Friday, June 18, 2010

RT protocol compliance and outcome for H&N cancer

JCO: In addition to reporting out the negative results of tirapazamine, the TROG investigators reported on those with protocol violations, and found at SS worse over all survival (HR = 2!) and local control. i.e. - expertise does matter, at least for H&N RT.

Link and Abstract:

Critical Impact of Radiotherapy Protocol Compliance and Quality in the Treatment of Advanced Head and Neck Cancer: Results From TROG 02.02 [Head and Neck Cancer]: "Purpose

To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer.

Patients and Methods

The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality.


At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; ≥ 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): –2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively.


These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.


Tirapazamine for H&N cancer

JCO: A phase three trial looking at the addition of tipazamine (a selective hypoxic cytotoxin) is reported in JCO this week. Unfortunately there were no significant differences.

Link and Abstract:

Tirapazamine, Cisplatin, and Radiation Versus Cisplatin and Radiation for Advanced Squamous Cell Carcinoma of the Head and Neck (TROG 02.02, HeadSTART): A Phase III Trial of the Trans-Tasman Radiation Oncology Group [Head and Neck Cancer]: "Purpose

Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial.

Patients and Methods

Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m2) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m2) plus TPZ (290 mg/m2/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m2/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69).


Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS – CIS: 95% CI, –5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy–Head and Neck.


We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.


Monday, June 14, 2010

HPV and H&N cancer


The RTOG 0129 protocol of altered fractionation with chemo vs. standard fractionation with chemo in head and neck cancers is a negative trial, however, published in the NEJM this week is the results of the trial broken down by prognostic factor. Unsurprisingly HPV plays a large role in oropharynx cancers, and clearly needs to be taken into account when designing future trials.


Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer

Sunday, June 6, 2010

ASCO 2010: Sequential Chemo then RT vs concurrent CTRT in Cervical Cancer

ASCO 2010:

A phase III trial of induction carboplatin and paclitaxel followed by WPRT and brachy compared to standard concurrent chemoradiotherapy followed by brachy in cervical cancer. They find no significant difference in OS or PFS, but trends favored induction treatment. The toxicity profiles also favored the sequential (experimental) arm.

So what's not to like? Well, as Dr. Eifel stated in her excellent discussion of the data, multiple trials of induction treatment prior to the concurrent CDDP era were negative for benefit, perhaps due to accelerated repopulation. This is a small trial, and occurs in the setting of multiple large randomized trials demonstrating a dramatic benefit to concurrent cddp and radiation. Her conclusion in the discussion were that large international trials should be designed to confirm the use of either induction or adjuvant chemotherapy, and especially before abandoning concurrent cisplatin.


Randomized phase III adjuvant study in high-risk cervical cancer: Simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): A NOGGO-AGO-Intergroup Study.

Saturday, June 5, 2010

TMZ alone or RT alone for elderly patients with GBM

ASCO 2010:

Two similarly sized and designed trials are reported which randomized patients >65 in the NOA-08 and >60 Malmstrom abstract to temozolomide vs RT alone and came to different conclusions. In the NOA-08 trial TMZ alone was not non-inferior (i.e. it was worse) than RT - which is the current standard. In the Malmstrom abstract they looked at conventional RT(60Gy in 2Gy/day) vs a hypofractionated regimen vs TMZ, and found no difference (even the trend was against RT). The TMZ was also different between the trials (1week on and off in the NOA trial vs d1-5 Q28 in the Malmstrom abstract). Regardless of which treatment paradigm was pursued, the outcome comparisons are poor no matter what, and better treatment stratagies should be explored.

Addendum - The abstract discussion was lively, primarily focused on the Malmstrom piece. There were some concerns that this trial had a poorer prognosis group which may not have benefited by 60Gy in 2Gy/fx.

Dr. Grossman discussed the trial - and pointed out that in the Stupp EORTC trial, there is a subgroup analysis in those >60 years of age - which seem to have a benefit in the tail of the curve with combined TMZ/RT. Therefore in a good PS patient, between 60-70yrs, combined treatment is the standard in this group. He also points out that MGMT status also matters in elderly patients (Gerstner). And lastly, the control arm of the Stupp trial (RT alone) between years of 60-70 performed much better than any of the arms of these two trials, suggesting that patient selection is driving a lot of these differences.


Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).

IORT (20Gy x 1) for early stage breast cancer

ASCO 2010:
The international TARGIT trial reports 24 month median follow up for local control, their primary endpoint. This randomized 2,231 patients to a single intraoperative treatment vs. standard WBRT. At early followup, there was no difference between the arms (0.31% for IORT and 0.29% for WBRT). There was a small and non-significant increase in wound healing issues with IORT, and the overall incidence of RTOG G3 toxicity was significantly lower in the IORT arm. While followup is clearly needed from this abstract, this data is quite provocative and the manuscript is already available showing no difference at a 4 year endpoint (published early online at the Lancet). This potentially could affect practice quite dramatically and replace APBI for the lowest risk patients...


Safety and efficacy of targeted intraoperative radiotherapy (TARGIT) for early breast cancer: First report of a randomized controlled trial at 10-years maximum follow-up.

NSABP B-32 confirming the safety of SNB in clinically node negative breast cancer

ASCO 2010:
This abstract is the 8 year follow up of the NSABP B-32 trial, which compared SNB (sentinel node biopsy) alone vs axillary dissection in clinically node negative patients. 5,611 patients were randomized in this trial, with the power to detect a 2% difference in DFS at 5 years. Thankfully for current practice, there was no difference between the two groups.

Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients.

Wednesday, June 2, 2010

Neurocognitive effects of Partial Brain Irradiation

In the Red Journal - 9402 was a randomized trial of RT +/- PCV for AO, but one of the strengths of the trial was that prospective analysis of neurocognition was built in. What I find interesting in this report is that both arms had a stable "Brain quality of life" through the follow up period even compared to baseline (though not surprisingly this did decline in the last year of life for those who died on trial). As such little is known on the long term effects of partial brain irradiation, this observation adds significantly to our understanding of this.

Link and Abstract

Cognition and Quality of Life After Chemotherapy Plus Radiotherapy (RT) vs. RT for Pure and Mixed Anaplastic Oligodendrogliomas: Radiation Therapy Oncology Group Trial 9402: "Purpose: Radiation Therapy Oncology Group 9402 compared procarbazine, lomustine, and vincristine (PCV) chemotherapy plus radiation therapy (PCV + RT) vs. RT alone for anaplastic oligodendroglioma. Here we report longitudinal changes in cognition and quality of life, effects of patient factors and treatments on cognition, quality of life and survival, and prognostic implications of cognition and quality of life.Methods and Materials: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL). Scores were analyzed for survivors and within 5 years of death. Shared parameter models evaluated MMSE/B-QOL with survival.Results: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those who died, MMSE scores remained stable initially, whereas B-QOL slowly declined; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (p = 0.0413 for MMSE; p = 0.0016 for B-QOL) and were superior with age <50 years (p < 0.001 for MMSE; p = 0.0554 for B-QOL) and Karnofsky Performance Score (KPS) 80–100 (p < 0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV + RT (HR = 0.66, 95% CI = 0.49–0.9, p = 0.0084; HR = 0.74, 95% CI = 0.54–1.01, p = 0.0592) in models with MMSE and B-QOL. In addition, there were no differences in MMSE and B-QOL scores between arms (p = 0.4752 and p = 0.2767, respectively); higher scores predicted longer survival.Conclusion: MMSE and B-QOL scores held steady in the upper range in both arms for survivors. Younger, fitter patients had better MMSE and B-QOL and longer survival."

Tuesday, June 1, 2010

40Gy at 2Gy BID vs 20GY in 5Gy QD for WBRT

In the Red Journal: A randomized trial of 40Gy at 2Gy BID vs 20Gy in 5Gy fractions is reported, showing improved control with more fractionation and high total doses. How this would compare to a more standard US approach of 30Gy at 3Gy/day or 35 at 2.5Gy per day is uncertain, however it does show that these issues matter even when palliating brain metastases.

Link and Abstract:

Randomized Comparison of Whole Brain Radiotherapy, 20 Gy in Four Daily Fractions Versus 40 Gy in 20 Twice-Daily Fractions, for Brain Metastases: "Purpose: The present study compared the intracranial control rate and quality of life for two radiation fractionation schemes for cerebral metastases.Methods and Materials: A total of 113 patients with a Eastern Cooperative Oncology Group performance status <3; and stable (>2 months), absent, or concurrent presentation of extracranial disease were randomized to 40 Gy in 20 twice-daily fractions (Arm A) or 20 Gy in four daily fractions (Arm B), stratified by resection status. The European Organization for Research and Treatment of Cancer Quality of Life 30-item questionnaire was administered monthly during Year 1, bimonthly during Year 2, and then every 6 months to Year 5.Results: The patient age range was 28–83 years (mean 62). Of the 113 patients, 41 had undergone surgical resection, and 74 patients had extracranial disease (31 concurrent and 43 stable). The median survival time was 6.1 months in Arm A and 6.6 months in Arm B, and the overall 5-year survival rate was 3.5%. Intracranial progression occurred in 44% of Arm A and 64% of Arm B patients (p = .03). Salvage surgery or radiotherapy was used in 4% of Arm A patients and 21% of Arm B patients (p = .004). Death was attributed to central nervous system progression in 32% of patients in Arm A and 52% of patients in Arm B (p = .03). The toxicity was minimal, with a minor increase in short-term cutaneous reactions in Arm A. The patients’ quality of life was not impaired by the more intense treatment in Arm A.Conclusion: Intracranial disease control was improved and the quality of life was maintained with 40 Gy in 20 twice-daily fractions. This schema should be considered for better prognosis subgroups of patients with cerebral metastases."

Chemo + Hyperthermia for STS

In the Lancet Oncology - a phase III trial of chemo plus or minus hyperthermia is published resulting in a survival benefit.


[Articles] Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study: "The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy."

Six fractions of RT per week for H&N

In Lancet Oncology this week a Phase III international trial comparing 5 vs 6 fractions of RT per week of H&N cancers demonstrates an improvement in local control (HR 0.63), comparable to the improvements seen with other altered fractionation, and significantly simpler than concominant boost or BID treatments.

Link below -

[Articles] Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial: "Several large randomised studies from western Europe and the USA have shown that accelerated fractionation of radiotherapy might be beneficial in the treatment of squamous-cell carcinoma of the head and neck (HNSCC). The aim of this study—the International Atomic Energy Agency (IAEA) ACC trial—was to determine whether accelerated fractionation could be applied in developing countries, where there are fewer therapeutic resources and where tumour burdens can be heavier."