Matched Pair Analysis Comparing Surgery Followed By Radiotherapy and Radiotherapy Alone for Metastatic Spinal Cord Compression [Palliative and Supportive Care]

In the JCO this week:

A retrospective international series, calls into question the results of the Patchell Study of decompressive surgery before RT in spinal cord compression. The Patchell study demostrated a significant benefit in terms of recovery of amulation in addition to other neurologic endpoints, as well as survival. This study matched pairs of 1:2 for surgery + RT and RT alone, and, in short, found no differences. The authors of this JCO article conclude that the population in the randomized trial was very selected, and that perhaps, in a broader population the question should be subject to another randomized trial.

I don't know how much enthusiasm there would be to run such a trial again, and at least in our experience, surgery is reserved for the most selected population, mostly likely to benefit (single tumors, controlled primaries, etc.). Additionally, like the Patchell study, laminectomies (which make up a fair portion of the retrospective study) are not routinely recommended, as direct decompressions are a superior surgery in these situation.

Nonetheless, this is an interesting article looking at a common situation that has little randomized data to guide treatment.

Link and Abstract

Matched Pair Analysis Comparing Surgery Followed By Radiotherapy and Radiotherapy Alone for Metastatic Spinal Cord Compression [Palliative and Supportive Care]: "Purpose

The appropriate treatment for MSCC is controversial. A small randomized trial showed that decompressive surgery followed by radiotherapy was superior to radiotherapy alone. That study was limited to highly selected patients. Additional studies comparing surgery plus radiotherapy to radiotherapy could better clarify the role of surgery.

Methods

Data from 108 patients receiving surgery plus radiotherapy were matched to 216 patients (1:2) receiving radiotherapy alone. Groups were matched for 11 potential prognostic factors and compared for post-treatment motor function, ambulatory status, regaining ambulatory status, local control, and survival. Subgroup analyses were performed for patients receiving adequate surgery (direct decompressive surgery plus stabilization of involved vertebrae), patients receiving laminectomy, patients with solid tumors, patients with solid tumors receiving adequate surgery, and patients with solid tumors receiving laminectomy.

Results

Improvement of motor function occurred in 27% of patients after surgery plus radiotherapy and 26% after radiotherapy alone (P = .92). Post-treatment ambulatory rates were 69% after surgery plus radiotherapy and 68% after radiotherapy alone (P = .99). Of the nonambulatory patients, 30% and 26%, respectively, (P = .86) regained ambulatory status after treatment. One-year local control rates were 90% after surgery plus radiotherapy and 91% after radiotherapy alone (P = .48). One-year overall survival rates were 47% and 40%, respectively (P = .50). The subgroup analyses did not show significant differences between both groups. Surgery-related complications occurred in 11% of patients.

Conclusion

In this study, the outcomes of the end points evaluated after radiotherapy alone appeared similar to those of surgery plus radiotherapy. A new randomized trial comparing both treatments is justified.

"

Lancet: IORT for Breast - the TARGIT-A trial

In the Lancet

Previously available online and presented at ASCO, the TARGIT-A trial is published in Lancet today. To briefly recap - this multinational randomized trial looked at conventional fracitonation vs 20Gy in a single treatment intraoperatively. 4 year data shows similar local control, with potentially slightly less toxicity, and clearly less time and resources devoted. While the time points evaluated are still too early to replace the standard of care in all patients, in selected patients, this approach is potentially very attractive.

Link:

[Articles] Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial: "After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy."

JCO: RT for advanced HD and unfavorable early HD

This weeks JCO:

A very compelling analysis is presented looking at non-randomized results with consolidation RT after chemotherapy in a prospective chemo trial for advanced stage and early unfavorable Hodgkin Disease. Despite the fact that the RT group had more "bulky" disease and more incomplete responders, a benefit was seen across the board for PFS and OS, with HRs for all subgroups <= to 0.5. Also interestingly they looked at dose (see figure 5), showing no compelling dose response beyond 30Gy.

Link and Abstract

Consolidation Radiotherapy in Patients With Advanced Hodgkin's Lymphoma: Survival Data From the UKLG LY09 Randomized Controlled Trial (ISRCTN97144519) [Hematologic Malignancies]: "Purpose

This study analyzed the outcomes of nonrandomized consolidation radiotherapy (RT) given after chemotherapy in the initial treatment of advanced Hodgkin's lymphoma (HL). The results were collected prospectively within a randomized controlled trial of induction chemotherapy.

Patients and Methods

Patients were randomly assigned between doxorubicin, bleomycin, vinblastine, and dacarbazine and one of two prespecified multidrug regimens. At least six cycles of chemotherapy were planned, with up to eight for patients showing slower response. Involved-field RT was recommended for incomplete response to chemotherapy or bulk disease at presentation. The primary outcome measure was progression-free survival (PFS), landmarked from the end of chemotherapy.

Results

Among 807 patients randomly assigned, 702 achieved objective response. Postchemotherapy RT for consolidation was reported in 300 (43%). With median follow-up of 6.9 years, 161 PFS events and 83 deaths were reported. Baseline characteristics showed more patients with bulk disease having RT (190 [63%] v 111 [28%]) and only partial response after chemotherapy (150 [50%] v 36 [9%]). Other baseline characteristics were similar. PFS was superior for patients having RT (hazard ratio [HR], 0.43; 95% CI, 0.30 to 0.60) with 5-year PFS 71% without RT, 86% with RT. A similar advantage was seen for overall survival (HR, 0.47; 95% CI, 0.29 to 0.77). There was no evidence of heterogeneity of treatment effect across subgroups.

Conclusion

Patients who received consolidation RT apparently had better outcomes, consistently across all prognostic groups which persisted in multivariate analysis. This suggests that RT contributes significantly to the cure rate for advanced HL, although patient selection for combined modality treatment requires better definition in prospective trials.

"

JCO: Gefitinib integration into CTRT for H&N cancer

JCO this week:

An interesting phase II looking at the integration of gefitinib (an EGFR TKI), with concurrent chemoradiotherapy. The overall approach is different than what many centers would call standard treatment with induction carbo/paclitaxel, followed by 5FU, HU, and gefinitib with BID RT, then continuing gefitinib afterwards. The results however are good in comparison to historical controls, and it will be very interesting to see how integration of EGFR inhibition in ongoing phase III trials will fair when result mature over the next ~5 years.

Link and abstract

Epidermal Growth Factor Receptor Inhibitor Gefitinib Added to Chemoradiotherapy in Locally Advanced Head and Neck Cancer [Head and Neck Cancer]: "Purpose

Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations.

Patients and Methods

Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization.

Results

Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02).

Conclusion

Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

"

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."