Preoperative Multimodality Therapy Improves Disease-Free Survival in Patients With Carcinoma of the Rectum: NSABP R-03 [Gastrointestinal Cancer]

JCO this week: the NSABP R03 is published. A preop vs postop CTRT trial for rectal cancer, similar to the practice defining German trial. Unfortunately underpowered, it nonetheless demonstrates a DFS benefit. How to interpret this benefit in the light of no difference in LC is slightly more problematic, especially comparing to the larger German trial.

Link and Abstract:

Preoperative Multimodality Therapy Improves Disease-Free Survival in Patients With Carcinoma of the Rectum: NSABP R-03 [Gastrointestinal Cancer]: "Purpose

Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma.

Patients and Methods

Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS).

Results

From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence.

Conclusion

Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

"

[Articles] Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial

Presented at ASTRO last year as a plenary, the MDA randomized trial of SRS alone vs SRS + WBRT is published in Lancet Oncology. This is an interesting trial, as it had a neurocognitive primary endpoint, which is one of the larger concerns with WBRT. This trial certainly adds to the data on the neurocognitive effects of WBRT, however, one can't help but focus on the survival difference between the arms. I would venture that the data presented in the paper, especially the lack of any differences in neurologic deaths and the lack of any difference in the larger RTOG and Japanese trials, that this is not a treatment effect. Then the question remains, what did cause this, and could it have influenced the primary endpoint? Another point that I will add to this is the trial was stopped due to a 4 month evaluation of memory, as opposed to a later time point. I would suggest that this may be too early of a measurement time for the long term effects of WBRT.

Nonetheless, this trial does support the use of SRS alone in this population and the prospective nature of the neurocognitive evaluation is to be applauded.

Link:

[Articles] Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial: "It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction."

History of Health Insurance in the US

This American Life had an entertaining show on Health Insurance in the US a few weeks ago. Worth a listen.

Link

Someone Else's Money

Use of Axillary Deodorant and Effect on Acute Skin Toxicity During Radiotherapy for Breast Cancer: A Prospective Randomized Noninferiority Trial

From the Red Journal:

This seems like a silly randomized trial, but it adds information to a question that comes up in clinic all the time: Can I wear deodorant while getting RT? Answer: yes per this trial, but aluminum containing antiperspirants are not tested. I like that they added a less sweating end point with a statistically significant result!

Link and abstract:

Use of Axillary Deodorant and Effect on Acute Skin Toxicity During Radiotherapy for Breast Cancer: A Prospective Randomized Noninferiority Trial: "Purpose: To prospectively determine the effect of deodorant use on acute skin toxicity and quality of life during breast radiotherapy (RT).Methods and Materials: Before breast RT, 84 patients were randomly assigned to the deodorant group (n = 40) or the no-deodorant group (n = 44). The patients were stratified by axillary RT and previous chemotherapy. Toxicity evaluations were always performed by the principal investigator, who was unaware of the group assignment, at the end of RT and 2 weeks after completion using the Radiation Therapy Oncology Group acute skin toxicity criteria. Symptoms of acute skin toxicity (i.e., discomfort, pain, pruritus, sweating) and quality of life were self-evaluated. For each criterion, the point estimate of rate difference with the 95% one-sided upper confidence limit was computed. To claim noninferiority owing to deodorant use, the 95% one-sided upper confidence limit had to be lower than the noninferiority margin, fixed to 12.8%.Results: In the deodorant vs. no-deodorant groups, Grade 2 axillary radiodermatitis occurred in 23% vs. 30%, respectively, satisfying the statistical criteria for noninferiority (p = .019). Grade 2 breast radiodermatitis occurred in 30% vs. 34% of the deodorant vs. no-deodorant groups, respectively, also satisfying the statistical criteria for noninferiority (p = .049). Similar results were observed for the self-reported evaluations. The deodorant group reported less sweating (18% vs. 39%, p = .032). No Grade 3 or 4 radiodermatitis was observed.Conclusion: According to our noninferiority margin definition, the occurrence of skin toxicity and its related symptoms were statistically equivalent in both groups. No evidence was found to prohibit deodorant use (notwithstanding the use of an antiperspirant with aluminum) during RT for breast cancer."

Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort [Genitourinary Cancer]

JCO this week:
An interesting report from the Health Professionals Follow-up Study looking at those who "deferred treatment" for prostate cancer. They find no difference in rates of death or clinical metastases with those that pursued this approach, though 49% had been treated by 7.7 years.

This is clearly an important piece of information in the debate over prostate cancer screening and treatment decisions. However, to poke a few holes:
1. This is a study of professionals who may not represent a larger population.
2. There is no data on how many men needed long term or indefinite hormone ablation, which may well have been different between the approaches.
3. The death and metastasis rate may not have matured yet due to the well known indolent nature of this disease.
4. The hazard ratio on the multivariate analysis is informative in how broad it is (0.61- 1.75). Thus there could have been up to a 75% increase in the metastasis or death rate in the deferred treatment cohort, and the result would have remained non-significant.

That said, we obviously treat many if not a majority of prostate cancers without affecting a man's life span or QOL except in the negative with treatment related events. The next step is to better identify those in whom we can forgoe any therapy with minimal risks of progression.

Link and Abstract:

Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort [Genitourinary Cancer]: "Purpose

To examine consequences of deferred treatment (DT) as initial management of prostate cancer (PCa) in a contemporary, prospective cohort of American men diagnosed with PCa.

Participants and Methods

We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis.

Results

From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively.

Conclusion

In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients."

Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial [Breast Cancer]

JCO this week: Presented two ASTROs ago, a reanalysis of the EORTC boost trial is now published using centralized path review.

Perhaps one of the interesting conclusions was that margin status did not influence local control. Does this mean that we should not re-excise women that have positive margins, and proceed directly to radiotherapy? One must remember that the entry criteria to this trial was negative margins, therefore all of the positive margins discovered on central path review were presumably missed on the initial interpretation. One might also then assume that these are therefore relatively small regions of margin positivity, and thus very different from patients with known positive margins up front. This should be taken into account when interpreting the results.

Link and Abstract:

Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial [Breast Cancer]: "Purpose

To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT).

Patients and Methods

In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed.

Results

The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively.

Conclusion

Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

"

Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy

JAMA this week: more on Robotic Surgery for Prostate Cancer. The short on this retrospective study looking the robotic assisted laparoscopic prostatectomy - fewer blood transfusions, 1 day less in the hospital, increased incontinence and erectile dysfunction, same efficacy for cancer. The increased adverse event profile is a bit of a surprise here, and may cool some jets with this technique.

Of course, like any surgery, individual technique and skill probably matter, and this was a broad group from the SEER database. An individual surgeons results may be different that the broader group, and there is a significant learning curve on this procedure. Toxicity is also a notoriously hard thing to pin down in uncontrolled studies, and patients may have very different expectations going into a robotic procedure compared to an open.

Link and Abstract:

ORIGINAL CONTRIBUTION: Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy: "

Context Minimally invasive radical prostatectomy (MIRP) has diffused rapidly despite limited data on outcomes and greater costs compared with open retropubic radical prostatectomy (RRP).

Objective To determine the comparative effectiveness of MIRP vs RRP.

Design, Setting, and Patients Population-based observational cohort study using US Surveillance, Epidemiology, and End Results Medicare linked data from 2003 through 2007. We identified men with prostate cancer who underwent MIRP (n = 1938) vs RRP (n = 6899).

Main Outcome Measures We compared postoperative 30-day complications, anastomotic stricture 31 to 365 days postoperatively, long-term incontinence and erectile dysfunction more than 18 months postoperatively, and postoperative use of additional cancer therapies, a surrogate for cancer control.

Results Among men undergoing prostatectomy, use of MIRP increased from 9.2% (95% confidence interval [CI], 8.1%-10.5%) in 2003 to 43.2% (95% CI, 39.6%-46.9%) in 2006-2007. Men undergoing MIRP vs RRP were more likely to be recorded as Asian (6.1% vs 3.2%), less likely to be recorded as black (6.2% vs 7.8%) or Hispanic (5.6% vs 7.9%), and more likely to live in areas with at least 90% high school graduation rates (50.2% vs 41.0%) and with median incomes of at least $60 000 (35.8% vs 21.5%) (all P < .001). In propensity score–adjusted analyses, MIRP vs RRP was associated with shorter length of stay (median, 2.0 vs 3.0 days; P<.001) and lower rates of blood transfusions (2.7% vs 20.8%; P < .001), postoperative respiratory complications (4.3% vs 6.6%; P = .004), miscellaneous surgical complications (4.3% vs 5.6%; P = .03), and anastomotic stricture (5.8% vs 14.0%; P < .001). However, MIRP vs RRP was associated with an increased risk of genitourinary complications (4.7% vs 2.1%; P = .001) and diagnoses of incontinence (15.9 vs 12.2 per 100 person-years; P = .02) and erectile dysfunction (26.8 vs 19.2 per 100 person-years; P = .009). Rates of use of additional cancer therapies did not differ by surgical procedure (8.2 vs 6.9 per 100 person-years; P = .35).

Conclusion Men undergoing MIRP vs RRP experienced shorter length of stay, fewer respiratory and miscellaneous surgical complications and strictures, and similar postoperative use of additional cancer therapies but experienced more genitourinary complications, incontinence, and erectile dysfunction.

"

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial

From the Lancet this week:

More bad news from the WHI - Women had a trend (NS) towards more NSCLC diagnoses in the HRT arm, and statistically significant worse survival from lung cancer. Of course this is post-hoc, and should be treated as hypothesis generating more than definitive evidence. Regardless, enthusiasm for HRT has been sufficiently curbed.

Link:

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial: "In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period."

Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer [Breast Cancer]

In interesting contrast to a prior study from the NEJM earlier this year, this weeks JCO has another retrospective study looking at isolated tumor cells and micromets in SLN biopsies from women with breast cancer. In this study, there was no difference in outcome for patients with isolated tumor cells or micromets (<2mm). Do I detect the need for a randomized trial?

Abstract and Link from the JCO


Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer [Breast Cancer]:
"Purpose

Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria.

Patients and Methods

Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i–), no evidence of tumor (n = 486); pN0(i+), tumor deposit ≤ 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but ≤ 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups.

Results

At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS.

Conclusion

Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN.

"