Management of locally advanced adenocarcinoma of the pancreas

Pancreatic cancer is one of the deadliest malignancies and is fatal in more than 95% of affected individuals. For locally advanced disease, the combination of 5-FU and radiation appears to offer the best chance for delaying disease progression. The introduction of gemcitabine into chemoradiotherapy regimens may provide additional improvements in the management of patients. Preoperative therapy has proved feasible but has not shown improvement in overall survival.     

Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas

Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.     

Radiation dose intensification in pre-operative chemo-radiotherapy for locally advanced rectal cancer

Background

To assess the role of radiation dose intensification with simultaneous integrated boost guided by 18-FDG-PET/CT in pre-operative chemo-radiotherapy (ChT-RT) for locally advanced rectal cancer.

Methods

A prospective study was approved by the Internal Review Board. Inclusion criteria were: age >18 years old, World Health Organization performance status of 0–1, locally advanced histologically proven adenocarcinoma of the rectum within 10 cm of the anal verge, signed specific informed consent. High-dose volumes were defined including the hyper-metabolic areas of 18-FDG-PET/CT of primary tumor and the corresponding mesorectum and/or pelvic nodes with at least a standardized uptake values (SUV) of 5. A dose of 60 Gy/30 fractions was delivered. A total dose of 54 Gy/30 fractions was delivered to prophylactic areas. Capecitabine was administered concomitantly with RT for a dose of 825 mg/mq twice daily for 5 days/every week.

Results

Between September 2011 and July 2015 fortypatients were recruited. At the time of the analysis, median follow up was 20 months (range 5–51). The median interval from the end of ChT-RT to surgery was 9 weeks (range 8–12). Thirty-seven patients (92.5 %) were submitted to sphincter preservation. Tumor Regression Grade (Mandard scale) was recorded as follows: grade 1 in 7 (17.5 %), grade 2 in 17 (42.5 %), grade 3 in 15 (37.5 %) and grade 4 in 1 (2.5 %). Post-surgical circumferential resection margin was negative in all patients. A tumor downstaging was reported in 62.5 % (95 % CI: 0.78–0.47). A nodes downstaging was registered in 85 % (95 % CI: 0.55–0.25). 18-FDG-PET/CT was not able to predict pCR. No correlation was found between pre-treatment SUV-max values and pCR. A metabolic tumor volume >127 cc was related to ypT ≥2 (p 0.01). Patients with TRG >2 had higher tumor lesion glycolysis values (p 0.05).

Conclusion

Preliminary results did not confirm some advantages in terms of primary tumor downstaging/downsizing compared to conventional schedules reported in historical series. The role of 18-FDG-PET/CT in neoadjuvant rectal cancer management needs to be confirmed in further investigations. Long terms results are necessary.

     

Combination radiotherapy and chemotherapy in the treatment of locally advanced adenocarcinoma of the pancreas. Experiences of the Gustave Roussy Institute

Non-resectable pancreatic adenocarcinomas (PA) are of poor prognosis with median survival of 4-6 months. Radiotherapy (RT) and chemotherapy (CT) association are potential palliative treatments recently investigated. We have tested such an association in a pilot study. Twelve patients (pts) with non-resectable PA and localized tumors were treated by 2 cycles of CT (5-FU + adriamycin + cisplatinum) and then 2 or 3 split courses of RT (20 Gy/12 days and 8 fractions with a 16 day interval). CT was reintroduced, if initially active, for 3 cycles. Results were: 3 CR (11+, 13+, 16 months) for a response rate of 25%, 1 MR (4 months) and 5 stabilizations longer than 6 months. The 1 year survival was 56 +/- 15% with no patient surviving longer than 2 years. Tolerance was acceptable for RT and toxicity with CT was digestive (grade II) for all pts, leucopenia grade III for 3 pts and thrombopenia grade II for 2 pts. Two pts experienced digestive hemorrhage for anastomatic ulceration, responsible for death in one case. This pilot study confirms the transient efficacy of RT + CT association for non-resectable PA. However, the toxicity and treatment duration lead us to recommend other studies of less toxic association before initiation of randomized trials.     

Radiation therapy for the treatment of locally advanced and metastatic prostate cancer

Radiation therapy for locally advanced PCa continues to evolve. A current treatment recommendation for nonmetastatic, high-risk disease includes AS combined with RT. The precise duration and sequencing of AS has not been established but most frequently includes treatment in the neoadjuvant, concomitant and, occasionally, adjuvant periods. As technology allows higher doses without significant increases in morbidity and as clinical data provide proof of a radiation dose response, RT doses continue to escalate. The goal of therapy for metastatic disease continues to focus on the relief of pain and the improvement in quality of life. Multiple studies document the significant role RT plays in achieving these goals. Focal RT and systemic radioisotopes have become the mainstay of management in this patient group and the development of newer isotopes that cause less marrow toxicity will improve the therapeutic ratio and provide an opportunity for their use with systemic chemotherapy. As molecular and genomic technologies advance, directed targeting of critical cellular radiation-response pathways hold the promise of improved radiation response and individualized, tailored therapy.     

Phase II trial of menogarol in the treatment of advanced adenocarcinoma of the pancreas

Fifteen patients with advanced adenocarcinoma of the pancreas were treated with menogarol 150-225 mg/m2 i.v. every 3 weeks. All patients had bidimensionally measurable disease. This regimen and dosage schedule are well tolerated, with minimal toxicity that included myelosupression; median white blood cell (WBC) count nadir of 2,700 cells/mm3 (range 1,400-7,100 cells/mm3) and median platelet nadir of 162,000 cells/mm3 (range 53,000-390,000 cells/mm3). Anorexia occurred in one patient, nausea or vomiting in six, phlebitis in one, and alopecia in six patients. No patients responded. At this dosage and schedule, there is no role for menogarol in the treatment of advanced pancreatic adenocarcinoma.     

Etoposide (VP-16) in the treatment of advanced adenocarcinoma of the pancreas

Twenty-six patients with advanced adenocarcinoma of the pancreas were treated with etoposide (VP-16), 100-180 mg/m2 i.v., days 1, 2, and 3, monthly. Twenty-five had bidimensionally measurable disease and one had evaluable disease only. This regimen and dosage schedule were well tolerated, with minimal toxicity including myelosuppression; a median WBC count nadir of 3,600 cells/mm3 (range 200-2,400); and a median platelet nadir of 215,000 cells/mm3 (range 15,000-405,000). However, no patients responded and only two had stable disease for 3.5 and 4 months, respectively. At this dosage and schedule, there is no role for VP-16 in the treatment of advanced pancreatic adenocarcinoma.     

局部进展期GEJA综合治疗的现状与思考

胃食管交界部腺癌（gastroesophageal junction adenocarcinoma,GEJA）具有独特的生物学特性和预后,且发病率显著增加,但其诊断和治疗仍存在争议。新辅助治疗和辅助治疗联合手术治疗较单纯手术均可改善局部进展期GEJA患者生存。而新辅助治疗中的新辅助放化疗较新辅助化疗可提高患者手术切除率和局部控制率,改善患者生活质量,联合分子靶向药物可进一步增加疗效。局部进展期GEJA患者的综合治疗数据多来源于食管癌或胃癌的随机临床研究,应开展更多大样本前瞻性随机对照研究,优化新辅助和辅助综合治疗,改善局部进展期GEJA患者的生存。本文对局部进展期GEJA综合治疗的研究进展进行综述。      

Radiotherapy for locally advanced pancreatic ductal adenocarcinoma

Locally advanced, unresectable pancreatic ductal adenocarcinoma has a poor prognosis with a median overall survival of 10-16 months. It is defined by tumor involvement of neighboring blood vessels that precludes resection. Standard doses of conventionally fractionated radiation have had little effect on overall survival in this setting, although they are associated with improved progression-free survival and time off chemotherapy. Evolving radiotherapy techniques have allowed for higher, ablative doses of radiotherapy to target tumor while also respecting normal tissue constraints of neighboring radiosensitive structures in the gastrointestinal tract. Moreover, advancements in image guidance, organ motion management, and the use of adaptive planning have enabled safe delivery of higher, ablative doses of radiation. This has resulted in improved survival. This review will summarize the expanding role of radiotherapy in the management of locally advanced, unresectable pancreatic cancer.     

Management of unresectable,locally advanced pancreatic adenocarcinoma

The diagnosis of unresectable locally advanced pancreatic adenocarcinoma (LAPC) requires confirmation, through imaging tests, of the unfeasibility of achieving a complete surgical resection, in the absence of metastatic spread. The increase in overall survival (OS), together with an appropriate symptom management is the therapeutic target in LAPC, maintaining an acceptable quality of life and, if possible, increasing the time until the appearance of metastasis. Chemoradiation (CRT) improves OS compared to best support treatment or radiotherapy (RT) but with greater toxicity. No significant increase in OS has been achieved with CRT when compared to chemotherapy (QT) alone in patients without disease progression after four months of treatment with QT. However, a significantly better local control, that is, a significant increase in the time to disease progression was associated with this approach. The greater effectiveness of the schemes FOLFIRINOX and gemcitabine (Gem) + Nab-paclitaxel compared to gemcitabine alone, has been extrapolated from metastatic disease to LAPC, representing a possible alternative for patients with good performance status (ECOG 0–1). In the absence of randomized clinical trials, Gem is the standard treatment in LAPC. If disease control is achieved after 4–6 cycles of QT, the use of CRT for consolidation can be considered an option vs QT treatment maintenance. Capecitabine has a better toxicity profile and effectiveness compared to gemcitabine as a radiosensitizer. After local progression, and without evidence of metastases, treatment with RT or CRT, in selected patients, can support to maintain the regional disease control.     

Hormones and radiation therapy in locally advanced adenocarcinoma of the prostate

Hormonal dependency of prostate cancer was first described in 1895 by White who showed the initial observation between castration and the treatment of prostatic disease in men with bladder outlet obstruction secondary to benign prostatic hypertrophy. Subsequently, in 1940 Huggins and Hodges demonstrated the association between normal and hyperplastic epithelium of canine prostate glands and adequate levels of circulating androgens. This pioneering work led extensive investigation of the role of androgens in both prostatic growth for benign and malignant disease. The goal of this article is to review the role of hormonal manipulation in prostate cancer in general and more specifically to focus on the role of radiation therapy and hormonal manipulation in locally advanced adenocarcinoma of the prostate. The article is divided into sections that outline the role of different types of hormonal manipulation that are currently available along with the early work combining hormonal manipulation and radiation therapy for prostate cancer. Subsequently, a thorough review of the phase III trials performed to evaluate the potential role of hormonal manipulation in addition to radiation therapy in locally advanced adenocarcinoma of the prostate. Included in that discussion is a section on the potential toxicities of hormonal manipulation. Finally, the current recommendations for the use of hormonal manipulation combined with radiation therapy in locally advanced adenocarcinoma of the prostate is described.     

Patient preferences for palliative treatment of locally advanced or metastatic gastric cancer and adenocarcinoma of the gastroesophageal junction: a choice-based conjoint analysis study from Germany

Background

Decisions on palliative chemotherapy (CT) for locally advanced or metastatic gastric cancer (mGC) require trade-offs between potential benefits and risks for patients. Healthcare providers and payers agree that patient-preferences should be considered. We conducted a choice-based conjoint (CBC) analysis study in pre-treated patients from Germany with mGC or locally advanced or metastatic adenocarcinoma of the gastroesophageal junction (mGEJ-Ca), to evaluate their preferences when hypothetically selecting a CT regimen.

Methods

German oncologists and gastroenterologists were contacted to identify patients with mGC or mGEJ-Ca who had completed ≥2 cycles of palliative CT in first or later lines of therapy (CT ongoing or complete). The primary objective was to quantify patient preferences for palliative CT by CBC analysis. Six in-depth qualitative interviews identified 3 attributes: treatment tolerability, quality of life in terms of ability of self-care, and additional survival benefit. The CBC matrix was constructed with 4 factor levels per attribute and each participant was presented with 15 different iterations of these levels. A minimum of 50 participants was needed. Consenting patients completed the CBC survey, choosing systematically among profiles. CBC models were estimated by multinomial logistic regression (MLR) and hierarchical Bayesian (HB) analysis. Estimates of importance for each attribute and factor-level were calculated.

Results

Fifty-five patients participated in the CBC survey (78.2% male, median age 63 years, 81.8% currently receiving CT). Across this sample, low treatment toxicity was ranked highest (44.6% relative importance, MLR analysis), followed by ability to self-care (32.3%), and an additional survival benefit of up to 3 months (3 months 23.1%, 2 months 18.3%, 1 month 11.2%). The MLR analysis showed high validity (certainty 37.9%, chi square p?<?0.01, root-likelihood 0.505). The HB analysis yielded similar results.

Conclusions

Patients’ preferences related to a new hypothetical palliative CT of mGC or mGEJ-Ca can be assessed by CBCanalysis. Although in real-life, patients initially need to decide on CT before they have any experience, and patients’ varied experiences with CT will have impacted specific responses, low toxicity and self-care ability were considered as most important by this group of patients with mGC or mGEJ-Ca.

     

Prolonged neoadjuvant treatment in locally advanced tumours: A novel concept based on biological considerations

Background: Neoadjuvant chemotherapy is increasingly applied in patients with locally advanced cancers of many tumour types. Usually three cycles of chemotherapy are administered to reduce the tumour size prior to local therapy, and another three cycles thereafter. The chemotherapy certainly contributes to the improved outcome of this approach. However, biological factors within the primary tumour have been neglected, while they might also contribute to the eradication of micrometastases. We believe that the neoadjuvant strategy can be improved by optimally exploiting certain biological factors inherent to the primary tumour. In a group of patients with locally advanced breast cancer (LABC) we studied this concept. Recently we described the clinical results of this phase II study in patients with LABC treated with neoadjuvant chemotherapy plus granulocyte-macrophage colony-stimulating factor (GM-CSF). A remarkable good response and survival was seen. In contrast to other studies we applied six cycles of neoadjuvant treatment in stead of a sandwich approach consisting of three cycles before and three cycles after local therapy, leaving the primary tumour and draining lymph nodes in situ for a prolonged period. In addition, GM-CSF was administered as a haematopoietic growth factor in stead of granulocyte colony-stimulating factor (G-CSF) as GM-CSF has also immuno-stimulating properties. Our findings definitely warrant further exploration of prolonged neoadjuvant systemic treatment in combination with GM-CSF in other high risk primary tumours.Hypotheses: The promising results of our study may be attributable to two potential biological phenomena. Firstly, the conservation of the tumour and its draining lymph nodes may prove to be an essential part of this approach, with particular emphasis on the activation of tumour specific cytotoxic T cells. Secondly, circulating angiogenesis inhibitors originating from the primary tumour may enhance the effect of chemotherapy on micrometastases.     

Non-infusional 5-fluorouracil, doxorubicin and cisplatin in the treatment of locally advanced or metastatic gastro-oesophageal adenocarcinoma

To reduce the Hickman line-associated morbidity of continuous infusion 5-fluorouracil combined with epirubicin and cisplatin (ECF) and to investigate the need for infusional regimens, we conducted a retrospective study in patients with advanced gastro-oesophageal adenocarcinoma. Thirty-six patients, with histologically proven irresectable gastro-oesophageal adenocarcinoma were given: 60 mg/m 2 cisplatin on day 1, 35 mg/m 2 doxorubicin on day 1 and 500 mg/m 2 5-fluorouracil on days 1 and 8 (NIACF) every 3-weeks. A median of 3 cycles was administered. The principal toxicity was myelosuppression with grade III/IV neutropenia in 47% of cycles. Neutropenic fever occurred in 5% of the cycles; non-haematological toxicity was mild and there were no treatment-related deaths. Administered dose intensity was 96.1% for doxorubicin, 93.6% for cisplatin and 90.5% for 5-fluorouracil. There were 16 partial responses and 1 complete response (overall response rate 47%, 95% confidence interval CI 31-63%); 8 patients had stable disease. Median progression-free and overall survival rates were 5 months (95% CI 4-6) and 8 months (95% CI 6-10), respectively. NIACF is a well-tolerated regimen in advanced gastro-oesophageal adenocarcinoma that precludes the need for central venous access, with activity similar to that observed with ECF.     

The role of palliative radiation therapy in symptomatic locally advanced gastric cancer

PURPOSE: To review the outcome of palliative radiotherapy (RT) alone in patients with symptomatic locally advanced or recurrent gastric cancer. METHODS AND MATERIALS: Patients with symptomatic locally advanced or recurrent gastric cancer who were managed palliatively with RT at The Cancer Institute, Singapore were retrospectively reviewed. Study end points included symptom response, median survival, and treatment toxicity (retrospectively scored using the Common Toxicity Criteria v3.0 [CTC]). RESULTS: Between November 1999 and December 2004, 33 patients with locally advanced or recurrent gastric cancer were managed with palliative intent using RT alone. Median age was 76 years (range, 38-90 years). Twenty-one (64%) patients had known distant metastatic disease at time of treatment. Key index symptoms were bleeding (24 patients), obstruction (8 patients), and pain (8 patients). The majority of patients received 30 Gy/10 fractions (17 patients). Dose fractionation regimen ranged from an 8-Gy single fraction to 40 Gy in 16 fractions. Median survival was 145 days, actuarial 12-month survival 8%. A total of 54.3% of patients (13/24) with bleeding responded (median duration of response of 140 days), 25% of patients (2/8) with obstruction responded (median duration of response of 102 days), and 25% of patients (2/8) with pain responded (median duration of response of 105 days). No obvious dose-response was evident. One Grade 3 CTC equivalent toxicity was recorded. CONCLUSION: External beam RT alone is an effective and well tolerated modality in the local palliation of gastric cancer, with palliation lasting the majority of patients' lives.     

Adjuvant chemoradiotherapy with or without intraoperative radiotherapy for the treatment of resectable locally advanced gastric adenocarcinoma

Purpose

To document the long-term efficacy of intraoperative electron radiotherapy (IOERT) followed by concurrent chemotherapy and external-beam radiotherapy (EBRT) in the management of locally advanced gastric cancer.

Materials and methods

A total of 97 consecutive patients with T3/4 or N+ gastric adenocarcinoma were enrolled. Fifty-one patients received adjuvant chemoradiotherapy (EBRT group) and 46 received IOERT (dose range, 12-15 Gy) followed by chemoradiotherapy (EBRT + IOERT group).

Results

The 5-year locoregional control rates were 50% and 35% in the two groups with or without IOERT, respectively (p = 0.04). Two patients had recurrence within the IOERT field in the EBRT + IOERT group and 14 patients recurred in the same area in the EBRT group (p = 0.02). Multivariate analyses revealed that adjuvant IOERT was an independent prognosticator for both local-regional control (p = 0.02) and disease-free survival (p = 0.05). G3/4 late toxicity was observed in 5 patients in the EBRT + IOERT group, but none in the EBRT group (p = 0.02).

Conclusions

Higher radiation dose may contribute to the improvement of local control, especially in the field encompassed by IOERT. The addition of IOERT to surgery and adjuvant chemoradiation deserves further investigation in a randomized trial.     

External beam radiotherapy plus single-fraction high dose rate brachytherapy in the treatment of locally advanced prostate cancer

Purpose

To evaluate the efficacy and toxicity of external beam radiation therapy (EBRT) plus high-dose-rate brachytherapy (HDRB) as a boost in patients (pts) with intermediate or high-risk prostate cancer.

Methods and materials

From 2002 to July 2012, 377 pts with a diagnosis of intermediate or high-risk prostate cancer were treated with EBRT plus HDRB. Median patient age was 66 years (range, 41–86). Most patients (347 pts; 92%) were classified as high-risk (stage T2c–T3, or PSA > 20 ng/mL, or GS ? 8), with 30 patients (8%) considered intermediate risk. All patients underwent EBRT at a prescribed dose of 60.0 Gy (range, 45–70 Gy) to the prostate and seminal vesicles. A total of 120 pts (31%) received a dose of 46 Gy (45–50 Gy) to the true pelvis. All pts received a single-fraction 9 Gy (9–15 Gy) HDR boost. Most patients (353; 94%) were prescribed complete androgen deprivation therapy (ADT). Overall survival (OS), cause-specific survival (CSS), and biochemical relapse-free survival (BRFS) rates were calculated. In the case of BRFS, patients with <26 months of follow-up (n = 106) were excluded to minimize the impact of ADT.

Results

The median follow-up for the entire sample was 50 months (range, 12–126), with 5-year actuarial OS and CSS, respectively, of 88% (95% confidence interval [CI]: 84–92) and 98% (95% CI: 97–99). The 5-year BRFS was 91% (95% CI: 87–95) in the 271 pts with ?26 months (median, 60 months) of follow-up. Late toxicity included grade 2 and 3 gastrointestinal toxicity in 17 (4.6%) and 6 pts (1.6%), respectively, as well as grades 2 and 3 genitourinary toxicity in 46 (12.2%) and 3 pts (0.8%), respectively.

Conclusion

These long-term outcomes confirm that EBRT plus a single-fraction HDRB boost provides good results in treatment-related toxicity and biochemical control. In addition to the excellent clinical results, this fractionation schedule reduces physician workload, treatment-related expenses, patient discomfort and risks associated with anaesthesia. We believe these findings support the use of single-fractionation boost techniques.