NEJM: neoadjuvant CTRT for esophageal cancer

NEJM this week

Dutch investigators publish a randomized phase III trial looking at carbo-taxol+RT followed by surgery vs surgery alone for esophageal/GEJ cancers: they confirm a survival benefit to combined modality for both squams and adenos.  While prior studies did show a benefit (the Walsh trial and the CALGB trial) both had low numbers and other concerns (such as the low survival in the surgery alone arm of the Walsh trial).  This will hopefully close the book on surgery alone for all but the most early stages of disease.  There still remains the question of whether the RT is adding anything to this (there are the perioperative chemo alone trials from the UK which are also positive), but for now it seems the weight of data is clearly towards multimodal treatment for this aggressive disease.

Link to NEJM

Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer: New England Journal of Medicine, Volume 366, Issue 22, Page 2074-2084, May 2012.

RT for prevention of nodal recurrences of Melanoma

Lancet Oncology this week:

The  Australian trial of adjuvant RT for nodal basins for melanoma, initially presented in ASTRO several years ago, has finally seen publication - again confirming a local control benefit to 48Gy in 24 fractions.  The entry criteria was slightly complex, depending on size and # of nodes that was different per site, with extranodal extension always qualifying.  Perhaps not surprisingly, there was no benefit for survival in such a small trial, but it was not powered for this regardless.  In light of the relative lack of efficacy of standard chemotherapy, RT still seems to be the most reasonable option of any treatment outside of those with BRAF mutations.

Link:

[Articles] Adjuvant radiotherapy versus observation alone for patients at risk of lymph-node field relapse after therapeutic lymphadenectomy for melanoma: a randomised trial: Adjuvant radiotherapy improves lymph-node field control in patients at high risk of lymph-node field relapse after therapeutic lymphadenectomy for metastatic melanoma. Adjuvant radiotherapy should be discussed with patients at high risk of relapse after lymphadenectomy.

Capecitabine for Rectal Cancer

In Lancet Oncology:

A phase III trial comparing RT + capecitabine vs 5FU for rectal cancer - fortunately has confirmed what is already common practice in the US - capecitabine proved no worse (by their criteria).  All trends as well favored capcitabine for disease control.  Capcitabine proved more toxic however, in all but leukopenia.

Link:

[Articles] Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial: Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.

Pazopanib for study tissue sarcoma

from the Lancet this week: a new option where there are so few to start... [Articles] Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial

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