Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity

In Cancer this week:

An analysis from Dr Alektiar at MSKCC retrospectively examines their experience with IMRT treating STS (soft tissue sarcoma), compared to a historical cohort of brachytherapy patients. Of course there are significant limitations in any retrospective analysis, but the local control was quite good with IMRT, with no significant difference in toxicity. Obviously one would prefer randomized data before accepting a new modality as standard of care, however, given the overall rarity of STS, and the broad acceptance of EBRT, it seems likely that this will be the treatment of choice moving forward.

Link and Abstract:

Local control comparison of adjuvant brachytherapy to intensity-modulated radiotherapy in primary high-grade sarcoma of the extremity: "

Abstract

BACKGROUND:

Based on results of a prospective randomized trial, brachytherapy (BRT) had been the preferred form of adjuvant radiotherapy for patients with high-grade extremity soft tissue sarcoma (STS) at our institution. In recent years, intensity-modulated radiotherapy IMRT had been increasingly used. This study compared local control by IMRT versus by BRT in primary-extremity STS.

METHODS:

Between January 1995 and December 2006, 134 adult patients with high-grade primary nonmetastatic STS of the extremity were treated at this institution with limb-sparing surgery and adjuvant radiotherapy (RT). Low-dose-rate BRT was given to 71 patients between January 1995 and November 2003 to a median dose of 45 Gray (Gy). IMRT was given between February 2002 and December 2006: preoperatively to 10 (50 Gy) and postoperatively to 53 (median, 63 Gy). Median follow-up was 46 months.

RESULTS:

Treatment groups were comparable in terms of gender, age, site, depth, histology (malignant fibrous histiocytoma vs other), and use of adjuvant chemotherapy. More IMRT patients had positive/close margins (<1 mm), large tumors (>10 cm), and bone or nerve stripping/resection (P = 0.006, 0.005, 0.02, and 0.002, respectively). Median follow-up was 46 months for IMRT and 47 months for BRT. Five-year local control was 92% (95% confidence interval [CI], 85-100) for IMRT versus 81% (95% CI, 71-90) for BRT, P = 0.04. On multivariate analysis, IMRT was the only predictor of improved local control, P = 0.04.

CONCLUSIONS:

Local control with IMRT was significantly better than BRT despite higher rates of adverse features for IMRT in this nonrandomized comparison. IMRT should be further examined as the treatment of choice for primary high-grade extremity sarcoma. Cancer 2011. © 2011 American Cancer Society.

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DVH parameters for Cervical HDR brachytherapy

In the Red Journal this week:

A very interesting article from the Vienna group, exploring thresholds for late toxicity with cervical brachytherapy. They review 141 patients, and arrive at a threshold for significant (G2-4) late effects for the rectal D2cc of 75Gy. Their data for bladder is a little less well established, but they arrive at a threshold of 100Gy for D2cc. They could determine no thresholds for sigmoid toxicity as it was a very rare occurrence in their cohort.

One thing to note when interpreting this data is that the Vienna group gives 7Gy x 4 over the course of 1 weeks application, which is different that most US practice with brachy (5-6Gy in 5 fractions, with a frequency of ~2/week). While the doses reported are in EQD2 terms, one must realize that these conversions are based on theory and assumptions about alpha beta ratios which may not entirely apply to each brachy schedule. Nonetheless, this remains the best data around for modern 3D dosimetry in cervical brachytherapy.

Link and abstract

Dose–Volume Histogram Parameters and Late Side Effects in Magnetic Resonance Image–Guided Adaptive Cervical Cancer Brachytherapy: "Purpose: To evaluate the predictive value of dose–volume histogram (DVH) parameters for late side effects of the rectum, sigmoid colon, and bladder in image-guided brachytherapy for cervix cancer patients.Methods and Materials: A total of 141 patients received external-beam radiotherapy and image-guided brachytherapy with or without chemotherapy. The DVH parameters for the most exposed 2, 1, and 0.1 cm3 (D2cc, D1cc, and D0.1cc) of the rectum, sigmoid, and bladder, as well as International Commission on Radiation Units and Measurements point doses (DICRU) were computed. Total doses were converted to equivalent doses in 2 Gy by applying the linear-quadratic model (α/β = 3 Gy). Late side effects were prospectively assessed using the Late Effects in Normal Tissues–Subjective, Objective, Management and Analytic score. The following patient groups were defined: Group 1: no side effects (Grade 0); Group 2: side effects (Grade 1–4); Group 3: minor side effects (Grade 0–1); and Group 4: major side effects (Grade 2–4).Results: The median follow-up was 51 months. The overall 5-year actuarial side effect rates were 12% for rectum, 3% for sigmoid, and 23% for bladder. The mean total D2cc were 65 ± 12 Gy for rectum, 62 ± 12 Gy for sigmoid, and 95 ± 22 Gy for bladder. For rectum, statistically significant differences were observed between Groups 1 and 2 in all DVH parameters and DICRU. Between Groups 3 and 4, no difference was observed for D0.1cc. For sigmoid, significant differences were observed for D2cc and D1cc, but not for D0.1cc in all groups. For bladder, significant differences were observed for all DVH parameters only comparing Groups 3 and 4. No differences were observed for DICRU.Conclusions: The parameters D2cc and D1cc have a good predictive value for rectal toxicity. For sigmoid, no prediction could be postulated because of limited data. In bladder, DVH parameters were predictive only for major toxicity."

PCI for NSCLC

The RTOG 0214 reports out in the JCO this week: This was a randomized trial looking at PCI in NSCLC for stage III NSCLC. Unfortunately the trial closed after 356 accrued; their goal was just over 1,000, and the trial was not going to achieve it's objectives. The survival rates at 1year were identical, even with a very significant reduction in the amount of brain metastases (HR 2.5). Of course, one could say that the trial simply didn't have the power to detect the difference, but even with ~350 patients, one would like to at least see a signal of benefit, which was lacking in at least the current analysis.

Looking at the rates of brain mets in the control arm 18%, one must wonder if we could better select those that are likely to develop mets in the future, and run a trial in an enriched cohort with a higher likelihood of disease. This is were I think the future of PCI for NSCLC lies.

In a companion piece, the QOL portion was reported. Not surprisingly there were primarily deteriorations seen in memory and recall - without significant decreases in overall function or global QOL. Nonetheless - this underlines the importance of selecting a group more likely to benefit, in light of known risks.

Link and Abstract from the JCO:

Phase III Comparison of Prophylactic Cranial Irradiation Versus Observation in Patients With Locally Advanced Non-Small-Cell Lung Cancer: Primary Analysis of Radiation Therapy Oncology Group Study RTOG 0214 [Thoracic Oncology]: "Purpose

This study was conducted to determine if prophylactic cranial irradiation (PCI) improves survival in locally advanced non–small-cell lung cancer (LA-NSCLC).

Patients and Methods

Patients with stage III NSCLC without disease progression after treatment with surgery and/or radiation therapy (RT) with or without chemotherapy were eligible. Participants were stratified by stage (IIIA v IIIB), histology (nonsquamous v squamous), and therapy (surgery v none) and were randomly assigned to PCI or observation. PCI was delivered to 30 Gy in 15 fractions. The primary end point of the study was overall survival (OS). Secondary end points were disease-free survival (DFS), neurocognitive function (NCF), and quality of life. Kaplan-Meier and log-rank analyses were used for OS and DFS. The incidence of brain metastasis (BM) was evaluated with the logistic regression model.

Results

Overall, 356 patients were accrued of the targeted 1,058. The study was closed early because of slow accrual; 340 of the 356 patients were eligible. The 1-year OS (P = .86; 75.6% v 76.9% for PCI v observation) and 1-year DFS (P = .11; 56.4% v 51.2% for PCI v observation) were not significantly different. The hazard ratio for observation versus PCI was 1.03 (95% CI, 0.77 to 1.36). The 1-year rates of BM were significantly different (P = .004; 7.7% v 18.0% for PCI v observation). Patients in the observation arm were 2.52 times more likely to develop BM than those in the PCI arm (unadjusted odds ratio, 2.52; 95% CI, 1.32 to 4.80).

Conclusion

In patients with stage III disease without progression of disease after therapy, PCI decreased the rate of BM but did not improve OS or DFS.

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JCO: SRS or Surgery +/- WBRT for 1-3 brain mets

JCO this week:

The EORTC publishes a randomized trial looking at the effect of WBRT after surgical or SRS treatment of 1-3 brain mets. Their primary endpoint was time of functional independence, and found no differences in this outcome with the addition of WBRT. Additionally OS was no different, though recurrences were reduced both at the initial site and elsewhere within the brain. The late toxicity was not significantly different between the arms as evaluated by the trial, but the investigators admit that extensive neurocognitive testing was not performed.

The findings were not significantly different than what has been seen in other trials looking at both surgery and SRS. One thing I can't help but observe is that the failures were at least numerically higher in the surgery arm at the primary site. There are certainly reasons why this may be so (and indeed the size of lesions in the surgery cohort were larger), there certainly is no signal that SRS is worse than surgery in appropriately selected patients.

Link and Abstract:

Adjuvant Whole-Brain Radiotherapy Versus Observation After Radiosurgery or Surgical Resection of One to Three Cerebral Metastases: Results of the EORTC 22952-26001 Study [Neurooncology]: "Purpose

This European Organisation for Research and Treatment of Cancer phase III trial assesses whether adjuvant whole-brain radiotherapy (WBRT) increases the duration of functional independence after surgery or radiosurgery of brain metastases.

Patients and Methods

Patients with one to three brain metastases of solid tumors (small-cell lung cancer excluded) with stable systemic disease or asymptomatic primary tumors and WHO performance status (PS) of 0 to 2 were treated with complete surgery or radiosurgery and randomly assigned to adjuvant WBRT (30 Gy in 10 fractions) or observation (OBS). The primary end point was time to WHO PS deterioration to more than 2.

Results

Of 359 patients, 199 underwent radiosurgery, and 160 underwent surgery. In the radiosurgery group, 100 patients were allocated to OBS, and 99 were allocated to WBRT. After surgery, 79 patients were allocated to OBS, and 81 were allocated to adjuvant WBRT. The median time to WHO PS more than 2 was 10.0 months (95% CI, 8.1 to 11.7 months) after OBS and 9.5 months (95% CI, 7.8 to 11.9 months) after WBRT (P = .71). Overall survival was similar in the WBRT and OBS arms (median, 10.9 v 10.7 months, respectively; P = .89). WBRT reduced the 2-year relapse rate both at initial sites (surgery: 59% to 27%, P < .001; radiosurgery: 31% to 19%, P = .040) and at new sites (surgery: 42% to 23%, P = .008; radiosurgery: 48% to 33%, P = .023). Salvage therapies were used more frequently after OBS than after WBRT. Intracranial progression caused death in 78 (44%) of 179 patients in the OBS arm and in 50 (28%) of 180 patients in the WBRT arm.

Conclusion

After radiosurgery or surgery of a limited number of brain metastases, adjuvant WBRT reduces intracranial relapses and neurologic deaths but fails to improve the duration of functional independence and overall survival.

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RT and Tamoxifen for DCIS - update of the UK/ANZ trial

In Lancet Oncology this week:

An update of the 2x2 trial of tam and RT for locally excised DCIS is published, confirming the benefit of RT in reducing both non-invasive and invasive disease. Similarly tamoxifen is confirmed to benefit ipisilateral DCIS and contralateral disease, though not ipsilateral invasive recurrence. One of the things that is interesting in this trial, though it is a subgroup analysis, is that the benefit of tamoxifen in ipsilateral recurrences was largely seen in the absence of radiotherapy (see the forest plot on figure 3). Another gratifying conclusion is that there were no increases in contralateral breast events with RT due to carcinogenesis.

Link:

[Articles] Effect of tamoxifen and radiotherapy in women with locally excised ductal carcinoma in situ: long-term results from the UK/ANZ DCIS trial: "This updated analysis confirms the long-term beneficial effect of radiotherapy and reports a benefit for tamoxifen in reducing local and contralateral new breast events for women with DCIS treated by complete local excision."

Lancet: Aspirin and reduction in risk of cancer related mortality (Meta-Analysis)

In the Lancet this week there is an interesting article looking at the long term reduction in cancer related mortality in trials looking a daily aspirin use. The investigators performed an individual case meta-analysis of several trials and found a reduction in all cancer related mortality of 0.79 (odd-ratio). This held out to 20 years. The greatest benefit was seen in GI tumors, though it was not confined to them.

Link:

[Articles] Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials: "Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention."