Controversies in the Multimodality Management of Locally Advanced Esophageal Cancer: Evidence-Based Review of Surgery Alone and Combined-Modality Therapy

Most patients with esophageal cancer present with locoregional disease, and the optimal initial management is controversial. The current National Comprehensive Cancer Network (NCCN) practice guidelines support diverse treatment options for locoregional disease, including surgical resection alone, definitive chemoradiation therapy, and preoperative combined-modality (neoadjuvant/trimodality) therapy. Many cancer centers worldwide favor a neoadjuvant approach, although the evidence supporting this practice is inconsistent. A concise review of the literature is presented. The topics discussed do not necessarily reflect each authors opinions or clinical practices.     

Prognostic Factors in Patients with Locally Advanced Rectal Adenocarcinoma Treated with Preoperative Radiotherapy and Surgery

Preoperative radiation therapy (PRT) prior to potential curative resection for rectal adenocarcinoma is not widely accepted. This report evaluates the prognostic factors affecting local recurrence and 5-year survival. This is a retrospective study of 214 patients with primary rectal adenocarcinoma treated from January 1986 to December 1994. A PRT dosage of 45 Gy in 20 fractions was administered to patients with clinically tethered or fixed tumors, and 4 to 8 weeks later surgery was performed (group I). Patients with clinically mobile tumors were treated by surgery alone (group II). There were 130 men and 84 women. The median age was 58 years (range 19–85 years). There were 111 patients in group I: 7 patients had no microscopic residual tumor, 80 had Dukes' A and B, and 24 had Dukes' C. There were 103 patients in group II: 70 patients were classified as Dukes' A and B and 33 as Dukes' C. The mean follow-up of the entire cohort was 62 months (range 2–132 months). Local recurrence was seen in 17% of patients in group I and 35% in group II (p= 0.002). Distant recurrence in patients with metastatic lymph nodes was seen in 79% of group I and in 34% of group II (p= 0.001). The favorable prognostic factors for local control were the administration of PRT and well differentiated cancer. The favorable prognostic factors for survival were age < 50 years and the absence of lymph node metastasis. The administration of PRT diminishes the risk of local recurrence. The presence of metastatic lymph nodes in the postirradiated specimen is an ominous prognostic factor for survival. Therefore such patients should be considered for adjuvant chemotherapy.     

Preoperative Chemoradiation for Patients With Locally Advanced Adenocarcinoma of the Pancreas

Background: Improved resectability is a major theoretical benefit of preoperative chemoradiation for pancreatic cancer. Since 1994, patients at Duke University Medical Center with locally advanced pancreatic cancer have been treated with multimodality preoperative therapy. The purpose of this study was to review our experience with preoperative therapy for locally advanced pancreatic cancer and determine if an aggressive neoadjuvant regimen would not only downstage these tumors pathologically but also improve the odds of complete surgical resection.Methods: The charts of 25 patients treated with neoadjuvant chemoradiation at Duke University Medical Center with biopsy-proven, locally advanced adenocarcinoma of the pancreas were reviewed. Tumors were defined as locally advanced based on radiographic or intraoperative evidence of disease that abuts the superior mesenteric artery or vein (n = 22) or involves lymph nodes that are within the proposed radiation field (n = 3). All 25 patients received external beam radiotherapy (median dose 4500 cGy) in daily fractions of 180 cGy over 5 weeks. All patients concurrently received 5-fluorouracil (FU), and many also received mitomycin C or cisplatin, or both. Patients were given a 3- to 4-week break before a restaging computed tomographic (CT) scan was performed. Three patients were not restaged: one died from metastatic disease; one was reclassified as having a neuroendocrine tumor; and one was lost to follow-up.Results: On restaging after neoadjuvant therapy, 64% of patients had stable or decreased primary tumor size. Radiographically, two patients appeared potentially resectable, and seven others developed evidence of metastatic disease. Eight patients underwent exploration, but only five could be resected. Of the five patients resected, only one had negative margins and negative lymph nodes. This patient had significant pancreatitis on initial exploration. After neoadjuvant therapy, he had a complete response radiographically, and there was no residual cancer in his resection specimen. Pathologic examination of the other resection specimens suggested that despite significant tumor fibrosis, malignant cells persist even at the periphery of the lesions.Conclusion: Although neoadjuvant chemoradiation has many theoretical advantages in managing pancreatic malignancy, true pathologic downstaging of locally advanced lesions into tumors that can be removed with negative nodes and margins appears to be a rare event with currently used therapeutic regimens.     

15-Year Experience with Multimodality Therapy Including Esophagectomy for Elderly Patients with Locoregional Esophageal Cancer

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The Usefulness of Neoadjuvant Chemoradiation Therapy for Locally Advanced Esophageal Cancer with Multiple Lymph-Node Metastases

Background

The prognosis of patients with esophageal squamous-cell cancer (ESCC) and multiple lymph-node metastases is quite poor. We examined whether neoadjuvant chemoradiation therapy (CRT) has a beneficial effect in such patients.

Methods

A total of 50 consecutive patients with T3–4 tumors and without organ metastases were prospectively enrolled. Of those patients, 20, who had four or more nodal metastases, underwent neoadjuvant CRT (CRT group), and the remaining 30 patients, who had three or fewer nodal metastases, underwent surgery alone (surgery group). CRT consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The groups’ clinical outcomes were compared.

Results

Surgery was performed in 48 patients: all enrolled patients except for 2 who had organ metastasis after CRT. In the CRT group, the number of patients with pathological complete response was observed in 8 patients (44 %), mean nodal metastases number was changed from 8.2 to 2.6 and 9 patients had pN0. The 3-year survival rate was 76 % in the CRT group (4 patients relapsed) and 68 % in the surgery group (8 patients relapsed), which is not a statistically significant difference (P = 0.61).

Conclusions

Neoadjuvant CRT is beneficial for locally advanced ESCC with four or more lymph-node metastases.     

Image-Guided Stereotactic Radiosurgery for Locally Advanced Pancreatic Adenocarcinoma Results of First 85 Patients

Background  

Locally advanced unresectable pancreatic adenocarcinoma is characterized by poor survival despite chemotherapy and conventional radiation therapy (RT). Recent advances in real-time image-guided stereotactic radiosurgery (SRS) have made it possible to treat these cancers in two to four fractions followed by systemic chemotherapy.     

Distal Pancreatectomy with En Bloc Celiac Axis Resection for Locally Advanced Pancreatic Adenocarcinoma Following Neoadjuvant Therapy

Background

Celiac trunk encasement by adenocarcinoma of the pancreatic body is generally regarded as a contraindication for surgical resection. Recent studies have suggested that a subset of stage III patients will succumb to their disease in the absence of distant metastases. We hypothesized that patients with stage III tumors invading the celiac trunk, who are free of distant disease following neoadjuvant therapy, may derive prolonged survival benefit from aggressive surgical resection.

Methods

We performed a retrospective review of distal pancreatectomies with en bloc celiac axis resection for pancreatic adenocarcinoma.

Results

Eleven patients underwent a distal pancreatectomy with en bloc celiac axis resection after completing neoadjuvant chemoradiation therapy. Median operative time was 8?h, 14?min, and median estimated blood loss was 700?ml. Median length of stay was 9?days. Five patients (45%) had postoperative complications; three were Clavien grade I. Four patients (35%) had pancreatic leaks; two were ISGPF grade B, and two were grade A. There were two 90-day perioperative deaths. Ten patients had R0 resections (91%). After a median follow-up of 41?weeks, six patients recurred. Four of the five patients with SMAD4 loss recurred, and two of the five patients with intact SMAD4 recurred. Median disease-free and overall survival were 21?weeks and 26?months, respectively.

Conclusions

Resection of pancreatic body adenocarcinoma with celiac axis resection is technically feasible with acceptable perioperative morbidity and mortality.     

Is There an Optimal Definition for a Positive Circumferential Resection Margin in Locally Advanced Esophageal Cancer?

Annals of Surgical Oncology -     

Chemoradiotherapy Before and After Surgery for Locally Advanced Esophageal Cancer: A SEER-Medicare Analysis

Purpose

The optimal combination and timing of therapy for esophageal cancer remains controversial. The Surveillance, Epidemiology, and End Results (SEER)-Medicare registry was used to assess neoadjuvant and adjuvant therapy.

Methods

Patients diagnosed with nonmetastatic T3+ or N1+ esophageal adenocarcinoma (ACA) or squamous cell carcinoma (SCC) from 1995 to 2002 who underwent surgical resection within 6 months of diagnosis were studied. Medicare data defined preoperative chemoradiotherapy (preCRT), preoperative radiotherapy (preRT), postoperative CRT (postCRT), chemotherapy and surgery (CT + S), and surgery alone.

Results

Of 419 eligible patients, 126 received preCRT, 55 preRT, 40 postCRT, 29 CT + S, and 169 surgery alone. PreCRT yielded median overall survival (OS) of 37 months, greater than surgery alone (17 months, p = 0.002) and postCRT (17 months, p = 0.06). PreRT (20 months, p = 0.20), postCRT (p = 0.88), and CT + S (20 months, p = 0.42) were not associated with OS benefit versus surgery alone. For SCC, preCRT improved survival versus surgery alone (p = 0.01), with a trend for ACA (p = 0.07). ACA (22 months) had greater OS than SCC (17 months) (p = 0.03). ACA, younger age, and married status were associated with increased OS. Adjusting for these, preCRT had longer OS versus surgery alone (p = 0.02) and postCRT (p = 0.03). Chemotherapy agents and surgical approach did not affect OS.

Conclusions

In the SEER-Medicare cohort, preCRT significantly improved survival versus surgery alone and postCRT for locally advanced esophageal cancer, particularly for SCC. PreRT, postCRT, and CT + S were not associated with longer survival.     

Pancreatic Surgery with Vascular Reconstruction in Patients with Locally Advanced Pancreatic Neuroendocrine Tumors

Introduction

Pancreatic neuroendocrine tumors (PNET) are rare neoplasms with better prognosis than most pancreatic malignancies. Surgery of locally advanced PNET remains controversial, and the role of vascular reconstruction in this patient group has yet to be defined. The aim of this study was to evaluate the feasibility and outcome of pancreatic resections with vascular reconstruction in patients with locally advanced PNET.

Methods

Retrospective analysis of patients who underwent pancreatic surgery with vascular reconstruction for locally advanced PNET at a single institution. Furthermore, a review of the relevant literature on the topic was performed.

Results

Seven patients who had undergone vascular reconstruction for locally advanced PNET were identified. Four patients had liver metastases at time of surgery. Postoperative complications developed in four patients with no mortality. Median follow-up time of all patients was 21 (range, 3–58) months. Three patients had disease in remission after 58, 42 and 3 months, respectively. One patient died 35 months postoperatively due to progressive disease, whereas three patients had progression of disease after 21, 9, and 4 months postoperatively.

Conclusion

Pancreatic surgery with vascular reconstruction in patients with locally advanced PNET is feasible with acceptable outcome.     

Margin Positive Pancreaticoduodenectomy Is Superior to Palliative Bypass in Locally Advanced Pancreatic Ductal Adenocarcinoma

Background

Pancreatic ductal adenocarcinoma is an aggressive disease. Surgical resection with negative margins (R0) offers the only opportunity for cure. Patients who have advanced disease that limits the chance for R0 surgical resection may undergo margin positive (MP) pancreaticoduodenectomy (PD), palliative surgical bypass (PB), celiac plexus neurolysis alone (PX), or neoadjuvant chemoradiation therapy in anticipation of future resection.

Objective

The aim of this study was to determine if there is a difference in the perioperative outcomes and survival patterns between patients who undergo MP PD and those who undergo PB for locally advanced disease in the treatment of pancreatic ductal adenocarcinoma.

Methods

We reviewed our pancreatic surgery database (January 2005–December 2007) to identify all patients who underwent exploration with curative intent of pancreatic ductal adenocarcinoma of the head/neck/uncinate process of the pancreas. Four groups of patients were identified, R0 PD, MP PD, PB, and PX.

Results

We identified 126 patients who underwent PD, PB, or PX. Fifty-six patients underwent R0 PD, 37 patients underwent MP PD, 24 patients underwent a PB procedure, and nine patients underwent PX. In the PB group, 58% underwent gastrojejunostomy (GJ) plus hepaticojejunostomy (HJ), 38% underwent GJ alone, and 4% underwent HJ alone. Of these PB patients, 25% had locally advanced disease and 75% had metastatic disease. All nine patients in the PX group had metastatic disease. The mean age, gender distribution, and preoperative comorbidities were similar between the groups. For the MP PD group, the distribution of positive margins on permanent section was 57% retroperitoneal soft tissue, 19% with more than one positive margin, 11% pancreatic neck, and 8% bile duct. The perioperative complication rates for the respective groups were R0 36%, MP 49%, PB 33%, and PX 22%. The 30-day perioperative mortality rate for the entire cohort was 2%, with all three of these deaths being in the R0 group. The median follow-up for the entire cohort was 14.4 months. Median survival for the respective groups was R0 27.2 months, MP 15.6 months, PB 6.5 months, and PX 5.4 months.

Conclusions

Margin positive pancreaticoduodenectomy in highly selected patients can be performed safely, with low perioperative morbidity and mortality. Further investigation to determine the role of adjuvant treatment and longer-term follow-up are required to assess the durability of survival outcomes for patients undergoing MP PD resection.     

Irreversible Electroporation of Locally Advanced Pancreatic Head Adenocarcinoma

Irreversible electroporation of locally advanced pancreatic adenocarcinoma has been used to palliate appropriate patients with locally advanced pancreatic adenocarcinoma. The setting was at a university tertiary care center. Subjects are patients with locally advanced pancreatic adenocarcinoma who have undergone appropriate induction chemotherapy for at least 3 to 4 months in duration. Technique of open irreversible electroporation of locally advanced pancreatic adenocarcinoma is described. The technique of open irreversible electroporation with continuous intraoperative ultrasound imaging and consideration of intraoperative navigational system is described. Irreversible electroporation of locally advanced pancreatic adenocarcinoma is feasible for locally advanced unresectable pancreatic cancer.