Wednesday, March 31, 2010

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).


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).


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."

Tuesday, March 16, 2010

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


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.


Tuesday, March 9, 2010

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.


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.


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%.


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.


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.


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.


Friday, March 5, 2010

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.


[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."

Wednesday, March 3, 2010

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.