Monday, July 25, 2011

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 Identifier: NCT00311636"

Thursday, July 14, 2011

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...


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

Monday, July 11, 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.


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).


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.


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.


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.


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.