A Phase II Trial of Cetuximab, Gemcitabine, 5-Fluorouracil, and Radiation Therapy in Locally Advanced Nonmetastatic Pancreatic Adenocarcinoma.

BACKGROUND: Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. A minority of patients present with localized disease and surgical resection still offers patients the only hope for long-term survival. Locally advanced pancreatic cancer is defined as surgically unresectable, but has no evidence of distant metastases. The purpose of this study is to evaluate the efficacy and safety of cetuximab in combination with gemcitabine and 5-FU along with radiation therapy in locally advanced non-resectable, pancreatic adenocarcinoma, using progression free survival as the primary end point. METHODS: This was a prospective, single arm, open label pilot phase II study to evaluate the anti-tumor activity of gemcitabine (200 mg/m(2) per week) and cetuximab (250 mg/m(2) per week after an initial 400 mg/m(2) loading dose) with continuous infusion 5-FU (800 mg/m(2) over 96 hours) and daily concurrent external beam radiation therapy (50.4 Gy total dose) for six weeks (cycle 1) in patients with non-metastatic, locally advanced pancreatic adenocarcinoma. Following neoadjuvant treatment, subjects were re-evaluated for response and surgical candidacy with restaging scans. After resection, or also if not resected; subjects received further therapy with four 28-day cycles (cycles 2-5) of weekly gemcitabine (1000 mg/m(2)) and cetuximab (250 mg/m(2)) on days 1, 8, and 15. RESULTS: Between 2006 and 2011, twenty-six patients were screened and eleven of them were enrolled in the study. Most common reasons for screen failures were having resectable disease, metastatic disease or co-morbidity. Ten patients were able to tolerate and complete cycle 1 of chemoradiotherapy. One patient stopped the study prematurely due to grade III diarrhea. All except this one patient received planned radiation therapy. The response evaluation after cycle 1 showed one Partial Response, eight Stable Disease and two Progressive Disease. Four patients subsequently underwent surgical resection of the tumor. All patients had R0 resections. There was one preoperative mortality due to multiple organ failure. Median progression free survival (PFS) for four resected patients was 9.0 months while for unresected patients median PFS was 7.1 months. Median overall survival (OS) for four resected patients was 47.4 months and for unresected patients median OS was 17.0 months. Most common adverse events were hematologic (27%). Only two patients developed grade 3 neutropenia. Most common treatment related non-hematologic adverse events were diarrhea (10 of 11), nausea (8 of 11) and skin rash (10 of 11 patients). Only 9.5% of all reported non-hematologic adverse events were grade 3 or higher. CONCLUSIONS: The combination of cetuximab, weekly gemcitabine and continuous infusion of 5-FU with radiotherapy was quite well tolerated with intriguing clinical benefit and survival results in carefully selected patients with locally advanced pancreatic adenocarcinoma. A trial with larger sample size will be necessary to confirm these results.

Volume Modulated Arc Therapy (VMAT) for pulmonary Stereotactic Body Radiotherapy (SBRT) in patients with lesions in close approximation to the chest wall.

PURPOSE: Chest wall pain and discomfort has been recognized as a significant late effect of radiation therapy in historical and modern treatment models. Stereotactic Body Radiotherapy (SBRT) is becoming an important treatment tool in oncology care for patients with intrathoracic lesions. For lesions in close approximation to the chest wall with motion management, SBRT techniques can deliver high dose to the chest wall. As an unintended target of consequence, there is possibility of imposing significant chest wall pain and discomfort as a late effect of therapy. The purpose of this paper is to evaluate the potential role of Volume Modulated Arc Therapy (VMAT) technologies in decreasing chest wall dose in SBRT treatment of pulmonary lesions in close approximation to the chest wall. MATERIALS AND METHODS: Ten patients with pulmonary lesions of various sizes and tomography in close approximation to the chest wall were selected for retrospective review. All volumes including tumor target, chest wall, ribs, and lung were contoured with maximal intensity projection maps and four-dimensional computer tomography planning. Radiation therapy planning consisted of static techniques including Intensity Modulated Radiation Therapy compared to VMAT therapy to a dose of 60 Gy in 12 Gy fraction dose. Dose volume histogram to rib, chest wall, and lung were compared between plans with statistical analysis. RESULTS: In all patients, dose and volume were improved to ribs and chest wall using VMAT technologies compared to static field techniques. On average, volume receiving 30 Gy to the chest wall was improved by 74%; the ribs by 60%. In only one patient did the VMAT treatment technique increase pulmonary volume receiving 20 Gy (V20). CONCLUSIONS: VMAT technology has potential of limiting radiation dose to sensitive chest wall regions in patients with lesions in close approximation to this structure. This would also have potential value to lesions treated with SBRT in other body regions where targets abut critical structures.

Primary mucosa-associated lymphoid tissue lymphoma of the salivary glands: a multicenter Rare Cancer Network study.

PURPOSE: Involvement of salivary glands with mucosa-associated lymphoid tissue (MALT) lymphoma is rare. This retrospective study was performed to assess the clinical profile, treatment outcome, and prognostic factors of MALT lymphoma of the salivary glands. METHODS AND MATERIALS: Thirteen member centers of the Rare Cancer Network from 10 countries participated, providing data on 63 patients. The median age was 58 years; 47 patients were female and 16 were male. The parotid glands were involved in 49 cases, submandibular in 15, and minor glands in 3. Multiple glands were involved in 9 patients. Staging was as follows: IE in 34, IIE in 12, IIIE in 2, and IV in 15 patients. RESULTS: Surgery (S) alone was performed in 9, radiotherapy (RT) alone in 8, and chemotherapy (CT) alone in 4 patients. Forty-one patients received combined modality treatment (S + RT in 23, S + CT in 8, RT + CT in 4, and all three modalities in 6 patients). No active treatment was given in one case. After initial treatment there was no tumor in 57 patients and residual tumor in 5. Tumor progression was observed in 23 (36.5%) (local in 1, other salivary glands in 10, lymph nodes in 11, and elsewhere in 6). Five patients died of disease progression and the other 5 of other causes. The 5-year disease-free survival, disease-specific survival, and overall survival were 54.4%, 93.2%, and 81.7%, respectively. Factors influencing disease-free survival were use of RT, stage, and residual tumor (p < 0.01). Factors influencing disease-specific survival were stage, recurrence, and residual tumor (p < 0.01). CONCLUSIONS: To our knowledge, this report represents the largest series of MALT lymphomas of the salivary glands published to date. This disease may involve all salivary glands either initially or subsequently in 30% of patients. Recurrences may occur in up to 35% of patients at 5 years; however, survival is not affected. Radiotherapy is the only treatment modality that improves disease-free survival.

Early-stage primary bone lymphoma: a retrospective, multicenter Rare Cancer Network (RCN) Study.

PURPOSE: Primary bone lymphoma (PBL) represents less than 1% of all malignant lymphomas. In this study, we assessed the disease profile, outcome, and prognostic factors in patients with Stages I and II PBL. PATIENTS AND METHODS: Thirteen Rare Cancer Network (RCN) institutions enrolled 116 consecutive patients with PBL treated between 1987 and 2008 in this study. Eighty-seven patients underwent chemoradiotherapy (CXRT) without (78) or with (9) surgery, 15 radiotherapy (RT) without (13) or with (2) surgery, and 14 chemotherapy (CXT) without (9) or with (5) surgery. Median RT dose was 40 Gy (range, 4-60). The median number of CXT cycles was six (range, 2-8). Median follow-up was 41 months (range, 6-242). RESULTS: The overall response rate at the end of treatment was 91% (complete response [CR] 74%, partial response [PR] 17%). Local recurrence or progression was observed in 12 (10%) patients and systemic recurrence in 17 (15%). The 5-year overall survival (OS), lymphoma-specific survival (LSS), and local control (LC) were 76%, 78%, and 92%, respectively. In univariate analyses (log-rank test), favorable prognostic factors for OS and LSS were International Prognostic Index (IPI) score ≤1 (p = 0.009), high-grade histology (p = 0.04), CXRT (p = 0.05), CXT (p = 0.0004), CR (p < 0.0001), and RT dose >40 Gy (p = 0.005). For LC, only CR and Stage I were favorable factors. In multivariate analysis, IPI score, RT dose, CR, and CXT were independently influencing the outcome (OS and LSS). CR was the only predicting factor for LC. CONCLUSION: This large multicenter retrospective study confirms the good prognosis of early-stage PBL treated with combined CXRT. An adequate dose of RT and complete CXT regime were associated with better outcome.

A neoadjuvant strategy for pancreatic adenocarcinoma increases the likelihood of receiving all components of care: lessons from a single-institution database.

BACKGROUND: Recent studies have shown adjuvant therapy improves outcomes from pancreatic cancer (PC). This study investigates receipt and timing of PC treatments, and association with outcomes. METHODS: The analysis cohort consisted of patients with newly-diagnosed PC at a single institution over 5 years. Primary Endpoints were (i) receipt of recommended therapy, and (ii) overall survival (OS). RESULTS: Among 102 patients, 52 underwent resection. Out of 36 localized resected and 16 locally advanced resected (LAR) patients, 26 and 13, respectively, received adjuvant therapy. Six of the latter group received neoadjuvant therapy. Median OS for resected patients was 15.7 months (range 0.6-51.4), compared with 7.7 for unresected patients (range 0.4-32.0) (P < 0.001), and 14.0 months for patients with resection alone (range 0.6-24.4) vs. 16.1 for patients who also received adjuvant therapy (range 3.2-51.4) (P= 0.027). Out of 46 patients undergoing up-front resection, 33 had R0 surgical margins. For the six LAR patients undergoing neoadjuvant therapy, all margins were R0. CONCLUSION: After resection, a substantial proportion of patients do not receive adjuvant therapy, and have worse survival. In this study, neoadjuvant treatment increased both the proportion of patients receiving all components of recommended therapy and the R0 resection rate.

A national propensity-adjusted analysis of adjuvant radiotherapy in the treatment of resected pancreatic adenocarcinoma.

BACKGROUND: The benefit of adjuvant radiotherapy (RT) for resected pancreatic adenocarcinoma remains controversial after randomized clinical trials. In this national-level US study, a propensity score (conditional probability of receiving RT) was used to adjust for potential confounding in nonrandomized designs from treatment group differences. METHODS: Patients were identified from the Surveillance, Epidemiology, and End Results (SEER) registry (1988-2005 dataset). Multivariate analyses to determine the effect of RT on overall survival were performed using propensity-adjusted Cox proportional hazards and Kaplan-Meier analyses. RESULTS: In total, 5676 patients with resected pancreatic adenocarcinoma were identified, and 40.8% of those patients had received adjuvant RT. Univariate predictors of survival included age, race, marital status, disease stage, tumor size, tumor extension, tumor grade, lymph node status, year of diagnosis, type of resection, and receipt of RT (all P < .002). In a Cox model, independent predictors of improved survival included white race, married status, earlier stage, smaller tumors, well differentiated tumors, negative lymph node (N0) status, recent diagnosis, and receipt of RT (all P < .05). In a propensity-adjusted proportional hazards regression, the benefit of adjuvant treatment that included RT remained significant after adjusting for the likelihood of receiving RT (hazard ratio, 0.773; 95% confidence interval, 0.714-0.836; P < .0001). Within all 5 propensity strata, Kaplan-Meier survival differed significantly (P < .0001 [lowest and highest probability strata] and P = .0165 [middle stratum with a "pseudorandom" probability of RT]). CONCLUSIONS: Adjuvant RT for resected pancreatic adenocarcinoma was associated with a significant survival advantage in a large national database, even after using propensity score methods to adjust for differences between treatment groups. The authors concluded that adjuvant RT should be considered for all appropriate patients who have resected pancreatic adenocarcinoma.

Initial experience with volumetric IMRT (RapidArc) for intracranial stereotactic radiosurgery.

PURPOSE: Initial experience with delivering frameless stereotactic radiotherapy (SRT) using volumetric intensity-modulated radiation therapy (IMRT) delivered with RapidArc is presented. METHODS AND MATERIALS: Treatment details for 12 patients (14 targets) with a mean clinical target volume (CTV) of 12.8 ± 4.0 cm(3) were examined. Dosimetric indices for conformality, homogeneity, and dose gradient were calculated and compared with published results for other frameless, intracranial SRT techniques, including CyberKnife, TomoTherapy, and static-beam IMRT. Statistics on setup and treatment times and per patient dose validations were examined. RESULTS: Dose indices compared favorably with other techniques. Mean conformality, gradient, and homogeneity index values were 1.10 ± 0.11, 64.9 ± 14.1, 1.083 ± 0.026, respectively. Median treatment times were 4.8 ± 1.7 min. CONCLUSION: SRT using volumetric IMRT is a viable alternative to other techniques and enables short treatment times. This is anticipated to have a positive impact on radiobiological effect and for facilitating wider use of SRT.

The results of surgery, with or without radiotherapy, for primary spinal myxopapillary ependymoma: a retrospective study from the rare cancer network.

PURPOSE: The aim of this study was to assess the outcome of patients with primary spinal myxopapillary ependymoma (MPE). MATERIALS AND METHODS: Data from a series of 85 (35 females, 50 males) patients with spinal MPE were collected in this retrospective multicenter study. Thirty-eight (45%) underwent surgery only and 47 (55%) received postoperative radiotherapy (RT). Median administered radiation dose was 50.4 Gy (range, 22.2-59.4). Median follow-up of the surviving patients was 60.0 months (range, 0.2-316.6). RESULTS: The 5-year progression-free survival (PFS) was 50.4% and 74.8% for surgery only and surgery with postoperative low- (<50.4 Gy) or high-dose (>or=50.4 Gy) RT, respectively. Treatment failure was observed in 24 (28%) patients. Fifteen patients presented treatment failure at the primary site only, whereas 2 and 1 patients presented with brain and distant spinal failure only. Three and 2 patients with local failure presented with concomitant spinal distant seeding and brain failure, respectively. One patient failed simultaneously in the brain and spine. Age greater than 36 years (p = 0.01), absence of neurologic symptoms at diagnosis (p = 0.01), tumor size >or=25 mm (p = 0.04), and postoperative high-dose RT (p = 0.05) were variables predictive of improved PFS on univariate analysis. In multivariate analysis, only postoperative high-dose RT was independent predictors of PFS (p = 0.04). CONCLUSIONS: The observed pattern of failure was mainly local, but one fifth of the patients presented with a concomitant spinal or brain component. Postoperative high-dose RT appears to significantly reduce the rate of tumor progression.

Phyllodes tumor of the breast.

PURPOSE: To better identify prognostic factors for local control and survival, as well as the role of different therapeutic options, for phyllodes tumors, a rare fibroepithelial neoplasm of the breast. METHODS AND MATERIALS: Data from 443 women treated between 1971 and 2003 were collected from the Rare Cancer Network. The median age was 40 years (range, 12-87 years). Tumors were benign in 284 cases (64%), borderline in 80 cases (18%), and malignant in 79 cases (18%). Surgery consisted of breast-conserving surgery (BCS) in 377 cases (85%) and total mastectomy (TM) in 66 cases (15%). Thirty-nine patients (9%) received adjuvant radiotherapy (RT). RESULTS: After a median follow-up of 106 months, local recurrence (LR) and distant metastases rates were 19% and 3.4%, respectively. In the malignant and borderline group (n = 159), RT significantly decreased LR (p = 0.02), and TM had better results than BCS (p = 0.0019). Multivariate analysis revealed benign histology, negative margins, and no residual disease (no RD) after initial treatment and RT delivery as independent favorable prognostic factors for local control; benign histology and low number of mitosis for disease-free survival; and pathologic tumor size < or = 3 cm and no tumor necrosis for overall survival. In the malignant and borderline subgroup multivariate analysis TM was the only favorable independent prognostic factor for disease-free survival. CONCLUSIONS: This study showed that phyllodes tumor patients with no RD after treatment have better local control. Benign tumors have a good prognosis after surgery alone. In borderline and malignant tumors, TM had better results than BCS. Thus, in these forms adjuvant RT should be considered according to histologic criteria.

Radiation therapy toxicity to the skin.

Radiation therapy has been integral to cancer patient care. The skin is an intentional and unintentional target of therapy, and is sensitive to the volume of normal tissue in the radiation therapy treatment field, daily treatment dose (fractionation), and total treatment dose. We must understand the relationship of these factors to patient outcome as we move toward hypofractionation treatment strategies (radiosurgery). Chemotherapy agents and prescription medications may influence therapy-associated sequelae. Understanding this may prevent significant injury and discomfort. This article reviews established platforms of radiation therapy and sequelae associated with skin therapy. Interactions with other agents and possible predisposition to sequelae are reviewed. Skin cancer resulting from treatment and disease processes associated with possible limited outcome are also reviewed.

Outcome and prognostic factors in breast sarcoma: a multicenter study from the rare cancer network.

BACKGROUND AND PURPOSE: Breast sarcoma (BS) is a rare tumour. While surgical resection is the primary treatment, the role of radiation therapy (RT) and chemotherapy remains unclear. This study aimed at defining prognostic factors and treatment strategies. MATERIALS AND METHODS: Data from 103 patients treated between 1976 and 2002 were collected. The median age was 55 years (range: 13-86); the median histological tumour size was 4.45 cm (range: 0.8-22). There were 42 angiosarcomas. Surgery consisted of wide excision in 34 cases, and total mastectomy in 69 cases. A total dose of 50 Gy in 25 fractions was delivered in 50 patients. At the completion of treatment, 89 patients had no residual tumour. RESULTS: After a median follow-up of 64 months, 56 patients developed recurrent disease: 38 presented a local relapse and 37 developed distant metastases. The 5-year disease-free survival (DFS) and overall survival (OS) were 44% (95% confidence interval [CI], 39-49%) and 55% (95% CI, 50-60%), respectively. In multivariate analysis, favourable prognostic factors for better local control were: no residual tumour after treatment, no cellular pleomorphism, and histology other than angiosarcoma. For DFS, the five favourable prognostic factors were non-menopausal status, no residual tumour after treatment, non-angiosarcoma histology, absence of tumour necrosis, and grade 1-2 histology. CONCLUSION: While angiosarcoma has the worst prognosis, the outcome of the other types of sarcomas may be worsened by residual tumour after loco-regional treatment and high grade histology, a classical prognostic factor of the other soft tissue sarcomas. During surgical procedure axillary dissection is not mandatory.

The effect of radiation therapy on normal tissue function.

As more patients are treated for their primary malignancy with cure or increased disease-free intervals, injury to normal tissues will become more detectable and an important endpoint for study. Future protocols will probably be modified based on toxicity endpoints. In Hodgkin's disease, current protocols use response-based treatment strategies to limit therapy. The objective is to provide the same level of tumor control and follow normal tissue endpoints for outcome analysis. DVH analysis has improved the ability to analyze endpoint data for normal tissues. These image-guided platforms will provide the infrastructure needed to continue efforts in improving the delivery of radiation therapy.

Outcomes and patterns of failure in solitary plasmacytoma: a multicenter Rare Cancer Network study of 258 patients.

PURPOSE: To assess the outcomes and patterns of failure in solitary plasmacytoma (SP). METHODS AND MATERIALS: The data from 258 patients with bone (n = 206) or extramedullary (n = 52) SP without evidence of multiple myeloma (MM) were collected. A histopathologic diagnosis was obtained for all patients. Most (n = 214) of the patients received radiotherapy (RT) alone; 34 received chemotherapy and RT, and 8 surgery alone. The median radiation dose was 40 Gy. The median follow-up was 56 months (range 7-245). RESULTS: The median time to MM development was 21 months (range 2-135), with a 5-year probability of 45%. The 5-year overall survival, disease-free survival, and local control rate was 74%, 50%, and 86%, respectively. On multivariate analyses, the favorable factors were younger age and tumor size <4 cm for survival; younger age, extramedullary localization, and RT for disease-free survival; and small tumor and RT for local control. Bone localization was the only predictor of MM development. No dose-response relationship was found for doses >30 Gy, even for larger tumors. CONCLUSION: Progression to MM remains the main problem. Patients with extramedullary SP had the best outcomes, especially when treated with moderate-dose RT. Chemotherapy and/or novel therapies should be investigated for bone or bulky extramedullary SP.

Can I treat this small larynx lesion with radiation alone? Update on the radiation management of early (T1 and T2) glottic cancer.

This article endeavors to explain the advantages and disadvantages of radiotherapy (RT) versus transoral laser excision (TLE)and to suggest when each modality may be employed for optimal treatment of patients with this heterogeneous group of tumors. It compares RT and TLE using the criteria of cure and local control rates, posttreatment voice quality, side effects and morbidity, cost,convenience, and salvage potential.

RSR13 plus cranial radiation therapy in patients with brain metastases: comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database.

PURPOSE: This phase II, open-label, multicenter study assessed the efficacy and safety of the potential radiation enhancer RSR13 plus cranial radiation therapy (RT) in patients with brain metastases. The primary end point was patient survival in comparison with the Radiation Therapy Oncology Group Recursive Partitioning Analysis Brain Metastases Database (RTOG RPA BMD). PATIENTS AND METHODS: Eligibility criteria were age > or = 18 years, Karnofsky performance score > or = 70, and brain metastases with solid tumor histology. Patients received cranial RT, 30 Gy in 10 fractions of 3 Gy each, preceded by RSR13, 50 to 100 mg/kg intravenously over 30 minutes. Univariate and multivariate comparisons of survival and cause of death were made between class II study patients and RTOG BMD patients. RESULTS: Fifty-seven RPA class II patients were enrolled. With a minimum follow-up of 24 months, the median survival time and 1- and 2-year survival rates were 6.4 months, 23%, and 11% for the RSR13-treated patients compared with 4.1 months, 15%, and 3% for the RTOG BMD patients (P =.0174). In an exact-matched case analysis (n = 38), median survival time for RSR13 patients was 7.3 months versus 3.4 months for the RTOG BMD patients (P =.006). There was a 54% reduction in the risk of death for RSR13 patients (P =.0267). RSR13-related adverse events of greater than or equal to grade 3 toxicity that occurred in more than one patient included hypoxia, headache, anemia, fatigue, hypertension, and intracranial hypertension. CONCLUSION: RSR13 plus cranial RT resulted in a significant improvement in survival, as well as a reduction in death due to brain metastases, compared with class II patients in the RTOG BMD.