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."

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer [Preliminary Communication]

In JAMA:

Preliminary results of RTOG-0236 with 3 year clinical endpoints are published in JAMA this week. This confirms that Timmerman's 3 fraction approach, piloted at Indiana University is applicable in a multi-center phase II trial. Local control was 91%, with an OS of 56%, which is pretty excellent considering that these are all inoperable patients from the start. Very low incidence in G3 or 4 toxicity, and no deaths - perhaps by excluding the central tumors which had resulted in most of the life threatening toxicity in the Indiana data.

Link and Abstract:

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer [Preliminary Communication]: "

Context Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management.

Objective To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer.

Design, Setting, and Patients Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non–small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 11/2 and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009.

Main Outcome Measures The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival.

Results A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported.

Conclusion Patients with inoperable non–small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.

"

SLNB for Oral Cavity Cancers

JCO: Sentinel lymph node biopsy has become a standard procedure in breast cancer and melanoma, and emerging data suggests it may be useful in other tumor sites as well (vulvar for one). The JCO this week reports on a multiinstitutional trial in early stage oral cavity tumors suggests that it may be very useful in that primary site as well.

Link and Abstract.

Sentinel Lymph Node Biopsy Accurately Stages the Regional Lymph Nodes for T1-T2 Oral Squamous Cell Carcinomas: Results of a Prospective Multi-Institutional Trial [Head and Neck Cancer]: "Purpose

The validity of sentinel lymph node biopsy (SLNB) for T1 or T2, clinically N0, oral cancer was tested by correlation of sentinel node pathologic status with that of nodes within the completion neck dissection.

Methods

This prospective, cooperative group trial involved 25 institutions over a 3-year period. One hundred forty patients with invasive oral cancers, stage T1 and T2, N0 including 95 cancers of the tongue, 26 of the floor of mouth, and 19 other oral cancers were studied. The study excluded lesions with diameter smaller than 6 mm or minimal invasion. Imaging was used to exclude nonpalpable gross nodal disease. Patients underwent injection of the lesion with ^99mTc-sulfur colloid, nuclear imaging, narrow-exposure SLNB, and completion selective neck dissection. The major end point was the negative-predictive value (NPV) of SLNB.

Results

In the 106 SLNBs, which were found to be pathologically and clinically node-negative by routine hematoxylin and eosin stain, 100 patients were found to have no other pathologically positive nodes, corresponding to a NPV of 94%. With additional sectioning and immunohistochemistry, NPV was improved to 96%. In the forty patients with proven cervical metastases, the true-positive rate was 90.2% and was superior for tongue tumors relative to floor of mouth. For T1 lesions, metastases were correctly identified in 100%.

Conclusion

For T1 or T2 N0 oral squamous cell carcinoma, SLNB with step sectioning and immunohistochemistry, performed by surgeons of mixed experience levels, correctly predicted a pathologically negative neck in 96% of patients (NPV, 96%).

"

Individualized Dose Escalation for NSCLC

JCO has an interesting article looking at individualized dose escalation depending on normal tissue constraints. This was an aggressive sequential CTRT study, which dose escalated to normal tissue tolerance depending on individual anatomy, and the toxicity/survival numbers are not bad in comparison to the standard 60-66Gy with concurrent drug.

Link and Abstract:

Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non-Small-Cell Lung Cancer [Thoracic Oncology]: "Purpose

We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach.

Patients and Methods

In total, 166 patients with stage III or medically inoperable stage I to II non–small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide ≥ 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0.

Results

The median prescribed TTD was 64.8 Gy (standard deviation, ± 11.4 Gy) delivered in 25 ± 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable.

Conclusion

Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

"

PORTEC 2: VB vs WPRT for Early Endometrial Cancer

From the Lancet:

The PORTEC 2 efficacy results are published. These were previously reported at ASCO 2008, and to review, this was a randomized trial of 427 patients >= 60 years of age with IC grade 1 or 2, IB grade 3, or any age and IIA disease (excluding grade 3 with >50% myometrial invasion). After surgery they were randomized between vaginal brachytherapy (7Gy q week x 3, or 30Gy LDR) and WPRT (46Gy, 2Gy/day). Note the inclusion criteria; this excludes the IC grade 3 risk group which at the time of the trial design were at too high of a risk not to treat with WPRT. This is especially relevant as these patients had no nodal dissection.

5-year vaginal recurrence was 1.8% (95% CI 0.6—5.9) for VBT and 1.6% (0.5—4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17—3.49; p=0·74). 5-year LR was 5.1% (2.8—9.6) for VBT and 2.1% (0.8—5.8) for WPRT (HR 2.08, 0.71—6.09; p=0.17); 1.5% (0.5—4.5) versus 0.5% (0.1—3.4) for isolated pelvic recurrence (HR 3·.0, 0.32—29.9; p=0.30). 5 year rate of distant metastasis was no different (8.3% [5.1—13.4] vs 5.7% [3.3—9.9]; HR 1.32, 0.63—2.74; p=0.46). 5yr OS was 84.8% (95% CI 79.3—90.3] vs 79.6% [71.2—88.0]; HR 1·17, 0·69—1·98; p=0·57, and DFS was 82.7% (76.9—88.6) vs 78.1% (69.7—86.5); HR 1.09, 0.66—1.78; p=0.74.

This, in light of the previous toxicity data presented in the JCO, they make a strong case of VBT alone in most stage I endometrial cancer.

Link:

[Articles] Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial: "After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life."

QUANTEC Published - Replacing the 1991 Emami Paper

This week, as a supplement to the Red Journal, the results of the QUANTEC (Quantitative Analysis of Normal Tissue Effects in the Clinic) initiative are published. The second article in the supplement has a table that is sure to become the radiation oncology resident's best friend - a concise summation of the normal tissue constraints for sensitive normal tissues within the body. The remainder of the articles are concise discussions of specific organ systems and the response to radiation. As an update to the LENT-SOMA effort of the the mid to late 90s, these articles are an excellent reference, and truly, this effort should replace (with all due respect) the famed "Emami Paper" of 1991, which has guided normal tissue tolerance discussions for so long.

Secondary malignancies in pediatic HL survivors

In the JCO:

A report from Stanford comes out with long follow up from pediatric HL survivors, treated with lower dose radiation looking at secondary malignancy rates. The twenty year rate of secondary malignancy was 17%, consisting of leukemias and solid tumors including breast, thyroid and sarcoma primaries. Again this underlines the potential for malignancy induction in the pediatric patients.

Link and Abstract

Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy [Pediatric Oncology]: "Purpose

Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.

Patients and Methods

Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.

Results

One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (± SE) 5-year disease-free and overall survival were 76% ± 12% and 85% ± 10% with median follow-up 5 years from SMN diagnosis.

Conclusion

Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.

"

Cisplatin for triple negative breast cancer

This weeks JCO -

Triple negative breast cancer is a challenge in the era of targeted therapy for breast cancer. There have been hints that cisplatin may be particularly useful for this subset, specifically in those with BRCA-1 pathway disruptions. Below is some of the initial experience with exploring this in a small prospective trial looking at responses in triple negative tumors treated neoadjuvantly with cisplatin.

Link and Article.

Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer [Breast Cancer]: "Purpose

Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response.

Patients and Methods

Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m² every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers.

Results

Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03).

Conclusion

Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.

"

Dose escalation for Prostate Cancer

10 year results of the PROG trial of proton dose escalation for low-intermediate risk prostate cancer are published in the weeks JCO. No big surprises, the same trends hold with improvements in biochemical control, no difference in OS (though a 5% trend does exist favoring high dose). The 10 year data does solidify support of dose escalation, and the lack of delayed toxicity is quite encouraging.

Link and abstract

Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09 [Genitourinary Cancer]:

"Purpose

To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes.
Patients and Methods

Men with T1b-T2b prostate cancer and prostate-specific antigen ≤ 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes.
Results

A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade ≥ 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade ≥ 3 GI toxicity.
Conclusion

This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade ≥ 3 late urinary or rectal morbidity.
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SBRT vs Wedge resection (retrospective)

This weeks JCO:

A retrospective comparison of wedge resection and SBRT for stage I NSCLC is reported by Beaumont. They find improved local and regional recurrence rates with SBRT, similar cause specific survival, and worse OS in with SBRT. They explain the worse OS by patient selection (i.e. the healthier patients were taken for wedge).

I think from this, you see a signal that SBRT seems at least equivalent to wedge and potentially less toxic. I think it is hard to say that it is superior for local control, because if one is censoring out the patients who die (as one does in with the local control endpoint), the more patients die from other causes, the less events are possible for local failure. Thus the LRC may have been higher with SBRT due to the lower OS. In addition the followup was not as long for SBRT patients.

Regardless, this is an interesting paper, and supports the use of SBRT in medically inoperable patients.

Link and Abstract:

Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non-Small-Cell Lung Cancer [Thoracic Oncology]: "Purpose

To compare outcomes between lung stereotactic radiotherapy (SBRT) and wedge resection for stage I non–small-cell lung cancer (NSCLC).

Patients and Methods

One hundred twenty-four patients with T1-2N0 NSCLC underwent wedge resection (n = 69) or image-guided lung SBRT (n = 58) from February 2003 through August 2008. All were ineligible for anatomic lobectomy; of those receiving SBRT, 95% were medically inoperable, with 5% refusing surgery. Mean forced expiratory volume in 1 second and diffusing capacity of lung for carbon monoxide were 1.39 L and 12.0 mL/min/mmHg for wedge versus 1.31 L and 10.14 mL/min/mmHg for SBRT (P = not significant). Mean Charlson comorbidity index and median age were 3 and 74 years for wedge versus 4 and 78 years for SBRT (P < .01, P = .04). SBRT was volumetrically prescribed as 48 (T1) or 60 (T2) Gy in four to five fractions.

Results

Median potential follow-up is 2.5 years. At 30 months, no significant differences were identified in regional recurrence (RR), locoregional recurrence (LRR), distant metastasis (DM), or freedom from any failure (FFF) between the two groups (P > .16). SBRT reduced the risk of local recurrence (LR), 4% versus 20% for wedge (P = .07). Overall survival (OS) was higher with wedge but cause-specific survival (CSS) was identical. Results excluding synchronous primaries, nonbiopsied tumors, or pathologic T4 disease (wedge satellite lesion) showed reduced LR (5% v 24%, P = .05), RR (0% v 18%, P = .07), and LRR (5% v 29%, P = .03) with SBRT. There were no differences in DM, FFF, or CSS, but OS was higher with wedge.

Conclusion

Both lung SBRT and wedge resection are reasonable treatment options for stage I NSCLC patients ineligible for anatomic lobectomy. SBRT reduced LR, RR, and LRR. In this nonrandomized population of patients selected for surgery versus SBRT (medically inoperable) at physician discretion, OS was higher in surgical patients. SBRT and surgery, however, had identical CSS.

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Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer

In the NEJM this week:

10 year results of the Canadian Hypofractionation trial for breast cancer are published, showing no difference in local control, toxicity, or cosmetic appearance. Interestingly, a new subset analysis in this paper seems to suggest that high grade cancers were not the best candidate for hypofractionation due to a higher failure rate. However in a low risk patient, this has become a standard option at Duke for the treatment of node-megative disease. Of course the caveats is that this trial does not apply to patients who are node positive and in those who have a separation >25cm. Boost was not also used in the trial; though we will occasionally offer a boost of 200cGy x 5 with the 2.66Gy x 16fx regimen extrapolating from the boost trials.

Link to the NEJM:

Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer: "The optimal schedule of radiation treatment after breast-conserving surgery for invasive breast cancer is unknown. In this study, two groups of patients received either hypofractionated radiation or a standard schedule of radiation treatment. Ten years later, the two groups had similar risks of local recurrence and a similar appearance of the breast."

[Articles] Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial

This weeks Lancet:

An interesting article on the potential utility for MRI in initial work up of breast cancer. While a prior trial in the NEJM (link) demonstrated that one could detect occult cancers in the contralateral breast in 3% of patients (by biopsying 12%), this trial looked at the utility of MRI in surgical planning in the ipsilateral breast. The short of it: no difference in reoperation rates for positive or close margins. MRI seems to becoming more of a standard preoperative test, however the only clinically relevant outcome reported as yet is an increase in the mastectomy rate (link).

Link to the Lancet

[Articles] Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial: "MRI might improve diagnosis of breast cancer, reducing rates of reoperation. We assessed the clinical efficacy of contrast-enhanced MRI in women with primary breast cancer."