Friday, July 20, 2012
The PIVOT trial is published in the NEJM, a randomized comparison of observation vs radical prostatectomy for localized prostate cancer. The headline findings: no difference in overall survival. However, this one is worth looking a little more closely at.
The first item that strikes me is the low numbers of this trial. This is in theory a non-inferiority trial of observation, however, one can rarely design these with any relevant power with less than a couple of thousand. And in fact when reviewing the statistical design, the investigators downgraded their definition of non-inferiority due to poor accrual - to at 25% reduction in mortality. This is a pretty low bar for non-inferiority. The trial was initially designed to accrue 2000.
Moreover, in the observation arm 20% of the enrollee's entered into a curative treatment, 10% prostatectomy, and 10% radiation (mix of EBRT and brachy). This further dilutes the potential power of this study. 15% of the prostatectomy arm also underwent observation.
And in fact, when one looks at the forest plots in figure 3, the hazard ratios for benefit are pretty consistently in the favoring prostatectomy side, with only the confidence intervals overlapping one. Only in the low risk subgroup did the HR cross to favoring observation.
I feel the investigators should have qualified their conclusions a little more in this trial. When a study is underpowered one expected not to see a significant result: however, in non-inferiority trials, when a positive result hinges on there being no difference in results between two arms - these issues of power, accrual and crossover become much more troublesome. All these factors work to deteriorate the quality of a trial, and make a non-statisically significant result more likely.
Radical Prostatectomy versus Observation for Localized Prostate Cancer: New England Journal of Medicine, Volume 367, Issue 3, Page 203-213, July 2012.
Monday, July 2, 2012
A trial from German is published reported the results of a phase III trial of RT alone vs Temozolomide alone in the elderly. They find that temozolomide is "non-inferior" to RT alone - however, they define "non-inferior"as not >25% worse that RT. This would be a hard sell for a new standard therapy in almost any other setting, and if one looks at the survival curves, RT does appear to do better for the first 6 months or so for RFS, and most paitents crossed over so that most patients on this trial eventually recieved both. I find the MGMT findings quite interesting (though only 'hypothesis generating'), in that MGMT methylation predicted for a benefit of temozolomide alone, but had little predictive power in the RT alone group. The larger question I guess is that if most of these patients received both treatments anyway, why not have a go at concurrent treatment for the most benefit?
[Articles] Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making.
An interesting phase III study from Germany is reported, finding a modest increase in pathologic complete response in patients treated with oxaliplatin + 5FU + RT, vs 5FU + RT alone. This is interesting in that a prior report in the JCO, demonstrated no such increase. How to square these two accounts? I think firstly the benefit is modest with a pCR rate of 17% with oxaliplating and 14% without. This could have been missed in the STAR-01 trial as it was a smaller study. I think fundamentally, however, we need to follow both of these trials for long term outcome. Oxaliplatin surely has not been a slam dunk for increasing the pCR rates to 30%+ as some may have hoped; it may however still have some benefit in long term followup.
[Articles] Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial: Inclusion of oxaliplatin into modified fluorouracil-based combined modality treatment was feasible and led to more patients achieving a pathological complete response than did standard treatment. Longer follow-up is needed to assess DFS.
A Phase III trial from Japan is reported, showing a survival benefit with the addition of a modest dose of carboplatin with Thoracic RT. What I think is perhaps most interesting in this trial lies in the introduction: A prior JCOG study was halted prematurely due to excess deaths in the carbo arm - turns out that much of the toxicity related to poor radiotherapy design. With more stringent QA, this trial was conceived and executed - now demonstrating a significant effect. I would find this as cautionary tale for trial design moving forward - treatment escalation is well and good, but needs to be very carefully.
[Articles] Thoracic radiotherapy with or without daily low-dose carboplatin in elderly patients with non-small-cell lung cancer: a randomised, controlled, phase 3 trial by the Japan Clinical Oncology Group (JCOG0301): For a select group of elderly patients with locally advanced NSCLC, combination chemoradiotherapy provides a clinically significant benefit over radiotherapy alone, and should be considered for this population.
INT-0116 (or the "Macdonald" trial) is updated with longer followup. The OS and DFS benefit remains at long follow up, confirming this as a standard of care. I would hesitate to make too much of the subgroup analysis, which should be interpreted as a hypothesis generating exercise.
Updated Analysis of SWOG-Directed Intergroup Study 0116: A Phase III Trial of Adjuvant Radiochemotherapy Versus Observation After Curative Gastric Cancer Resection [Gastrointestinal Cancer]: Purpose
Surgical resection of gastric cancer has produced suboptimal survival despite multiple randomized trials that used postoperative chemotherapy or more aggressive surgical procedures. We performed a randomized phase III trial of postoperative radiochemotherapy in those at moderate risk of locoregional failure (LRF) following surgery. We originally reported results with 4-year median follow-up. This update, with a more than 10-year median follow-up, presents data on failure patterns and second malignancies and explores selected subset analyses.
Patients and Methods
In all, 559 patients with primaries ≥ T3 and/or node-positive gastric cancer were randomly assigned to observation versus radiochemotherapy after R0 resection. Fluorouracil and leucovorin were administered before, during, and after radiotherapy. Radiotherapy was given to all LRF sites to a dose of 45 Gy.
Overall survival (OS) and relapse-free survival (RFS) data demonstrate continued strong benefit from postoperative radiochemotherapy. The hazard ratio (HR) for OS is 1.32 (95% CI, 1.10 to 1.60; P = .0046). The HR for RFS is 1.51 (95% CI, 1.25 to 1.83; P < .001). Adjuvant radiochemotherapy produced substantial reduction in both overall relapse and locoregional relapse. Second malignancies were observed in 21 patients with radiotherapy versus eight with observation (P = .21). Subset analyses show robust treatment benefit in most subsets, with the exception of patients with diffuse histology who exhibited minimal nonsignificant treatment effect.
Intergroup 0116 (INT-0116) demonstrates strong persistent benefit from adjuvant radiochemotherapy. Toxicities, including second malignancies, appear acceptable, given the magnitude of RFS and OS improvement. LRF reduction may account for the majority of overall relapse reduction. Adjuvant radiochemotherapy remains a rational standard therapy for curatively resected gastric cancer with primaries T3 or greater and/or positive nodes.
Monday, June 11, 2012
Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma: New England Journal of Medicine,
Monday, June 4, 2012
Normal tissue contouring guidelines are released for normal tissue contouring in this week red journal. Extremely useful for those early in their career, and for defining a common criteria for OAR definition for clinical trial:
Link and Abstract:
Pelvic Normal Tissue Contouring Guidelines for Radiation Therapy: A Radiation Therapy Oncology Group Consensus Panel Atlas: Purpose: To define a male and female pelvic normal tissue contouring atlas for Radiation Therapy Oncology Group (RTOG) trials.Methods and Materials: One male pelvis computed tomography (CT) data set and one female pelvis CT data set were shared via the Image-Guided Therapy QA Center. A total of 16 radiation oncologists participated. The following organs at risk were contoured in both CT sets: anus, anorectum, rectum (gastrointestinal and genitourinary definitions), bowel NOS (not otherwise specified), small bowel, large bowel, and proximal femurs. The following were contoured in the male set only: bladder, prostate, seminal vesicles, and penile bulb. The following were contoured in the female set only: uterus, cervix, and ovaries. A computer program used the binomial distribution to generate 95% group consensus contours. These contours and definitions were then reviewed by the group and modified.Results: The panel achieved consensus definitions for pelvic normal tissue contouring in RTOG trials with these standardized names: Rectum, AnoRectum, SmallBowel, Colon, BowelBag, Bladder, UteroCervix, Adnexa_R, Adnexa_L, Prostate, SeminalVesc, PenileBulb, Femur_R, and Femur_L. Two additional normal structures whose purpose is to serve as targets in anal and rectal cancer were defined: AnoRectumSig and Mesorectum. Detailed target volume contouring guidelines and images are discussed.Conclusions: Consensus guidelines for pelvic normal tissue contouring were reached and are available as a CT image atlas on the RTOG Web site. This will allow uniformity in defining normal tissues for clinical trials delivering pelvic radiation and will facilitate future normal tissue complication research.
Friday, June 1, 2012
The German Rectal trial is updated. Again, local control benefit is confirmed out to long follow up, but this has not converted to an OS benefit. Of course preventing local recurrence remains an important endpoint for this disease, and confirms what has been standard of care in the US since it's initial publication in the NEJM.
Link and Abstract
Preoperative Versus Postoperative Chemoradiotherapy for Locally Advanced Rectal Cancer: Results of the German CAO/ARO/AIO-94 Randomized Phase III Trial After a Median Follow-Up of 11 Years [Gastrointestinal Cancer]: Purpose
Preoperative chemoradiotherapy (CRT) has been established as standard treatment for locally advanced rectal cancer after first results of the CAO/ARO/AIO-94 [Working Group of Surgical Oncology/Working Group of Radiation Oncology/Working Group of Medical Oncology of the Germany Cancer Society] trial, published in 2004, showed an improved local control rate. However, after a median follow-up of 46 months, no survival benefit could be shown. Here, we report long-term results with a median follow-up of 134 months.
Patients and Methods
A total of 823 patients with stage II to III rectal cancer were randomly assigned to preoperative CRT with fluorouracil (FU), total mesorectal excision surgery, and adjuvant FU chemotherapy, or the same schedule of CRT used postoperatively. The study was designed to have 80% power to detect a difference of 10% in 5-year overall survival as the primary end point. Secondary end points included the cumulative incidence of local and distant relapses and disease-free survival.
Of 799 eligible patients, 404 were randomly assigned to preoperative and 395 to postoperative CRT. According to intention-to-treat analysis, overall survival at 10 years was 59.6% in the preoperative arm and 59.9% in the postoperative arm (P = .85). The 10-year cumulative incidence of local relapse was 7.1% and 10.1% in the pre- and postoperative arms, respectively (P = .048). No significant differences were detected for 10-year cumulative incidence of distant metastases (29.8% and 29.6%; P = .9) and disease-free survival.
There is a persisting significant improvement of pre- versus postoperative CRT on local control; however, there was no effect on overall survival. Integrating more effective systemic treatment into the multimodal therapy has been adopted in the CAO/ARO/AIO-04 trial to possibly reduce distant metastases and improve survival.
Dutch investigators publish a randomized phase III trial looking at carbo-taxol+RT followed by surgery vs surgery alone for esophageal/GEJ cancers: they confirm a survival benefit to combined modality for both squams and adenos. While prior studies did show a benefit (the Walsh trial and the CALGB trial) both had low numbers and other concerns (such as the low survival in the surgery alone arm of the Walsh trial). This will hopefully close the book on surgery alone for all but the most early stages of disease. There still remains the question of whether the RT is adding anything to this (there are the perioperative chemo alone trials from the UK which are also positive), but for now it seems the weight of data is clearly towards multimodal treatment for this aggressive disease.
Link to NEJM
Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer: New England Journal of Medicine, Volume 366, Issue 22, Page 2074-2084, May 2012.
Tuesday, May 29, 2012
The Australian trial of adjuvant RT for nodal basins for melanoma, initially presented in ASTRO several years ago, has finally seen publication - again confirming a local control benefit to 48Gy in 24 fractions. The entry criteria was slightly complex, depending on size and # of nodes that was different per site, with extranodal extension always qualifying. Perhaps not surprisingly, there was no benefit for survival in such a small trial, but it was not powered for this regardless. In light of the relative lack of efficacy of standard chemotherapy, RT still seems to be the most reasonable option of any treatment outside of those with BRAF mutations.
[Articles] Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial: Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy.
A phase III trial comparing RT + capecitabine vs 5FU for rectal cancer - fortunately has confirmed what is already common practice in the US - capecitabine proved no worse (by their criteria). All trends as well favored capcitabine for disease control. Capcitabine proved more toxic however, in all but leukopenia.
[Articles] Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.
Tuesday, May 22, 2012
Friday, October 7, 2011
Johns Hopkins reports a sizeable series of vestibular schwannomas treated with FSRT. Interestingly, the failure rate (as defined by the need for salvage series) was quite low as expected at 3%, however a fairly large portion had some evidence of radiologic progression (30%).
Link and Abstract
Long-Term Outcomes of Vestibular Schwannomas Treated With Fractionated Stereotactic Radiotherapy: An Institutional Experience: Purpose: We assessed clinical outcome and long-term tumor control after fractionated stereotactic radiotherapy (FSRT) for unilateral schwannoma.Methods and Materials: Between 1995 and 2007, 496 patients were treated with fractionated stereotactic radiotherapy at Johns Hopkins Hospital (Baltimore, MD); 385 patients had radiologic follow-up that met the inclusion criteria. The primary endpoint was treatment failure. Secondary endpoints were radiologic progression and clinical outcome. Logistic regression analysis assessed the association of age, race, tumor side, sex, and pretreatment symptoms.Results: In 11 patients (3%) treatment failed, and they required salvage (microsurgical) treatment. Radiologic progression was observed in 116 patients (30.0%), including 35 patients (9%) in whom the treatment volume more than doubled during the follow-up period, although none required surgical resection. Tumors with baseline volumes of less than 1 cm3 were 18.02 times more likely to progress than those with tumor volumes of 1 cm3 or greater (odds ratio, 18.02; 95% confidence interval, 4.25–76.32). Treatment-induced neurologic morbidity included 8 patients (1.6%) with new facial weakness, 12 patients (2.8%) with new trigeminal paresthesias, 4 patients (0.9%) with hydrocephalus (1 communicating and 3 obstructive), and 2 patients (0.5%) with possibly radiation-induced neoplasia.Conclusions: Although the rate of treatment failure is low (3%), careful follow-up shows that radiologic progression occurs frequently. When reporting outcome, the “no salvage surgery needed” and “no additional treatment needed” criteria for treatment success need to be complemented by the radiologic data.
A simpler RPA limited to GBM is present from the RTOG, demonstrating a much more practical means of prognostic clasification.
Link and Abstract
Validation and Simplification of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification for Glioblastoma: Purpose: Previous recursive partitioning analysis (RPA) of patients with malignant glioma (glioblastoma multiforme [GBM] and anaplastic astrocytoma [AA]) produced six prognostic groups (I–VI) classified by six factors. We sought here to determine whether the classification for GBM could be improved by using an updated Radiation Therapy Oncology Group (RTOG) GBM database excluding AA and by considering additional baseline variables.Methods and Materials: The new analysis considered 42 baseline variables and 1,672 GBM patients from the expanded RTOG glioma database. Patients receiving radiation only were excluded such that all patients received radiation+carmustine. “Radiation dose received” was replaced with “radiation dose assigned.” The new RPA models were compared with the original model by applying them to a test dataset comprising 488 patients from six other RTOG trials. Fitness of the original and new models was evaluated using explained variation.Results: The original RPA model explained more variations in survival in the test dataset than did the new models (20% vs. 15%) and was therefore chosen for further analysis. It was reduced by combining Classes V and VI to produce three prognostic classes (Classes III, IV, and V+VI), as Classes V and VI had indistinguishable survival in the test dataset. The simplified model did not further improve performance (explained variation 18% vs. 20%) but is easier to apply because it involves only four variables: age, performance status, extent of resection, and neurologic function. Applying this simplified model to the updated GBM database resulted in three distinct classes with median survival times of 17.1, 11.2, and 7.5 months for Classes III, IV, and V+VI, respectively.Conclusions: The final model, the simplified original RPA model combining Classes V and VI, resulted in three distinct prognostic groups defined by age, performance status, extent of resection, and neurologic function. This classification will be used in future RTOG GBM trials.
Monday, July 25, 2011
Premature ovarian failure with chemotherapy is a well known phenomena, and may well be of benefit in premenopausal women with hormone sensitive cancers. However in Her-2 positive, or Triple negative cancers, this may result in additional morbidity with no therapeutic benefit. The use of GNRH analogues to reduce the effect of chemo on the ovaries has been suggested in the past, however in an article from Italy in this weeks JAMA, they show a significant reduction in the risk of premature ovarian failure. This may be quite useful in helping with the morbidity of treatment particularly in young women with hormone insensitive disease.
Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast Cancer: A Randomized Trial [Original Contribution]: "
Context Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available.Objective To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.
Design, Setting, and Patients The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data.Interventions Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy.
Main Outcome Measure Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy).Results The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of –17% (95% confidence interval, –26% to –7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).
Conclusion The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause.Trial Registration clinicaltrials.gov Identifier: NCT00311636"
Thursday, July 14, 2011
RTOG 9408 is published, a randomized trial for prostate cancer, T1b-T2b, PSA<=20. 1,979 were randomized between 66.6Gy RT alone, and with 4 months of neoadjuvant and concurrent ADT. Impressively, a survival advantage was seen at 10years, at 62% (RT + STADT) vs 57% (RT alone), with corresponding benefits in disease specific survival. The ADT was also reasonably well tolerated. In post-hoc analysis the benefit seemed confined to the intermediate and high risk patients on study.
However, as the authors appropriately acknowledge, we have moved away from 66.6Gy due to multiple positive dose escalation trials, and the applicability of this data with current treatment is unknown. Insert plug for RTOG 08-15 now...
At the end of the day, I think this bolsters the current practice, based on the D'Amico trial, of STADT in intermediate risk patients. I would hesitate to start lower risk patients on ADT just because of this trial...
Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer: "New England Journal of Medicine, Volume 365, Issue 2, Page 107-118, July 2011."
Monday, July 11, 2011
To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer.Patients and Methods
Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m2/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m2 weekly x 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here.Results
Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014).Conclusion
Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points."
Radiochemotherapy of head and neck cancer causes severe mucositis in most patients. We investigated whether palifermin reduces this debilitating sequela.Methods
We conducted a multicenter, double-blind, randomized, placebo-controlled trial in 186 patients with stages II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received 60 or 66 Gy after complete (R0) or incomplete resection (R1), respectively, at 2 Gy/fraction and five fractions per week. Cisplatin 100 mg/m2 was administered on days 1 and 22 (and on day 43 with R1). Patients were randomly assigned to receive weekly palifermin 120 µg/kg or placebo from 3 days before and continuing throughout radiochemotherapy. Trained evaluators performed oral assessments twice weekly. The primary end point was the incidence of severe oral mucositis (WHO grades 3 to 4). Overall survival and time to locoregional progression were also assessed. Analysis was by intention to treat.Results
Severe oral mucositis was seen in 47 (51%) of 92 patients administered palifermin and 63 (67%) of 94 administered placebo (P = .027). Palifermin decreased the duration (median, 4.5 v 22.0 days) and prolonged the time to develop (median, 45 v 32 days) severe mucositis. Neither patient-reported mouth and throat soreness scores nor treatment breaks differed between treatment arms. After median follow-up of 32.8 months, 23 deaths (25%) had occurred in both treatment arms, and disease had recurred in 25 (27%) and 22 (24%) of palifermin- and placebo-treated patients, respectively.Conclusion
Palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful."