Thursday, February 25, 2010

Secondary malignancies in pediatic HL survivors

In the JCO:

A report from Stanford comes out with long follow up from pediatric HL survivors, treated with lower dose radiation looking at secondary malignancy rates. The twenty year rate of secondary malignancy was 17%, consisting of leukemias and solid tumors including breast, thyroid and sarcoma primaries. Again this underlines the potential for malignancy induction in the pediatric patients.

Link and Abstract

Second Malignant Neoplasms in Survivors of Pediatric Hodgkin's Lymphoma Treated With Low-Dose Radiation and Chemotherapy [Pediatric Oncology]: "Purpose

Survivors of childhood Hodgkin's lymphoma (HL) are at risk for second malignant neoplasms (SMNs). It is theorized that this risk may be attenuated in patients treated with lower doses of radiation. We report the first long-term outcomes of a cohort of pediatric survivors of HL treated with chemotherapy and low-dose radiation.

Patients and Methods

Pediatric patients with HL (n = 112) treated at Stanford from 1970 to 1990 on two combined modality treatment protocols were identified. Treatment included six cycles of chemotherapy with 15 to 25.5 Gy involved-field radiation with optional 10 Gy boosts to bulky sites. Follow-up through September 1, 2007, was obtained from retrospective chart review and patient questionnaires.


One hundred ten children completed HL therapy; median follow-up was 20.6 years. Eighteen patients developed one or more SMNs, including four leukemias, five thyroid carcinomas, six breast carcinomas, and four sarcomas. Cumulative incidence of first SMN was 17% (95% CI, 10.5 to 26.7) at 20 years after HL diagnosis. The standard incidence ratio for any SMN was 22.9 (95% CI, 14.2 to 35) with an absolute excess risk of 93.7 cases per 10,000 person-years. All four secondary leukemias were fatal. For those with second solid tumors, the mean (± SE) 5-year disease-free and overall survival were 76% ± 12% and 85% ± 10% with median follow-up 5 years from SMN diagnosis.


Despite treatment with low-dose radiation, children treated for HL remain at significant risk for SMN. Sarcomas, breast and thyroid carcinomas occurred with similar frequency and latency as found in studies of children with HL who received high-dose radiation.


Cisplatin for triple negative breast cancer

This weeks JCO -

Triple negative breast cancer is a challenge in the era of targeted therapy for breast cancer. There have been hints that cisplatin may be particularly useful for this subset, specifically in those with BRCA-1 pathway disruptions. Below is some of the initial experience with exploring this in a small prospective trial looking at responses in triple negative tumors treated neoadjuvantly with cisplatin.

Link and Article.

Efficacy of Neoadjuvant Cisplatin in Triple-Negative Breast Cancer [Breast Cancer]: "Purpose

Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response.

Patients and Methods

Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m2 every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers.


Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03).


Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.


Wednesday, February 24, 2010

Dose escalation for Prostate Cancer

10 year results of the PROG trial of proton dose escalation for low-intermediate risk prostate cancer are published in the weeks JCO. No big surprises, the same trends hold with improvements in biochemical control, no difference in OS (though a 5% trend does exist favoring high dose). The 10 year data does solidify support of dose escalation, and the lack of delayed toxicity is quite encouraging.

Link and abstract

Randomized Trial Comparing Conventional-Dose With High-Dose Conformal Radiation Therapy in Early-Stage Adenocarcinoma of the Prostate: Long-Term Results From Proton Radiation Oncology Group/American College of Radiology 95-09 [Genitourinary Cancer]:
To test the hypothesis that increasing radiation dose delivered to men with early-stage prostate cancer improves clinical outcomes.
Patients and Methods
Men with T1b-T2b prostate cancer and prostate-specific antigen ≤ 15 ng/mL were randomly assigned to a total dose of either 70.2 Gray equivalents (GyE; conventional) or 79.2 GyE (high). No patient received androgen suppression therapy with radiation. Local failure (LF), biochemical failure (BF), and overall survival (OS) were outcomes.
A total of 393 men were randomly assigned, and median follow-up was 8.9 years. Men receiving high-dose radiation therapy were significantly less likely to have LF, with a hazard ratio of 0.57. The 10-year American Society for Therapeutic Radiology and Oncology BF rates were 32.4% for conventional-dose and 16.7% for high-dose radiation therapy (P < .0001). This difference held when only those with low-risk disease (n = 227; 58% of total) were examined: 28.2% for conventional and 7.1% for high dose (P < .0001). There was a strong trend in the same direction for the intermediate-risk patients (n = 144; 37% of total; 42.1% v 30.4%, P = .06). Eleven percent of patients subsequently required androgen deprivation for recurrence after conventional dose compared with 6% after high dose (P = .047). There remains no difference in OS rates between the treatment arms (78.4% v 83.4%; P = .41). Two percent of patients in both arms experienced late grade ≥ 3 genitourinary toxicity, and 1% of patients in the high-dose arm experienced late grade ≥ 3 GI toxicity.
This randomized controlled trial shows superior long-term cancer control for men with localized prostate cancer receiving high-dose versus conventional-dose radiation. This was achieved without an increase in grade ≥ 3 late urinary or rectal morbidity.

Friday, February 19, 2010

SBRT vs Wedge resection (retrospective)

This weeks JCO:

A retrospective comparison of wedge resection and SBRT for stage I NSCLC is reported by Beaumont. They find improved local and regional recurrence rates with SBRT, similar cause specific survival, and worse OS in with SBRT. They explain the worse OS by patient selection (i.e. the healthier patients were taken for wedge).

I think from this, you see a signal that SBRT seems at least equivalent to wedge and potentially less toxic. I think it is hard to say that it is superior for local control, because if one is censoring out the patients who die (as one does in with the local control endpoint), the more patients die from other causes, the less events are possible for local failure. Thus the LRC may have been higher with SBRT due to the lower OS. In addition the followup was not as long for SBRT patients.

Regardless, this is an interesting paper, and supports the use of SBRT in medically inoperable patients.

Link and Abstract:

Outcomes After Stereotactic Lung Radiotherapy or Wedge Resection for Stage I Non-Small-Cell Lung Cancer [Thoracic Oncology]: "Purpose

To compare outcomes between lung stereotactic radiotherapy (SBRT) and wedge resection for stage I non–small-cell lung cancer (NSCLC).

Patients and Methods

One hundred twenty-four patients with T1-2N0 NSCLC underwent wedge resection (n = 69) or image-guided lung SBRT (n = 58) from February 2003 through August 2008. All were ineligible for anatomic lobectomy; of those receiving SBRT, 95% were medically inoperable, with 5% refusing surgery. Mean forced expiratory volume in 1 second and diffusing capacity of lung for carbon monoxide were 1.39 L and 12.0 mL/min/mmHg for wedge versus 1.31 L and 10.14 mL/min/mmHg for SBRT (P = not significant). Mean Charlson comorbidity index and median age were 3 and 74 years for wedge versus 4 and 78 years for SBRT (P < .01, P = .04). SBRT was volumetrically prescribed as 48 (T1) or 60 (T2) Gy in four to five fractions.


Median potential follow-up is 2.5 years. At 30 months, no significant differences were identified in regional recurrence (RR), locoregional recurrence (LRR), distant metastasis (DM), or freedom from any failure (FFF) between the two groups (P > .16). SBRT reduced the risk of local recurrence (LR), 4% versus 20% for wedge (P = .07). Overall survival (OS) was higher with wedge but cause-specific survival (CSS) was identical. Results excluding synchronous primaries, nonbiopsied tumors, or pathologic T4 disease (wedge satellite lesion) showed reduced LR (5% v 24%, P = .05), RR (0% v 18%, P = .07), and LRR (5% v 29%, P = .03) with SBRT. There were no differences in DM, FFF, or CSS, but OS was higher with wedge.


Both lung SBRT and wedge resection are reasonable treatment options for stage I NSCLC patients ineligible for anatomic lobectomy. SBRT reduced LR, RR, and LRR. In this nonrandomized population of patients selected for surgery versus SBRT (medically inoperable) at physician discretion, OS was higher in surgical patients. SBRT and surgery, however, had identical CSS.


Tuesday, February 16, 2010

Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer

In the NEJM this week:

10 year results of the Canadian Hypofractionation trial for breast cancer are published, showing no difference in local control, toxicity, or cosmetic appearance. Interestingly, a new subset analysis in this paper seems to suggest that high grade cancers were not the best candidate for hypofractionation due to a higher failure rate. However in a low risk patient, this has become a standard option at Duke for the treatment of node-megative disease. Of course the caveats is that this trial does not apply to patients who are node positive and in those who have a separation >25cm. Boost was not also used in the trial; though we will occasionally offer a boost of 200cGy x 5 with the 2.66Gy x 16fx regimen extrapolating from the boost trials.

Link to the NEJM:

Long-Term Results of Hypofractionated Radiation Therapy for Breast Cancer: "The optimal schedule of radiation treatment after breast-conserving surgery for invasive breast cancer is unknown. In this study, two groups of patients received either hypofractionated radiation or a standard schedule of radiation treatment. Ten years later, the two groups had similar risks of local recurrence and a similar appearance of the breast."

[Articles] Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial

This weeks Lancet:

An interesting article on the potential utility for MRI in initial work up of breast cancer. While a prior trial in the NEJM (link) demonstrated that one could detect occult cancers in the contralateral breast in 3% of patients (by biopsying 12%), this trial looked at the utility of MRI in surgical planning in the ipsilateral breast. The short of it: no difference in reoperation rates for positive or close margins. MRI seems to becoming more of a standard preoperative test, however the only clinically relevant outcome reported as yet is an increase in the mastectomy rate (link).

Link to the Lancet

[Articles] Comparative effectiveness of MRI in breast cancer (COMICE) trial: a randomised controlled trial: "MRI might improve diagnosis of breast cancer, reducing rates of reoperation. We assessed the clinical efficacy of contrast-enhanced MRI in women with primary breast cancer."

Tuesday, February 9, 2010

Induction Chemo for Rectal Cancer

This weeks JCO has a randomized phase II study examining induction chemotherapy for rectal cancer. The endpoint was pCR, a reasonable surrogate for clinical outcome.

Randomized phase II studies are always a bit of an enigma to me. They are not powered to show differences between the arms (that would be a phase III), and yet they are randomized. The practical significance is that it is much easier to get these done because the accrual goals are much lower than a true phase III. In this case, the goals of the researchers was to "drop" a less effective arm, i.e. assuming that the better arm would have a pCR rate of 15%, they had 90% power to detect a difference if the worse arm was 10%.

Either way, their results are similar to what has been seen in other induction trials for solid tumors, no differences in the clinically significant disease endpoints. What they did show is better tolerance of the chemotherapy, and thus more exposure to drug. One other thing that is obviously important is to look for the ability to deliver radiation and go to surgery afterwards, which fortunately was no different between the arms.

They conclude that it was reasonable to move onto phase III comparing these approaches.

Link and Abstract:

The optimal therapeutic sequence of the adjuvant chemotherapy component of preoperative chemoradiotherapy (CRT) for patients with locally advanced rectal cancer is controversial. Induction chemotherapy before preoperative CRT may be associated with better efficacy and compliance.

Patients and Methods

A total of 108 patients with locally advanced rectal cancer were randomly assigned to arm A—preoperative CRT with capecitabine, oxaliplatin, and concurrent radiation followed by surgery and four cycles of postoperative adjuvant capecitabine and oxaliplatin (CAPOX)—or arm B—induction CAPOX followed by CRT and surgery. The primary end point was pathologic complete response rate (pCR).


On an intention-to-treat basis, the pCR for arms A and B were 13.5% (95% CI, 5.6% to 25.8%) and 14.3% (95% CI, 6.4% to 26.2%), respectively. There were no statistically significant differences in other end points, including downstaging, tumor regression, and R0 resection. Overall, chemotherapy treatment exposure was higher in arm B than in arm A for both oxaliplatin (P < .0001) and capecitabine (P < .0001). During CRT, grades 3 to 4 adverse events were similar in both arms but were significantly higher in arm A during postoperative adjuvant CT than with induction CT in arm B. There were three deaths in each arm during the treatment period.


Compared with postoperative adjuvant CAPOX, induction CAPOX before CRT had similar pCR and complete resection rates. It did achieve more favorable compliance and toxicity profiles. On the basis of these findings, a phase III study to definitively test the induction strategy is warranted."

Monday, February 8, 2010

Cancer During Pregnancy: An Analysis of 215 Patients Emphasizing the Obstetrical and the Neonatal Outcomes [Gynecologic Cancer]

This weeks JCO -

An interesting report on outcomes for patients treated for malignancy with surgery, chemotherapy, and or radiation. The numbers are small for radiation; largely the focus is on cytotoxic treatments. The data however is invaluable to clinicians and patients that find themselves in this challenging situation.

Link and Abstract.

Cancer During Pregnancy: An Analysis of 215 Patients Emphasizing the Obstetrical and the Neonatal Outcomes [Gynecologic Cancer]: "Purpose

The aim of this study was to assess the management and the obstetrical and neonatal outcomes of pregnancies complicated by cancer.

Patients and Methods

In an international collaborative setting, patients with invasive cancer diagnosed during pregnancy between 1998 and 2008 were identified. Clinical data regarding the cancer diagnosis and treatment and the obstetric and neonatal outcomes were collected and analyzed.


Of 215 patients, five (2.3%) had a pregnancy that ended in a spontaneous miscarriage and 30 (14.0%) pregnancies were interrupted. Treatment was initiated during pregnancy in 122 (56.7%) patients and postpartum in 58 (27.0%) patients. The most frequently encountered cancer types were breast cancer (46%), hematologic malignancies (18%), and dermatologic malignancies (10%). The mean gestational age at delivery was 36.3 ± 2.9 weeks. Delivery was induced in 71.7% of pregnancies, and 54.2% of children were born preterm. In the group of patients prenatally exposed to cytotoxic treatment, the prevalence of preterm labor was increased (11.8%; P = .012). Furthermore, in this group a higher proportion of small-for-gestational-age children (birth weight below 10th percentile) was observed (24.2%; P = .001). Of all neonates, 51.2% were admitted to a neonatal intensive care unit, mainly (85.2%) because of prematurity. There was no increased incidence of congenital malformations.


Pregnant cancer patients should be treated in a multidisciplinary setting with access to maternal and neonatal intensive care units. Prevention of iatrogenic prematurity appears to be an important part of the treatment strategy."

Pregabalin (Lyrica) for Hot Flashes

This weeks JCO - Pregabalin (trade name Lyrica) is a new drug on the market for depression and neuropathic pain. It also is studied for reduction in hot flashes; a common problem for those with either breast or prostate cancer. This study demonstrates efficacy with a dose of 75mg BID. Wether it is more or less effective than other measures is unknown.

Link and Abstract

Phase III, Randomized, Double-Blind, Placebo-Controlled Evaluation of Pregabalin for Alleviating Hot Flashes, N07C1 [Palliative and Supportive Care]: "Purpose

Hot flashes are a common problem for which effective and safe treatments are needed. The current trial was conducted on the basis of preliminary promising data that pregabalin decreased hot flashes.

Patients and Methods

A double-blind, placebo-controlled, randomized trial design was used to compare pregabalin at target doses of 75 mg twice daily and 150 mg twice daily with a placebo. Hot flash frequencies and scores (frequency times mean severity) were recorded daily during a baseline week and for six treatment weeks. The primary end point for this study was the change-from-baseline hot flash score during treatment week 6 between the 150 mg twice daily target pregabalin treatment and placebo. Nonparametric Wilcoxon rank sum tests, two-sample t tests, and 2 tests were used to compare the primary and secondary hot flash efficacy end points between pregabalin treatments and placebo.


Hot flash score changes available for 163 patients during the sixth treatment week compared with a baseline week decreased by 50%, 65%, and 71% in the placebo, and target 75 mg twice daily and 150 mg twice daily pregabalin arms, respectively (P = .009 and P = .007, comparing respective pregabalin arms to the placebo arm). While some toxicities were significantly more common in the pregabalin arms, being more evident with the higher dose, pregabalin was generally well tolerated by most patients.


Pregabalin decreases hot flashes and is reasonably well tolerated. A target dose of 75 mg twice daily is recommended. Its effects appear to be roughly comparable to what has been reported with gabapentin and with some newer antidepressants."

Monday, February 1, 2010

Venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for Hot Flushes in Men taking GNrH analogues

An interesting phase III trial looking at options for treating hot flushes in men recieving androgren deprivation for prostate cancer. The short - all reduced hot flushes, but cyproterone and medroxyprogesterone were superior. The authors conclude that medroxyprogesterone 20mg daily is the perferred treatment, as cyproterone also has an effect on the treatment of prostate cancer and as such may confound the overall management of the prostate cancer. In the US megestrol (Megace) may be preferable, but was not used in this trial as it was not available for use in France.


[Articles] Efficacy of venlafaxine, medroxyprogesterone acetate, and cyproterone acetate for the treatment of vasomotor hot flushes in men taking gonadotropin-releasing hormone analogues for prostate cancer: a double-blind, randomised trial: "Hot flushes are the most common complaints reported by men undergoing androgen suppression treatment for prostate cancer. We designed a randomised double-blind trial to compare the efficacy of three drugs, each of which has proven effective for preventing hot flushes in previous studies."