The Beam's Eye View

Radical Prostatectomy versus Observation for Localized Prostate Cancer

2012-07-20T12:34:00.001-07:00

This weeks NEJM:

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.

Link:

Radical Prostatectomy versus Observation for Localized Prostate Cancer: New England Journal of Medicine, Volume 367, Issue 3, Page 203-213, July 2012.

Temozolomide vs RT in the Elderly with GBM

2012-07-02T14:22:00.001-07:00

In the Lancet Oncology this week:

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?

Link:

[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.

5FU Oxaliplatin in Rectal Cancer

2012-07-02T14:09:00.001-07:00

In the Lancet Oncology this week,

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.

Link

[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.

Carbo + RT in the elderly with NSCLC

2012-07-02T13:56:00.001-07:00

In the Lancet Oncology this week:

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.

Link

[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 updated: Adjuvant CTRT for Gastric Cancer

2012-07-02T13:43:00.001-07:00

In The JCO this week:

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.

link:

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.

Results
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.

Conclusion
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.

NEJM: Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma

2012-06-11T08:21:00.001-07:00

The Trametinib trial for BRAF-Mutated Melanoma hits the NEJM this week. The difference in OS despite crossover is remarkable for a chemo/targeted trial, and speaks to how much promise this treatment has in this subset of patients.

Link:

Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma: New England Journal of Medicine,

RTOG released pelvic normal tissue atlas

2012-06-04T08:16:00.001-07:00

In the Red Journal:

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.

11 year update on the German Rectal Cancer Trial

2012-06-01T12:45:00.001-07:00

In the JCO this week:

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.

Results
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.

Conclusion
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.

NEJM: neoadjuvant CTRT for esophageal cancer

2012-06-01T04:58:00.001-07:00

NEJM this week

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.

RT for prevention of nodal recurrences of Melanoma

2012-05-29T13:19:00.001-07:00

Lancet Oncology this week:

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.

Link:

[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.

Capecitabine for Rectal Cancer

2012-05-29T13:06:00.001-07:00

In Lancet Oncology:

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.

Link:

[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.

Pazopanib for study tissue sarcoma

2012-05-22T12:45:00.001-07:00

from the Lancet this week: a new option where there are so few to start... [Articles] Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised , double-blind, placebo-controlled phase 3 trial

Vestibular Schwannoma treated with FSRT

2011-10-07T09:30:00.000-07:00

In the Red Journal this week.

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 for GBM

2011-10-07T08:28:00.000-07:00

In the red journal this week:

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.

GNRH analogues with Chemo for prevention of Chemo induced ovarian failure

2011-07-25T09:32:00.000-07:00

in JAMA this week

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"

Short Term ADT and RT in Prostate: RTOG9408 in the NEJM

2011-07-14T08:37:00.000-07:00

In the NEJM today:

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...

Link:

Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer: "New England Journal of Medicine, Volume 365, Issue 2, Page 107-118, July 2011."

Oxaliplatin for Neoadjuvant CTRT for Rectal Cancer

2011-07-11T15:47:00.000-07:00

In the JCO:

An initial report of a randomized trial looking at the addition of oxaliplatin to the standard 5FU based CTRT for neoadjuvant treatment for rectal cancer shows no difference in immediate pathologic outcomes, despite increased toxicity. While pCR rates might not be the whole story, this trial is another bucket of cold water on this approach for neoadjuvant treatment of rectal cancer.

Link and Abstract:

Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial [Gastrointestinal Cancer]: "Purpose

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.

JCO Palifermin for Mucositis Prevention in H&N cancer

2011-07-11T14:37:00.000-07:00

In the JCO this week:

An interesting randomized trial of palifermin for mucositis prevention in patients recieving CTRT postoperatively for H&N cancer. They do find a moderate benefit to the drug, with decreased duration and longer time to developement of severe mucositis. There was also no evidence of disease protection. Interesting to see however if this breaks into common usage, or if it stays on the shelf with Amifostine.

Link and Abstract:

Palifermin Decreases Severe Oral Mucositis of Patients Undergoing Postoperative Radiochemotherapy for Head and Neck Cancer: A Randomized, Placebo-Controlled Trial [Head and Neck Cancer]: "Purpose

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.

Treatment of cancer pain

2011-06-27T10:38:00.000-07:00

In the Lancet:

A reasonable review of the management of cancer related pain:

Link:

[Series] Treatment of cancer pain: "SummaryIn patients with active cancer, the management of chronic pain is an essential element in a comprehensive strategy for palliative care. This strategy emphasises multidimensional assessment and the coordinated use of treatments that together mitigate suffering and provide support to the patient and family. This review describes this framework, an approach to pain assessment, and widely accepted techniques to optimise the safety and effectiveness of opioid drugs and other treatments. The advances of recent decades suggest a future that includes increased evidence-based targeting of specific analgesic interventions within an individualised plan of care that is appropriate throughout the course of illness."

Meta analysis: Neoadjuvant treatment for Esophageal Cancer

2011-06-27T10:33:00.000-07:00

In the Lancet Oncology:

A meta-analysis is updated, again suggesting that neoadjuvant treatment results in superior results over surgery alone for esophageal cancer. The comparison between chemoradiotherapy and chemotherapy was not quite significant, but there was a strong trend towards better results with chemoradiation.

Link:

[Articles] Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis: "SummaryBackgroundIn a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy or chemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysis with results from new or updated randomised trials presented in the past 3 years. We also compared the benefits of preoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy.MethodsTo identify additional studies and published abstracts from major scientific meetings, we searched Medline, Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manually searched for abstracts from major conferences from the same period."

secondary breast cancer after RT for HL

2011-06-17T07:02:00.000-07:00

In the JCO this week:

An interesting article looking at the prognosis of patients developing a secondary breast cancer after RT for Hodgkin's Lymphoma, compared to sporadic disease. Perhaps not surprisingly, the cancers were detected earlier (due to more intensive screening), and was more likely to be bilateral. Additionally, there was increased risk to the other breast later in the woman's life. There was an increased risk of all cause mortality, and a non-significant increase in breast cancer specific mortality.

What this trial doesn't answer however is how patients with HL who did not recieve RT do with respect to breast cancer outcomes; therefor making it a little more difficulty to tease out the true effect of radiotherapy. That said, the finding are very consistent with the known increased risk of breast cancer induction from RT, and appropriately recommends close surveillance of these patients.

Abstract and Link:

Characteristics and Outcomes of Breast Cancer in Women With and Without a History of Radiation for Hodgkin's Lymphoma: A Multi-Institutional, Matched Cohort Study [Breast Cancer]: "Purpose

To compare characteristics and outcomes of breast cancer in women with and without a history of radiation therapy (RT) for Hodgkin's lymphoma (HL).

Patients and Methods

Women with breast cancer diagnosed from 1980 to 2006 after RT for HL were identified from eight North American hospitals and were matched three-to-one with patients with sporadic breast cancer by age, race, and year of breast cancer diagnosis. Information on patient, tumor and treatment characteristics, and clinical outcomes was abstracted from medical records.

Results

A total of 253 patients with breast cancer with a history of RT for HL were matched with 741 patients with sporadic breast cancer. Median time from HL to breast cancer diagnosis was 18 years. Median age at breast cancer diagnosis was 42 years. Breast cancer after RT for HL was more likely to be detected by screening, was more likely to be diagnosed at an earlier stage, and was more likely to be bilateral at diagnosis. HL survivors had an increased risk of metachronous contralateral breast cancer (adjusted hazard ratio [HR], 4.3; 95% CI, 1.7 to 11.0) and death as a result of any cause (adjusted HR, 1.9; 95% CI, 1.1 to 3.3). Breast cancer–specific mortality was also elevated, but this difference was not statistically significant (adjusted HR, 1.6; 95% CI, 0.7 to 3.4).

Conclusion

In women with a history of RT for HL, breast cancer is diagnosed at an earlier stage, but these women are at greater risk for bilateral disease and are more likely to die as a result of causes other than breast cancer. Our findings support close follow-up for contralateral tumors in these patients and ongoing primary care to manage comorbid conditions.

Sentinel Nodes for Endometrial Cancer

2011-05-09T13:06:00.000-07:00

In Lancet Oncology

Results of a sentinel node lymph node biopsy in endometrial cancer are published, and they report a high NPV. Though it is buried in the paper, the sensitivity was 84%, which is a little bit lower than other SNLB series. As I count it, there were 3 patients who had a negative SLNB out of a total of 20 patients with nodal positivity, for a false negative rate of 15%.

This is a little less compelling than the more established vulvar sentinel studies, or the more recently reported cervical cancer series, but does raise some interesting possibilities. As the utility of dissection is debatable in endometrial cancer (as opposed to vuvla or cervix) - is a simple, less morbid, though admittedly less accurate means of staging "good enough?"

Link:

[Articles] Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO): "SLN biopsy with cervical dual labelling could be a trade-off between systematic lymphadenectomy and no dissection at all in patients with endometrial cancer of low or intermediate risk. Moreover, our study suggests that SLN biopsy could provide important data to tailor adjuvant therapy."

Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer

2011-05-09T08:19:00.000-07:00

In the NEJM

An update to the Scandinavian randomized trial of Prostatectomy vs Watchful Waiting appears in the NEJM this week. Very useful for it's delineation of the natural history of early stage prostate cancer and the expected results with radical local therapy. Of course, it is impossible to know what the results of brachytherapy or EBRT would be in comparison to RP; nonetheless, it gives one ballpark numbers when counseling patients on their options.

Link:

Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer: New England Journal of Medicine, Volume 364, Issue 18, Page 1708-1717, May 2011.

Long term toxicity of WPRT for endometrial cancer (results of PORTEC 1)

2011-05-09T08:12:00.000-07:00

In the JCO

Long term toxicity data for the PORTEC 1 trial sees manuscript publication (previously presented at ASTRO 2 years ag0). Worth a read, as the investigators find significant long term toxicity from WPRT. These results should be taken with some caveats however, as the surveys were sent out after the fact (only 351 surveys were sent out, of 714 in the full trial, and there was a 70% responsed rate for those 351). This raises the question of recall and selection bias. One can easily speculate that the patients continuing in followup were those that had complications. Additionally, one could also speculate that one is more likely to answer a QOL survey if one has significant symptoms.

That said, this should give the practicing radiation oncologist pause when recommending WPRT if there are alternatives (VBT) or a low risk of recurrence even in the absence of adjuvant therapy.

Link and Abstract:

Long-Term Outcome and Quality of Life of Patients With Endometrial Carcinoma Treated With or Without Pelvic Radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) Trial [Gynecologic Cancer]: "Purpose

To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial.

Patients and Methods

Between 1990 and 1997, 714 patients with stage IC grade 1 to 2 or IB grade 2 to 3 EC were randomly allocated to pelvic external-beam radiotherapy (EBRT) or no additional treatment (NAT). HRQL was evaluated with the Short Form 36-Item (SF-36) questionnaire; subscales from the European Organisation for Research and Treatment of Cancer (EORTC) PR25 module for bowel and bladder symptoms and the OV28 and CX24 modules for sexual symptoms; and demographic questions. Analysis was by intention-to-treat.

Results

Median follow-up was 13.3 years. The 15-year actuarial locoregional recurrence rates were 5.8% for EBRT versus 15.5% for NAT (P < .001), and 15-year overall survival was 52% versus 60% (P = .14). Of the 351 patients confirmed to be alive with correct address, 246 (70%) returned the questionnaire. Patients treated with EBRT reported significant (P < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after EBRT (day and night use, 42.9% v 15.2% for NAT; P < .001). Patients treated with EBRT reported lower scores on the SF-36 scales "physical functioning" (P = .004) and 'role-physical' (P = .003).

Conclusion

EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower physical and role-physical functioning, even 15 years after treatment. Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC.

Sentinel Nodes in Cervical Cancer

2011-05-09T07:35:00.000-07:00

In the JCO

Sentinel node mapping is making an appearance in all of the gynecologic cancers, most notably vulvar cancer, however two recent studies have examined the technique in cervix and endometrial cancer. The current study is in IA1-IB1 cervical lesions undergoing surgical staging and management, all of who were evaluated with a SNLB and then with a full dissection. The false negative rate was 8% (2/25), which is similar to the experience in breast. The investigators also noted that if bilateral nodes were mapped, there were no false negatives, but I would apply that with some caution as it appears to be a post hoc analysis.

While the rate false negative rate is similar to breast cancer, it remains to be seen if the clinical results will be the same as breast cancer. While this is a great step in the path towards integrating this into the management of early cervical cancer, one awaits a clinical trial in which the completion dissection is not performed, with careful follow up of the results. One must also be mindful of what we are actually accomplishing by performing less extensive dissections - while there are some adverse events associated with pelvic and PA dissections, in general they are relatively rare. The benefit of less extensive nodal sampling is much clearer in vulvar and breast cancer, where the risk of morbidity due to lymphedema is correspondingly higher.

Link and Abstract:

Bilateral Negative Sentinel Nodes Accurately Predict Absence of Lymph Node Metastasis in Early Cervical Cancer: Results of the SENTICOL Study [Gynecologic Cancer]: "Purpose

Sentinel lymph node (SLN) biopsy may be used to target lymph node metastases in patients with early cervical cancer. Whether SLN biopsy only is acceptable in the staging and surgical management of early cervical cancer remains unknown. This prospective multicenter study (SENTICOL [Ganglion Sentinelle dans le Cancer du Col]) assessed the sensitivity and negative predictive value (NPV) of SLN biopsy.

Patients and Methods

Adults with cervical carcinoma who met the International Federation of Gynecology and Obstetrics criteria for stage IA1 with lymphovascular space invasion to stage IB1 underwent technetium 99 lymphoscintigraphy and Patent Blue injection followed by laparoscopic lymph node mapping, SLN removal, and lymph node dissection. Only surgeons trained in SLN biopsy in cervical carcinoma participated in the study. SLNs and nonsentinel lymph nodes underwent routine staining. Negative SLNs were subjected to ultrastaging. The reference method was pelvic and/or para-aortic lymphadenectomy with histologic examination of all nodes.

Results

One hundred forty-five patients were enrolled, and 139 were included in a modified intention-to-diagnose analysis. Intraoperative radioisotope-blue dye mapping detected at least one SLN in 136 patients (97.8%; 95% CI, 93.8% to 99.6%), 23 of whom had true-positive results and two who had false-negative results, yielding 92.0% sensitivity (23 of 25; 95% CI, 74.0% to 99.0%) and 98.2% NPV (111 of 113; 95% CI, 74.0% to 99.0%) for node metastasis detection. No false-negative results were observed in the 104 patients (76.5%) in whom SLN were identified bilaterally.

Conclusion

Combined labeling for node mapping was associated with high rates of SLN detection and with high sensitivity and NPV for metastasis detection. However, SLN biopsy was fully reliable only when SLNs were detected bilaterally.