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.

Results

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.

Conclusion

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).

Results

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.

Conclusions

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.

"

HPV and H&N cancer

NEJM:

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.

Link:

Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer

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.

Link:

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.

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.

Links:

NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem).

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...

Abstract:

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.

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."

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.

Link:

[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."

Hypofractionated Radiotherapy for Breast Cancer: is Grade 3 an exclusion criteria

A very interesting letter to the editor in the NEJM about the Whelan Hypofractionation trial for breast cancer. In the manuscript, a subset analysis was performed suggesting that high grade cancers did worse with hypofractionation. In a letter, the investigators of the START A and B trial reanalyzed their data looking for a similar finding and found no difference, in fact the trend was for G3 cancers to do better with hypofx in their data set.

I have been shying away from hypofx in G3 patients until now, but this data will make me much more comfortable offering it to our patients.

Link:

Hypofractionated Radiotherapy for Breast Cancer:

JCO: Meta-Analysis of Concurrent Versus Sequential CTRT in NSCLC

In the JCO this week -

A meta-analysis from Auperin is published confirming a survival benefit from concurrent CTRT vs sequential chemo then RT, at the expense of acute esophageal symptoms. No surprise here, and concurrent CTRT has been the standard in our department for quite a while, however, it is good to have more data to support a new standard of care.

Link and Abstract

Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non-Small-Cell Lung Cancer [Thoracic Oncology]: "Purpose

The previous individual patient data meta-analyses of chemotherapy in locally advanced non–small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy.

Methods

Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity.

Results

Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity.

Conclusion

Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

"

JCO: Prognosis with Radiation Associated Sarcomas

From the JCO:

An interesting series of radiation associated soft tissue sarcomas from MSKCC, which attempts to determine if there are differences in the prognosis with a matched cohort of sporadic STS. The DSS was indeed different with an HR of 1.7(p=0.007) on MVA, however, it is significant to note that the radiation associated tumors were not given RT as often (~50% less). How this difference in treatment may have affected outcomes is uncertain, however this could certainly contribute to the difference outcomes. Regardless, it is a worthwhile subject of study, and the mansucript is worth review for the practicing radiation oncologist.

Link and Abstract:

Do Radiation-Associated Soft Tissue Sarcomas Have the Same Prognosis As Sporadic Soft Tissue Sarcomas? [Sarcomas]: "Purpose

To determine the prognostic significance of histologic type in radiation-associated soft tissue sarcomas (RASs) and determine whether RASs are associated with an inferior prognosis compared with sporadic soft tissue sarcomas (STSs).

Patients and Methods

One hundred thirty primary RASs were identified from 7,649 STS patients from 1982 to 2007. Multivariate analysis of clinicopathologic factors for disease-specific survival (DSS) was performed for RASs, and a multivariate analysis of radiation exposure was also performed for RASs and sporadic sarcomas. A matched-cohort analysis was performed for radiation-associated and sporadic malignant fibrous histiocytoma (MFH).

Results

Most RASs were high grade (83%), deep (87%), and truncal (61.5%). The median interval between radiation therapy and RAS development was 10 years (range, 1.3 to 74 years), which varied significantly by histologic type (P = .003). The 5-year DSS was 58%, and independent predictors were size > 5 cm, margin positivity, and histologic type. Multivariate analysis of histologic types of primary, high-grade radiation-associated and sporadic STSs showed that RAS was associated with a worse DSS (hazard ratio, 1.7; range, 1.1 to 2.4; P = .007). For pleomorphic MFH—the most common RAS type—the 5-year DSS was 44% versus 66% in a matched cohort of sporadic MFH patients (P = .07). DSS was significantly worse in primary RAS malignant peripheral nerve sheath tumors (MPNSTs) compared with unmatched sporadic MPNSTs (P = .001).

Conclusion

Histologic type, margin status, and tumor size are the most important independent predictors of DSS in patients with RASs. DSS in patients with primary RAS is significantly worse compared with sporadic STS independent of sarcoma histologic type."

Predictive Nomogram for Brain Metastases in Metastatic Breast Cancer

In the JCO:

Investigators from MDACC have developed a nomogram which calculates the risk of brain metastases in patients with metastatic breast cancer, validated in the current manuscript with a cohort from Canada. Risk factors are what one might expect (high grade, low age, multiple sites of metastasis, HER2 positivity). Of course this then begs the question of what to do with the information, and opens the door to discussion of a PCI trial in high risk metastatic breast cancer...

Abstract and Link

Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer [Breast Cancer]: "Purpose

Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials.

Patients and Methods

Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada).

Results

Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities.

Conclusion

We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.

"

CHART results in H&N cancer

An interesting article in the Red Journal about CHART in H&N cancer. Essentially this randomized trial saw no difference in disease outcomes with CHART compared to conventional fractionation, but a reduction in toxicity, as one would expect with reduced dose per fraction. Of course this CHART is a logistical challenge to many rad onc departments, and this doesn't address the larger issue of chemotherapy (see other post about RTOG 0129). I would also venture that the doses are a little low compared to the standard 70-80Gy often uses without chemo for advanced disease.

Link and Abstract:

Mature Results of a Randomized Trial of Accelerated Hyperfractionated Versus Conventional Radiotherapy in Head-and-Neck Cancer: "Purpose: To evaluate long-term late adverse events and treatment outcome of a randomized, multicenter Phase III trial of continuous, hyperfractionated, accelerated radiotherapy (CHART) compared with conventional radiotherapy (CRT) in 918 patients with advanced squamous cell carcinomas of the head and neck.Methods and Materials: Survival estimates were obtained for locoregional relapse-free survival, local relapse-free survival, overall survival, disease-specific survival, disease-free survival and for late adverse events.Results: The 10-year estimates (±1 standard error) for locoregional relapse-free survival, overall survival, disease-free survival, and disease-specific survival were 43% ± 2% for CHART and 50% ± 3% with CRT (log-rank p = 0.2); 26% ± 2% and 29% ± 3% (p = 0.4), respectively; 41% ± 2% and 46% ± 3% (p = 0.3), respectively; and 56% ± 3% and 58% ± 3% (p = 0.5), respectively. There was a small but significant reduction in the incidence of slight or worse and moderate or worse epidermal adverse events with CHART (p = 0.002 to 0.05). Severe xerostomia, laryngeal edema, and mucosal necrosis were also significantly lower with CHART (p = 0.02 to 0.05).Conclusions: Despite the reduction in total dose from 66 Gy to 54 Gy, control of locoregional disease and survival with CHART were similar to those with CRT. These findings, together with the low incidence of long-term severe adverse events, suggest that CHART is a treatment option for patients with low-risk disease and for those unable to withstand the toxicity of concurrent chemoradiotherapy."

RTOG 0129 - Accelerated concomitant boost confers no benefit if chemo is used in H&N cancers

Another abstract sees the light of day in the Red Journal:

~700 patients with stage III and IV H&N cancer were randomized to either altered fracitonation (concomitant boost) vs standard fractionation with concurrent CDDP. No differences were seen in any of the endpoints (toxicity, OS, DFS, LRC, or DM). This confirms findings from the GORTEC trial that CDDP may supersede the effect of altered fractionation in the treatment of H&N cancers. Again - the manuscript will be eagerly awaited...

Link

A Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination with Concurrent Cisplatin for Head and Neck Carcinomas (RTOG 0129): Report of Efficacy and Toxicity: "A phase III trial was completed to test the efficacy-toxicity of combining cisplatin with an accelerated concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC)."

Short Term ADT improves survival in intermediate risk prostate cancer: RTOG 94-08

The abstract for the initial results of RTOG 9408 are published in the Red Journal - ~2000 patients with T1b-2b prostate cancer were randomized to 66.6Gy +/- 4 months of ADT starting 2 months prior to RT start. 61% had GS 6 or less, about half were T1, half T2. Result demonstrated a statistically significant improvement in OS at 12years (51% vs 46%, p=0.03).

Of course one critique is that the overall RT dose is too low by todays standards, but this supports the D'Amico trial's findings and confirms potential benefit of brief ADT in intermediate and even some low risk patients. The manuscript will be eagerly awaited...

Link:

Short-term Endocrine Therapy Prior to and during Radiation Therapy Improves Overall Survival in Patients with T1b-T2b Adenocarcinoma of the Prostate and PSA ≤ 20: Initial Results of RTOG 94-08: "To test if short-term endocrine therapy prior to and during radiation therapy will improve overall survival in patients with good prognosis, locally confined, adenocarcinoma of the prostate."

NSCLC chemo meta-analysis

In the Lancet this week:

Two meta-analyses looking at the absolute benefit of chemo after surgery both with and without adjuvant radiotherapy. They found similar results in both settings with HR hovering aound 0.88 for overall survival, corresponding to a 4% absolute benefit in both groups at 5 years.

Link:

[Articles] Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data: "Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy."

Adding Oxaliplatin in Neoadjuvant CTRT for Rectal Cancer

From the JCO this week:

The ACCORD trial is a randomized phase III trial looking at two CTRT regimens for T3-T4 rectal tumors: 45Gy/25fx + Capecitabine vs 50Gy/25fx + Capecitabine and Oxaliplatin. It is a bit perplexing as to why the investigators decided to add a slightly different RT regimen to the randomization, as it makes the more important question (that of the addition of oxaliplatin) more difficult to evaluate. Nonetheless, their primary endpoint was pCR, and they powered the study to detect an increase from 11% in the control arm to 20% in with oxalipatin (and 5 more Gy).

Results demonstrate a non-significant difference in pCR of 13.9% in the control arm, and a 19.2% with oxaliplatin and 5 additional Gy (p=0.09). G3-4 toxicities were increased at 10.9% 45Gy + capecitabine vs 25.4% 50Gy + capox. The investigators state in their conclusions that oxaliplatin should not be used, and 50Gy with capcitabine should be explored. I would not necessarily be so quick to dismiss oxaliplatin, as the absolute difference in pCR was 5.3%, a result which might not be stasticaly significant, but may be clinical relevant, given the other interventions we pursue for a 5% benefit.

I think at the end of the day, we are left in the same position as before, with oxaliplatin being unproven but potentially worthwhile, and waiting for the NSABP-R04 trial to accrue and report (goal of 1,606 patient accrual, 2x2 randomization of capecitabine vs 5-FU and oxaliplatin vs no-oxaliplatin).

Link and abstract -

Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2 [Gastrointestinal Cancer]: "Purpose

Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin.

Patients and Methods

We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m² twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m² twice daily 5 days per week and oxaliplatin 50 mg/m² once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR).

Results

Five hundred ninety-eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02).

Conclusion

The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers."