Vestibular Schwannoma treated with FSRT

In the Red Journal this week.

Johns Hopkins reports a sizeable series of vestibular schwannomas treated with FSRT. Interestingly, the failure rate (as defined by the need for salvage series) was quite low as expected at 3%, however a fairly large portion had some evidence of radiologic progression (30%).

Link and Abstract

Long-Term Outcomes of Vestibular Schwannomas Treated With Fractionated Stereotactic Radiotherapy: An Institutional Experience: Purpose: We assessed clinical outcome and long-term tumor control after fractionated stereotactic radiotherapy (FSRT) for unilateral schwannoma.Methods and Materials: Between 1995 and 2007, 496 patients were treated with fractionated stereotactic radiotherapy at Johns Hopkins Hospital (Baltimore, MD); 385 patients had radiologic follow-up that met the inclusion criteria. The primary endpoint was treatment failure. Secondary endpoints were radiologic progression and clinical outcome. Logistic regression analysis assessed the association of age, race, tumor side, sex, and pretreatment symptoms.Results: In 11 patients (3%) treatment failed, and they required salvage (microsurgical) treatment. Radiologic progression was observed in 116 patients (30.0%), including 35 patients (9%) in whom the treatment volume more than doubled during the follow-up period, although none required surgical resection. Tumors with baseline volumes of less than 1 cm3 were 18.02 times more likely to progress than those with tumor volumes of 1 cm3 or greater (odds ratio, 18.02; 95% confidence interval, 4.25–76.32). Treatment-induced neurologic morbidity included 8 patients (1.6%) with new facial weakness, 12 patients (2.8%) with new trigeminal paresthesias, 4 patients (0.9%) with hydrocephalus (1 communicating and 3 obstructive), and 2 patients (0.5%) with possibly radiation-induced neoplasia.Conclusions: Although the rate of treatment failure is low (3%), careful follow-up shows that radiologic progression occurs frequently. When reporting outcome, the “no salvage surgery needed” and “no additional treatment needed” criteria for treatment success need to be complemented by the radiologic data.

A Simpler RPA for GBM

In the red journal this week:

A simpler RPA limited to GBM is present from the RTOG, demonstrating a much more practical means of prognostic clasification.

Link and Abstract

Validation and Simplification of the Radiation Therapy Oncology Group Recursive Partitioning Analysis Classification for Glioblastoma: Purpose: Previous recursive partitioning analysis (RPA) of patients with malignant glioma (glioblastoma multiforme [GBM] and anaplastic astrocytoma [AA]) produced six prognostic groups (I–VI) classified by six factors. We sought here to determine whether the classification for GBM could be improved by using an updated Radiation Therapy Oncology Group (RTOG) GBM database excluding AA and by considering additional baseline variables.Methods and Materials: The new analysis considered 42 baseline variables and 1,672 GBM patients from the expanded RTOG glioma database. Patients receiving radiation only were excluded such that all patients received radiation+carmustine. “Radiation dose received” was replaced with “radiation dose assigned.” The new RPA models were compared with the original model by applying them to a test dataset comprising 488 patients from six other RTOG trials. Fitness of the original and new models was evaluated using explained variation.Results: The original RPA model explained more variations in survival in the test dataset than did the new models (20% vs. 15%) and was therefore chosen for further analysis. It was reduced by combining Classes V and VI to produce three prognostic classes (Classes III, IV, and V+VI), as Classes V and VI had indistinguishable survival in the test dataset. The simplified model did not further improve performance (explained variation 18% vs. 20%) but is easier to apply because it involves only four variables: age, performance status, extent of resection, and neurologic function. Applying this simplified model to the updated GBM database resulted in three distinct classes with median survival times of 17.1, 11.2, and 7.5 months for Classes III, IV, and V+VI, respectively.Conclusions: The final model, the simplified original RPA model combining Classes V and VI, resulted in three distinct prognostic groups defined by age, performance status, extent of resection, and neurologic function. This classification will be used in future RTOG GBM trials.

GNRH analogues with Chemo for prevention of Chemo induced ovarian failure

in JAMA this week

Premature ovarian failure with chemotherapy is a well known phenomena, and may well be of benefit in premenopausal women with hormone sensitive cancers. However in Her-2 positive, or Triple negative cancers, this may result in additional morbidity with no therapeutic benefit. The use of GNRH analogues to reduce the effect of chemo on the ovaries has been suggested in the past, however in an article from Italy in this weeks JAMA, they show a significant reduction in the risk of premature ovarian failure. This may be quite useful in helping with the morbidity of treatment particularly in young women with hormone insensitive disease.

Effect of the Gonadotropin-Releasing Hormone Analogue Triptorelin on the Occurrence of Chemotherapy-Induced Early Menopause in Premenopausal Women With Breast Cancer: A Randomized Trial [Original Contribution]: "

Context Premenopausal patients with breast cancer are at high risk of premature ovarian failure induced by systemic treatments, but no standard strategies for preventing this adverse effect are yet available.

Objective To determine the effect of the temporary ovarian suppression obtained by administering the gonadotropin-releasing hormone analogue triptorelin during chemotherapy on the incidence of early menopause in young patients with breast cancer undergoing adjuvant or neoadjuvant chemotherapy.

Design, Setting, and Patients The PROMISE-GIM6 (Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients–Gruppo Italiano Mammella 6) study, a parallel, randomized, open-label, phase 3 superiority trial, was conducted at 16 sites in Italy and enrolled 281 patients between October 2003 and January 2008. The patients were premenopausal women with stage I through III breast cancer who were candidates for adjuvant or neoadjuvant chemotherapy. Assuming a 60% rate of early menopause in the group treated with chemotherapy alone, it was estimated that 280 patients had to be enrolled to detect a 20% absolute reduction in early menopause in the group treated with chemotherapy plus triptorelin. The intention-to-treat analysis was performed by including all randomized patients and using imputed values for missing data.

Interventions Before beginning chemotherapy, patients were randomly allocated to receive chemotherapy alone or combined with triptorelin. Triptorelin was administered intramuscularly at a dose of 3.75 mg at least 1 week before the start of chemotherapy and then every 4 weeks for the duration of chemotherapy.

Main Outcome Measure Incidence of early menopause (defined as no resumption of menstrual activity and postmenopausal levels of follicle-stimulating hormone and estradiol 1 year after the last cycle of chemotherapy).

Results The clinical and tumor characteristics of the 133 patients randomized to chemotherapy alone and the 148 patients randomized to chemotherapy plus triptorelin were similar. Twelve months after the last cycle of chemotherapy (last follow-up, August 18, 2009), the rate of early menopause was 25.9% in the chemotherapy-alone group and 8.9% in the chemotherapy plus triptorelin group, an absolute difference of –17% (95% confidence interval, –26% to –7.9%; P < .001). The odds ratio for treatment-related early menopause was 0.28 (95% confidence interval, 0.14 to 0.59; P < .001).

Conclusion The use of triptorelin-induced temporary ovarian suppression during chemotherapy in premenopausal patients with early-stage breast cancer reduced the occurrence of chemotherapy-induced early menopause.

Trial Registration clinicaltrials.gov Identifier: NCT00311636"

Short Term ADT and RT in Prostate: RTOG9408 in the NEJM

In the NEJM today:

RTOG 9408 is published, a randomized trial for prostate cancer, T1b-T2b, PSA<=20. 1,979 were randomized between 66.6Gy RT alone, and with 4 months of neoadjuvant and concurrent ADT. Impressively, a survival advantage was seen at 10years, at 62% (RT + STADT) vs 57% (RT alone), with corresponding benefits in disease specific survival. The ADT was also reasonably well tolerated. In post-hoc analysis the benefit seemed confined to the intermediate and high risk patients on study.

However, as the authors appropriately acknowledge, we have moved away from 66.6Gy due to multiple positive dose escalation trials, and the applicability of this data with current treatment is unknown. Insert plug for RTOG 08-15 now...

At the end of the day, I think this bolsters the current practice, based on the D'Amico trial, of STADT in intermediate risk patients. I would hesitate to start lower risk patients on ADT just because of this trial...

Link:

Radiotherapy and Short-Term Androgen Deprivation for Localized Prostate Cancer: "New England Journal of Medicine, Volume 365, Issue 2, Page 107-118, July 2011."

Oxaliplatin for Neoadjuvant CTRT for Rectal Cancer

In the JCO:

An initial report of a randomized trial looking at the addition of oxaliplatin to the standard 5FU based CTRT for neoadjuvant treatment for rectal cancer shows no difference in immediate pathologic outcomes, despite increased toxicity. While pCR rates might not be the whole story, this trial is another bucket of cold water on this approach for neoadjuvant treatment of rectal cancer.

Link and Abstract:

Primary Tumor Response to Preoperative Chemoradiation With or Without Oxaliplatin in Locally Advanced Rectal Cancer: Pathologic Results of the STAR-01 Randomized Phase III Trial [Gastrointestinal Cancer]: "Purpose

To investigate oxaliplatin combined with fluorouracil-based chemoradiotherapy as preoperative treatment for locally advanced rectal cancer.

Patients and Methods

Seven hundred forty-seven patients with resectable, locally advanced (cT3-4 and/or cN1-2) adenocarcinoma of the mid-low rectum were randomly assigned to receive pelvic radiation (50.4 Gy in 28 daily fractions) and concomitant infused fluorouracil (225 mg/m²/d) either alone (arm A, n = 379) or combined with oxaliplatin (60 mg/m² weekly x 6; arm B, n = 368). Overall survival is the primary end point. A protocol-planned analysis of response to preoperative treatment is reported here.

Results

Grade 3 to 4 adverse events during preoperative treatment were more frequent with oxaliplatin plus fluorouracil and radiation than with radiation and fluorouracil alone (24% v 8% of treated patients; P < .001). In arm B, 83% of the patients treated with oxaliplatin had five or more weekly administrations. Ninety-one percent, compared with 97% in the control arm, received ≥ 45 Gy (P < .001). Ninety-six percent versus 95% of patients underwent surgery with similar rates of abdominoperineal resections (20% v 18%, arm A v arm B). The rate of pathologic complete responses was 16% in both arms (odds ratio = 0.98; 95% CI, 0.66 to 1.44; P = .904). Twenty-six percent versus 29% of patients had pathologically positive lymph nodes (arm A v arm B; P = .447), 46% versus 44% had tumor infiltration beyond the muscularis propria (P = .701), and 7% versus 4% had positive circumferential resection margins (P = .239). Intra-abdominal metastases were found at surgery in 2.9% versus 0.5% of patients (arm A v arm B; P = .014).

Conclusion

Adding oxaliplatin to fluorouracil-based preoperative chemoradiotherapy significantly increases toxicity without affecting primary tumor response. Longer follow-up is needed to assess the impact on efficacy end points.

"

JCO Palifermin for Mucositis Prevention in H&N cancer

In the JCO this week:

An interesting randomized trial of palifermin for mucositis prevention in patients recieving CTRT postoperatively for H&N cancer. They do find a moderate benefit to the drug, with decreased duration and longer time to developement of severe mucositis. There was also no evidence of disease protection. Interesting to see however if this breaks into common usage, or if it stays on the shelf with Amifostine.

Link and Abstract:

Palifermin Decreases Severe Oral Mucositis of Patients Undergoing Postoperative Radiochemotherapy for Head and Neck Cancer: A Randomized, Placebo-Controlled Trial [Head and Neck Cancer]: "Purpose

Radiochemotherapy of head and neck cancer causes severe mucositis in most patients. We investigated whether palifermin reduces this debilitating sequela.

Methods

We conducted a multicenter, double-blind, randomized, placebo-controlled trial in 186 patients with stages II to IVB carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx. Patients received 60 or 66 Gy after complete (R0) or incomplete resection (R1), respectively, at 2 Gy/fraction and five fractions per week. Cisplatin 100 mg/m² was administered on days 1 and 22 (and on day 43 with R1). Patients were randomly assigned to receive weekly palifermin 120 µg/kg or placebo from 3 days before and continuing throughout radiochemotherapy. Trained evaluators performed oral assessments twice weekly. The primary end point was the incidence of severe oral mucositis (WHO grades 3 to 4). Overall survival and time to locoregional progression were also assessed. Analysis was by intention to treat.

Results

Severe oral mucositis was seen in 47 (51%) of 92 patients administered palifermin and 63 (67%) of 94 administered placebo (P = .027). Palifermin decreased the duration (median, 4.5 v 22.0 days) and prolonged the time to develop (median, 45 v 32 days) severe mucositis. Neither patient-reported mouth and throat soreness scores nor treatment breaks differed between treatment arms. After median follow-up of 32.8 months, 23 deaths (25%) had occurred in both treatment arms, and disease had recurred in 25 (27%) and 22 (24%) of palifermin- and placebo-treated patients, respectively.

Conclusion

Palifermin reduced the occurrence of severe oral mucositis in patients with head and neck cancer undergoing postoperative radiochemotherapy. Additional clinical exploration of palifermin with postoperative radiochemotherapy would be useful.

"

Treatment of cancer pain

In the Lancet:

A reasonable review of the management of cancer related pain:

Link:

[Series] Treatment of cancer pain: "SummaryIn patients with active cancer, the management of chronic pain is an essential element in a comprehensive strategy for palliative care. This strategy emphasises multidimensional assessment and the coordinated use of treatments that together mitigate suffering and provide support to the patient and family. This review describes this framework, an approach to pain assessment, and widely accepted techniques to optimise the safety and effectiveness of opioid drugs and other treatments. The advances of recent decades suggest a future that includes increased evidence-based targeting of specific analgesic interventions within an individualised plan of care that is appropriate throughout the course of illness."

Meta analysis: Neoadjuvant treatment for Esophageal Cancer

In the Lancet Oncology:

A meta-analysis is updated, again suggesting that neoadjuvant treatment results in superior results over surgery alone for esophageal cancer. The comparison between chemoradiotherapy and chemotherapy was not quite significant, but there was a strong trend towards better results with chemoradiation.

Link:

[Articles] Survival after neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal carcinoma: an updated meta-analysis: "SummaryBackgroundIn a previous meta-analysis, we identified a survival benefit from neoadjuvant chemotherapy or chemoradiotherapy before surgery in patients with resectable oesophageal carcinoma. We updated this meta-analysis with results from new or updated randomised trials presented in the past 3 years. We also compared the benefits of preoperative neoadjuvant chemotherapy compared with neoadjuvant chemoradiotherapy.MethodsTo identify additional studies and published abstracts from major scientific meetings, we searched Medline, Embase, and Central (Cochrane clinical trials database) for studies published since January, 2006, and also manually searched for abstracts from major conferences from the same period."

secondary breast cancer after RT for HL

In the JCO this week:

An interesting article looking at the prognosis of patients developing a secondary breast cancer after RT for Hodgkin's Lymphoma, compared to sporadic disease. Perhaps not surprisingly, the cancers were detected earlier (due to more intensive screening), and was more likely to be bilateral. Additionally, there was increased risk to the other breast later in the woman's life. There was an increased risk of all cause mortality, and a non-significant increase in breast cancer specific mortality.

What this trial doesn't answer however is how patients with HL who did not recieve RT do with respect to breast cancer outcomes; therefor making it a little more difficulty to tease out the true effect of radiotherapy. That said, the finding are very consistent with the known increased risk of breast cancer induction from RT, and appropriately recommends close surveillance of these patients.

Abstract and Link:

Characteristics and Outcomes of Breast Cancer in Women With and Without a History of Radiation for Hodgkin's Lymphoma: A Multi-Institutional, Matched Cohort Study [Breast Cancer]: "Purpose

To compare characteristics and outcomes of breast cancer in women with and without a history of radiation therapy (RT) for Hodgkin's lymphoma (HL).

Patients and Methods

Women with breast cancer diagnosed from 1980 to 2006 after RT for HL were identified from eight North American hospitals and were matched three-to-one with patients with sporadic breast cancer by age, race, and year of breast cancer diagnosis. Information on patient, tumor and treatment characteristics, and clinical outcomes was abstracted from medical records.

Results

A total of 253 patients with breast cancer with a history of RT for HL were matched with 741 patients with sporadic breast cancer. Median time from HL to breast cancer diagnosis was 18 years. Median age at breast cancer diagnosis was 42 years. Breast cancer after RT for HL was more likely to be detected by screening, was more likely to be diagnosed at an earlier stage, and was more likely to be bilateral at diagnosis. HL survivors had an increased risk of metachronous contralateral breast cancer (adjusted hazard ratio [HR], 4.3; 95% CI, 1.7 to 11.0) and death as a result of any cause (adjusted HR, 1.9; 95% CI, 1.1 to 3.3). Breast cancer–specific mortality was also elevated, but this difference was not statistically significant (adjusted HR, 1.6; 95% CI, 0.7 to 3.4).

Conclusion

In women with a history of RT for HL, breast cancer is diagnosed at an earlier stage, but these women are at greater risk for bilateral disease and are more likely to die as a result of causes other than breast cancer. Our findings support close follow-up for contralateral tumors in these patients and ongoing primary care to manage comorbid conditions.

"

Sentinel Nodes for Endometrial Cancer

In Lancet Oncology

Results of a sentinel node lymph node biopsy in endometrial cancer are published, and they report a high NPV. Though it is buried in the paper, the sensitivity was 84%, which is a little bit lower than other SNLB series. As I count it, there were 3 patients who had a negative SLNB out of a total of 20 patients with nodal positivity, for a false negative rate of 15%.

This is a little less compelling than the more established vulvar sentinel studies, or the more recently reported cervical cancer series, but does raise some interesting possibilities. As the utility of dissection is debatable in endometrial cancer (as opposed to vuvla or cervix) - is a simple, less morbid, though admittedly less accurate means of staging "good enough?"

Link:

[Articles] Detection rate and diagnostic accuracy of sentinel-node biopsy in early stage endometrial cancer: a prospective multicentre study (SENTI-ENDO): "SLN biopsy with cervical dual labelling could be a trade-off between systematic lymphadenectomy and no dissection at all in patients with endometrial cancer of low or intermediate risk. Moreover, our study suggests that SLN biopsy could provide important data to tailor adjuvant therapy."

Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer

In the NEJM

An update to the Scandinavian randomized trial of Prostatectomy vs Watchful Waiting appears in the NEJM this week. Very useful for it's delineation of the natural history of early stage prostate cancer and the expected results with radical local therapy. Of course, it is impossible to know what the results of brachytherapy or EBRT would be in comparison to RP; nonetheless, it gives one ballpark numbers when counseling patients on their options.

Link:

Radical Prostatectomy versus Watchful Waiting in Early Prostate Cancer: New England Journal of Medicine, Volume 364, Issue 18, Page 1708-1717, May 2011.

Long term toxicity of WPRT for endometrial cancer (results of PORTEC 1)

In the JCO

Long term toxicity data for the PORTEC 1 trial sees manuscript publication (previously presented at ASTRO 2 years ag0). Worth a read, as the investigators find significant long term toxicity from WPRT. These results should be taken with some caveats however, as the surveys were sent out after the fact (only 351 surveys were sent out, of 714 in the full trial, and there was a 70% responsed rate for those 351). This raises the question of recall and selection bias. One can easily speculate that the patients continuing in followup were those that had complications. Additionally, one could also speculate that one is more likely to answer a QOL survey if one has significant symptoms.

That said, this should give the practicing radiation oncologist pause when recommending WPRT if there are alternatives (VBT) or a low risk of recurrence even in the absence of adjuvant therapy.

Link and Abstract:

Long-Term Outcome and Quality of Life of Patients With Endometrial Carcinoma Treated With or Without Pelvic Radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) Trial [Gynecologic Cancer]: "Purpose

To determine the long-term outcome and health-related quality of life (HRQL) of patients with endometrial carcinoma (EC) treated with or without pelvic radiotherapy in the Post Operative Radiation Therapy in Endometrial Carcinoma 1 (PORTEC-1) trial.

Patients and Methods

Between 1990 and 1997, 714 patients with stage IC grade 1 to 2 or IB grade 2 to 3 EC were randomly allocated to pelvic external-beam radiotherapy (EBRT) or no additional treatment (NAT). HRQL was evaluated with the Short Form 36-Item (SF-36) questionnaire; subscales from the European Organisation for Research and Treatment of Cancer (EORTC) PR25 module for bowel and bladder symptoms and the OV28 and CX24 modules for sexual symptoms; and demographic questions. Analysis was by intention-to-treat.

Results

Median follow-up was 13.3 years. The 15-year actuarial locoregional recurrence rates were 5.8% for EBRT versus 15.5% for NAT (P < .001), and 15-year overall survival was 52% versus 60% (P = .14). Of the 351 patients confirmed to be alive with correct address, 246 (70%) returned the questionnaire. Patients treated with EBRT reported significant (P < .01) and clinically relevant higher rates of urinary incontinence, diarrhea, and fecal leakage leading to more limitations in daily activities. Increased symptoms were reflected by the frequent use of incontinence materials after EBRT (day and night use, 42.9% v 15.2% for NAT; P < .001). Patients treated with EBRT reported lower scores on the SF-36 scales "physical functioning" (P = .004) and 'role-physical' (P = .003).

Conclusion

EBRT for endometrial cancer is associated with long-term urinary and bowel symptoms and lower physical and role-physical functioning, even 15 years after treatment. Despite its efficacy in reducing locoregional recurrence, EBRT should be avoided in patients with low- and intermediate-risk EC.

"

Sentinel Nodes in Cervical Cancer

In the JCO

Sentinel node mapping is making an appearance in all of the gynecologic cancers, most notably vulvar cancer, however two recent studies have examined the technique in cervix and endometrial cancer. The current study is in IA1-IB1 cervical lesions undergoing surgical staging and management, all of who were evaluated with a SNLB and then with a full dissection. The false negative rate was 8% (2/25), which is similar to the experience in breast. The investigators also noted that if bilateral nodes were mapped, there were no false negatives, but I would apply that with some caution as it appears to be a post hoc analysis.

While the rate false negative rate is similar to breast cancer, it remains to be seen if the clinical results will be the same as breast cancer. While this is a great step in the path towards integrating this into the management of early cervical cancer, one awaits a clinical trial in which the completion dissection is not performed, with careful follow up of the results. One must also be mindful of what we are actually accomplishing by performing less extensive dissections - while there are some adverse events associated with pelvic and PA dissections, in general they are relatively rare. The benefit of less extensive nodal sampling is much clearer in vulvar and breast cancer, where the risk of morbidity due to lymphedema is correspondingly higher.

Link and Abstract:

Bilateral Negative Sentinel Nodes Accurately Predict Absence of Lymph Node Metastasis in Early Cervical Cancer: Results of the SENTICOL Study [Gynecologic Cancer]: "Purpose

Sentinel lymph node (SLN) biopsy may be used to target lymph node metastases in patients with early cervical cancer. Whether SLN biopsy only is acceptable in the staging and surgical management of early cervical cancer remains unknown. This prospective multicenter study (SENTICOL [Ganglion Sentinelle dans le Cancer du Col]) assessed the sensitivity and negative predictive value (NPV) of SLN biopsy.

Patients and Methods

Adults with cervical carcinoma who met the International Federation of Gynecology and Obstetrics criteria for stage IA1 with lymphovascular space invasion to stage IB1 underwent technetium 99 lymphoscintigraphy and Patent Blue injection followed by laparoscopic lymph node mapping, SLN removal, and lymph node dissection. Only surgeons trained in SLN biopsy in cervical carcinoma participated in the study. SLNs and nonsentinel lymph nodes underwent routine staining. Negative SLNs were subjected to ultrastaging. The reference method was pelvic and/or para-aortic lymphadenectomy with histologic examination of all nodes.

Results

One hundred forty-five patients were enrolled, and 139 were included in a modified intention-to-diagnose analysis. Intraoperative radioisotope-blue dye mapping detected at least one SLN in 136 patients (97.8%; 95% CI, 93.8% to 99.6%), 23 of whom had true-positive results and two who had false-negative results, yielding 92.0% sensitivity (23 of 25; 95% CI, 74.0% to 99.0%) and 98.2% NPV (111 of 113; 95% CI, 74.0% to 99.0%) for node metastasis detection. No false-negative results were observed in the 104 patients (76.5%) in whom SLN were identified bilaterally.

Conclusion

Combined labeling for node mapping was associated with high rates of SLN detection and with high sensitivity and NPV for metastasis detection. However, SLN biopsy was fully reliable only when SLNs were detected bilaterally.

"

Gem + CDDP + RT with adjuvant CDDP + Gem vs standard CTRT for cervical cancer

In the JCO:

I posted previously about this trial from Argentina when presented at ASCO 2 years ago, now the manuscript is published in the JCO. Essentially this trial asks two questions, the utility of concurrent gem with CDDP, and the utility of adjuvant chemotherapy. The overall effect is compelling in this manuscript, improved local control, DFS and OS, compared to standard CTRT with brachy, albeit at the cost of increased toxicity. I don't feel that a change in standard practice will occur in the US yet due to these results, as most US practitioners would like a confirmatory trial, preferably examining the gem question and the adjuvant chemo question separately. That said, for certain high risk patients, some of the Gynecologic Oncologists I work with have been giving adjuvant chemotherapy (CDDP based) due in part to these results.

Link and Abstract.

Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients With Stage IIB to IVA Carcinoma of the Cervix [Gynecologic Cancer]: "Purpose

To determine whether addition of gemcitabine to concurrent cisplatin chemoradiotherapy and as adjuvant chemotherapy with cisplatin improves progression-free survival (PFS) at 3 years compared with current standard of care in locally advanced cervical cancer.

Patients and Methods

Eligible chemotherapy- and radiotherapy-naive patients with stage IIB to IVA disease and Karnofsky performance score ≥ 70 were randomly assigned to arm A (cisplatin 40 mg/m² and gemcitabine 125 mg/m² weekly for 6 weeks with concurrent external-beam radiotherapy [XRT] 50.4 Gy in 28 fractions, followed by brachytherapy [BCT] 30 to 35 Gy in 96 hours, and then two adjuvant 21-day cycles of cisplatin, 50 mg/m² on day 1, plus gemcitabine, 1,000 mg/m² on days 1 and 8) or to arm B (cisplatin and concurrent XRT followed by BCT only; dosing same as for arm A).

Results

Between May 2002 and March 2004, 515 patients were enrolled (arm A, n = 259; arm B, n = 256). PFS at 3 years was significantly improved in arm A versus arm B (74.4% v 65.0%, respectively; P = .029), as were overall PFS (log-rank P = .0227; hazard ratio [HR], 0.68; 95% CI, 0.49 to 0.95), overall survival (log-rank P = .0224; HR, 0.68; 95% CI, 0.49 to 0.95), and time to progressive disease (log-rank P = .0012; HR, 0.54; 95% CI, 0.37 to 0.79). Grade 3 and 4 toxicities were more frequent in arm A than in arm B (86.5% v 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A.

Conclusion

Gemcitabine plus cisplatin chemoradiotherapy followed by BCT and adjuvant gemcitabine/cisplatin chemotherapy improved survival outcomes with increased but clinically manageable toxicity when compared with standard treatment.

"

JCO long term follow up of Tamoxifen

In the JCO:

A very interesting article on the long term benefits of tamoxifen for breast cancer patients, emphasizing the curative nature of adjuvant hormone modulation in breast cancer patients. Also of interest is the reduction in CV events with longer term tamoxifen and the stability of the endometrial cancer risk at ~1.5% for both.

Link and Abstract:

Long-Term Benefits of 5 Years of Tamoxifen: 10-Year Follow-Up of a Large Randomized Trial in Women at Least 50 Years of Age With Early Breast Cancer [Breast Cancer]: "Purpose

The Cancer Research UK 'Over 50s' trial compared 5 and 2 years of tamoxifen in women with early breast cancer. Results are reported after median follow-up of 10 years.

Patients and Methods

Between 1987 and 1997, 3,449 patients age 50 to 81 years with operable breast cancer who had been taking 20 mg of tamoxifen for 2 years were randomly assigned to either stop or continue for an additional 3 years, if they were alive and recurrence free. Data on recurrences, new tumors, deaths, and cardiovascular events were obtained (April 2010).

Results

There were 1,103 recurrences, 755 deaths as a result of breast cancer, 621 cardiovascular (CV) events, and 236 deaths as a result of CV events. Fifteen years after starting treatment, for every 100 women who received tamoxifen for 5 years, 5.8 fewer experienced recurrence, compared with those who received tamoxifen for 2 years. The risk of contralateral breast cancer was significantly reduced (hazard ratio, 0.70; 95% CI, 0.48 to 1.00). Among women age 50 to 59 years, there was a 35% reduction in CV events (P = .005) and 59% reduction in death as a result of a CV event (P = .02); in older women, the effect was much smaller and not statistically significant.

Conclusion

Taking tamoxifen for the recommended 5 years reduces the risk of recurrence or contralateral breast cancer 15 years after starting treatment. It also lowers the risk of CV disease and death as a result of a CV event, particularly among those age 50 to 59 years. Women should therefore be encouraged to complete the full course. Although aromatase inhibitors improve disease-free survival, tamoxifen remains a cheap and highly effective alternative, particularly in developing countries.

"

3mo, 6 mo or no ADT for locally advance prostate cancer

Lancet Oncology this month:

The TROG investigators have published 10 year results of their no ADT, 3mo ADT, vs 6mo ADT, 3 armed randomized trial. The results show that while there are some benefits to 3mo ADT (such as decreased PSA recurrences, and improved DFS), but the larger benefits (distant metastases and overall survival) only became significant with 6 month. Of note, the majority of these patients were high risk, so the EORTC trial would already suggest that even 6months treatment doesn't give the full benefit, but, nonetheless, it does appear that even a few more months add benefit.

Link

NEJM: Potential health effects of the Fukushima disaster

NEJM this week has a good review of the nature and potential health effects of the reactor disaster in Fukushima. Definitely worth a read, and has some interesting comparisons to the Chernobyl disaster as well as Three Mile Island.

Link: http://www.nejm.org/doi/full/10.1056/NEJMra1103676

Carbo vs RT for stage I seminoma

In JCO this week:

the Carbo vs RT trial from the MRC and EORTC is updated with 5 year results - the short of it is that there is no difference in disease control, and a reduction in the rate of contralateral GCT.

Link and abstract:

Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214) [Urologic Oncology]: "Purpose

Initial results of a randomized trial comparing carboplatin with radiotherapy (RT) as adjuvant treatment for stage I seminoma found carboplatin had a noninferior relapse-free rate (RFR) and had reduced contralateral germ cell tumors (GCTs) in the short-term. Updated results with a median follow-up of 6.5 years are now reported.

Patients and Methods

Random assignment was between RT and one infusion of carboplatin dosed at 7 x (glomerular filtration rate + 25) on the basis of EDTA (n = 357) and 90% of this dose if determined on the basis of creatinine clearance (n = 202). The trial was powered to exclude a doubling in RFRs assuming a 96-97% 2-year RFR after radiotherapy (hazard ratio [HR], approximately 2.0).

Results

Overall, 1,447 patients were randomly assigned in a 3-to-5 ratio (carboplatin, n = 573; RT, n = 904). RFRs at 5 years were 94.7% for carboplatin and 96.0% for RT (RT-C 90% CI, 0.7% to 3.5%; HR, 1.25; 90% CI, 0.83 to 1.89). One death as a result of seminoma (in RT arm) occurred. Patients receiving at least 99% of the 7 x AUC dose had a 5-year RFR of 96.1% (95% CI, 93.4% to 97.7%) compared with 92.6% (95% CI, 88.0% to 95.5%) in those who received lower doses (HR, 0.51; 95% CI, 0.24 to 1.07; P = .08). There was a clear reduction in the rate of contralateral GCTs (carboplatin, n = 2; RT, n = 15; HR, 0.22; 95% CI, 0.05 to 0.95; P = .03), and elevated pretreatment follicle-stimulating hormone (FSH) levels (> 12 IU/L) was a strong predictor (HR, 8.57; 95% CI, 1.82 to 40.38).

Conclusion

These updated results confirm the noninferiority of single dose carboplatin (at 7 x AUC dose) versus RT in terms of RFR and establish a statistically significant reduction in the medium term of risk of second GCT produced by this treatment.

"

Kyphoplasty for Malignant Compression Fractures

An interesting arcticle in the Lancet Oncology reporting a randomized trial on using kyphoplasty for malignant compression fractures.

What they show is that kyphoplasty pretty safe and effective, and I am encouraged by the fact that the interventional radiology literature on these sorts of maneuvers is improving with prospective and randomized evaluations of care. What it doesn't show is that it should replace RT in these situations, as the control arm was simply whatever care the treating physicians wished to deliver. The authors do skirt the subject of the downsides of RT in their discussion, suggesting that this could be a replacement, but I would view that with significant skepticism. I would instead look at these as complimentary treatments, as there is no doubt that kyphoplasty holds the promise of much more rapid pain relief, and RT actually treats the tumor responsible for the fracture in the first place.

Link

Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors

In Cancer this week:

An interesting randomized trial looking at the use of Boswelliaserrata (an extract of Indian Frankincense) on cerebral edema, for patients undergoing radiation therapy for brain tumors (metastatic or primary). It is a modest trial with only 22pts in each arm, but they were able to demonstrate a significant decrease in T2 signal volume with the extract vs placebo. This did not however translate into a reduction in the use of steroids, nor in any clinically relevant endpoint. Of course, confirmation will be needed before this is ready for prime time, but this study is an intriguing demonstration of a novel approach at limiting steroid use.

Link and Abstract.

Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: "

Abstract

BACKGROUND:

Patients irradiated for brain tumors often suffer from cerebral edema and are usually treated with dexamethasone, which has various side effects. To investigate the activity of Boswelliaserrata (BS) in radiotherapy-related edema, we conducted a prospective, randomized, placebo-controlled, double-blind, pilot trial.

METHODS:

Forty-four patients with primary or secondary malignant cerebral tumors were randomly assigned to radiotherapy plus either BS 4200 mg/day or placebo. The volume of cerebral edema in the T2-weighted magnetic resonance imaging (MRI) sequence was analyzed as a primary endpoint. Secondary endpoints were toxicity, cognitive function, quality of life, and the need for antiedematous (dexamethasone) medication. Blood samples were taken to analyze the serum concentration of boswellic acids (AKBA and KBA).

RESULTS:

Compared with baseline and if measured immediately after the end of radiotherapy and BS/placebo treatment, a reduction of cerebral edema of >75% was found in 60% of patients receiving BS and in 26% of patients receiving placebo (P = .023). These findings may be based on an additional antitumor effect. There were no severe adverse events in either group. In the BS group, 6 patients reported minor gastrointestinal discomfort. BS did not have a significant impact on quality of life or cognitive function. The dexamethasone dose during radiotherapy in both groups was not statistically different. Boswellic acids could be detected in patients' serum.

CONCLUSIONS:

BS significantly reduced cerebral edema measured by MRI in the study population. BS could potentially be steroid-sparing for patients receiving brain irradiation. Our findings will need to be further validated in larger studies. Cancer 2011. © 2011 American Cancer Society.

"

Lancet: TAX 324 update

In the Lancet this week:

An update of TAX 324 is published confirming long term benefit for PFS and OS for TPF vs PF induction chemotherapy for locally advanced head and neck cancer. Clearly I think this confirms that this is the best induction regimen, however, wether induction chemotherapy is truly the best strategy remains uncertain (versus optimal up front concurrent chemo-radiotherapy), and further randomized work will be needed to establish this as the standard of care.

link

[Articles] Induction chemotherapy with cisplatin and fluorouracil alone or in combination with docetaxel in locally advanced squamous-cell cancer of the head and neck: long-term results of the TAX 324 randomised phase 3 trial: "Induction chemotherapy with TPF provides long-term survival benefit compared with PF in locally advanced head and neck cancer. Patients who are candidates for induction chemotherapy should be treated with TPF."

Collins Law and Estimating a Tumors Age before diagnosis

In Oncology last week:

An interesting article from Larry Marks - which gets at a question often heard in the clinic: "How long have I had this?" Marks uses a variation on Collins Law (well described in the paper) to estimate how long a tumor may have existed from the development of the first clonogen to the time of detection based on local recurrence rates after a curative resection, and finds that some tumors may have existed for many years prior to detection (3-6 years for the sites studied).

Now obviously there are huge assumptions: first that growth rates are similar before and after a curative surgery, and it excludes tumors which may have been treated more aggressively, and recurred distantly. Therefore, one can really only apply this to low grade cancers that are likely to fail locally only. Nonetheless, it's an interesting thought experiment.

Link (requires free membership to login)

How Long Have I Had My Cancer, Doctor? - Cancer Network

How Long Have I Got? Estimating Typical, Best-Case, and Worst-Case Scenarios for Patients Starting First-Line Chemotherapy for Metastatic Breast Cancer: A Systematic Review of Recent Randomized Trials [REVIEW ARTICLE]

In the JCO:

A relatively simple way to approach estimating a patient's long term prognosis with metastatic breast cancer is put forward in the JCO this week. I liked this as it is simple, in a way that hopefully will be useful to patients when considering their prognosis, going beyond the simple median survivals that immediately come to mind. Of course, one has to take into account that these are based on published clinical trials, which tend to attract and accrue the most motivated and healthy of patients.

Link and Abstract.

How Long Have I Got? Estimating Typical, Best-Case, and Worst-Case Scenarios for Patients Starting First-Line Chemotherapy for Metastatic Breast Cancer: A Systematic Review of Recent Randomized Trials [REVIEW ARTICLE]: "Purpose

To estimate scenarios for survival for women with metastatic breast cancer (MBC) who are starting chemotherapy.

Patients and Methods

We sought randomized, first-line chemotherapy trials for MBC published from 1999 to 2009. We recorded median progression-free survival (PFS) and median overall survival (OS) and extracted the following percentiles (represented scenario) from each OS curve: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We also estimated these scenarios for each OS curve by multiplying its median by four simple multiples: 0.25 (worst-case), 0.5 (lower-typical), 2 (upper-typical), and 3 (best-case). Estimates were deemed accurate if they were within 0.75 to 1.33 times the actual value.

Results

From 36 trials (13,083 women), the mean for median PFS was 7.6 months (interquartile range [IQR], 6.0 to 9.0 months), the mean for median OS was 21.7 months (IQR,18.2 to 24.0 months), and the mean for the ratio of median OS to median PFS was 3.0 (IQR, 2.4 to 3.5). The mean for each OS scenario was worst-case, 6.3 months (IQR, 4.8 to 7.5 months); lower-typical, 11.9 months (IQR, 9.9 to 13.2 months); upper-typical, 36.2 months (IQR, 31.1 to 41.3 months); and best-case, 55.8 months (IQR, 47.5 to 60.2 months). Simple multiples of the median gave accurate estimates of the worst-case scenario in 73% of OS curves, lower-typical in 97%, upper-typical in 95%, and best-case in 96%. OS was longer in trials with higher proportions of estrogen receptor–positive tumors (P = .001) and in trials of trastuzumab-treated human epidermal growth factor receptor 2–positive tumors (P = .001).

Conclusion

Simple multiples of an OS curve's median can accurately estimate typical (half to double the median), best-case (triple the median), and worst-case (one quarter of the median) scenarios for survival.

"

MDS in Atomic Bomb survivors

In the JCO:

Fortunately there are very few populations in which the late effects of single instance low dose whole body radiation can be studied. Fortunately also, the Japanese and US government have been very helpful in performing large scale studies of the long term effects of the two bombs dropped. While a fair amount of the secondary cancer risk has been published, from the data presented in JCO this week, MDS is clearly another risk that should be monitored for.

Links and Abstract:

Risk of Myelodysplastic Syndromes in People Exposed to Ionizing Radiation: A Retrospective Cohort Study of Nagasaki Atomic Bomb Survivors [Epidemiology]: "Purpose

The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb survivors.

Patients and Methods

We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk.

Results

There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young.

Conclusion

A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.

"

Results of the SPIRIT trial (Surgery vs Brachy) for Prostate

In the JCO:

Few disease sites would benefit from a randomized trial more than prostate cancer would, though we can't seem to accrue anything except for varying lengths of hormonal treatment and different postoperative strategies. The SPIRIT trial valiantly tried to correct this issue, however unfortunately failed to accrue. Fortunately, at lease some data from this attempt is published in JCO this week, and the QOL in urinary and sexual domains favor brachytherapy. Link and abstract below.

Comparison of Health-Related Quality of Life 5 Years After SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial [Urologic Oncology]: "Purpose

The American College of Surgeons Oncology Group phase III Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial comparing radical prostatectomy (RP) and brachytherapy (BT) closed after 2 years due to poor accrual. We report health-related quality of life (HRQOL) at a mean of 5.3 years for 168 trial-eligible men who either chose or were randomly assigned to RP or BT following a multidisciplinary educational session.

Patients and Methods

After initial lack of accrual, a multidisciplinary educational session was introduced for eligible patients. In all, 263 men attended 47 sessions. Of those, 34 consented to random assignment, 62 chose RP, and 94 chose BT. Five years later, these 190 men underwent HRQOL evaluation by using the cancer-specific 50-item Expanded Prostate Cancer Index Composite, the Short Form 12 Physical Component Score, and Short Form 12 Mental Component Score. Response rate was 88.4%. The Wilcoxon rank sum test was used to compare summary scores between the two interventions.

Results

Of 168 survey responders, 60.7% had BT (9.5% randomly assigned) and 39.3% had RP (9.5% randomly assigned). Median age was 61.4 years for BT and 59.4 for RP (P = .05). Median follow-up was 5.2 years (range, 3.2 to 6.5 years). For BT versus RP, there was no difference in bowel or hormonal domains, but men treated with BT scored better in urinary (91.8 v 88.1; P = .02) and sexual (52.5 v 39.2; P = .001) domains, and in patient satisfaction (93.6 v 76.9; P < .001).

Conclusion

Although treatment allocation was random in only 19%, all patients received identical information in a multidisciplinary setting before selecting RP, BT, or random assignment. HRQOL evaluated 3.2 to 6.5 years after treatment showed an advantage for BT in urinary and sexual domains and in patient satisfaction.

"

Lancet Oncology: Urorad and IMRT

A very blunt interview with Anthony Zeitman is published in Lancet Oncology, blasting the Urorad business model.

[News] US urology clinics overprescribe prostate radiotherapy: "The US Government Accountability Office is investigating allegations that urologists are reaping hundreds of millions of dollars by overprescribing intensity-modulated radiotherapy (IMRT) for prostate cancer. Since 2002, Medicare, the federal health insurance programme for elderly patients, has paid generously for IMRT—up to US$40 000 per patient."

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

In Cancer this week:

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

Link and Abstract:

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

Abstract

BACKGROUND:

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

METHODS:

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

RESULTS:

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

CONCLUSIONS:

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

"

DVH parameters for Cervical HDR brachytherapy

In the Red Journal this week:

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

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

Link and abstract

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

PCI for NSCLC

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

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

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

Link and Abstract from the JCO:

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

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

Patients and Methods

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

Results

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

Conclusion

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

"

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

JCO this week:

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

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

Link and Abstract:

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

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

Patients and Methods

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

Results

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

Conclusion

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

"

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

In Lancet Oncology this week:

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

Link:

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

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

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

Link:

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