy. Inclusion criteria must be precisely defined and the following factors recorded: standardized preoperative staging procedures extent of tumor disease (histology, stage, vascular infiltration, lymph node involvement, etc.) detailed surgical approach in respect to the extent of pancreas resection and lymph node dissection. Pancreas resections tend to have a higher postoperative complication rate when compared with other tumours and substantial postoperative weight loss often is observed. This may result in a delay or even impossibility of starting adjuvant therapy right in time in a relevant part of patients (up to 1/3 according to literature data) which is a major disadvantage of all adjuvant therapy concepts.     

Adjuvant chemoradiotherapy for resected pancreas cancer

The purpose of this article is to review pertinent literature assessing the evidence regarding adjuvant chemoradiotherapy for adenocarcinoma of the pancreas following curative resection. This review looks at randomized controlled studies with the emphasis on adjuvant chemoradiotherapy. In assessing the evidence from the studies reviewed in this article, the trials have been grouped according to the positive or negative results for or against adjuvant treatment. In addition, data from two large, single-institution studies affirming the role for adjuvant chemoradiotherapy has been included. Understanding the evidence from all of the randomized studies is important in shaping current practice recommendations for adjuvant therapy of surgically resected pancreas cancer. Adjuvant chemoradiotherapy following surgery is the current approach at many cancer treatment centers in the United States. In Europe, chemotherapy alone is the preferred adjuvant therapy. However, the type of adjuvant treatment recommended remains controversial due to conflicting study results. The debate will likely continue. Current practice should be based on the weight of evidence available at this time, which is in favor of adjuvant chemotherapy with chemoradiotherapy.     

Postoperative adjuvant treatment for pancreatic cancer

To improve surgical results after resection of pancreatic cancer, clinical trials of postoperative adjuvant treatment have been aggressively performed worldwide. In the USA, postoperative chemoradiation therapy is supported on the basis of the results of the Gastrointestinal Tumor Study Group (GITSG) trial published in 1985. In Europe, chemotherapy was approved as postoperative adjuvant therapy based on the results of the European Study Group for Pancreatic Cancer-1 (ESPAC-1) trial published in 2004 and Charité Onkologie (CONKO)-001 study published in 2007. As in Europe, postoperative chemotherapy is recommended in Japan based on the results of the Japanese Study Group of Adjuvant Therapy for Pancreatic Cancer-02 (JSAP-02) trial published in 2009. In recent years, gemcitabine has been recognized as the first choice for adjuvant chemotherapy after surgery. Clinical trials with gemcitabine, fluorouracil, and molecular targeting agents are currently under way.     

Chemotherapy in the post-MVAC era: the case for adjuvant chemotherapy

Radical cystectomy for muscle invasive and locally advanced bladder cancer is the standard treatment modality in most of the Western industrialised countries. Rates of perioperative mortality from radical cystectomy have decreased to less than 2% over the past two decades due to advances in surgical technique and perioperative care. However, at least 40% of patients with pT3 bladder cancer and 70% of patients with lymph node-positive disease develop tumour recurrence after radical treatment within the first 5 years when treated with radical cystectomy alone. After the efficacy of combination chemotherapy for metastatic urothelial cancer using methotrexate, vinblastine, adriamycin and cisplatin (MVAC) was first described in 1985, several cisplatin-based systemic regimens have been investigated as adjunctive treatment before or after therapy for locally advanced bladder cancer by radical surgery or radiation therapy. Three randomised studies have reported superior results of postoperative adjuvant systemic chemotherapy compared to radical cystectomy alone for locally advanced bladder cancer. All three studies demonstrated a significant survival benefit for bladder cancer patients receiving adjuvant combination therapy. Studies have been criticised for small patient numbers and statistical shortcomings. New effective antineoplastic agents, such as paclitaxel and gemcitabine, have evolved during the past decade as promising substances for the treatment of urothelial cancer. This article reviews adjuvant studies from the era of MVAC combination chemotherapy, as well as contemporary studies that discuss new antineoplastic agents for systemic adjuvant chemotherapy of locally advanced bladder cancer.     

Neo-adjuvant and adjuvant treatment of locally invasive bladder cancer

Since Sternberg et al. in 1985 first published preliminary results of polychemotherapy in patients with metastatic bladder cancer, it became apparent that transitional carcinoma of the bladder is highly responsive to chemotherapy. Response rates up to 70% with combination therapy regimens like methotrexate, vinblastine, doxorubicin or adriamycin and cisplatin promised that transitional carcinoma might be able to cure even in advanced stages. Chemotherapy has either been applied prior to the local treatment (such as radical cystectomy or radiotherapy) in a neo-adjuvant regimen, or after local therapy in an adjuvant regimen. Although a large number of studies have been published in the past 20 years, the role of the different chemotherapeutic approaches has not been clearly defined. Therefore, neither neo-adjuvant nor adjuvant chemotherapy can be recommended as 'gold standard' treatment for advanced bladder cancer.     

Neoadjuvant and adjuvant chemotherapy for locally advanced bladder carcinoma: development of novel bladder preservation approach, Osaka Medical College regimen

Cisplatin-based chemotherapy has been widely used in a neoadjuvant as well as adjuvant setting. Furthermore, trimodal approaches including complete transurethral resection of the bladder tumor followed by combined chemotherapy and radiation have generally been performed as bladder preservation therapy. However, none of the protocols have achieved a 5-year survival rate of more than 70%. Additionally, the toxicity of chemotherapy and/or a decreased quality of life due to urinary diversion cannot be ignored, as most patients with bladder cancer are elderly. We therefore newly developed the novel trimodal approach of "combined therapy using balloon-occluded arterial infusion of anticancer agent and hemodialysis with concurrent radiation, which delivers an extremely high concentration of anticancer agent to the site of a tumor without systemic adverse effects ("Osaka Medical College regimen" referred to as the OMC regimen). We initially applied the OMC regimen as neoadjuvant chemotherapy for locally advanced bladder cancer. However, since more than 85% of patients with histologically-proven urothelial cancer achieved complete response with no evidence of recurrence after a mean follow-up of 170 (range 21-814) weeks, we have been applying the OMC-regimen as a new approach for bladder sparing therapy. We summarize the advantage and/or disadvantage of chemotherapy in neoadjuvant as well as adjuvant settings, and show the details of our newly developed bladder sparing approach OMC regimen in this review.     

Should Adjuvant Therapy Remain the Standard of Care for Patients With Resected Adenocarcinoma of the Pancreas?

Adenocarcinoma of the pancreas continues to be a formidable disease. In the United States, patients who have had resected disease are generally offered adjuvant chemoradiation. The current National Comprehensive Cancer Network practice guidelines uniformly support this practice. We reviewed seven selected series to evaluate the efficacy of adjuvant therapy for patients who had resected adenocarcinoma of the pancreas. Current evidence-based analysis demonstrates that an adjuvant therapy regimen as a standard of care is lacking. We, therefore, believe that it should be used judiciously because its benefit is confined to only a fraction of patients treated by complete resection (R0); patients with residual microscopic disease (R1) derived negligible benefits. Given the financial constraints and the small effect that current therapies have on this fatal disease, clinicians should concentrate on developing novel therapies and new paradigms to address this age-old problem.     

Therapeutisches Vorgehen bei Gallenblasen- und extrahepatischen Gallengangskarzinomen

Background

Although the treatment and diagnostic regimens of gall bladder carcinoma and extrahepatic bile duct cancer have improved over the past years, the outcome and overall survival as prognostic values still remain poor. Early tumor stages of gall bladder carcinoma are the only exception.

Objective

This article focuses on the latest surgical therapy approaches including neoadjuvant, adjuvant and palliative therapy regimens.

Results

Neoadjuvant treatment concepts have so far been insufficiently evaluated and can therefore only be recommended within the framework of studies. In patients with primary resectable tumors there are so far no indications for improved results after neoadjuvant therapy. Radical R0 resection still remains the only curative treatment option; however, an advanced and inoperable stage is often already present at the time of diagnosis There are no uniform adjuvant treatment concepts and no standards evaluated by studies. Due to the currently available data, adjuvant radiochemotherapy and chemotherapy can also only be recommended within or as part of clinical trials. Palliative chemotherapy should only be used in advanced tumor stages and depending on the condition of the patient.

Conclusion

To sustainably improve treatment strategies for advanced gall bladder carcinoma and extrahepatic bile duct cancer, uniform adjuvant as well as neoadjuvant therapy regimens need to be developed after evaluation in prospective randomized trials. This is the only way to improve the still poor prognosis of these tumor entities.

     

Molecular alterations associated with improved survival in pancreatic cancer patients treated with radiation or chemotherapy

Multiple genetic alterations, several of which may be important prognostic markers, characterize the development of cancer in pancreas. We review our findings from previously published studies with regard to molecular alterations associated with survival differences in patients treated with conventional radiation and chemotherapies used as adjuvant or palliative therapy. K-ras-negative patients with pancreas cancer show improved survival with radiation therapy compared to K-ras-positive patients with pancreas cancer. p53 expression is associated with shorter survival when compared to no p53 expression in pancreas cancer patients treated with radiation therapy or chemotherapy. Pancreas cancer patients whose tumors express p21 show significant survival advantages when treated with chemotherapy or radiation therapy. An inverse relationship is observed with respect to p21 and p53 expression and clinical stage. Although stage and surgical resectability remain the most important variables with respect to pancreas cancer survival, these findings suggest promising opportunities for gene therapies designed to enhance p21 expression or restore wild-type K-ras or p53 function in pancreatic tumors. Received for publication on June 17, 1998; accepted on July 27, 1998     

Evaluating the role of photodynamic therapy in the management of pancreatic cancer

Background and Objective: Cancer of the pancreas constitutes one of the major causes of cancer related death throughout the world. A 5-year survival rate of only 2% and a maximum of 20 months median survival in multi modality treatment studies dealing with the most favorable patients only, has been demonstrated. This review analyzes the principal treatments and available experimental data in view of a clinical application of photodynamic therapy (PDT) for the treatment of pancreatic cancer. Study Design/Materials and Methods: On the basis of published results, we examined the palliation of pancreatic cancer by chemotherapy alone; radiation alone and multimodality schedules (radiation and chemotherapy). Radical tumor resection was examined as attempted curative treatment. Results: In reported therapeutic procedures, palliative or potentially curative, median survival was below 2 years. The GTSG reported survival time increases from 10.9 to 21.0 months when surgery is followed by adjuvant chemotherapy and radiation. This combination postoperatively does not increase mortality, but adds 30% morbidity. Photodynamic therapy has been demonstrated in preclinical studies to have a selective effect on malignant versus the normal pancreas. Conclusion: PDT is highly effective in eliciting the destruction of experimental pancreatic tumors with the lack of significant effect on the normal pancreas. The poor prognosis for patients with this disease, especially those patients with advanced disease, warrants closer examination of PDT for the treatment of pancreatic cancer.     

Carcinoma of the pancreas: current status of multimodal therapy

Only multimodal treatment concepts may potentially improve the persisting poor prognosis of the carcinoma of the pancreas. In specialized centres surgery has reached a high level of security with a very low level of mortality. Infiltrations of the mesenterico-portal axis are not a contraindication to a curative oncological surgery. R0 and R1 resections should be followed by adjuvant chemotherapy with gemcitabine. Currently there is no evidence of benefit for a neoadjuvant radiochemotherapy in primary resectable carcinomas of the pancreas. The survival rates of primary resectable carcinoma patients with neoadjuvant pre-treatment correspond to those of primary resectable carcinoma patients with adjuvant therapy. Due to the high perioperative morbidity, some patients do not gain access to the adjuvant therapy within a reasonable time frame. Therefore, the significance of neoadjuvant therapy for resectable tumours should be re-evaluated in prospective randomised trials. In about one third of the patients with primary irresectable carcinomas of the pancreas, a radical resection can be performed after neoadjuvant radiochemotherapy. For this patient group randomised prospective trials are urgently needed. In this context, however, only an experienced pancreatic surgeon can decide about the resectability or irresectability of a pancreatic tumour.     

Adjuvant Therapy for Adenocarcinoma of the Pancreas: Analysis of Reported Trials and Recommendations for Future Progress

The delivery of postoperative combined modality adjuvant therapy for completely resected pancreatic cancer was initially shown to be beneficial on the basis of a prospective, randomized trial published in 1985. Since then, oncologists have debated whether chemotherapy, chemoradiation, or both is optimal adjuvant therapy after pancreatectomy for ductal adenocarcinoma of the pancreas; no global consensus has emerged. Unfortunately, despite the completion of a number of subsequent randomized trials of adjuvant therapy since 1985, no further improvements in overall survival have materialized. This lack of progress is not simply the result of ineffective systemic therapies, but in part the result of poor trial design and calls for a more disciplined approach to the selection of patients for surgery, pathologic assessment of surgical resection margins, and postoperative (pretreatment) imaging. This is the only way to ensure that patients who receive adjuvant therapy are actually receiving therapy for radiographically occult possible microscopic disease, rather than therapy for incompletely resected locally advanced disease or early postoperative metastases. A critical analysis of completed adjuvant trials will be provided and a framework for the conduct of future trials of adjuvant therapy proposed.