Aggressive Combined Modality Therapy Research Articles

A National Cancer Database analysis of treatment utilization and associated outcomes in elderly patients with locally advanced esophageal cancer.

138 Background: Elderly patients with locally advanced esophageal cancer pose a therapeutic challenge since definitive treatment involves aggressive combined-modality therapy. Whether these individuals are offered or benefit from these approaches in the modern, trimodality era has not been widely explored. Methods: Patients ≥ 70 years old with clinical stage II and III esophageal cancer diagnosed between 1998 and 2012 were identified from the National Cancer Database and stratified based on treatment. Variables independently associated with treatment utilization were evaluated using logistic regression and mortality hazard evaluated using Cox-proportional hazards analysis. The primary aim was to compare overall survival by treatment group. The secondary aim was to identify variables associated with receiving each modality. Results: A total of 21,593 patients were identified. Median and maximum ages were 77 and 90 respectively. In 12.9%, no therapy was delivered, 24.3% received palliative therapy, 37.1% received definitive chemoradiation, 5.6% received esophagectomy alone, and 10.0% received trimodality therapy. On multivariate analysis, age ≥ 80 (OR 0.73, p < 0.001), female gender (OR 0.81, p < 0.001), and treatment at high-volume centers (OR 0.83, p = 0.008) were associated with a decreased likelihood of palliative therapy over no treatment. Age ≥ 80 (OR 0.15, p < 0.001), female gender (OR 0.80, p = 0.03), and non-Caucasian race (OR 0.63, p < 0.001) were associated with decreased trimodality use compared to definitive chemoradiation. Each treatment independently demonstrated improved survival compared to no therapy: palliative treatment (HR 0.49), concurrent chemoradiation (HR 0.36), esophagectomy (HR 0.31), trimodality therapy (HR 0.25), all p < 0.001. Conclusions: Any therapy, including palliative care, was associated with improved survival compared to no treatment in elderly patients with esophageal cancer. Subsets of patients are less likely to receive aggressive therapy based on social and institutional factors. Care should be taken to not unnecessarily deprive elderly patients of treatment that may improve survival.

Impact of aggressive combined-modality primary therapy in anaplastic thyroid carcinoma (ATC): An updated single-institution experience.

e17042 Background: Historical outcomes in ATC have been highly discouraging. However, in response to aggressive first-line therapy combining intensity modulated radiation therapy (IMRT) and multiagent chemotherapy, we had previously observed apparently improved outcomes; we now update our experience. Methods: From January 1, 2003 to January 31, 2013 all newly diagnosed ATC patients seen at Mayo Clinic Rochester were offered aggressive therapy, individualized based upon patient conditions and preferences. Of 40 treated patients, 9 (22.5%), 20 (50%), and 11 (27.5%) had stage IVA, IVB, or IVC ATC respectively. Mean age was 66 years (range, 37-89); half were women. Twenty three patients underwent primary surgery [8 IVA (88.8%), 14 IVB (70%) and 1 IVC (9%)]. Complete (R0) resection was achieved in only 2 IVA (22.2%) and 3 IVB (15%) patients. Twenty-six patients (65%) received definitive intention chemo-radiation therapy: 8 IVA, 17 IVB, and 1 IVC, most receiving doxorubicin + docetaxel + IMRT. Results: Kaplan-Meier median and 1-year overall survival (OS) for the 40 patients combined were 10.1 months (95% CI: 3.9-55) and 48% - compared to 3 months and 20% observed among 134 analogous patients treated at our center over a preceding 50 year period. Median survival for stages IVA, IVB and IVC patients were 61.5 (95% CI: 55-67.9), 5.1 (95% CI: 3.5-22.1), and 2.8 months (95% CI: 0.8-29.6) respectively (p<0.001). One year OS was 100, 33 and 34% for stage IVA, IVB and IVC patients respectively. For IVA patients, Kaplan-Meier survival was 100% at 4 years. There were no treatment-related deaths. Stage at diagnosis, total doses and number of fractions of radiation therapy administered, and response to treatment were each significantly positively associated with OS by univariate analysis. Conclusions: Concordant with a practice change offering more aggressive combined-modality therapy, we observed improved outcomes in ATC. Further multi-center, randomized controlled trials are needed to define optimal treatments for this rare cancer, but continued efforts to pursue aggressive primary combined-modality therapeutic approaches in ATC appear justified.

Palliative Hypofractionated Radiotherapy For Non-Small Cell Lung Cancer (NSCLC) Patients Previously Treated By Induction Chemotherapy: Is It For Many, Some, All, Or None?

pproximatelyis 30% of patients with non-smallpatients with adequate performance status, many disease that surgically unresectable (1). In current practice guidelines recommend that these patients be treated with a combination of chemotherapy and external beam irradiation (2). Over the last several years, the use of chemotherapy with radiation has been supported by several phase III multi-institutional randomized studies, with patients diagnosed with locally advanced NSCLC, having a better progression-free (PFS) and overall survival (OS) when treated with combination therapy than with radiation alone (3, 4). Despite improvements in outcome, results remain modest with aggressive combined modality therapy, with 2 and 5 year survivals in the range of 30% and 20%, respectively (4, 5). In addition, these combined modality approaches are associated with significant toxicity in a patient population that in many cases is already limited in terms of functional reserve before they even initiate definitive therapy. Despite curative efforts, many patients have disease progression or are overly symptomatic either from treatment or from their disease. It could be argued that for certain locally advanced patients, aggressive systemic and local treatment causes more harm than good.

Abstract 4855: Role of HDACi-induced autophagy in malignant peripheral nerve sheath tumors (MPNST)

Abstract Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors that remain incurable mainly due to their high metastatic potential. These biologically aggressive tumors account for 3-10% of soft tissue sarcoma (STS). Roughly 50-60% of MPNSTs develop within the background of an inherited disease known as neurofibromatosis type-1 (NF1), while the rest develop sporadically. Despite aggressive combined modality therapy, the 5 year survival rates range from 35% to 50%. Thus, the understanding of MPNST resistance and development of a more efficient and targeted therapeutic approachs is essential to improve the otherwise dismal prognosis for these patients. Histone deacetylase inhibitors (HDACi) are novel compounds with efficacious in vitro and in vivo anti-tumor effects in a variety of tumor types including STS. Human MPNST cells treated with HDACi exhibit significant growth arrest. However, no apoptosis is observed but rather a dramatic induction of autophagy as assayed by multiple approaches. Whether drug-induced autophagy's role is to protect or kill the cells remains to be determined. Autophagy blockade via siRNA (Beclin 1 and Atg 5) or pharmacological manipulation with bafilomycin A1 and chloroquine significantly enhances HDACi pro-apoptotic effects. Furthermore, in vivo studies revealed that single agent HDACi or chloroquine alone had a modest effect on tumor growth, whereas combined treatment resulted in marked growth inhibition. These findings suggest that autophagy may mediate a potential protective response in MPNST and strongly support further study of combined HDACi with autophagy blockers as a novel therapeutic approach for MPNST. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4855.

Aggressive Combined Modality Therapy for Recurrent Colorectal Cancer Involving the Duodenum and Pancreas: A Report of 5 Cases

We report 5 cases in which the recurrence of colorectal cancer (CRC) presented as a mass involving the duodenum and pancreas. The treatment approach for such recurrences is not standardized, and in particular, the benefits of pancreaticoduodenectomy for such cases are not known. We describe the successful use of aggressive multimodality treatment with chemotherapy, radiation, and en bloc surgical resection. Such trimodality therapy can result in durable palliation of symptoms and long-term survival for patients with recurrent CRC involving the duodenum and pancreas, even when other metastases are present.

Expanded Criteria for Surgery for Liver Metastases: Thoughtful Science or Diamond Mining?

Expanded Criteria for Surgery for Liver Metastases: Thoughtful Science or Diamond Mining?

Patterns of failure in supratentorial primitive neuroectodermal tumors treated in Children's Cancer Group Study 921, a phase III combined modality study

Purpose To analyze the patterns of failure in patients with supratentorial primitive neuroectodermal tumors (ST-PNETs) treated with combined modality therapy in a large, randomized, multi-institutional study. Methods and materials A total of 44 prospectively staged patients with ST-PNET confirmed by central pathology review were treated in the Children's Cancer Group Study 921, which compared two chemoradiotherapy regimens. The patterns of initial sites of failure were analyzed. These were compared with the failure patterns of 188 children with posterior fossa (PF) PNETs treated in the same protocol. Results The major determinant for progression-free survival was the initial metastatic stage. The 3-year progression-free survival for M0 patients was 53% ± 8.5% compared with 14% ± 9.4% for M+ patients. The cumulative 5-year relapse incidence was 71.4% ± 21% for M+ patients compared with 47.5% ± 8.6% for M0 patients. The overall failure rate for both M0 and M+ ST-PNETs was greater than that for PF-PNETs (47.5% ± 8.6% vs. 29.3% ± 4.7% for M0 and 71.4% ± 21% vs. 48.4% ± 5.5% for M+). Failure at the primary site, either as the sole site or as a component of initial failure, was also seen more frequently in ST-PNETs than in PF-PNETs. For M0 patients, the 5-year local failure rate as a component of initial failure was 42.0% ± 8.5% for ST-PNETs compared with 17.7% ± 3.9% for PF-PNETs. For patients with primary tumors either in the ST or PF, the 5-year spinal axis failure rate as a component of initial failure was not significantly different statistically when compared by M stage. For M+ patients, the 5-year spinal axis failure rate as a component of initial failure was 42.9% ± 22.8% for ST-PNETs and 34.6% ± 5.2% for PF-PNETs. Conclusion Despite aggressive combined modality therapy, ST-PNETs had high rates of failure, with M+ patients faring especially poorly. Both local and spinal failure rates remained high, indicating the need to maximize both local and regional/systemic therapies. Overall, these patients fared worse than those with high-risk PF-PNETs in terms of progression-free survival and failure rates.

Survival following intensive preoperative combined modality therapy with paclitaxel, cisplatin, 5-fluorouracil, and radiation in resectable esophageal carcinoma: A phase I report

Purpose To assess the benefits of aggressive chemoradiation therapy followed by surgery in resectable esophageal carcinoma. Method Twenty-nine patients with resectable carcinoma were treated with 60 Gy of radiation (2 Gy daily for 6 weeks) and concurrent chemotherapy consisting of continuous infusion of 5-fluorouracil (200-225 mg/m 2/d), paclitaxel (25, 40, 50, or 60 mg/m 2) weekly over 1 hour, and cisplatin (25 mg/m 2) weekly immediately following paclitaxel throughout radiation. Patients received either 4 cycles of postoperative paclitaxel 175 mg/m 2 over 3 hours and cisplatin 75 mg/m 2 every 3 weeks or paclitaxel 175 mg/m 2 over 3 hours and cisplatin 75 mg/m 2 every 3 weeks prior to the initiation of chemoradiation. After induction therapy and restaging, esophagectomy was performed 4 to 6 weeks later. Results Twenty-seven patients were eligible for study (26 men, 23 with adenocarcinoma). Median age was 58 years (range 30-73). The maximum tolerated dose combination was paclitaxel 50 mg/m 2 over 1 hour weekly, cisplatin 25 mg/m 2 over 1 hour weekly, 5-fluorouracil 200 mg/m 2/d by continuous infusion throughout radiotherapy and radiation to 60 Gy. Twenty-two patients completed therapy and underwent surgical resection. Four patients had complete pathological responses and 18 had partial responses with no mortality. The commonest dose-limiting toxicity was mucositis and esophagitis (n = 7). Median follow-up of 27 patients was 150 weeks (range 7-303). At 2-year follow-up 16/27 (59%) were alive and 15/27 (56%) were free of disease. At 4-year follow-up 12/27 (44%) were alive and free of disease. Median follow-up of 22 patients undergoing esophagectomy was 205 weeks (range 26-303). At 4-year follow-up 10/22 (45%) were alive and free of disease. For the 18 patients treated at or above the maximum tolerated dose, median follow-up was 151 weeks (range 35-206) and at 3-year follow-up 9/18 (50%) were alive and free of disease. Conclusion Aggressive combined modality therapy of esophageal carcinoma was associated with excellent long-term survival in this phase I trial.

P-585 Long-term results of aggressive combined modality therapy employing induction and concurrent carboplatin/paclitaxel with dose-escalated thoracic conformal radiation therapy

P-585 Long-term results of aggressive combined modality therapy employing induction and concurrent carboplatin/paclitaxel with dose-escalated thoracic conformal radiation therapy

Intraoperative electron radiotherapy as a component of salvage therapy for patients with colorectal cancer and advanced nodal metastases

Purpose To define the survival rates and relapse patterns in patients with isolated advanced nodal metastases secondary to colorectal cancer, treated with curative intent using aggressive combined-modality treatment. Methods and materials Forty-eight patients with isolated advanced lymph node metastases secondary to colorectal cancer received intraoperative radiotherapy as part of curative-intent treatment. Forty-seven patients also received external beam radiotherapy (EBRT). Chemotherapy was delivered concomitantly with EBRT in 35 patients. The median intraoperative radiotherapy dose was 1250 cGy. End points included local failure within the EBRT field, central failure within the intraoperative radiotherapy field, distant metastases, survival, and toxicity. Results The median survival time and 5-year survival rate were 35 months and 34%, respectively. At 3 years, the local control and central control rates were 81% and 93%, respectively. Macroscopically complete resection and colonic primary site were predictors of survival and disease control. The median survival time and 5-year survival rate in patients with colonic primary sites and macroscopically complete resection were 53 months and 49%, respectively. Intraoperative radiotherapy–related neuropathy occurred in 3 patients and ureteral fibrosis in 1. Conclusion With aggressive combined-modality therapy that includes intraoperative radiotherapy, long-term survival is achievable in colorectal cancer patients presenting with nodal relapse or advanced nodal disease. Survival and disease control rates are highest in those without gross residual disease.

Intraoperative irradiation for locally recurrent colorectal cancer in previously irradiated patients

Purpose: Information in the literature regarding salvage treatment for patients with locally recurrent colorectal cancer who have previously been treated with high or moderate dose external beam irradiation (EBRT) is scarce. A retrospective review was therefore performed in our institution to determine disease control, survival, and tolerance in patients treated aggressively with surgical resection and intraoperative electron irradiation (IOERT) ± additional EBRT and chemotherapy. Methods and Materials: From 1981 through 1994, 51 previously irradiated patients with recurrent locally advanced colorectal cancer without evidence of distant metastatic disease were treated at Mayo Clinic Rochester with surgical resection and IOERT ± additional EBRT. An attempt was made to achieve a gross total resection before IOERT if it could be safely accomplished. The median IOERT dose was 20 Gy (range, 10–30 Gy). Thirty-seven patients received additional EBRT either pre- or postoperatively with doses ranging from 5 to 50.4 Gy (median 25.2 Gy). Twenty patients received 5-fluorouracil ± leucovorin during EBRT. Three patients received additional cycles of 5-fluorouracil ± leucovorin as maintenance chemotherapy. Results: Thirty males and 21 females with a median age of 55 years (range 31–73 years) were treated. Thirty-four patients have died; the median follow-up in surviving patients is 21 months. The median, 2-yr, and 5-yr actuarial overall survivals are 23 months, 48% and 12%, respectively. The 2-yr actuarial central control (within IOERT field) is 72%. Local control at 2 years has been maintained in 60% of patients. There is a trend toward improved local control in patients who received ≥30 Gy EBRT in addition to IOERT as compared to those who received no EBRT or <30 Gy with 2-yr local control rates of 81% vs. 54%. Distant metastatic disease has developed in 25 patients, and the actuarial rate of distant progression at 2 and 4 years is 56% and 76%, respectively. Peripheral neuropathy was the main IOERT-related toxicity; 16 (32%) patients developed neuropathies (7 mild, 5 moderate, 4 severe). Ureteral narrowing or obstruction occurred in seven patients. All but one patient with neuropathy or ureter fibrosis received IOERT doses ≥20 Gy. Conclusion: Long-term local control can be obtained in a substantial proportion of patients with aggressive combined modality therapy, but long-term survival is poor due to the high rate of distant metastasis. Re-irradiation with EBRT in addition to IOERT appears to improve local control. Strategies to improve survival in these poor-risk patients may include the more routine use of conventional systemic chemotherapy or the addition of novel systemic therapies.

Tissue/dose compensation to reduce toxicity from combined radiation and chemotherapy for advanced head and neck cancers.

This study was undertaken to quantify the reduction in normal tissue complications resulting from the aggressive management of advanced head and neck cancers (AHNCs) utilizing tissue/dose compensation (TDC). Thirty-nine patients with AHNC were treated on an intensive chemotherapy + radiation regimen. Eighteen of 39 patients were treated using TDC; the remaining 21 patients were radiated without TDC (NTDC). Acute and chronic toxicities, swallowing, speech function, and quality of life were assessed. The TDC group had a smaller radiation dose gradient across the entire treatment volume. Unscheduled treatment breaks were required in 11% of TDC patients as compared with 43% of the NTDC group (P = 0.04). The TDC group had fewer Grade 3 or 4 acute and chronic toxicities and lower SOMA scores. At 3 months posttreatment, patients in the TDC group had better oral intake, lower pharyngeal residue, and better oropharyngeal swallowing efficiency and were able to swallow more bolus types. Patients in the TDC group also had better articulation. Use of TDC resulted in reduced treatment-related interruptions, decreased acute and chronic toxicities, and better speech and swallowing functions. Techniques to improve radiation dose conformality around the target tissues while decreasing the radiation dose to the normal tissues should be an integral part of aggressive combined modality therapy.

Positron emission tomography with f18-fluorodeoxyglucose in the staging and preoperative evaluation of malignant pleural mesothelioma

Objectives: The purpose of this study was to evaluate the utility of positron emission tomography with F18-fluorodeoxyglucose in the preoperative evaluation and staging of malignant mesothelioma in patients who were candidates for aggressive combined modality therapy. Methods: Eighteen consecutive patients with biopsy-proven malignant mesothelioma underwent positron emission tomographic scanning. The results of positron emission tomographic imaging were compared with results obtained by computed tomography, mediastinoscopy, thoracoscopy, and pathologic examination of surgical specimens. All patients fasted and received an average of 14.5 ± 2.7 mCi of F18-fluorodeoxyglucose for positron emission tomographic scanning. Attenuation-corrected whole-body and regional emission images of the chest and upper abdomen were acquired and formatted into transaxial, coronal, and sagittal images. Results: All primary malignant mesotheliomas accumulated F18-fluorodeoxyglucose, and the mean standardized uptake value was 7.6 (range, 3.33-14.85; n = 9). There were no false-negative results of positron emission tomography. Identification of occult extrathoracic metastases by positron emission tomography was the basis for excluding two patients from surgical therapy. There were two false-positive results of positron emission tomography: increased F18-fluorodeoxyglucose uptake in the contralateral chest that was negative by thoracoscopic biopsy (n = 1) and increased abdominal F18-fluorodeoxyglucose uptake after partial colectomy for diverticular disease (n = 1). Conclusions: Positron emission tomography can identify malignant pleural mesothelioma and appears to be a useful noninvasive staging modality for patients being considered for aggressive combined modality therapy. (J Thorac Cardiovasc Surg 2000;120:128-33)

Bcl-xL and Bcl-2 expression in squamous cell carcinoma of the head and neck

Inhibition of apoptosis, or programmed cell death, may be critical both in the development of cancer and in determining response to therapy. The authors examined the expression of two related apoptotic inhibitors, Bcl-2 and Bcl-xL, in pretreatment biopsies from a series of 42 patients with squamous cell carcinoma of the head and neck. The observed pattern of apoptotic inhibitor expression was compared with that of the p53 gene product, another factor implicated in carcinogenesis and therapeutic responsiveness. Formalin fixed, paraffin embedded tumor biopsies from 42 patients with locally advanced squamous cell carcinoma of the head and neck were analyzed by immunohistochemistry using antibodies specific for Bcl-xL, Bcl-2, and p53. Measures of clinical outcome, including disease specific survival and overall survival, were compared among the groups. The majority of the tumors demonstrated enhanced expression of either Bcl-2 or Bcl-xL compared with surrounding normal epithelium. Fifty-two percent of the tumors had up-regulated Bcl-xL, and 17% had up-regulated Bcl-2. There was no overlap between these groups. Expression of Bcl-2, but not Bcl-xL, was correlated with improved disease specific survival. Immunohistochemically detectable p53 expression (48% of tumors) was not found to correlate with expression of either Bcl-xL or Bcl-2 and, in this series, was not a predictor of clinical outcome. These results suggest that disruption of apoptotic control pathways is an important event in the evolution of squamous cell carcinoma of the head and neck. A common mechanism for this disruption involves overexpression of Bcl-xL, Patients whose tumors demonstrate Bcl-2 positivity, even with locoregionally advanced disease, appear to have a high likelihood of cure with aggressive combined modality therapy and may be treated successfully with less toxic therapy.

Treatment Toxicities in Long-Term Survivors of Limited Small Cell Lung Cancer

A total of 211 patients with limited small cell lung cancer were assessed retrospectively for long-term toxicities, treatment-related deaths, and second primaries. All had received treatment with various combinations of doxorubicin, vincristine, cisplatin, lomustine, cyclophosphamide, and etoposide with or without split-course thoracic radiotherapy (4,000 cGy/10 fractions) and/or split-course prophylactic cranial irradiation (3,600 cGy/10 fractions). Sixty-eight (32%) of the patients survived longer than 1.5 years and formed the basis of this study. Debilitating pulmonary, cardiac, and neurologic toxicity was noted in 12%, 14%, and 15%, respectively, of long-term survivors. These complications were the result of aggressive combined modality therapy. Certain drugs appeared to cause additive toxicity when combined with radiation. Three patients developed new primary tumors of squamous cell origin. Attention must be directed to defining the safest way to employ aggressive combined modality treatment for these patients.

Inflammatory breast cancer: advances in therapy.

Inflammatory breast cancer is the most aggressive breast neoplasm and one of the most ominous solid tumors. Because of distinct clinical characteristics, diagnosis can usually be made on clinical grounds. Biopsy including the overlying skin may demonstrate dermal lymphatic invasion, although the absence of dermal lymphatic invasions should not deter aggressive therapy. Surgery or irradiation alone has little effect on the natural history of this disease since lymphatic invasion and distant metastases are often present at presentation. Inflammatory breast cancer should be considered a systemic disease. Accordingly, aggressive combined modality therapy including multi-drug chemotherapy, surgery, and irradiation have prolonged disease-free survival and overall survival.

Radiation and chemical injury in the bone marrow.

Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the known drug-x-ray interactions using tissue culture systems are extended to the bone marrow compartment. Two hypotheses prevail for late bone marrow failure: (1) stromal damage to the vasculature with subsequent fibrosis and (2) irreversible stem cell depletion in the irradiated site. Clinical extensions of the experimental data for bone marrow kinetics in the animal model have not proven successful to date. The future strategies for therapy of malignancies in which both radiation and chemotherapy are employed may require dose modification or treatment planning to limit bone marrow toxicity.

Radiation and Chemical Injury in the Bone Marrow

Hematopoietic system toxicity is a major limiting factor in the use of aggressive combined modality therapy in the treatment of malignant disease. In this review, the known drug-x-ray interactions using tissue culture systems are extended to the bone marrow compartment. Two hypotheses prevail for late bone marrow failure: (1) stromal damage to the vasculature with subsequent fibrosis and (2) irreversible stem cell depletion in the irradiated site. Clinical extensions of the experimental data for bone marrow kinetics in the animal model have not proven successful to date. The future strategies for therapy of malignancies in which both radiation and chemotherapy are employed may require dose modification or treatment planning to limit bone marrow toxicity.