Need For Dose Escalation Research Articles

P472 Infliximab therapy for inflammatory bowel disease in patients post liver transplatation

Background: Infliximab (IFX) is effective in treating luminal Crohn’s disease (CD) in children (Hyams, 2007), but data about durability of response are limited. We reviewed the effectiveness of IFX treatment in achieving shortand longterm clinical remission and normal linear growth in a singlecenter cohort. Methods: From 2000 to 2011 at SickKids, Toronto, 195 children (63% male; median age 14.1 yrs, IQR 3.3) with luminal inflammatory CD (20% L1; 17% L2; 63% L3) received standard IFX 3-dose induction. Median duration of diagnosed CD at initiation was 19.9 mos (range 0.3 136.8). Responders continued scheduled maintenance treatment +/ immunomodulator (IM). Records were retrospectively reviewed to extract at yearly intervals: physician global assessment (PGA) of continued response/remission vs. loss of response (LoR), PCDAI, linear growth, colonoscopic data and levels of IFX and antibodies (ATI). Durability of response was explored using survival analysis. Results: Rates of clinical response (judged by PGA) and remission (judged by PGA and PCDAI 10) were respectively, 91% and 80%. Longer time from diagnosis to IFX induction and being female were associated with a lower response rate. 20% of primary responders later stopped IFX (LoR: 56%; intolerance/complication: 30%). LoR rate was linear (6 to 8%/year) over 5 years. Over the follow-up period, 52% required dose escalation or interval shortening. In subjects with LoR, ATI were present in 88%. Concurrent IM use did not significantly alter LoR, ATI or need for dose escalation. Data for growth are shown in the figure. Growth was significantly improved for those who were Tanner 1 or 2 at induction. Being younger at diagnosis and induction were significantly associated with improved height. Follow-up endoscopy was performed in 26 patients after IFX induction. Healing was observed in 50% (35% substantial, 15% complete).

Recent developments in gastroesophageal reflux disease and Barrett's esophagus: ANNO 2012

The incidence of gastroesophageal reflux disease (GERD) and esophageal columnar metaplasia is rising worldwide. Both mechanical and functional factors perturb the double sphincter barrier at the esophagogastric junction (EGJ). Discovery of the acid pocket is fundamental in understanding postprandial acid reflux. Adding impedencemetry to pH measurements allows detection of non-acid or weakly acidic reflux. Histologic and endoscopic injury of the squamous mucosa rises from dilation of the intercellular spaces, papillary extension, accentuated intrapapillary looping, red streaks, erosive tissue loss, etc., graded with the Los Angeles system. Seventy percent of patients have no recognizable abnormalities (non-erosive or neGERD). Treatment of GERD mainly relates to the control of acid secretion but a revival of alginate/antacid obliterating the acid pocket is to be expected. Weaker heartburn control in neGERD is a misnomer because most studies included patients with no evidence of reflux disease. Traditional (delayed-release) proton pump inhibitors (PPIs) are powerful suppressors of acid secretion but do have limitations such as gradual build up of acid control, weak control of nocturnal acid recovery, possibility of rebound, occasional need for dose escalation, etc. Barrett's esophagus (BE) is endoscopically diagnosed also in the absence of intestinal metaplasia. A prerequisite is the precise location of the EGJ (proximal end of gastric folds, esophageal sphincter pinch, distal extent of palisade vessels). BE is graded with the Prague C & M system. Barrett's cancer develops usually via low-grade and high-grade dysplasia. Endoscopic examination may indicate suspicious areas, amenable for targeted biopsy. Otherwise, four quadrant biopsies are obtained when searching for neoplasia. Low-grade dysplasia, especially when it is multifocal and p53 positive, high-grade dysplasia and mucosal cancer should be treated with endoscopic resection of the target area, followed by radiofrequency ablation of the adjacent non-neoplastic columnar mucosa, followed with powerful acid suppressant therapy. The long-term results of the combination of resection and ablation are exiting and at least comparable to surgical resection.

1160 Adding Ciprofloxacin to Adalimumab Results in a Higher Fistula Closure Rate in Perianal Fistulizing Crohn's Disease

Background: There is clear benefit of combination therapy for infliximab (IFX) with immunosuppressive drugs (IS), whether commenced together, or later, but no data are available for ADA. The aim was to assess whether IS combotherapy (CoT) was more effective than monotherapy for Crohn’s disease (CD) patients treated with ADA, using the semester approach. Methods: Retrospective study of patients with CD (n = 181) treated for at least one year with ADA in Oxford, UK or Liege, Belgium. Treatment periods were divided into 6 month semesters and the treatment failure compared between semesters with or without CoT (thiopurines or methotrexate). ADA failure was defined as dose modification during therapy, drug modification, perineal complications, or surgery for active CD. Results: 569 semesters were studied in 181 patients (Oxford n = 98, Liege 83), including 147 semesters in 45 patients having received CoT during the first semester. More patients in Oxford received CoT than Liege (OR: 4.82, p < 0.0001) and fewer females (OR 0.50, p = 0.01). When considering only patients on CoT during the first semester, treatment failures were less frequent in semesters with IS (20%) compared to semesters without IS (80%; OR 0.30, p = 0.02). This protective effect of the CoT was maintained over time (p = 0.01). When considering all the patients, CoT in the first semester was associated with a lower frequency of treatment failures (34% vs 66%, OR 0.69, p = 0.046) in univariate analysis but not in multivariate analysis. CoT later after induction of ADA was not associated with treatment failures. Female gender (OR 1.68, p = 0.01), previous surgery (OR 1.89, p = 0.001) and active perianal disease (OR 1.57, p = 0.02) were risk factors of failure on multivariate analysis. Although failures were less common in Oxford (OR 0.52, p = 0.001), more failures in Oxford had surgery (OR 8.85, p = 0.001) or perianal complications (OR 3.33, p = 0.01) and fewer had ADA weekly (OR 0.24, p = 0.0003) on multivariate analysis. The overall number of operations and perianal complications did not differ between CoT and ADA monotherapy. Thiopurines appeared more effective than methotrexate for preventing failure (OR 0.35, p = 0.03). The probablility of failure did not increase over the semesters (p = 0.86). Conclusions: When it was given during the first semester, CoT with ADA in CD was associated with fewer semesters with treatment failures (essentially the need for dose escalation or treatment modification, but not the rate of surgery or perianal complications). OP16 Adding ciprofloxacin to adalimumab results in a higher fistula closure rate in perianal fistulizing Crohn’s disease P. Dewint1 *, B. Hansen1, E. Verhey1, B. Oldenburg2, D.W. Hommes3, M. Pierik4, C. Ponsioen5, H. van Dullemen6, M.G. Russel7, A. van Bodegraven8, C.J. van der Woude1, on behalf of ICC (Initative on Crohn’s and Colitis). 1Erasmus Medical Center, Department of Gastroenterology & Hepatology, Rotterdam, Netherlands, 2University Medical Centre Utrecht, Department of Gastroenterology, Utrecht, Netherlands, 3UCLA, Division of Digestive Diseases, Los Angeles, United States, 4Maastricht University Medical Center, Dept of Gastroenterology, Maastricht, Netherlands, 5Academic Medical Center, Gastroenterology and Hepatology, Amsterdam, Netherlands, 6UMC Groningen, Gastroenterology, Groningen, Netherlands, 7Medisch Spectrum Twente, Gastroenterology, Enschede, Netherlands, 8VU University Medical Center, Gastroenterology, Amsterdam, Netherlands

Sa1925 Does Obesity Impact Treatment Efficacy of Adalimumab and Certolizumab Pegol in Crohn's Disease?

BACKGROUND: Adalimumab (ADA) and certolizumab pegol (CZP) are injectable biologics currently approved for moderate to severe Crohn's disease (CD) failing to respond adequately to conventional therapy. Unlike infliximab, ADA and CZP do not use weight-based dosing. Recent data involving patients with psoriasis suggest that the efficacy of adalimumab may be reduced in obese patients, although this association has not been found in CD. The aim of this study was to determine whether obesity influences treatment efficacy and need for dose escalation of ADA or CZP in patients with CD. METHODS: A retrospective chart review was performed to identify patients with CD treated with ADA or CZP at our institution from January 2006 to October 2011. The primary outcomes of interest were the proportion of patients with a clinical response to induction with ADA and CZP, and the proportion of patients that underwent dose escalation (for ADA) or reinduction (for CZP) in obese v nonobese patients. Patients were defined as nonobese (body mass index (BMI) 30). Patients were excluded if less than 3 months of follow up data were available. Statistical analysis was done by chi-square analysis and student's t-test. RESULTS: 135 Crohn's patients (107 ADA, 28 CZP) were included. 35/135 patients had a BMI >30. Median age was 38 (range 19-73), 63% were female, and median disease duration was 11 years (range 0-37). There were no significant differences in clinical response to ADA induction (obese 23/29 79.3%, nonobese 58/78 74.4%; p =.80). A higher proportion of obese patients underwent dose escalation with ADA although this was not statistically significant (obese 12/29 41.4%, nonobese 21/78 26.9%; p =.16). There were no differences in response to dose escalation (obese 58%, nonobese 62%) or proportion of patients that remain on therapy (obese 55%, nonobese 55%). Patients receiving CZP had no significant differences in clinical response to induction (obese 2/6 33%, nonobese 12/22 54%; p=.64) or rates of reinduction (obese 20%, nonobese 36%; p=.64) and proportion of patients remaining on therapy (obese 17%, nonobese 14%). However these numbers are limited by small sample size. The mean duration of therapy was 12 months (range 4-56) for ADA and 7 months (range 3-26) for CZP. CONCLUSIONS: In this cohort of Crohn's patients, obesity was associated with similar rates of clinical response to ADA and CZP compared with nonobese patients. Obese patients had higher rates of dose escalation of ADA, although this difference was not statistically significant. Obesity did not impact the proportion of patients that remain on therapy.

Mo1689 SIBDQ Score Does Not Predict the Need for Dose Escalation of Infliximab in Inflammatory Bowel Disease Patients

Mo1689 SIBDQ Score Does Not Predict the Need for Dose Escalation of Infliximab in Inflammatory Bowel Disease Patients

Sa1926 Durability of Anti TNF α Therapy in Ulcerative Colitis: Switching is an Effective Strategy in a Small Subset of Patients

BACKGROUND: Adalimumab (ADA) and certolizumab pegol (CZP) are injectable biologics currently approved for moderate to severe Crohn's disease (CD) failing to respond adequately to conventional therapy. Unlike infliximab, ADA and CZP do not use weight-based dosing. Recent data involving patients with psoriasis suggest that the efficacy of adalimumab may be reduced in obese patients, although this association has not been found in CD. The aim of this study was to determine whether obesity influences treatment efficacy and need for dose escalation of ADA or CZP in patients with CD. METHODS: A retrospective chart review was performed to identify patients with CD treated with ADA or CZP at our institution from January 2006 to October 2011. The primary outcomes of interest were the proportion of patients with a clinical response to induction with ADA and CZP, and the proportion of patients that underwent dose escalation (for ADA) or reinduction (for CZP) in obese v nonobese patients. Patients were defined as nonobese (body mass index (BMI) 30). Patients were excluded if less than 3 months of follow up data were available. Statistical analysis was done by chi-square analysis and student's t-test. RESULTS: 135 Crohn's patients (107 ADA, 28 CZP) were included. 35/135 patients had a BMI >30. Median age was 38 (range 19-73), 63% were female, and median disease duration was 11 years (range 0-37). There were no significant differences in clinical response to ADA induction (obese 23/29 79.3%, nonobese 58/78 74.4%; p =.80). A higher proportion of obese patients underwent dose escalation with ADA although this was not statistically significant (obese 12/29 41.4%, nonobese 21/78 26.9%; p =.16). There were no differences in response to dose escalation (obese 58%, nonobese 62%) or proportion of patients that remain on therapy (obese 55%, nonobese 55%). Patients receiving CZP had no significant differences in clinical response to induction (obese 2/6 33%, nonobese 12/22 54%; p=.64) or rates of reinduction (obese 20%, nonobese 36%; p=.64) and proportion of patients remaining on therapy (obese 17%, nonobese 14%). However these numbers are limited by small sample size. The mean duration of therapy was 12 months (range 4-56) for ADA and 7 months (range 3-26) for CZP. CONCLUSIONS: In this cohort of Crohn's patients, obesity was associated with similar rates of clinical response to ADA and CZP compared with nonobese patients. Obese patients had higher rates of dose escalation of ADA, although this difference was not statistically significant. Obesity did not impact the proportion of patients that remain on therapy.

OP15 Immunosuppressive co-treatment with adalimumab (ADA) may be more effective than ADA monotherapy for maintaining remission in Crohn's disease (CD)

Background: There is clear benefit of combination therapy for infliximab (IFX) with immunosuppressive drugs (IS), whether commenced together, or later, but no data are available for ADA. The aim was to assess whether IS combotherapy (CoT) was more effective than monotherapy for Crohn’s disease (CD) patients treated with ADA, using the semester approach. Methods: Retrospective study of patients with CD (n = 181) treated for at least one year with ADA in Oxford, UK or Liege, Belgium. Treatment periods were divided into 6 month semesters and the treatment failure compared between semesters with or without CoT (thiopurines or methotrexate). ADA failure was defined as dose modification during therapy, drug modification, perineal complications, or surgery for active CD. Results: 569 semesters were studied in 181 patients (Oxford n = 98, Liege 83), including 147 semesters in 45 patients having received CoT during the first semester. More patients in Oxford received CoT than Liege (OR: 4.82, p < 0.0001) and fewer females (OR 0.50, p = 0.01). When considering only patients on CoT during the first semester, treatment failures were less frequent in semesters with IS (20%) compared to semesters without IS (80%; OR 0.30, p = 0.02). This protective effect of the CoT was maintained over time (p = 0.01). When considering all the patients, CoT in the first semester was associated with a lower frequency of treatment failures (34% vs 66%, OR 0.69, p = 0.046) in univariate analysis but not in multivariate analysis. CoT later after induction of ADA was not associated with treatment failures. Female gender (OR 1.68, p = 0.01), previous surgery (OR 1.89, p = 0.001) and active perianal disease (OR 1.57, p = 0.02) were risk factors of failure on multivariate analysis. Although failures were less common in Oxford (OR 0.52, p = 0.001), more failures in Oxford had surgery (OR 8.85, p = 0.001) or perianal complications (OR 3.33, p = 0.01) and fewer had ADA weekly (OR 0.24, p = 0.0003) on multivariate analysis. The overall number of operations and perianal complications did not differ between CoT and ADA monotherapy. Thiopurines appeared more effective than methotrexate for preventing failure (OR 0.35, p = 0.03). The probablility of failure did not increase over the semesters (p = 0.86). Conclusions: When it was given during the first semester, CoT with ADA in CD was associated with fewer semesters with treatment failures (essentially the need for dose escalation or treatment modification, but not the rate of surgery or perianal complications). OP16 Adding ciprofloxacin to adalimumab results in a higher fistula closure rate in perianal fistulizing Crohn’s disease P. Dewint1 *, B. Hansen1, E. Verhey1, B. Oldenburg2, D.W. Hommes3, M. Pierik4, C. Ponsioen5, H. van Dullemen6, M.G. Russel7, A. van Bodegraven8, C.J. van der Woude1, on behalf of ICC (Initative on Crohn’s and Colitis). 1Erasmus Medical Center, Department of Gastroenterology & Hepatology, Rotterdam, Netherlands, 2University Medical Centre Utrecht, Department of Gastroenterology, Utrecht, Netherlands, 3UCLA, Division of Digestive Diseases, Los Angeles, United States, 4Maastricht University Medical Center, Dept of Gastroenterology, Maastricht, Netherlands, 5Academic Medical Center, Gastroenterology and Hepatology, Amsterdam, Netherlands, 6UMC Groningen, Gastroenterology, Groningen, Netherlands, 7Medisch Spectrum Twente, Gastroenterology, Enschede, Netherlands, 8VU University Medical Center, Gastroenterology, Amsterdam, Netherlands

Frequency and predictors of loss of response to biological therapy in Crohn’s disease after one-year treatment period

Secondary loss of response (initial good response followed by loss of response and flare up) is a frequent event occurring during biological therapy. The aim of this study was to assess loss of efficacy in patients with Crohn’s disease treated with infliximab or adalimumab for a year. Secondary goals were to identify clinical or laboratory predictors of loss of response and to evaluate whether the frequency of dose escalation differs in patients receiving infliximab or adalimumab. Data were provided by a computerized database. Patients and methods: Sixty-one patients with Crohn’s disease achieved remission after induction therapy and received regular maintenance treatment. 35 of them were on infliximab, and 26 on adalimumab therapy. None of the patients treated with infliximab received previous biological therapy, while 10 of the adalimumab-treated patients were naïve to biological therapy. Authors compared the data of patients who relapsed with those who remained in remission and also the characteristics of infliximab-treated patients with adalimumab-naïve patients. Data were analyzed using Chi-square test. Kaplan Meier curve was used to show the time of loss of efficacy. Results: Remission was achieved in 70.5%, and response was achieved in 29.5% of the patients after induction. Loss of response occurred in 22 of the 61 patients after a year of therapy. The proportion of remission after induction was significantly lower in patients who lost response vs. those who remained in remission. More patients with sustained remission received immunosuppressive therapy before and during the biological therapy vs. those with loss of response. Loss of response was significantly more frequent and occurred earlier in adalimumab-naive patients vs. infliximab-treated patients. Conclusion: The need for dose escalation should be calculated in the budget in the majority of patients, especially in adalimumab-treated patients. Orv. Hetil., 2011, 152, 951–957.

Biological therapy for paediatric IBD: effective but associated with financial and safety issues

IntroductionBiological agents are increasingly used as treatment for paediatric inflammatory bowel disease (IBD) in the UK, yet the evidence base is very limited and safety concerns are rising. We aimed...

Exploring the Feasibility of Dose Escalation Positron Emission Tomography–Positive Disease with Intensity-Modulated Radiation Therapy and the Effects on Normal Tissue Structures for Thoracic Malignancies

The pattern of failure is one of the major causes of mortality among thoracic patients. Studies have shown a correlation between local control and dose. Intensity-modulated radiation therapy (IMRT) has resulted in conformal dose distributions while limiting dose to normal tissue. However, thoracic malignancies treated with IMRT to highly conformal doses up to 70 Gy still have been found to fail. Thus, the need for dose escalation through simultaneous integrated boost (SIB) may prove effective in minimizing reoccurrences. For our study, 28 thoracic IMRT plans were reoptimized via dose escalation to the gross tumor volume (GTV) and planning target volume (PTV) of 79.2 Gy and 68.4 Gy, respectively. Reoccurrences in surrounding regions of microscopic disease are rare therefore, dose-escalating regional nodes (outside GTV) were not included. Hence, the need to edit GTV margins was acceptable for our retrospective study. A median dose escalation of approximately 15 Gy (64.8–79.2 Gy) via IMRT using SIB was deemed achievable with minimal percent differences received by critical structures compared with the original treatment plan. The target's mean doses were significantly increased based on p-value analysis, while the normal tissue structures were not significantly changed.

Herpes simplex virus vector-mediated gene delivery for the treatment of lower urinary tract pain

Interstitial cystitis (IC)/painful bladder syndrome (PBS) is a painful debilitating chronic visceral pain disorder of unknown etiology that affects an estimated 1 million people in the United States alone. It is characterized by inflammation of the bladder that results in chronic pelvic pain associated with bladder symptoms of urinary frequency and urgency. Regardless of the etiology, IC/PBS involves either increased and/or abnormal activity in afferent nociceptive sensory neurons. Pain-related symptoms in patients with IC/PBS are often very difficult to treat. Both medical and surgical therapies have had limited clinical utility in this debilitating disease and numerous drug treatments, such as heparin, dimethylsulfoxide and amitriptyline, have proven to be palliative at best, and in some IC/PBS patients provide no relief whatsoever. Although opiate narcotics have been employed to help alleviate IC/PBS pain, this strategy is fraught with problems as systemic narcotic administration causes multiple unwanted side effects including mental status change and constipation. Moreover, chronic systemic narcotic use leads to dependency and need for dose escalation due to tolerance; therefore, new therapies are desperately needed to treat refractory IC/PBS. This has led our group to develop a gene therapy strategy that could potentially alleviate chronic pelvic pain using the herpes simplex virus-directed delivery of analgesic proteins to the bladder.

Use of mycophenolate mofetil in inflammatory bowel disease

To assess the efficacy and safety of mycophenolate mofetil (MMF) prospectively in inflammatory bowel disease (IBD) patients intolerant or refractory to conventional medical therapy. Crohn's disease (CD) or ulcerative colitis/IBD unclassified (UC/IBDU) patients intolerant or refractory to conventional medical therapy received MMF (500-2000 mg bid). Clinical response was assessed by the Harvey Bradshaw index (HBI) or colitis activity index (CAI) after 2, 6 and 12 mo of therapy, as were steroid usage and adverse effects. Fourteen patients (9 CD/5 UC/IBDU; 8M/6F; mean age 50.4 years, range 28-67 years) were treated and prospectively assessed for their response to oral MMF. Of the 11 patients who were not in remission on commencing MMF, 7/11 (63.6%) achieved remission by 8 wk. All 3 patients in remission on commencing MMF maintained their remission. Ten patients were still on MMF at 6 mo with 9/14 (64.3%) in remission, while of 12 patients followed for 12 mo, 8 were in remission without dose escalation (66.7%). Three patients were withdrawn from the MMF due to drug intolerance. There were no serious adverse events attributed due to the medication. MMF demonstrated efficacy in the management of difficult IBD. MMF appeared safe, well tolerated and efficacious for both short and long-term therapy, without the need for dose escalation. Further evaluation of MMF comparing it to conventional immunosuppressants is required.

Long-term Use of Controlled-release Oxycodone for Noncancer Pain: Results of a 3-year Registry Study

To evaluate the outcomes associated with the use of controlled-release (CR) oxycodone for up to 3 years in the treatment of noncancer pain. Adult patients who previously participated in controlled trials of CR oxycodone for osteoarthritis pain, diabetic neuropathy pain, or low back pain, and who continued to require opioid analgesia for moderate or severe pain, were enrolled in an open-label, uncontrolled, registry study. Data collected over time included dose, pain severity on a numeric scale, treatment acceptability, adverse events, and descriptions of problematic drug-related behavior. Two hundred thirty-three patients were enrolled. When the study closed, 141, 86, and 39 patients had taken CR oxycodone for at least 1, 2, and 3 years, respectively; mean duration of treatment was 541.5 days. Among the 219 intent-to-treat patients (received at least 1 dose and provided at least 1 postdose study observation), the mean (SD, range) daily dose was 52.5 (+/-38.5, 10.0 to 293.5) mg. Before the end of month 3, 44% required an increase in total daily dose; this dropped to 23% during months 4 to 6, to 17% during months 10 to 12, and remained at approximately 10% for each time interval thereafter (range 8% to 13%). Among the large majority of patients with stable or lower dose requirements after the initial 3 months of treatment, the average pain intensity ratings were unchanged or improved for approximately 70% to 80% of patients at all subsequent time points through month 33, and for 54% (7/13 patients) at month 36. A decrease in pain was initially seen by the end of month 3, and for the majority of patients, the Average Pain Intensity score remained the same, better, or minimally worse (<3 points) for the remainder of the 3-year study period. The most common adverse events were constipation and nausea, and the incidence of these events declined over time on treatment. Investigators reported 6 cases (2.6%) of possible drug misuse but no evidence of de novo addiction was observed. These registry data demonstrate that a subgroup of patients with noncancer pain experienced prolonged relief with tolerable side effects and modest need for dose escalation during long-term therapy with CR oxycodone.

Intensity Modulated Radiation Therapy (IMRT) in the Management of Prostate Cancer

Intensity modulated radiation therapy (IMRT) is gaining widespread use in the radiation therapy community. Prostate cancer is the ideal target for IMRT due to the growing body of literature supporting dose escalation and normal tissue limitations. The need for dose escalation and the limits of conventional radiation therapy necessitate precise patient and prostate localization as well as advanced treatment delivery. The treatment of prostate cancer has been dramatically altered by the introduction of technology that can focus on the target while avoiding normal tissue. IMRT is evolving as the treatment of the future for prostate cancer.

Carcinoma of the skin with perineural invasion.

To evaluate the outcome and patterns of relapse in patients treated for skin carcinoma of the head and neck with either microscopic or clinical perineural invasion. Radiotherapy alone or combined with surgery was used to treat 135 patients with microscopic or clinical evidence of perineural invasion of skin carcinoma. All patients had at least 2 years of follow-up. The 5-year local control rates without salvage therapy were 87% with microscopic perineural invasion and 55% with clinical perineural invasion. Overall, 88% of the local failures occurred in patients with positive margins. Almost half of the recurrences in patients with microscopic perineural invasion were limited to the first-echelon regional nodes. However, only 1 of 11 patients with basal cell carcinoma with microscopic perineural invasion had a nodal failure. Ninety percent of recurrences in patients with clinical perineural invasion occurred at the primary site. Cranial nerve deficits rarely improved after successful treatment of the primary disease. Radiographic abnormalities remained stable 30% of the time when patients had clinical evidence of progressive disease. Radiotherapy in patients with skin cancer with clinical perineural invasion should include treatment of the first-echelon regional lymphatics. The risk of regional node involvement is also relatively high for patients with squamous cell carcinoma with microscopic perineural invasion. In patients with clinical perineural invasion, the poor local control rates with conventional radiotherapy suggest a need for dose escalation with or without concomitant chemotherapy.

Technological advances in external-beam radiation therapy for the treatment of localized prostate cancer

The relative inability of conventional radiotherapy to control localized prostate cancer results from resistance of subpopulations of tumor clonogens to dose levels of 65 to 70 Gy, the maximum feasible with traditional two-dimensional (2D) treatment planning and delivery techniques. Several technological advances have enhanced the precision and improved the outcome of external-beam radiotherapy. The three-dimensional conformal radiotherapy (3D-CRT) approach has permitted significant increases in the tumor dose to levels beyond those feasible with conventional techniques. Intensity-modulated radiotherapy (IMRT), an advanced form of conformal radiotherapy, has resulted in reduced rectal toxicity, permitting tumor dose escalation to previously unattainable levels with a concomitant improvement in local tumor control and disease-free survival. The combination of androgen deprivation and conventional-dose radiotherapy, tested mainly in patients with locally advanced disease, has also produced significant outcome improvements. Whether androgen deprivation will preclude the need for dose escalation or whether high-dose radiotherapy will obviate the need for androgen deprivation remains unknown. In some patients, both approaches may be necessary to maximize the probability of cure. In view of the favorable benefit-risk ratio of high-dose IMRT, the design of clinical trials to resolve these critical questions is essential.

Lack of radiation dose response for patients with low-risk clinically localized prostate cancer: a retrospective analysis

Purpose: The need for dose escalation for patients with low-risk clinically localized prostate cancer remains controversial. In this study, we report our pooled institutional experience of low-risk patients treated with a range of “standard” radiation doses to assess outcome in regard to biochemical failure and to determine whether a dose-response relationship exists within this conventional dose range. Methods and Materials: Patients with low-risk clinically localized prostate cancer (T1 or T2a, Gleason grade ≤6, and prostate-specific antigen ≤10 ng/mL) treated at Joint Center for Radiation Therapy-affiliated institutions between October 1989 and September 1997 were retrospectively analyzed for freedom from biochemical failure. The dose was prescribed volumetrically with 95% normalization to between 5760 and 6900 cGy (6100 and 7300 cGy ICRU reference point dose). Patients were stratified into 3 groups with relatively equal numbers of patients (<6660, 6660, and >6660 cGy). To ensure that any differences in biochemical failure between patients at the lower and higher ends of the dose range used were not masked by analysis of the entire cohort, patients receiving ≤6500 cGy or ≥6800 cGy were subsequently analyzed separately. Biochemical failure was defined per the ASTRO consensus definition. The log-rank test was used to assess for differences in follow-up and time to biochemical failure. A Kaplan-Meier plot of time to biochemical failure for the initial 3 subgroups was generated. Results: A total of 264 patients were identified. Sixteen patients whose dose was not recorded in the database were excluded from analysis. The median follow-up was 35 months. No significant differences were found in baseline prostate-specific antigen, Gleason grade, or clinical stage among the groups. The overall actuarial rate of 5-year freedom from biochemical failure was 80.2%. By dose level, the 5-year biochemical failure-free rate was 79.2%, 78.4%, and 84.5% for <6660 cGy, 6660 cGy, and >6660 cGy, respectively. These differences were not significant. Subsequently, 45 patients receiving ≤6500 cGy were compared with 23 patients receiving ≥6800 cGy. The difference between these groups was not significant. The 5-year freedom from biochemical failure rate for the patients receiving ≤6500 cGy was 89.9%. Conclusion: Within a range of doses considered standard for treatment of low-risk clinically localized prostate cancer during an 8-year period, no improvement in biochemical freedom from failure was noted with the higher doses. The overall 5-year rate of freedom from biochemical failure is consistent with that reported by others with standard and escalated external beam doses used in this low-risk population. A prospective randomized study is necessary to define the optimal dose in this patient population.

3D conformal radiation therapy (3DCRT) for high grade prostate cancer: a multi-institutional review

Purpose: To evaluate the results of 3DCRT and the effect of higher than traditional doses in patients with high grade prostate cancer, we compiled data from three institutions and analyzed the outcome of this relatively uncommon subset of prostate cancer patients. Methods and Materials: The 180 patients with Gleason score 8–10 adenocarcinoma of the prostate were treated with 3DCRT at the University of Michigan Health System, University of California-San Francisco, or Fox Chase Cancer Center. Eligible patients had T1-T4 N0 or NX M0 adenocarcinoma with a pretreatment PSA. Pretreatment characteristics included: median age 72 years, 60.6% Gleason score 8 tumors, 57.6% T1-T2, and median pretreatment PSA 17.1 ng/ml (range 0.3–257.1). The total dose received was <70 Gy in 30%, 70–75 Gy in 37%, and >75 Gy in 33%; 27% received adjuvant or neoadjuvant hormonal therapy. The median follow-up was 3.0 years for all patients and 16% of patients were followed up for at least 5 years. Results: The 5-year freedom from PSA failure was 62.5% for all patients and 79.3% in T1-T2 patients. Univariate analysis revealed that T-stage (T1-T2 vs. T3-T4), pretreatment PSA, and RT dose predicted for freedom from PSA failure. A 5-year overall survival for all patients was 67.3%. Only RT dose was predictive of 5-year overall survival on univariate analysis. Because a significant association was seen between T-stage and RT dose, the Cox proportional hazards model was performed separately for T1-T2 and T3-T4 tumors. None of the prognostic factors reached statistical significance for overall survival or freedom from PSA failure in T3-T4 patients or for overall survival in T1-T2 patients. Lower RT dose and higher pretreatment PSA predicted for PSA failure on multivariate analysis in T1-T2 patients. Conclusion: This retrospective study from three institutions with experience in dose escalation suggests a dose effect for PSA control above 70 Gy in patients with T1-T2 high grade prostate cancer. These results are superior to surgery and emphasize the need for dose escalation in treating Gleason 8–10 prostate cancer.

Ergebnisse einer standardisierten Umfrage zur medizinischen Verwendung von Cannabisprodukten im deutschen Sprachraum

Results of a Standardized Survey on the Medical Use of Cannabis Products in the German-Speaking Area The plant Cannabis sativa has a long history of medical use in the treatment of pain and spasms, the promotion of sleep, and the suppression of nausea and vomiting. However, in the early 70s cannabis was classified in the Narcotic Acts in countries all over the world as having no therapeutic benefit; therefore, it cannot be prescribed by physicians or dispensed by pharmacists. In the light of this contradictory situation an increasing number of patients practices a self-prescription with cannabis products for relieving a variety of symptoms. An anonymous standardized survey of the medical use of cannabis and cannabis products of patients in Germany, Austria and Switzerland was conducted by the Association for Cannabis as Medicine (Cologne, Germany). During about one year 170 subjects participated in this survey; questionnaires of 128 patients could be included into the evaluation. 68% of these participants were males, 32% females, with a total mean age of 37.5 (± 9.6) years. The most frequently mentioned indications for medicinal cannabis use were depression (12.0%), multiple sclerosis (10.8%), HIV-infection (9.0%), migraine (6.6%), asthma (6.0%), back pain (5.4%), hepatitis C (4.8%), sleeping disorders (4.8%), epilepsy (3.6%), spasticity (3.6%), headache (3.6%), alcoholism (3.0%), glaucoma (3.0%), nausea (3.0%), disk prolapse (2.4%), and spinal cord injury (2.4%). The majority of patients used natural cannabis products such as marihuana, hashish and an alcoholic tincture; in just 5 cases dronabinol (Marinol^(r)) was taken by prescription. About half of the 128 participants of the survey (52.4%) had used cannabis as a recreational drug before the onset of their illness. To date 14.3% took cannabis orally, 49.2% by inhalation and in 36.5% of cases both application modes were used. 72.2% of the patients stated the symptoms of their illness to have ''much improved'' after cannabis ingestion, 23.4% stated to have ''slightly improved'', 4.8% experienced ''no change'' and 1.6% described that their symptoms got ''worse''. Being asked for the satisfaction with their therapeutic use of cannabis 60.8% stated to be ''very satisfied'', 24.0% ''satiesfied'', 11.2% ''partly satisfied'' and 4.0% were ''not satisfied''. 70.8% experienced no side effects, 26.4% described ''moderate'' and 3.3% ''strong'' side effects. 84.1% of patients have not felt any need for dose escalation during the last 3 months, 11.0% had to increase their cannabis dose ''moderately'' and 4.8% ''strongly'' in order to maintain the therapeutic effects. Thus, this survey demonstrates a successful use of cannabis products for the treatment of a multitude of various illnesses and symptoms. This use was usually accompanied only by slight and in general acceptable side effects. Because the patient group responding to this survey is presumably highly selected, no conclusions can be drawn about the quantity of wanted and unwanted effects of the medicinal use of the hemp plant for particular indications.