A Multi-Institutional Phase 2 Trial of Ablative 5-Fraction Stereotactic Magnetic Resonance-Guided On-Table Adaptive Radiation Therapy for Borderline Resectable and Locally Advanced Pancreatic Cancer.

PURPOSE: Magnetic resonance (MR) image guidance may facilitate safe ultrahypofractionated radiation dose escalation for inoperable pancreatic ductal adenocarcinoma. We conducted a prospective study evaluating the safety of 5-fraction Stereotactic MR-guided on-table Adaptive Radiation Therapy (SMART) for locally advanced (LAPC) and borderline resectable pancreatic cancer (BRPC). METHODS AND MATERIALS: Patients with LAPC or BRPC were eligible for this multi-institutional, single-arm, phase 2 trial after ≥3 months of systemic therapy without evidence of distant progression. Fifty gray in 5 fractions was prescribed on a 0.35T MR-guided radiation delivery system. The primary endpoint was acute grade ≥3 gastrointestinal (GI) toxicity definitely attributed to SMART. RESULTS: One hundred thirty-six patients (LAPC 56.6%, BRPC 43.4%) were enrolled between January 2019 and January 2022. Mean age was 65.7 (36-85) years. Head of pancreas lesions were most common (66.9%). Induction chemotherapy mostly consisted of (modified)FOLFIRINOX (65.4%) or gemcitabine/nab-paclitaxel (16.9%). Mean CA19-9 after induction chemotherapy and before SMART was 71.7 U/mL (0-468). On-table adaptive replanning was performed for 93.1% of all delivered fractions. Median follow-up from diagnosis and SMART was 16.4 and 8.8 months, respectively. The incidence of acute grade ≥3 GI toxicity possibly or probably attributed to SMART was 8.8%, including 2 postoperative deaths that were possibly related to SMART in patients who had surgery. There was no acute grade ≥3 GI toxicity definitely related to SMART. One-year overall survival from SMART was 65.0%. CONCLUSIONS: The primary endpoint of this study was met with no acute grade ≥3 GI toxicity definitely attributed to ablative 5-fraction SMART. Although it is unclear whether SMART contributed to postoperative toxicity, we recommend caution when pursuing surgery, especially with vascular resection after SMART. Additional follow-up is ongoing to evaluate late toxicity, quality of life, and long-term efficacy.

Lymph node ratio predicts the benefit of post-operative radiotherapy in oral cavity cancer.

BACKGROUND: The standard treatment for non-metastatic oral cavity squamous cell carcinoma (OCSCC) is surgical resection followed by post-operative radiotherapy (PORT) with/without chemotherapy in high risk patients. Given the substantial toxicity of PORT we assessed lymph node ratio (LNR) as a predictor of PORT benefit. DESIGN: By using the Surveillance, Epidemiology and End Results (SEER) database, we analyzed all node positive OCSCC patients diagnosed between 1988 and 2007 who underwent neck dissection. LNR was categorized into three groups: < 6%, 6-12.5% and > 12.5%. RESULTS: In 3091 subjects identified, median survival was 32, 25 and 16 months for LNR Groups 1, 2 and 3, respectively. On multivariate analysis, survival was associated with age, race, grade, tumor size, nodal stage, extra-capsular extension, use of PORT and LNR. When stratified by LNR group, PORT was associated with a survival benefit only in Group 3 (LNR > 12.5%): 2 year survival 25% vs 37%. No benefit to PORT was seen when the LNR ≤ 12.5%: 2 year survival 51% vs 54%. CONCLUSION: A low LNR is associated with extended survival in LN positive OCSCC. The survival benefit associated with PORT in this disease appears to be limited to those with a LNR > 12.5%. Validation is required prior to the clinical implementation of our findings.

Radiotherapy improves survival in unresected stage I-III bronchoalveolar carcinoma.

PURPOSE: To test the hypothesis that radiotherapy (RT) improves the outcome of patients with unresected, nonmetastatic bronchoalveolar carcinoma (BAC) by performing a population-based analysis within the Surveillance, Epidemiology, and End Results (SEER) registry. METHODS AND MATERIALS: Inclusion criteria were as follows: patients diagnosed with BAC, Stage I-III, between 2001 and 2007. Exclusion criteria included unknown stage, unknown primary treatment modality, Stage IV disease, and those diagnosed at autopsy. Demographic data, treatment details, and overall survival were retrieved from the SEER database. Survival was analyzed using the Kaplan-Meier method and log-rank test. RESULTS: A total of 6933 patients with Stage I-III BAC were included in the analysis. The median age at diagnosis was 70 years (range, 10-101 years). The majority of patients were diagnosed with Stage I (74.4%); 968 patients (14%) did not undergo surgical resection. Unresected patients were more likely to be older (p < 0.0001), male (p = 0.001), black (p < 0.0001), and Stage III (p < 0.0001). Within the cohort of unresected patients, 300 (31%) were treated with RT. The estimated 2-year overall survival for patients with unresected, nonmetastatic BAC was 58%, 44%, and 27% in Stage I, II, and III, respectively. Factors associated with improved survival included female sex, earlier stage at diagnosis, and use of RT. Median survival in those not receiving RT vs. receiving RT was as follows: Stage I, 28 months vs. 33 months (n = 364, p = 0.06); Stage II, 18 months vs. not reached (n = 31, nonsignificant); Stage III, 10 months vs. 17 months (n = 517, p < 0.003). CONCLUSIONS: The use of RT is associated with improved prognosis in unresected Stage I-III BAC. Less than a third of patients who could have potentially benefited from RT received it, suggesting that the medical specialists involved in the care of these patients underappreciate the importance of RT.

An interobserver study of prostatic fossa clinical target volume delineation in clinical practice: are regions of recurrence adequately targeted?

OBJECTIVES: To study interphysician variability of delineation of the prostatic fossa clinical target volume (pfCTV) to be irradiated in patients with residual or recurrent microscopic prostate cancer following radical prostatectomy and to estimate the risk for a geographical miss. METHODS: Thirty-eight pfCTV were delineated on postradical prostatectomy computerized tomography scans of 8 patients by 5 observers. To estimate the risk of a geographical miss, a high risk volume (HRV) was defined and the percentage of "missed" HRV was calculated for each pfCTV. RESULTS: Interphysician variability was considerable with a mean pfCTV of 39.09 cm (range, 11.8-72.5 cm). At least 25% of the HRV at the bladder neck/anastomosis and the retro-vesical space was excluded in 11 pfCTVs. The mean "missed" HRV was 27.5% (range, 2.3%-78.7%). A pfCTV of less than 30 cm was associated with a geographical miss in 66% of cases versus 17.2% for pfCTV of 30 cm or more (P = 0.006). Observer identity was significantly associated with excluded HRV (P = 0.03). CONCLUSIONS: pfCTV delineation is subject to considerable interobserver variability associated with a significant risk of inadequate targeting of the anastomosis/bladder neck region and the retrovesical space. The failure to recognize regions at high risk for harboring microscopic disease may be due to a lack of familiarity with tissue redistribution following radical surgery, and a lack of literature-based guidelines for pfCTV delineation. A strategy to improve pfCTV delineation is proposed.

Dosimetric comparison of tandem and Ovoids vs. tandem and ring for intracavitary gynecologic applications.

We evaluated dosimetric differences in tandem and ovoid (TO) and tandem and ring (TR) gynecologic brachytherapy applicators. Seventeen patients with cervical cancer (Stages II-IV) receiving 3 high-dose-rate (HDR) brachytherapy applications (both TO and TR) were studied. Patients underwent computed tomography (CT) scans with contrast in bladder, and were prescribed 8 Gy to ICRU points A, with additional optimization goals of maintaining the pear-shaped dose distribution and minimizing bladder and rectum doses. Bladder and rectum point doses, mean, and maximum doses were calculated. Total treatment time and volumes treated to 95%, 85%, 50%, and 20% or the prescription dose were compared. There were no significant differences between TO and TR applicators in doses to prescription points or critical organs. However, there were significant differences (p < 0.001) between the applicators in treated volumes and total treatment time. The TO treated larger volumes over a longer time. Within each patient, when the applicators were compared, treated volumes were also found to be significantly different (p < 0.01, chi(2)). Our results demonstrate that the 2 applicators, while delivering the prescribed dose to points A and keeping critical organ doses below tolerance, treat significantly different volumes. It is unclear if this difference is clinically meaningful. TO applicators may be treating surrounding healthy tissue unnecessarily, or TR applicators may be underdosing tumor tissue. Further investigation with appropriate imaging modalities is required for accurate delineation of target volumes. Clearly, the TO and TR are not identical, and should not be used interchangeably without further study.

Irradiation enhances the metastatic potential of prostatic small cell carcinoma xenografts.

BACKGROUND: Small cell carcinoma of the prostate (SCCP) is a rare subset of prostate cancer (0.5-2% of all prostatic carcinomas), predominantly composed of neuroendocrine (NE) cells, with a very poor prognosis. Irradiation is one of the mainstay options for SCCP local treatment, yet, little is known about the clinical response of these aggressive tumors to radiotherapy. METHODS: Using SCID mice, the response to fractionated ionizing radiation (IR) of two unique human NE xenografts of SCCP (WISH-PC2 and WM-4A) was investigated. RESULTS: Fractionated irradiation of WISH-PC2 xenografts using total doses of >24 Gy induced a delay in tumor growth, while total doses of >36 Gy led to local tumor eradication. However, most of the irradiated mice suffered from disseminated metastases. Similarly, in the WM-4A xenograft, a total dose of 20 Gy led to tumor growth delay and some of the mice also developed metastases. Non-irradiated local xenografts failed to disseminate, even following surgical excision of the main tumor mass; however, tumor cells administered intravenously did form metastases. Metastases of both xenografts were located in the adrenal/kidney and inter-scapular regions, areas rich in brown adipose tissue. A correlation was found between the appearance of irradiation-induced metastases and activation of the gelatinase activity of matrix metalloproteinase-9. CONCLUSIONS: Clinically, this study raises the possibility that radiation to SCCP may promote metastatic disease. For patients in whom prostate biopsy shows a predominance of small cell cancer, it may be necessary to deliver systemic therapy together with the radiotherapy in order to prevent the development of metastases.

A phase II study of Imatinib for advanced adenoid cystic carcinoma of head and neck salivary glands.

Adenoid cystic carcinoma of the salivary glands is characterized by a poor response to chemotherapy. Most cases of adenoid cystic carcinoma express the c-kit protein. Imatinib mesylate (Gleevec) inhibits several protein-tyrosine kinases, including c-kit. We therefore hypothesized that Imatinib may be an effective drug in patients with locally advanced or metastatic adenoid cystic carcinoma and conducted a phase 2 trial in order to study this. Patients with locally advanced or metastatic adenoid cystic carcinoma and c-kit positive tumours were eligible. Fourteen patients were screened and 10 patients (71%) with c-kit positive tumours entered the study. Treatment was begun at a dose of Imatinib of 400mg/day. Dose escalation was allowed in the absence of toxicity. The dose was increased to 600mg/d in three patients and 800mg/d in one patient. Three patients required dose reduction to 300mg/d, due to grade 3 toxicity. No grade 4 toxicity was seen. No objective responses were seen. Two patients (20%) exhibited stable disease for 11 and 14 months, respectively. All other patients stopped treatment after 2-14 (median 6) months due to progressive disease. Imatinib has no major effect on advanced adenoid cystic carcinoma of the head and neck.

Individual fraction optimization vs. first fraction optimization for multichannel applicator vaginal cuff high-dose-rate brachytherapy.

PURPOSE: To challenge the assumption of unchanged interfractional geometry changes in the course of fractionated multichannel vaginal cuff high-dose-rate brachytherapy. METHODS AND MATERIALS: Two methods of treatment planning for delivery of vaginal cuff brachytherapy were compared in 44 applications. Individual fraction optimization (IFO)-performed for the specific geometry of each individual fraction-was compared to first fraction optimization (FFO)-an optimized first fraction, applied unaltered for geometry of subsequent fractions in the same patient. Dose difference to critical organs was expressed as the percentage of the prescribed dose. RESULTS: In the paired analysis for IFO vs. FFO, mean and maximum rectal and bladder doses were similar. However for FFO, an excess of greater than 20% mean dose to either bladder or rectum was observed in 41% of cases. Maximum organ doses were exceeded by 20% in 54.5% of applications. CONCLUSIONS: On the basis of these findings, it can be concluded that IFO may be important to minimize doses to critical structures.

Radiation rescue for biochemical failure after surgery for prostate cancer: predictive parameters and an assessment of contemporary predictive models.

OBJECTIVES: To determine pretreatment prognostic variables that predict outcome of radiotherapy for biochemical failure after prostate cancer surgery and evaluate contemporary clinical decision tools for patient selection. METHODS: Fifty patients were identified with failure after rescue radiation was defined as a confirmed rise in PSA, distant metastases, prostate cancer death, or initiation of hormonal therapy. Univariate analysis and multivariate Cox models were constructed. Outcome was compared with decision tree and recursive partitioning predictive models. RESULTS: The median preradiation PSA (pre-RT PSA) was 1.2 ng/mL and the median dose of radiation was 66.6 Gy; median follow-up was 39.6 months. Overall, the estimated 3-year failure free survival was 54%, 95%CI [43,74]. Seminal vesicle involvement (SVI) (P = 0.003) and preradiation PSA Doubling Time (PSADT) <10 months (P = 0.01) were both significant predictors for treatment failure whereas pre-RT PSA was of borderline significance (P = 0.07). On multivariate analysis a pre-RT PSA of >1 and SVI were associated with hazard ratios of 6.2 and 7.3 (P = 0.01 and P = 0.004), respectively. An additional Cox model constructed for 31 patients for whom pre-RT PSADT could be calculated showed PSADT and SVI to be independent prognostic parameters. Two predictive models, a decision tree analysis, and a recursive partitioning model were moderately accurate in predicting outcome in this series, however, high-risk patients experienced less treatment failures than predicted. CONCLUSIONS: Pre-RT PSA <1 ng/mL, longer PSADT (>10 months) and no SVI are associated with improved outcome after rescue radiation. Contemporary clinical prediction tools are imperfect predictors of outcome for rescue radiation therapy.

Olfactory function in oncologic hospice patients.

INTRODUCTION: Normal sense of smell is important for well being. Although cancer is reported to be associated with impaired olfactory function, very few studies have directly evaluated this effect. PATIENTS AND METHODS: We performed a quantitative analysis of olfactory status in 42 hospice patients in a hospital-based hospice facility. Olfaction was assessed using the "Sniffin' Sticks" (Burghart Medical Technology, Tinsdaler, Germany) kit. RESULTS: Twenty-five patients (60%) were found to be hyposmic. CONCLUSION: Study results indicate the high incidence of decreased olfactory function among hospice patients.

Limited use of complementary and alternative medicine in Israeli head and neck cancer patients.

HYPOTHESIS/OBJECTIVE: The use of complementary or alternative medicine (CAM) is growing among cancer patients. A Medline search failed to reveal any dedicated report of CAM use specifically in patients with head and neck cancer (HNC). STUDY DESIGN: Use of CAM was evaluated in a cohort of treated HNC patients. METHODS: Patients treated for HNC were asked if they had used CAM since their diagnosis. Demographic data and data pertaining to mode of CAM, duration of treatment and effects were obtained. RESULTS: One hundred forty-three patients (mean age 61 years) were included. Only nine patients (6.3%) reported using disease related CAM. This included acupuncture (4), Reiki (2), naturopathy (2), hypnosis (1), shiatsu (1), chiropractic treatment (1), homeopathy (1), and selenium (1). CONCLUSION: Contrary to the reported use, few of our HNC patients used CAM. Although this could be related to good caregiver-patient relationship, further studies in comparable populations are warranted to evaluate if this is a local or a pervading finding in head and neck cancer patients.

A phase I study of oral UFT given concomitantly with standard preoperative radiotherapy for rectal cancer.

BACKGROUND: Preoperative radiotherapy is standard treatment for rectal cancer and is often combined with 5-fluorouracil-based chemotherapy. UFT, a new oral 5FU derivative, given daily during a course of radiotherapy mimics the effect of continuous-infusion 5FU. OBJECTIVES: To determine the maximum tolerated dose of oral UFT and leucovorin with preoperative pelvic irradiation for rectal cancer, and assess tumor response. METHODS: In this phase 1 trial, 16 patients aged 42-79 years with tumors within 12 cm of the anal verge received radiotherapy, 45 Gy over 5 weeks, an escalating dose of oral UFT, and a fixed dose of 30 mg/day leucovorin. UFT and leucovorin were given for 28 consecutive days concomitant with the first 4 weeks of radiotherapy. Surgery was scheduled for 4-6 weeks after completion of radiotherapy. The surgical procedure was determined by the surgeon at the time of surgery. RESULTS: No grade III toxicity was seen at 200 mg/m2/day UFT. Of eight patients who received 240 mg/m2/day UFT, one developed grade IV diarrhea; of four patients who received 270 mg/m2/day UFT, one was hospitalized with grade IV diarrhea and leukopenic fever and died during hospitalization. Of the 15 evaluable patients, 9 had pathologic tumor downstaging including 4 patients with complete response. Only one patient required a colostomy. CONCLUSIONS: The MTD of UFT together with leucovorin and preoperative radiotherapy for rectal cancer is 240 mg/m2. The major toxicity was diarrhea. Downstaging was noted in 60% of patients, allowing sphincter-preserving surgery even in patients with low tumors.

Orbital lymphoma: is it necessary to treat the entire orbit?

PURPOSE: Conformal radiotherapy (RT) has been used for all patients with orbital lymphoma treated at our institution since 1997. We retrospectively reviewed the charts of 23 consecutive patients to test the hypothesis that partial orbit RT is effective and less toxic than whole orbit RT. METHODS AND MATERIALS: Twelve patients with limited lesions were treated to partial orbital volumes and 11 patients (1 with bilateral disease) with more extensive lesions received whole orbit RT. The dose was 20-30 Gy (median, 25.2 Gy) for 19 patients with low-grade lymphoma and 24-40 Gy (median, 39.6 Gy) for 5 patients with intermediate- to high-grade lymphoma. The follow-up was 12-68 months (median, 34 months). RESULTS: All patients had a complete response to RT. Intraorbital recurrence developed in previously uninvolved areas not included in the initial target volume in 4 patients (33%) treated with partial orbit RT. All were salvaged by repeat RT or surgery. No patient treated with whole orbit RT developed intraorbital recurrence. The acute and long-term toxicity was similar in both groups. All but 1 patient retained good vision. CONCLUSION: Patients with orbital lymphoma should be treated to the entire orbit. An effective dose of RT for low-grade lesions is 25 Gy, which results in minimal morbidity even when delivered to the entire orbit.

The role of irradiation of the internal mammary lymph nodes in high-risk stage II to IIIA breast cancer patients after high-dose chemotherapy: a prospective sequential nonrandomized study.

PURPOSE: This phase II single-institution prospective, nonrandomized trial investigates high-dose adjuvant chemotherapy and locoregional radiotherapy in patients with breast cancer. We compared the outcome of patients in this study treated with radiotherapy fields including the internal mammary nodes (IMN) to a group of patients who did not receive IMN irradiation. PATIENTS AND METHODS: 100 patients with high-risk stage II-III breast cancer received doxorubicin-based adjuvant chemotherapy followed by high-dose chemotherapy, stem-cell support, and locoregional radiotherapy. The radiotherapy included electron-beam irradiation to the IMN. For 20 months during the study, no electron-beam facility was available and we were unable to deliver the IMN irradiation as planned to 33 patients. The remaining 67 patients (32 treated before and 35 treated after this period) received IMN irradiation. Patients with receptor-positive tumors received tamoxifen for 5 years. RESULTS: At a median follow-up of 77 months for all of the patients, disease-free survival (DFS) was significantly prolonged in patients receiving IMN radiation compared to those without IMN radiation (73% v 52%; P =.02). A trend was seen for overall survival (OS; 78% v 64%; P =.08). Cox regression multivariate analysis found IMN radiotherapy to be significant both for DFS and OS. Estrogen receptor positivity was also significant for DFS. There was no treatment related mortality. CONCLUSION: In patients with high-risk stage II to III breast cancer, the inclusion of the IMN in the radiotherapy field was associated with a statistically significant increase in DFS and a borderline increase in OS.

Linear accelerator radiosurgery for meningiomas in and around the cavernous sinus.

OBJECTIVE: A retrospective study to evaluate the efficacy and side effects of linear accelerator radiosurgery in the treatment of cavernous sinus meningiomas. METHODS: Between 1993 and 2001, 42 patients with meningiomas involving the cavernous sinus underwent linear accelerator radiosurgery at our institution. A mean radiation dose of 14 Gy was delivered to the tumor margin. The median tumor volume was 8.2 cm3 (mean, 8.4 cm3). Median follow-up was 36 months (mean, 38 mo). RESULTS: Control of tumor growth was achieved in 97.5% of the patients. There was no mortality or permanent extraocular motor or pituitary dysfunction. Treatment-related complications included new trigeminal neuropathy in 4.7% and a new visual field defect in 2.8%. Two patients required shunt placement after developing hydrocephalus. One patient with symptomatic temporal lobe edema underwent partial excision of the tumor. Improvement of existing cranial neuropathies was noted in 29% of affected trigeminal nerves, in 22% of oculomotor nerves, and in 13% of Cranial Nerves IV and VI. CONCLUSION: This study indicates that linear accelerator radiosurgery can achieve a high control rate of meningiomas involving the cavernous sinus with no mortality and a low incidence of morbidity.

Quality of life of nasopharyngeal carcinoma patients.

BACKGROUND: Quality of life (QOL) issues in patients with head and neck carcinoma are of importance beyond the incidence of these tumors because of the impact of the disease and its treatment on external appearance and function of the upper aerodigestive tract. Nasopharyngeal carcinoma (NPC) patients comprise a unique subgroup in whom, to our knowledge, QOL has not been studied directly. METHODS: Adult patients with NPC treated during the past 15 years at the Chaim Sheba Medical Center with a minimum follow-up of 6 months were included in the current study. Patients were mailed the revised University of Washington quality of life (UW-QOL) questionnaire and data pertaining to their disease were recorded. Patients with recurrent disease or another malignancy or those whose present status could not be ascertained were excluded from the study. QOL scores were analyzed based on treatment, disease stage, and patient age. RESULTS: Twenty-eight patients of 35 disease-free patients (80%) responded to the questionnaire sent to patients meeting the study criteria. The mean score for general health was 3.1 (range, 1-5). Pain was not a significant factor. Other domains without noteworthy problems were speech and shoulder disability. The majority of patients described their appearance as normal or with minor changes, and questions concerning activity, recreation/entertainment, employment, and swallowing all scored > 70 (range, 0-100). Dry mouth, chewing, and ear problems were of major concern with the majority of patients and affected the QOL indices. Nevertheless, the overall mean QOL score of these patients was rated as "good" (4.2 on a scale of 1-6). CONCLUSIONS: In the current study, patients with NPC reported ear problems, difficulties in chewing, and dry mouth but their overall QOL appeared to be good. Ear problems such as secretory otitis media should be recognized at the time of presentation and treated. Conformal radiotherapy techniques sparing the salivary glands and temporal bone most likely will be useful in reducing the morbidity associated with treatment.

Smoking-induced squamous-cell cancer of the nose.

Squamous-cell cancer (SCC) isolated to the anterior nose is uncommon. Numerous industrial and environmental contaminants have been implicated as causative factors in nasal carcinoma. The association between nasal cancer and smoking was recognized in the 1980s, but results have not been consistent and no possible mechanisms have been suggested. The case histories of 11 patients with SCC limited to the anterior nasal cavity were reviewed. The authors found no relationship with exposures to chemicals previously implicated in nasal cancer. Nine patients with SCC were exposed to cigarette smoke (mean = 103 pack-years). Cigarette smoke may induce cancer directly, thus affecting the mucosa, or by inducing genetic alterations. The authors favor the former mechanism.