Survival after attempted surgical resection and intraoperative radiation therapy for pancreatic and periampullary adenocarcinoma

PURPOSE: To evaluate a single institution's experience with intraoperative radiation therapy (IORT) in combination with attempted surgical resection for pancreatic and periampullary adenocarcinoma. METHODS AND MATERIALS: From May 1986 until June 2001, 77 patients at LDS Hospital underwent attempted surgical resection and IORT for pancreatic or periampullary adenocarcinoma. A potentially curative resection was defined as surgery with negative or microscopic positive margins. No patients had metastatic disease at the time of surgery and IORT. Forty-four patients with tumors located in the pancreas and 9 patients with periampullary tumors underwent potentially curative surgical resection and IORT. Twenty-four patients had pancreatic tumors deemed unresectable and underwent surgical bypass and IORT. Actuarial survival was calculated from the date of IORT until last follow-up or death by use of the Kaplan-Meier method. RESULTS: Patients undergoing a potentially curative resection and IORT for periampullary adenocarcinoma had a median survival of 167 months and a 56% 5-year actuarial survival, compared with a median survival of 16 months and a 19% 5-year actuarial survival for patients undergoing the same treatment for pancreatic adenocarcinoma (p = 0.03). Patients with unresectable disease who underwent bypass and IORT had a median survival of 11 months and a 0% 3-year survival, significantly worse than patients able to undergo surgical resection and IORT (p = 0.0002). The operative mortality for all patients undergoing potentially curative resection and IORT was 3.7%. CONCLUSIONS: Intraoperative radiation therapy is well tolerated and does not increase the morbidity or mortality of potentially curative surgical resection for pancreatic or periampullary adenocarcinoma. Patients with periampullary adenocarcinoma have a better prognosis than those with pancreatic adenocarcinoma, and patients with unresectable pancreatic disease fared worse.     

Stereotactic radiotherapy for unresectable adenocarcinoma of the pancreas

BACKGROUND:

The authors report on the local control and toxicity of stereotactic body radiotherapy (SBRT) for patients with unresectable pancreatic adenocarcinoma.

METHODS:

Seventy‐seven patients with unresectable adenocarcinoma of the pancreas received 25 gray (Gy) in 1 fraction. Forty‐five patients (58%) had locally advanced disease, 11 patients (14%) had medically inoperable disease, 15 patients (19%) had metastatic disease, and 6 patients (8%) had locally recurrent disease. Nine patients (12%) had received prior chemoradiotherapy. Sixteen patients (21%) received between 45 to 54 Gy of fractionated radiotherapy and SBRT. Various gemcitabine‐based chemotherapy regimens were received by 74 patients (96%), but 3 patients (4%) did not receive chemotherapy until they had distant failure.

RESULTS:

The median follow‐up was 6 months (range, 3‐31 months) and, among surviving patients, it was 12 months (range, 3‐31 months). The overall rates of freedom from local progression (FFLP) at 6 months and 12 months were 91% and 84%, respectively. The 6‐ and 12‐month isolated local recurrence rates were 5% and 5%, respectively. There was no difference in the 12‐month FFLP rate based on tumor location (head/uncinate, 91% vs body/tail, 86%; P = .52). The progression‐free survival (PFS) rates at 6 months and 12 months were 26% and 9%, respectively. The PFS rate at 6 months was superior for patients who had nonmetastatic disease versus patients who had metastatic disease (28% vs 15%; P = .05). The overall survival (OS) rates at 6 months and 12 months from SBRT were 56% and 21%, respectively. Four patients (5%) experienced grade ≥2 acute toxicity. Three patients (4%) experienced grade 2 late toxicity, and 7 patients (9%) experienced grade ≥3 late toxicity. At 6 months and 12 months, the rates of grade ≥2 late toxicity were 11% and 25%, respectively.

CONCLUSIONS:

SBRT for pancreatic adenocarcinoma was effective for local control with associated risk of toxicity and should be used with rigorous attention to quality assurance. Efforts to reduce complications are warranted. Distant metastases account for the vast majority of disease‐related mortality. Cancer 2009. © 2008 American Cancer Society.     

胰腺癌术中放射治疗的价值

目的：回顾总结诸多放射治疗方式对胰腺癌治疗的价值。方法：1986－1999年间收治的无法手术切除的晚期胰腺癌患者68例，伴有严理和中度腹背痛的65例作为研究对象，其中无腹背痛的3例除外，单纯接受术中放射治疗25例，术中放射治疗加体外放射治疗20例，单纯体外放射治疗20例，另外单纯手术治疗胰腺癌30例作对照。结果：（1）单纯术中放射治疗组患者背痛和腹痛的完全缓解率为47％，部分缓解率为34％，总疼痛缓解率为81％，术后2周内见效，中位生存期为5．9个月（从治疗开始计算）。（2）术中放射治疗加体外放射治疗组患者背痛和腹痛的缓解率同单纯疗后4周左右见效，中位生存期是4．5个月。（4）单纯手术治疗组中位生期7个月。结论：术中放射治疗加体外放射治疗能明显延长晚期胰腺癌患者的生存期，而且能明显缓解患者的疼痛，见效快，提高了患者的生活质量。     

Combined radiation and chemotherapy as primary management of adenocarcinoma of the esophagus and gastroesophageal junction

Between January 1981 and December 1986, 20 patients with adenocarcinoma of the esophagus and gastroesophageal junction were entered into a prospective study involving combined radiation therapy and chemotherapy (5-fluorouracil [5-FU] and mitomycin) as primary management. Nine patients with Stage I or II disease received definitive treatment consisting of 6000 cGy in 6 to 7 weeks and 5-FU (1000 mg/m2/24 hours) as a continuous intravenous (IV) infusion for 96 hours starting on days 2 and 29. Mitomycin (10 mg/m2) was administered as a bolus injection on day 2. Ten patients with extraesophageal and disseminated disease (Stages III and IV) and one patient with an unresectable anastomotic recurrence were considered palliative. Generally the palliative regimen did not differ from the definitive except for the radiation dose which in seven of the 11 patients was less than 6000 cGy (4000-5600 cGy). The range of follow-up was 6 to 74 months and no patient was lost to follow-up. Seven of the eight evaluable definitively treated patients were complete responders. The median relapse-free survival was 10 months and the median survival was 15 months in this group. In the palliative group, six of nine evaluable patients had relief of dysphagia until death or last follow-up with a median duration of 8 months. Our results indicate that combined modality treatment with infusional 5-FU, mitomycin, and radiation is an effective and well-tolerated treatment for adenocarcinoma of the esophagus and gastroesophageal junction. This treatment regimen offers palliation and some chance for cure to those patients who are inoperable, unresectable, or who refuse surgery.     

Results in the management of locally unresectable pancreatic carcinoma

Between 1973 and 1983, 43 patients with histologically proven unresectable pancreatic carcinoma were irradiated in the UCLA Department of Radiation Oncology. Ten patients received irradiation alone and 33 were nonrandomly assigned to receive chemotherapy in addition to irradiation. Of those patients receiving chemotherapy, 30 were given 5-fluorouracil and three were given a combination of agents. Forty-one of the 43 patients have died with a median survival of 7 months. Actuarial survival at 1 and 2 years was 24% and 3%. Local control was achieved in three of 43 patients. Two patients are alive with no evidence of disease at 11 and 30 months. The median survivals with and without chemotherapy were 9.5 and 4 months, respectively (p = 0.06). Survival dependent on nodal status, surgical bypass, primary site, and dose are also reported. No significant differences were found. Acute complications were noted in 23 patients but were a reason for discontinuing therapy in none. Late complications were noted in nine patients. Six patients with an upper gastrointestinal hemorrhage or a small bowel obstruction all had local recurrence. There were two patients with posttreatment diabetes mellitus and one with pancreatitis. The limits of conventional therapy for unresectable pancreatic cancer have been reached. Creative sequencing of induction combination chemotherapy, newer radiation modalities, and maintenance chemotherapy are required if systemic and local progression of this lethal disease is to be eliminated.     

The role of thoracic and cranial irradiation for small cell carcinoma of the lung

Since 1974, 120 previously untreated patients with small cell carcinoma of the lung seen in Therapeutic Radiology at The Medical College of Wisconsin have been entered into one of 4 successive studies. Study I used thoracic irradiation (TI) alone (4500-6000 rad in 3-6 weeks) with chemotherapy at progression. Study II randomized patients with limited disease to TI (3000 rad in 2 weeks) plus either cyclophosphamide, doxorubicin, vincristine (CAV) or total body irradiation (TBI); patients with extensive disease received TI + CAV. Study III employed prophylactic cranial irradiation (PCI) plus CAV and withheld TI unless there was incomplete response or recurrence. Of 93 evaluable patients from the first three studies, 55 had limited and 38 extensive disease. Study I (37 patients) showed a 62% complete response (CR) rate; 43% failed in the chest, 14% had brain metastases, and the median survival was only 22 weeks in spite of a preponderance of limited disease patients. Study II (27 patients) showed a CR of 59%; 30% had brain metastases and the median survival was 48 weeks. Study II patients (29) had a 69% rate; 72% failed in the chest, 4% with PCI developed brain metastases, and the median survival was 50 weeks. In March, 1979, Study IV was initiated; patients receive PCI (2500 rad in 2 weeks) plus high dose CAV, methotrexate and leucovorin. After 6 cycles, consolidation TI (3750 rad in 3 weeks) is given to patients with complete response. Preliminary results with 27 patients treated on this study show a 67% CR rate, a 41% chest failure rate (but only 11% for the patients who received thoracic irradiation) and no intracranial failures, but a 13% extracranial CNS failure rate. PCI, TI and spinal irradiation may be necessary to maximize the probability of long term disease free survival.     

Phase II study of gemcitabine plus docetaxel in advanced pancreatic cancer: a Hoosier Oncology Group study

OBJECTIVE: To determine the response rate, duration of response and survival with weekly gemcitabine plus docetaxel in metastatic or unresectable pancreatic cancer. METHODS: Forty patients were enrolled, and 38 patients were evaluable for survival and toxicity. Thirty-seven patients were evaluable for response. Nine patients (24%) had locally advanced disease and 29 (76%) had metastatic disease at the time of enrollment. Median Eastern Cooperative Oncology Group performance status was 1. Patients received gemcitabine 750 mg/m(2) i.v. and docetaxel 35 mg/m(2) i.v. weekly for 3 out of 4 weeks for a maximum of 6 cycles. RESULTS: Patients received a median of 4 cycles (range 1-6) of chemotherapy. An objective response was obtained in 10 patients (27%) with a median duration of 17 weeks. Median survival was 7 months, and 1-year survival was 19.3%. Eight patients experienced at least one form of grade 4 toxicity and 27 patients experienced at least one type of grade 3 toxicity. CONCLUSIONS: The combination of gemcitabine and docetaxel is a well-tolerated regimen with clinical efficacy. The ultimate role of this combination versus single-agent gemcitabine can only be determined by a randomized phase III trial.     

Total neoadjuvant therapy for pancreatic adenocarcinoma increases probability for a complete pathologic response

BackgroundMultiple neoadjuvant therapy protocols have been proposed in the treatment of pancreatic adenocarcinoma, including chemotherapy (CT), chemoradiation (CRT), and total neoadjuvant therapy (TNT), defined as a CT plus CRT. A pathologic complete response (pCR) can be achieved in a minority of cases. We hypothesize that TNT is more likely to confer pCR than other neoadjuvant therapies, which may improve overall survival (OS).MethodsA retrospective review of the National Cancer Database (NCDB) from 2006 to 2016 was performed, identifying patients who underwent any neoadjuvant therapy followed by definitive pancreatic resection for locally advanced or borderline resectable pancreatic adenocarcinoma. A pathologic complete response was defined as down-staging from any clinical stage to pathologic stage 0.ResultsA total of 5402 patients who received neoadjuvant therapy followed by resection were identified. 177 patients (3.3%) achieved a pCR. Of the patients who achieved a pCR, 57 received CT, 41 CRT and 79 received TNT. On multivariate analysis, TNT was more likely to confer a pCR than CRT (OR 1.67, CI 1.13–2.46, p = 0.0103) or CT (OR 2.61, CI 1.83–3.71, p < 0.0001). Patients who achieved pCR had a significantly higher OS, with median survival of 64.9 months, compared to 21.6 months in patients who did not achieve pCR (p < 0.0001).ConclusionTNT may be more likely to achieve a pCR than CT or CRT. Patients who achieve a pCR have a significant OS benefit as compared to those who have residual disease. TNT should be considered for patients requiring neoadjuvant therapy, as it may increase the likelihood of achieving a pCR, thus potentially improving OS.     

Survival and prognostic factors in patients with pancreatic squamous cell carcinoma

ObjectivesSquamous cell carcinoma (SCC) of pancreas is rare entity with poorly defined prognostic factors and therapeutic outcomes. We sought to determine the overall survival (OS) and prognostic factors of patients with pancreatic SCC using National Cancer Database (NCDB) (2004–15).MethodsKaplan-Meier method and log-rank test were used to perform OS analysis. Propensity-matched analysis was used to compare the OS of pancreatic SCC and adenocarcinoma.ResultsOf the 515 cases included in our analysis, 46% were female. Approximately half of the cohort (48%) received chemotherapy or radiation therapy or both. Twenty six percent (33/125) of stage I and II disease (localized disease), 11% (8/72) of stage III, and 2% (6/318) of stage IV disease underwent surgical resection of the primary tumor. Median OS for the entire cohort was 4 months and was significantly higher in patients who underwent surgical resection of the primary tumor (17 vs 4 months, p < 0.001). In localized disease, adjuvant chemotherapy was not associated with improved OS in early stage disease (20 vs 24 months, p = 0.60). Stage IV patients treated with chemotherapy had a better OS than those without (5 vs 2 months, p < 0.0001). Propensity matched analysis demonstrated no significant differences in median OS between pancreatic adenocarcinoma (4.8 months) and SCC (4 months, p = 0.09).ConclusionsPancreatic SCC had a diverse OS that varied significantly according to increasing age (>70 years) and stage of the disease at presentation (p < 0.01). Surgical resection of primary tumor was associated with longer OS in stages I-II, whereas chemotherapy was associated with longer OS in stage IV disease.     

Phase II trial of trimetrexate for patients with advanced gastric carcinoma: an Eastern Cooperative Oncology Group study (E1287).

BACKGROUND: A Phase II study was conducted to evaluate the response, duration of response, and duration of survival of patients with measurable gastric carcinoma treated with trimetrexate (TMTX) who had not had prior chemotherapy. METHODS: Thirty-three patients with unresectable or metastatic gastric adenocarcinoma who had not received previous chemotherapy were treated with intravenous TMTX 12 mg/m(2) daily for 5 days. The dosage of TMTX was reduced to 8 mg/m(2) daily for 5 days for those who had received prior radiotherapy. The cycle was repeated every 3 weeks until disease progression or unacceptable toxicity occurred. RESULTS: Thirty-three patients could be analyzed with follow-up data. There was one Grade 5 (lethal) toxicity and four Grade 4 toxicities. Hematologic toxicity was the most common. The overall response rate was 21%, the overall median progression free survival was 2.7 months, and the overall median survival was 5.9 months for the entire cohort. No patients were alive at last follow-up. CONCLUSIONS: Though TMTX as a single agent has activity in gastric carcinoma with manageable toxicity, it cannot be recommended for routine use as a single agent due to the brief duration of response and median survival.     

Gemcitabine combined with oxaliplatin in advanced pancreatic adenocarcinoma: final results of a GERCOR multicenter phase II study.

PURPOSE: Based on preclinical in vitro synergy data, this study evaluated the activity and toxicity of a gemcitabine/oxaliplatin combination in patients with metastatic and locally advanced pancreatic adenocarcinoma. PATIENTS AND METHODS: Previously untreated metastatic and locally advanced unresectable pancreatic adenocarcinoma patients were enrolled onto this multicenter phase II study. Patients received gemcitabine 1,000 mg/m(2) as a 10-mg/m(2)/min infusion on day 1 and oxaliplatin 100 mg/m(2) as a 2-hour infusion on day 2 every 2 weeks. Patients with metastatic disease were treated until evidence of progressive disease, whereas patients with locally advanced disease received six cycles in the absence of progression, followed when appropriate by concomitant radiochemotherapy. RESULTS: Among 64 eligible patients included in eight centers, 30 had locally advanced and 34 had metastatic disease. Response rate for the 62 patients with measurable disease was 30.6% (95% confidence interval, 19.7% to 42.3%), 31.0% for locally advanced and 30.3% for metastatic patients. Among 58 assessable patients, 40% had clinical benefit. Median progression-free survival and median overall survival (OS) were 5.3 and 9.2 months, respectively, with 36% of patients alive at 1 year. Median OS for patients with metastatic disease and locally advanced disease were 8.7 and 11.5 months, respectively. With 574 treatment cycles (median per patient, nine; range, zero to 27), grade 3/4 toxicity per patient was 11% for neutropenia and thrombocytopenia, 14% for nausea or vomiting, 6.2% for diarrhea, and 11% for peripheral neuropathy, with no toxic deaths. CONCLUSION: Palliative effects, response rate, and survival observed with this well-tolerated gemcitabine/oxaliplatin combination deserve additional evaluation. A comparative study of combination therapy versus gemcitabine alone is ongoing.     

Local Control and Toxicity of a Simultaneous Integrated Boost for Dose Escalation in Locally Advanced Esophageal Cancer: Interim Results from a Prospective Phase I/II Trial

IntroductionApproximately 50% of recurrences after standard-dose chemoradiation for locally advanced esophageal cancer occur within the gross tumor volume (GTV). In this prospective phase I/II clinical trial, we explored the use of a simultaneous integrated boost (SIB) dose to the GTV.MethodsForty-four patients with unresectable esophageal cancer received chemoradiation with an SIB of 58.8 to 63 Gy to the GTV and 50.4 Gy to the planning target volume, all in 28 fractions, with 5 weeks of concurrent docetaxel and fluorouracil or capecitabine. The end points were maximum tolerated dose, time to local failure, and clinical response.ResultsExcluding those with less than 6 months of follow-up, 38 patients were evaluated at the time of analysis. The median age was 65 years (range 37–84). Most patients (71%) were men; 84% had T3 disease, 37% had N1 disease, 26% had N2 disease, 13% had M1 disease, and 50% had adenocarcinoma. The maximum tolerated SIB dose was 63 Gy. None experienced Common Terminology Criteria for Adverse Events grade 4 or 5 toxicity. At a median follow-up time of 13.3 months (range 1.2–36.2), 11 (29%) had local failure (median time to local failure 2.5 months [range 1.5–23.9]). A comparison with 97 similar patients who received 50.4 Gy without an SIB showed that the SIB reduced the local failure rate for patients with node-positive disease (13% versus 56%, p = 0.04), adenocarcinoma (26% versus 59%, p = 0.02), or stage III–IV disease (29% versus 55%, p = 0.04).ConclusionsSIB intensity-modulated radiation therapy to gross primary disease may improve local control for patients with unresectable locally advanced esophageal cancer, especially those with adenocarcinoma.     

Postoperative adjuvant gemcitabine and concurrent radiation after curative resection of pancreatic head carcinoma: a phase II study

PURPOSE: The addition of radiation to adjuvant 5-fluorouracil for the treatment of pancreatic cancer has not yet shown any definite benefit. Gemcitabine (GEM) has potential activity in advanced pancreatic cancer and is a powerful radiosensitizer. We evaluated the feasibility of postoperative administration of GEM alone, followed by concurrent GEM and irradiation (RT) after curative resection for pancreatic adenocarcinoma. METHODS AND MATERIALS: GEM 1000 mg/m(2) on Days 1 and 8 every 21 days for three courses was given within 8 weeks after surgery and was followed by GEM 300 mg/m(2) weekly +40 Gy in a split course. Twenty-two patients (median age 59 years, range 39-74, Performance Status 0-1) with Stage II and III curatively resected pancreatic head adenocarcinoma were included. RESULTS: For GEM alone, all patients received the three planned courses, with dose reductions in 7 (32%) of 22 patients. All patients, except two, completed full chemoradiation; one received only 20 Gy because of both World Health Organization Grade 4 vomiting and thrombopenia and the other stopped RT after 32 Gy because of early disease progression. No reduction in GEM during RT was necessary; no toxic death was noted; and World Health Organization Grade 3-4 hematologic and nonhematologic toxicities occurred in 8 (36%) and 7 (nausea, vomiting) (32%) of 22 patients respectively. No late toxicity developed. After a median follow-up of 15 months, 11 patients were alive, and 2 patients had died of causes unrelated to their disease or toxicity, The median disease-free survival and overall survival was 6 and 15 months, respectively. CONCLUSION: This adjuvant regimen was well tolerated and can be easily administered after curative surgery for pancreatic cancer. Its intensification with continuous RT is currently being investigated.     

Length and quality of survival after external-beam radiotherapy with concurrent continuous 5-fluorouracil infusion for locally unresectable pancreatic cancer

PURPOSE: The purpose of this study was to evaluate whether external-beam radiotherapy (EBRT) with concurrent continuous 5-fluorouracil (5-FU) infusion affects the length and quality of survival in patients with locally unresectable pancreatic cancer. METHODS: Thirty-one patients with histologically proven locally advanced and unresectable pancreatic cancer without distant metastases were evaluated in this prospective randomized trial. Sixteen patients received EBRT (50.4 Gy/28 fractions) with concurrent continuous infusion of 5-FU (200 mg/m(2)/day), whereas 15 patients received no chemoradiation. The length and quality of survival was analyzed and compared for the two groups. RESULTS: The median survival of 13.2 months and the 1-year survival rate of 53.3% in the chemoradiation group were significantly better than the respective 6.4 months and 0% in the group without chemoradiotherapy (p = 0.0009). The average monthly Karnofsky score, a quality of life indicator, was 77.1 in the chemoradiation group, which was significantly higher than the 65.5 in the group without chemoradiotherapy (p < 0.0001). The number of hospital days per month of survival was significantly less in the chemoradiation than in the no-therapy group (12.3 vs. 19.0 days, p < 0.05). In the chemoradiation group, 5 patients (31%) had a partial response, and 9 (56%) had radiologically stable disease at a median duration of 6.1 months. The patients who had chemoradiation had a lower rate of liver and peritoneal metastases than patients without chemoradiotherapy (31% vs. 64%). Of 10 patients who experienced pain before chemoradiation, 8 (80%) received pain relief that lasted a median of 5.2 months. CONCLUSIONS: EBRT with concurrent continuous 5-FU infusion increased the length and quality of survival as compared to no chemoradiotherapy and provided a definite palliative benefit for patients with unresectable pancreatic cancer.     

Survival advantage of combined chemoradiotherapy compared with resection as the initial treatment of patients with regional pancreatic carcinoma. An outcomes trial

BACKGROUND: Resection of pancreatic carcinoma is resource-intensive with a limited impact on survival. Chemotherapy and/or radiotherapy (RT) have been shown to be effective palliation. To examine whether preoperative chemoradiotherapy as the initial treatment improves survival for patients with a regional pancreatic adenocarcinoma with a minimal chance of being resected successfully, an outcomes trial was conducted. METHODS: Patients with radiologically regional tumors were staged by laparotomy and/or computed tomography followed by endoscopic ultrasonography, angiography, and/or laparoscopy. Those with locally invasive, unresectable, regional pancreatic adenocarcinoma initially were treated with simultaneous split-course RT plus 5-fluorouracil, streptozotocin, and cisplatin (RT-FSP) followed by selective surgery (Group 1). Patients determined to have a resectable tumor initially underwent resection without preoperative chemoradiotherapy, with or without postoperative chemoradiotherapy (Group 2). RESULTS: Over 8 years 159 patients presenting with nonmetastatic pancreatic adenocarcinoma were administered RT-FSP or underwent surgery for resection. Group 1, comprised of 68 patients initially treated with RT-FSP, had a 0% mortality rate within 30 days of entry. In 20 of 30 patients undergoing surgery after RT-FSP, tumors were downstaged and resected. Group 2, comprised of 91 patients who initially underwent successful resection, had a 5% mortality rate within 30 days of entry. Postoperatively, 63 of these patients received chemotherapy with or without RT. The median survival for Group 1 was 23.6 months compared with 14.0 months for Group 2 (P = 0.006) despite more advanced disease cases in Group 1. Survival favored RT-FSP regardless of whether lymph nodes were malignant. The dominant prognostic factor of earlier stage pancreatic carcinoma having an expected survival advantage was reversed by the initial nonoperative treatment. CONCLUSIONS: Based on a reversal of the expected trend that patients with earlier stage resectable carcinoma (T1,2, N0,1, M0) who undergo removal of their tumors survive longer than patients with more advanced regional disease (T3, N0,1, M0), survival was found to improve significantly for patients reliably staged as having locally invasive, unresectable, nonmetastatic pancreatic adenocarcinoma when initially treated with RT-FSP.     

Multimodality treatment of recurrent pancreatic cancer: Mith or reality?

Pancreatic adenocarcinoma is the fourth cause of cancer-related death in the United States. Surgery is the only potentially curative treatment, but most patients present at diagnosis with unresectable or metastatic disease. Moreover, even with an R0 resection, the majority of patients will die of disease recurrence. Most recurrences occur in the first 2-year after pancreatic resection, and are commonly located in the abdomen, even if distant metastases can occur. Recurrent pancreatic adenocarcinoma remains a significant therapeutic challenge, due to the limited role of surgery and radio-chemotherapy. Surgical management of recurrence is usually unreliable because tumor relapse typically presents as a technically unresectable, or as multifocal disease with an aggressive growth. Therefore, treatment of patients with recurrent pancreatic adenocarcinoma has historically been limited to palliative chemotherapy or supportive care. Only few data are available in the Literature about this issue, even if in recent years more studies have been published to determine whether treatment after recurrence have any effect on patients outcome. Recent therapeutic advances have demonstrated the potential to improve survival in selected patients who had undergone resection for pancreatic cancer. Multimodality management of recurrent pancreatic carcinoma may lead to better survival and quality of life in a small but significant percentage of patients; however, more and larger studies are needed to clarify the role of the different therapeutic options and the optimal way to combine them.     

Preoperative irradiation of primarily unresectable colorectal carcinoma.

A series of 44 patients with colorectal carcinomas considered unresectable on presentation received preoperative irradiation to a dose of 4500--5000 rad (175--200 rad/day). After a waiting period averaging 6.5 weeks, 38 patients underwent exploration. Complete resection was possible in 27 patients. Of these, 22 patients remained disease-free with a median follow-up of 27 months. While longer follow-up periods are needed, the results indicate that the large percentage of unresectable and therefore surgically incurable colorectal carcinomas can be made resectable by preoperative irradiation, and a significant number of these may have been cured.     

High dose, external beam and intraoperative radiotherapy in the treatment of resectable and unresectable pancreatic cancer

Ninety patients with pancreatic cancer were treated by external beam radiotherapy (EBRT) and/or intraoperative radiotherapy (IORT) with or without surgical resection of the tumor, and the results were compared with those of a historical control comprising 112 patients treated by surgery alone. At an early stage of this study, postoperative EBRT (50-60 Gy) or IORT (25-33 Gy) was given alone, but recently the two modalities have been combined. The combination of high doses of EBRT and IORT was well tolerated provided that the gastrointestinal tract was not irradiated during IORT. Although EBRT plus IORT appeared to yield better results than either EBRT or IORT alone, the difference was not significant on multivariate analysis, and patients receiving EBRT, IORT, or EBRT + IORT were grouped together. Patients receiving radiotherapy in addition to macroscopically curative surgery had a slightly longer median survival time (14 months) than those receiving curative surgery alone (10 months), but the 3-year survival rate was similar (21% vs. 19%). In patients who underwent noncurative resection, the median survival time was significantly longer for the irradiated group (12 months) than for the control group (6.5 months). Also, in patients with unresectable lesions but no distant metastases, irradiation prolonged the median survival time significantly (8 vs. 3.5 months). In this group, there was one 5-year survivor, who received EBRT of 55 Gy plus IORT of 30 Gy to his unresectable pancreatic body lesion. Patients with metastases were also treated for palliation of symptoms, but it was found that irradiation prolonged the median survival time even in such cases (4.5 vs. 2.5 months). Based on these results, we plan to use EBRT plus IORT in all pancreatic cancer patients with no metastases.     

A pilot study of chronomodulated infusional 5-fluorouracil chemoradiation for pancreatic cancer

Background:Dose limiting acute toxicity from chemoradiation for pancreatic cancer occurs in 15%–20% of patients treated with post-operative adjuvant therapy. Reported here is a pilot study using chronomodulated infusional 5-fluorouracil (5-FU) chemoradiation (CIC) for pancreatic cancer, a treatment designed to reduce normal tissue toxicity and maintain efficacy, with specific evaluation of acute and late morbidity, patterns of disease progression, and survival. Patients and methods:Twenty-three patients with adenocarcinoma of the pancreas were treated with 5-FU CIC between January 1997 and September 1999. The median age was 64, and there were 9 males and 14 females. Six patients were considered unresectable and seventeen others were treated post-operatively. The median external beam irradiation dose was 50.4 Gy. 5-FU infusion was given five days per week (300 mg/m²/d) and the median total dose was 8.4 g/m². The chronomodulated 5-FU infusion consists of a low basal infusion rate for 16 hours followed by an eight-hour escalating-deescalating infusion peaking at 10 p.m. All patients were followed from the time of initial diagnosis until last follow-up or death; the median follow-up was 16 months. Results:No RTOG grade 3 or 4 hematologic toxicity occurred. Twelve of seventeen patients treated postoperatively have been controlled locally, and seven patients have no evidence of disease. The median survival is 28 months and one-year actuarial survival is 88% in the group of resected patients. The 6 patients treated for unresectable disease have a median survival of 13 months. Conclusions:Acute toxicity of 5-FU CIC appears to be less frequent and less severe than that reported with flat infusional or bolus 5-FU based chemoradiation used for adjuvant post-operative therapy for pancreatic cancer. This method may warrant further examination, as it may be attractive for the elderly or those who cannot tolerate the toxicity associated with standard post-operative treatment protocols.     

Precision radiotherapy for cancer of the pancreas: technique and results

Forty patients with locally extensive, unresectable adenocarcinoma of the pancreas received precision high dose (PHD) radiation therapy with a 45 MeV betatron. A histologic diagnosis of cancer was established at laparotomy in every case. The gross margins of the tumor were outlined with radio-opaque clips in all but one case. The clipped tumor volume plus a 1 to 3 cm margin was irradiated to a minimum dose of 5900 to 7000 rad in 180 rad fractions over 7 to 9 weeks. For slender patients, a “mixed beam” technique was employed: opposed lateral 45-MeV photon beams mated to an anterior “mixed beam” consisting of 50 % 45-MeV photons and 50% 15–35 MeV electrons. The choice of electron energy depended upon the depth of the posterior margin of the target volume. For non-slender patients, a “box” technique consisting of 3 or 4 fields of 45-MeV photons was used. Where indicated, fields were shaped to conform the isodose distribution to the shape of the target volume. PHD radiotherapy was generally well tolerated. During !treatment, only 7 patients experienced significant nausea, vomiting, diarrhea or anorexia. Late gastrointestinal radiation reactions were observed in 7 patients (severe in 3 patients). Twelve patients received adjuvant chemotherapy. Relief of pain occurred in $\text{22}\text{32}$ patients and anorexia improved in $\text{8}\text{15}$ patients following PHD radiotherapy. The projected survival of patients with unresectable pancreatic cancer treated with PHD radiotherapy is comparable to that of patients with resectable disease operated on for cure. The projected one year survival rate is 49%.