Regardless of your political persuasion, Ted Kennedy was a force in the Senate, and shaped much of the current dialogue on health care reform (in addition to many other issues over his long political career). As his treatment involved surgery at Duke and proton therapy in Boston, it may be of interest to read media reports of his treatment course:
Link to CNN article
Thursday, August 27, 2009
Exposure to Low-Dose Ionizing Radiation from Medical Imaging Procedures
Very interesting article on the use of medical imaging and the resulting dose in a broad population sample in this weeks NEJM.
Link:
Exposure to Low-Dose Ionizing Radiation from Medical Imaging Procedures: "The use of medical imaging procedures has been increasing, and this study estimated the exposure of U.S. patients to low-dose ionizing radiation from these procedures. The exposure was substantial, largely because of radiation from computed tomography and nuclear imaging. The highest average effective dose was attributable to myocardial perfusion imaging, and most imaging occurred in outpatient settings. These data indicate that the use of imaging can result in high radiation doses. "
Link:
Exposure to Low-Dose Ionizing Radiation from Medical Imaging Procedures: "The use of medical imaging procedures has been increasing, and this study estimated the exposure of U.S. patients to low-dose ionizing radiation from these procedures. The exposure was substantial, largely because of radiation from computed tomography and nuclear imaging. The highest average effective dose was attributable to myocardial perfusion imaging, and most imaging occurred in outpatient settings. These data indicate that the use of imaging can result in high radiation doses. "
Tuesday, August 25, 2009
Antioxidants and Cancer: More Caution
This week's nature has a very interesting article on a potential pro-survival effect of antioxidants on metastatic cells. This stems from the observation that cells that loose attachment to the extracellular matrix (ECM), have increased levels of reactive oxygen species (ROS) intracellularly, leading to a reduced atp levels. In this model, these defects were reversed by the application of antioxidants (NAC or a vitamin E derivative).
Of course we have been telling patients for years not to take large amounts of antioxidants during radiation therapy due to the potential reversal of the oxygen dependent indirect effect of RT. This however is a much broader cautionary tale, albiet without any direct human clinical data at this time...
Link:
Of course we have been telling patients for years not to take large amounts of antioxidants during radiation therapy due to the potential reversal of the oxygen dependent indirect effect of RT. This however is a much broader cautionary tale, albiet without any direct human clinical data at this time...
Link:
nature: Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment
Thursday, August 20, 2009
Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer
Banner day for oncology in this weeks NEJM:
The BIG 1-98 trial comparing different hormonal manipulations for the adjuvant treatment of postmenopausal women have finally reported on the "switching" arms of the trial. This trial has previously reported that the tamoxifen only arm was inferior to the letrozole arm, however there were those that believed that a switch between tamoxifen and letrozole would be beneficial. That has not been born out in these results, with the tamoxifen early arm demonstrating more early recurrences than the other arms.
Link:
Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer: "This study of adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive early breast cancer showed that disease-free survival was similar after 5 years of treatment with letrozole alone, 2 years of treatment with letrozole followed by 3 years with tamoxifen, or 2 years of treatment with tamoxifen followed by 3 years with letrozole. Five years of letrozole monotherapy may be superior to 5 years of tamoxifen monotherapy. "
The BIG 1-98 trial comparing different hormonal manipulations for the adjuvant treatment of postmenopausal women have finally reported on the "switching" arms of the trial. This trial has previously reported that the tamoxifen only arm was inferior to the letrozole arm, however there were those that believed that a switch between tamoxifen and letrozole would be beneficial. That has not been born out in these results, with the tamoxifen early arm demonstrating more early recurrences than the other arms.
Link:
Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer: "This study of adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive early breast cancer showed that disease-free survival was similar after 5 years of treatment with letrozole alone, 2 years of treatment with letrozole followed by 3 years with tamoxifen, or 2 years of treatment with tamoxifen followed by 3 years with letrozole. Five years of letrozole monotherapy may be superior to 5 years of tamoxifen monotherapy. "
Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer
The NEJM this week has an article directly relevant to patients receiving long term androgen deprivation with radiation therapy for high risk prostate cancer. In this phase III trial, patients undergoing androgen deprivation were randomized to receive denosumab, a monoclonal antibody targeting the NFKB ligand. The intervention resulted in improved bone density, and perhaps more importantly, resulted in decreased vertebral fractures, all at no significant observed toxicities.
This joins a number of randomized trials conducted by Dr. Smith and others on similar agents (see table below). What remains to be seen is what the best intervention is, both in terms of efficacy and cost.
Link:
Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer
This joins a number of randomized trials conducted by Dr. Smith and others on similar agents (see table below). What remains to be seen is what the best intervention is, both in terms of efficacy and cost.
Link:
Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
NEJM has two interesting articles on EGFR recepter mutations and response to targeted treatments. The first of these demonstrates the incidence of EGRF mutations in the NSCLC population, and highlights the known associated demographic characteristics: non or light female smokers with adenocarcinoma. The study also demonstrates increased benefit to erolotinib, a TKI targeting the receptor.
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer
Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma
This weeks NEJM has a quite striking phase III trial comparing a gefitinib to a carbo-taxol in a carefully selected cohort: non or light smokers from east asia with adenocarcinoma of the lung. This subset has been previously described as having an excellent response to treatment, but the very positive results of this trial prove a very significant benefit to disease free survival, and also demonstrate that the benefit in this subpopulation is related to EGFR mutation status.
Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma
Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma
Thursday, August 13, 2009
Weight Lifting in Women with Breast-Cancer-Related Lymphedema
From the NEJM this week: An interesting randomized trial looking at lymphedema after breast cancer treatment, and challenging some of the paradigms of prevention.
Weight Lifting in Women with Breast-Cancer-Related Lymphedema: "Weight lifting has generally been discouraged for women with breast-cancer-related lymphedema because of concern that it might worsen the lymphedema. In this randomized trial involving breast-cancer survivors with lymphedema, women undergoing a 1-year weight-lifting program were no more likely than controls to have increased arm swelling, had greater improvement in the severity of lymphedema symptoms and strength, and had a lower incidence of confirmed exacerbations of lymphedema."
Weight Lifting in Women with Breast-Cancer-Related Lymphedema: "Weight lifting has generally been discouraged for women with breast-cancer-related lymphedema because of concern that it might worsen the lymphedema. In this randomized trial involving breast-cancer survivors with lymphedema, women undergoing a 1-year weight-lifting program were no more likely than controls to have increased arm swelling, had greater improvement in the severity of lymphedema symptoms and strength, and had a lower incidence of confirmed exacerbations of lymphedema."
Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer
From the NEJM this week: One of the first studies showing that micromets are clinically significant (in a large retrospective series).
Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer: "This study involving women with early-stage breast cancer showed an association between the presence of isolated tumor cells or micrometastases in sentinel or axillary lymph nodes and the 5-year rate of disease-free survival. Women with such findings in these lymph nodes who received systemic adjuvant therapy had an improved outcome. "
Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer: "This study involving women with early-stage breast cancer showed an association between the presence of isolated tumor cells or micrometastases in sentinel or axillary lymph nodes and the 5-year rate of disease-free survival. Women with such findings in these lymph nodes who received systemic adjuvant therapy had an improved outcome. "
Friday, July 17, 2009
Endometrial Cancer: Vaginal Brachytherapy vs Whole Pelvis
In this weeks JCO, the first results of the PORTEC 2 trial are published.
In this randomized trial, 427 patients >= 60 years of age with IC grade 1 or 2, IB grade 3, or any age and IIA disease (excluding grade 3 with >50% myometrial invasion, were randomized between vaginal brachytherapy (7Gy q week x 3, or 30Gy LDR) and WPRT (46Gy, 2Gy/day). Note the inclusion criteria; this excludes the IC grade 3 risk group which at the time of the trial design were at too high of a risk not to treat with WPRT.
This is a QOL report, and not surprisingly, VBT comes out on top, particularly with GI toxicities, which let to better social functioning as well.
This is gratifying, as it proves that less is more as far as the adverse events are concerned. Of course, more importantly what is the efficacy data.
This was presented at ASCO 2008. At 3-years vaginal relapse occurred 0.9% in the VBT arm and 2.0% after EBRT (p=0.97), 3-year pelvic relapse was 3.6% and 0.7% (p=0.03), respectively. 3 year distant relapse was 6.4% in the VBT group and 6.0% in the EBRT group (NS). No difference in 3-year OS (90.4% vs. 90.8% p=0.55) and RFS (89.5% vs. 89.1% p=0.38).
So now it's time to step back to the primary study endpoint, which was vaginal relapse, and unfortunately the stats section is a little vague here, probably because this is a QOL report not the clinical results. What it clear is that this was not designed as a non-inferiority trial for pelvic relapse, which to be honest, is what it probably should have been. If you are trying to say that vaginal brachytherapy is safe and as effective as WPRT, then the endpoint should be either pelvic relapse, distant relapse or overall survival. The pelvic relapses were actually significantly worse with VBT, thought the absolute difference was small (~3%). What is important about this is that these patients are essentially unsalvageable, which may eventually show in the OS numbers (though I wouldn't hold my breath due to the power of the study and competing causes of death in this patient population).
That stated, clearly VBT is an option for these patients, and this study, with relatively minor flaws in comparison to others supports the approach.
In this randomized trial, 427 patients >= 60 years of age with IC grade 1 or 2, IB grade 3, or any age and IIA disease (excluding grade 3 with >50% myometrial invasion, were randomized between vaginal brachytherapy (7Gy q week x 3, or 30Gy LDR) and WPRT (46Gy, 2Gy/day). Note the inclusion criteria; this excludes the IC grade 3 risk group which at the time of the trial design were at too high of a risk not to treat with WPRT.
This is a QOL report, and not surprisingly, VBT comes out on top, particularly with GI toxicities, which let to better social functioning as well.
This is gratifying, as it proves that less is more as far as the adverse events are concerned. Of course, more importantly what is the efficacy data.
This was presented at ASCO 2008. At 3-years vaginal relapse occurred 0.9% in the VBT arm and 2.0% after EBRT (p=0.97), 3-year pelvic relapse was 3.6% and 0.7% (p=0.03), respectively. 3 year distant relapse was 6.4% in the VBT group and 6.0% in the EBRT group (NS). No difference in 3-year OS (90.4% vs. 90.8% p=0.55) and RFS (89.5% vs. 89.1% p=0.38).
So now it's time to step back to the primary study endpoint, which was vaginal relapse, and unfortunately the stats section is a little vague here, probably because this is a QOL report not the clinical results. What it clear is that this was not designed as a non-inferiority trial for pelvic relapse, which to be honest, is what it probably should have been. If you are trying to say that vaginal brachytherapy is safe and as effective as WPRT, then the endpoint should be either pelvic relapse, distant relapse or overall survival. The pelvic relapses were actually significantly worse with VBT, thought the absolute difference was small (~3%). What is important about this is that these patients are essentially unsalvageable, which may eventually show in the OS numbers (though I wouldn't hold my breath due to the power of the study and competing causes of death in this patient population).
That stated, clearly VBT is an option for these patients, and this study, with relatively minor flaws in comparison to others supports the approach.
Thursday, July 9, 2009
Bevacizumab for NF2 associated AN
An interesting article yesterday at NEJM, in which investigators at MGH gave bevacizumab to 10 patients with NF2 associated acoustic neuromas (vestibular schwannomas). 9/10 had reduction in tumor size after administration and 4/7 evaluable for changes in hearing had an improvement. Very interesting data, and may be useful in large tumors that would be difficult to treat with either surgery or RT.
SBRT for NSCLC
In this weeks JCO there is an interesting article from investigators in Sweden and Norway reporting a phase II trial of 15Gy x 3 for T1 and T2, medically inoperable NSCLC. Of import, the dose was prescribed to the 67% IDL, meaning that the dose to the center of many of these tumors was much higher.
57 patients were enrolled, the majority were T1 (70%). 3 year OS was 60%, but perhaps more importantly, given their comorbidities, the CSS was 88%. 3 year LC was 92%. 16 patients experienced grade 3 toxicity (28%), and there was one patient with grade 4 dyspnea. No grade 5 toxicities were seen.
This lends even greater support to the practice, and is a great improvement over the prior standard of 70Gy to a postage stamp field to those that are not healthy enough for lobectomy. The next step of course is to look at this in the medically operable patient... stay tuned to ongoing clinical trials on this subject.
57 patients were enrolled, the majority were T1 (70%). 3 year OS was 60%, but perhaps more importantly, given their comorbidities, the CSS was 88%. 3 year LC was 92%. 16 patients experienced grade 3 toxicity (28%), and there was one patient with grade 4 dyspnea. No grade 5 toxicities were seen.
This lends even greater support to the practice, and is a great improvement over the prior standard of 70Gy to a postage stamp field to those that are not healthy enough for lobectomy. The next step of course is to look at this in the medically operable patient... stay tuned to ongoing clinical trials on this subject.
Thursday, July 2, 2009
PET-CT for NSCLC
The NEJM this week has in interesting randomized trial on the utility of PET-CT in the preoperative workup of NSCLC.
Investigators from Denmark randomized 189 patients to receive either PET-CT or conventional CT as preoperative staging for NSCLC. Mediastinoscopy was performed in most patients in both arms(94%). After PET–CT, 38/98 patients were classified as having inoperable NSCLC compared to 18/91 patients in the CT arm. 60/98 in the PET–CT arm and 73/91 in the CT arm underwent thoracotomy (p=0.004). 21/60 surgeries in the PET–CT arm and 38/73 in the CT arm were futile (i.e. posiitive mediastinum, distant disease,p=0.05). Survival and number of curative surgeries were no different between the arms.
While it has been long known that PET added significantly to the sensitivity and specificity of lung cancer staging, this is the first study to demonstrate that it results in clinically meaningful results. A reduction in the number of unnecessary thoracotomies would represent a reduction in the cost of treating NSCLC, both financially and in terms of the morbidity and mortality of the procedure itself.
Investigators from Denmark randomized 189 patients to receive either PET-CT or conventional CT as preoperative staging for NSCLC. Mediastinoscopy was performed in most patients in both arms(94%). After PET–CT, 38/98 patients were classified as having inoperable NSCLC compared to 18/91 patients in the CT arm. 60/98 in the PET–CT arm and 73/91 in the CT arm underwent thoracotomy (p=0.004). 21/60 surgeries in the PET–CT arm and 38/73 in the CT arm were futile (i.e. posiitive mediastinum, distant disease,p=0.05). Survival and number of curative surgeries were no different between the arms.
While it has been long known that PET added significantly to the sensitivity and specificity of lung cancer staging, this is the first study to demonstrate that it results in clinically meaningful results. A reduction in the number of unnecessary thoracotomies would represent a reduction in the cost of treating NSCLC, both financially and in terms of the morbidity and mortality of the procedure itself.
Sunday, June 28, 2009
Cranial RT necessary for high risk ALL?
In this weeks NEJM there is an interesting article looking at the role of RT (or lack thereof) in preventing CNS relapse in newly diagnoses ALL.
This was a single arm trial which eliminated RT from the treatment protocol in all patients with newly diagnoses ALL. 498 were enrolled, however only 71 would have recieved prophylactic cranial irradiation (PCI) off protocol. These 71 were compared with 56 historical controls who did recieve PCI. Treatment intensity was risk based. "Triple intrathecal" therapy was used (consisting of MTX, cytarabine and hydrocoritsone).
5-yr EFS in 498 was 85.6% (95% CI, 79.9-91.3) and 5yr OS was 93.5% (95% CI, 89.8-97.2). 5yr isolated CNS relapse 2.7% (95% CI, 1.1-4.3), any CNS relapse was 3.9% (95% CI, 1.9-5.9). The 71 who did not have PCI had longer continuous complete remission than the 56 historical controls (P=0.04). Only one patient in the cohort that would have had PCI failed in the CNS.
CNS leukemia (CNS-3 status) or a traumatic LP with blasts and ≥1% residual disease after 6 weeks of remission induction had poorer EFS. CNS relapse risks included t(1;19), CNS involvement at diagnosis, and T-cell ALL. The authors however do not reccomend PCI in this cohort, as 90% of these patients would have recieved PCI unecessarily.
What the authors do not report (as it is not yet available) is on the long term neurocognitive and developemental consequences of intense intrathecal chemotherapy. The conclusions are predicated upon the assumption that this treatment will be an improvement over PCI (which may not be unreasonable), however only long term and in depth follow up will demonstrate this.
This was a single arm trial which eliminated RT from the treatment protocol in all patients with newly diagnoses ALL. 498 were enrolled, however only 71 would have recieved prophylactic cranial irradiation (PCI) off protocol. These 71 were compared with 56 historical controls who did recieve PCI. Treatment intensity was risk based. "Triple intrathecal" therapy was used (consisting of MTX, cytarabine and hydrocoritsone).
5-yr EFS in 498 was 85.6% (95% CI, 79.9-91.3) and 5yr OS was 93.5% (95% CI, 89.8-97.2). 5yr isolated CNS relapse 2.7% (95% CI, 1.1-4.3), any CNS relapse was 3.9% (95% CI, 1.9-5.9). The 71 who did not have PCI had longer continuous complete remission than the 56 historical controls (P=0.04). Only one patient in the cohort that would have had PCI failed in the CNS.
CNS leukemia (CNS-3 status) or a traumatic LP with blasts and ≥1% residual disease after 6 weeks of remission induction had poorer EFS. CNS relapse risks included t(1;19), CNS involvement at diagnosis, and T-cell ALL. The authors however do not reccomend PCI in this cohort, as 90% of these patients would have recieved PCI unecessarily.
What the authors do not report (as it is not yet available) is on the long term neurocognitive and developemental consequences of intense intrathecal chemotherapy. The conclusions are predicated upon the assumption that this treatment will be an improvement over PCI (which may not be unreasonable), however only long term and in depth follow up will demonstrate this.
Thursday, June 18, 2009
Dose response for AVMS
In re to chart rounds today, there was question about the dose response to SRS for AVMs. Flickinger published an excellent report in the red journal, 1996 addressing this issue.
Below is the dose response curve from their study:
Induction vs Concurrent chemotherapy in Head and Neck Cancer
In the green journal today there is an update of the Pignon Meta-analysis for radiation and chemotherapy.
87 trials with 16,485 patients. With chemotherapy in addition to radiotherapy, HR for death was 0.88 (p less than 0.0001) with an absolute reduction of mortality of4.5% at 5 year. There was an interaction (p less than 0.0001) in chemotherapy timing, i.e. adjuvant, induction or concomitant. Concomitant chemotherapy was superior to induction chemotherapy, with HR 0.81 (p less than 0.0001) absolute reduction of 6.5% at 5 years. Chemo was also of less utility with older patients (p = 0.003, test for trend).
Thus more fuel for the induction vs. concurrent debate. One must point out though that the Posner trial however used induction and concurrent chemotherapy, thus a comparison of optimal induction with concurrent treatment vs. optimal concurrent chemoradiotherapy remains unanswered...
Developing a Genomic Signature for Epirthelial Mesenchymal Tranrsition
KH presents on Developing a Genomic Signature for Epithelial Mesenchymal Transition (EMT)
Background in the Potti lab. NEJM 2006; 355:570.
Gene expression patterns were examined in a Cohort of Duke patients with early stage NSCLC, then validated in two independent cohorts (CALGB, ACOSOG). 133 genes in the developed signature (k-ras, MDR upregulation, and down regulation of tumor suppression). Strong predictions of recurrence and survival.
Currently the lab is working wuth a 52 gene signature for radiation sensitivity which was developed initially at the University of Chicago. Resistant clones were selected from a cell line that was serially irradiated and the gene signature differentiates between the resistant selected clones and the initial sensitive cell line. The Potti lab has confirmed this in previously unirradiated cell lines, and has predictive value in predicting radiation response in vitro.
This signature is then clinically tested in samples from patients with head and neck cancer and in group with rectal cancer. Accuracy for response to RT was on the order of 75% for association with pCR in the rectal cancer patients, and (?radiographic) response in the Head and Neck patients.
A current direction is integrating mircoRNAs into the gene chips, which requires no additional technology, just different probes.
Switching gears to EMT.
Epithelial Mesenchymal Transition (EMT) occurs in normal embyogenesis. It is also implicated in Lung and Kidney fibrosis, and possibly radiation resistance. Perhaps most intriguingly, EMT is also implicated in the invasion and metastasis process of carcinomas (and an MET [mesenchymal to epithelial tranisition] process then occurs after establishement of a distant colony).
E Cadherin and multiple other pathways (including the Hedgehog pathway) regulate this process. Coculturing with myofibroblasts release Hh(hedgehog) into the microenvironment, and this has been shown to produce EMT in cholangiocytes.
Plan will be two develop an EMT model in NSCLC lines via either coculturing with myofibroblasts or transfection with adenovirus vectors carrying Hh DNA, then developing a gene signature for this process.
Background in the Potti lab. NEJM 2006; 355:570.
Gene expression patterns were examined in a Cohort of Duke patients with early stage NSCLC, then validated in two independent cohorts (CALGB, ACOSOG). 133 genes in the developed signature (k-ras, MDR upregulation, and down regulation of tumor suppression). Strong predictions of recurrence and survival.
Currently the lab is working wuth a 52 gene signature for radiation sensitivity which was developed initially at the University of Chicago. Resistant clones were selected from a cell line that was serially irradiated and the gene signature differentiates between the resistant selected clones and the initial sensitive cell line. The Potti lab has confirmed this in previously unirradiated cell lines, and has predictive value in predicting radiation response in vitro.
This signature is then clinically tested in samples from patients with head and neck cancer and in group with rectal cancer. Accuracy for response to RT was on the order of 75% for association with pCR in the rectal cancer patients, and (?radiographic) response in the Head and Neck patients.
A current direction is integrating mircoRNAs into the gene chips, which requires no additional technology, just different probes.
Switching gears to EMT.
Epithelial Mesenchymal Transition (EMT) occurs in normal embyogenesis. It is also implicated in Lung and Kidney fibrosis, and possibly radiation resistance. Perhaps most intriguingly, EMT is also implicated in the invasion and metastasis process of carcinomas (and an MET [mesenchymal to epithelial tranisition] process then occurs after establishement of a distant colony).
E Cadherin and multiple other pathways (including the Hedgehog pathway) regulate this process. Coculturing with myofibroblasts release Hh(hedgehog) into the microenvironment, and this has been shown to produce EMT in cholangiocytes.
Plan will be two develop an EMT model in NSCLC lines via either coculturing with myofibroblasts or transfection with adenovirus vectors carrying Hh DNA, then developing a gene signature for this process.
Thursday, June 11, 2009
EORTC: 6 months vs 3 years Androgen Deprivation for Prostate Cancer
NEJM this week has published the EORTC 6 months vs 3 years of ADT trial.
This was a trial of 1113 men with T2c-T3, or pN1 prostate cancer, with 970 randomized to 6 months of ADT (starting with RT), vs 3 years ADT. RT was 50Gy WPRT with a 20Gy boost. The trial was a non-inferiority trial between the two regimens.
Median f/u was 6.4 years, and an interim analysis for futility crossed it's boundary. HR for death in the 6 month arm was 1.42 (p=0.65 for non-inferiority); 5 year OS was 84.8% in the 3 year arm vs 81.0% in the 6 month arm. DFS and BRFS were also both worse in the 6 month arm (SS). They have a number of nice QOL measures in the paper, showing decreased sexual function, increased insomnia and hot flashes in the 3 year arm, but the global QOL was similar between the arms.
There was also no difference in fatal cardiac events.
So conclusions: 6 months of ADT is "not non-inferior" to 3 years. This is a little different than saying 3 years is better than 6 months, but at the end of the day, it's hard to justify 6 months alone, in patients that would have entered on this trial.
However, that last statement is worth looking at: these T2c, T3a and T3b patients are a distinct and very small subset of high risk disease in the US in 2009. Many of the patients that we treat today are high risk because of high Gleason Grade rather than high T stage. The optimal treatment for this group is an unknown.
Comparing to the 92-02 results, which had a similar patient population, they showed a DFS and BRFS improvement, but only improved survival in the high grade sub-group. No data on subgroup analysis for this trial, but plan on seeing it in the next year or so in the JCO or similar...
MALT lymphoma
JP presents on MALT lymphoma.
68 yo with chronic nasal congestion. Sinus and chest CT revealed a R orbital mass (incidental finding). Biopsy obtained revealing an atypical lymphoid infiltrate, CD20+, monoclonal B-cell population. PET ct was positive in the R orbit alone. IEA MALT lymphoma of the orbit.
On exam conjuctival erythema noted with injected sclera, no other abnormalities.
Marginal Zone Lymphoma includes MALTs, Nodal marginal B-cell lymphoma (monocytoid lymphoma), Primary splenic marginal zone lymphoma.
3rd most common NHL (after DLBCL and FL). 7-8% of B-cell lymphomas. Most commonly occur in the stomach, and account for 50% of gastric lymphomas (the other half are DLBCLs).
Named due to subsite of origin within a lymph node/aggregate. Germinal center in the middle, mantle zone surrounding that, then the marginal zone surrounding that. Marginal zone residents are more mature lymphocytes.
Orbital subsite include the lacrimal gland, conjunctiva, retrobulbar region. Occaisionally the is bilateral presentations. (Technically this is a stage IV presentation, but biologically this would behave much more like a stage II).
Sjogren's syndrome associated with salivary gland MALT.
Infectious associations.
H. pylori has a large association with gastric MALT (92% of gastric MALTs show this).
C. psittaci associated with ocular adnexal MALT (80% of ocular adnexal MALTs from Italian work, though this is controversial in the US data).
C. jejuni and small intestine MALTs.
B. bordoferria and skin MALTs.
MALT B-cells are CD20+, CD21+, CD35+, IgM+
Gastric MALTs are initially treated with PPI, clarithromycin, amoxicillin, with a 50-80% response rate.
t11:18 (26-40% penetrance) trisomy 3, trisomy 18, all predict for antibiotic resistance. Occaisionally one also sees t14:18 (usually seen in follicular lyphoma).
Wundisch JCO 2005: 120 H pylori + with IAE gastric MALT, treated with H pylori eradication. 96/120 achieved CR with antiobiotic therapy, 24/120 went on to secondary treatment. With median f/u 6.3 years, continuous complete response in 77, histologic residual disease in 16 (all went into a CR with observation alone), 3 relapsed. contributions. 5 yr CCR rates were 71%. 5 yr OS was 90% in all patients, only 2 died of lymphoma (both transformed). 27% of CR patients showed an ongoing B-cell monoclonality.
Checter JCO 1998. MSKCC n=51 treated to 30Gy median dose, CR 96%, FFTF 4yr 89%, OS 4 yr, 83%, CSS 4 yr 100%.
Vrieling, Rad Onc 2008. Netherlands n=115 40 Gy median CR 96%, CaSS 10yr 94%.
Italian phase II. Ferreri JNCI 2006. 27 OAL (12 relapsed), 3 week course of doxycycline 100mg bid x 3 weeks. 41% positive for C. psittaci. FFS 3yr 66%. CR was 22%. Authors conclusion were that antiobiotics were promising, though certainly this is nowhere near the responses in gastric MALT to triple therapy.
Tsang IJROBP 2001. PMH. 70pts with MALT. Doses were 25-30Gy range. CR to RT was 96%. 5yr OS 96%. 5yr DFS 76% (only 69% in sites other than stomach and thyroid). LC with RT was 60/62 (crude). Failures tend to be in other regions were MALT occurs. Tsang JCO 2003 - (different patients?) with 5.1 yr median f/u, same results.
Bolek IJROBP 1999. UF. 38pt with 8.3 yr median f/u. All orbital lymphomas. Many had 20Gy or less, median dose 25Gy. In field local control 100%. In low grade tumors DFS at 5yrs was around 60%, worse for high grade tumors.
Pfeffer IJROBP 2004. 23 pts treated, 12 with partial orbital volumes, 11 with full orbit. No reccurences in the whole orbit. 4 recurrences (33%) in patients treated with partial orbital treatments. Therefore treat the region not the GTV alone with margin.
Treated with a wedge pair to the entire R orbit to 24Gy in 2Gy/fraction.
Potential Late Effects - Cataracts with this dose are extremely common. Dry eye may be common, but severity should be limited with <30Gy. Keratoconjunctivitis, corneal ulceration, retinitis, etc would be rare.
68 yo with chronic nasal congestion. Sinus and chest CT revealed a R orbital mass (incidental finding). Biopsy obtained revealing an atypical lymphoid infiltrate, CD20+, monoclonal B-cell population. PET ct was positive in the R orbit alone. IEA MALT lymphoma of the orbit.
On exam conjuctival erythema noted with injected sclera, no other abnormalities.
Marginal Zone Lymphoma includes MALTs, Nodal marginal B-cell lymphoma (monocytoid lymphoma), Primary splenic marginal zone lymphoma.
3rd most common NHL (after DLBCL and FL). 7-8% of B-cell lymphomas. Most commonly occur in the stomach, and account for 50% of gastric lymphomas (the other half are DLBCLs).
Named due to subsite of origin within a lymph node/aggregate. Germinal center in the middle, mantle zone surrounding that, then the marginal zone surrounding that. Marginal zone residents are more mature lymphocytes.
Orbital subsite include the lacrimal gland, conjunctiva, retrobulbar region. Occaisionally the is bilateral presentations. (Technically this is a stage IV presentation, but biologically this would behave much more like a stage II).
Sjogren's syndrome associated with salivary gland MALT.
Infectious associations.
H. pylori has a large association with gastric MALT (92% of gastric MALTs show this).
C. psittaci associated with ocular adnexal MALT (80% of ocular adnexal MALTs from Italian work, though this is controversial in the US data).
C. jejuni and small intestine MALTs.
B. bordoferria and skin MALTs.
MALT B-cells are CD20+, CD21+, CD35+, IgM+
Gastric MALTs are initially treated with PPI, clarithromycin, amoxicillin, with a 50-80% response rate.
t11:18 (26-40% penetrance) trisomy 3, trisomy 18, all predict for antibiotic resistance. Occaisionally one also sees t14:18 (usually seen in follicular lyphoma).
Wundisch JCO 2005: 120 H pylori + with IAE gastric MALT, treated with H pylori eradication. 96/120 achieved CR with antiobiotic therapy, 24/120 went on to secondary treatment. With median f/u 6.3 years, continuous complete response in 77, histologic residual disease in 16 (all went into a CR with observation alone), 3 relapsed. contributions. 5 yr CCR rates were 71%. 5 yr OS was 90% in all patients, only 2 died of lymphoma (both transformed). 27% of CR patients showed an ongoing B-cell monoclonality.
Checter JCO 1998. MSKCC n=51 treated to 30Gy median dose, CR 96%, FFTF 4yr 89%, OS 4 yr, 83%, CSS 4 yr 100%.
Vrieling, Rad Onc 2008. Netherlands n=115 40 Gy median CR 96%, CaSS 10yr 94%.
Italian phase II. Ferreri JNCI 2006. 27 OAL (12 relapsed), 3 week course of doxycycline 100mg bid x 3 weeks. 41% positive for C. psittaci. FFS 3yr 66%. CR was 22%. Authors conclusion were that antiobiotics were promising, though certainly this is nowhere near the responses in gastric MALT to triple therapy.
Tsang IJROBP 2001. PMH. 70pts with MALT. Doses were 25-30Gy range. CR to RT was 96%. 5yr OS 96%. 5yr DFS 76% (only 69% in sites other than stomach and thyroid). LC with RT was 60/62 (crude). Failures tend to be in other regions were MALT occurs. Tsang JCO 2003 - (different patients?) with 5.1 yr median f/u, same results.
Bolek IJROBP 1999. UF. 38pt with 8.3 yr median f/u. All orbital lymphomas. Many had 20Gy or less, median dose 25Gy. In field local control 100%. In low grade tumors DFS at 5yrs was around 60%, worse for high grade tumors.
Pfeffer IJROBP 2004. 23 pts treated, 12 with partial orbital volumes, 11 with full orbit. No reccurences in the whole orbit. 4 recurrences (33%) in patients treated with partial orbital treatments. Therefore treat the region not the GTV alone with margin.
Treated with a wedge pair to the entire R orbit to 24Gy in 2Gy/fraction.
Potential Late Effects - Cataracts with this dose are extremely common. Dry eye may be common, but severity should be limited with <30Gy. Keratoconjunctivitis, corneal ulceration, retinitis, etc would be rare.
Wednesday, May 27, 2009
Management of Breast Cancer in the BRCA positive population
Patrick (MSII) presents on the Management of BRCA positive patients.
Case: 30 yo AAF with a mass in the UIQ of the R breast. Maternal aunt with Breast CA at 44, also paternal grandmother with breast cancer and ovarian cancer at 86.
Biopsy: Poorly differentiated 1.3cm cancer. Triple negative. Lumpectomy and SLNB negative. (T1N0M0 triple negative). BRCA1 positive.
BRCA1: 17q21 activated by DNA damage. Interacts with CHK1 and CHK2
BRCA2: 13q12 regulates cell cycle, promotes S/G2 arrest
BRCA mutations in 1%
Enriched in the Ashkenazi Jewish population (Icelandic, Swedish, Hungarian populations as well).
Criteria for testing: Early breast cancer <=50. Two primaries in a single individual or close relative. Breast and ovarian primaries. Family member with male breast cancer.
Testing costs 300-3000$ depending on the extent of the test.
BRCA1 BRCA2
Breast Cancer 65-85% 45-85%
Ovarian Cancer 37-62% 11-23%
high grade low grade
triple negative er/pr + her2-
medullary
Early Screening. Self Breast exams at 18, clinical exams at 25. Mammograms and MRI testing at 25 or 10 years before the youngest age a relative was diagnosed with breast cancer.
Breast MRI Kriege NEJM 351:427. 1909 high risk patients (358 BRCA carriers), MRI sensitivity 80%, spec 90%, Mammo sens 33%, spec 95%.
Warner JAMA. 236 carriers. MRI sens 77%, spec 95.4%. Also looked at mammo, U/S, and CBE.
Meijers NEJM 2001;345:159. 139 carriers, 76 underwent prophylactic mastectomy, the rest choosing surveillance. With f/u of 3 years. 0/76 cancers in the mastectomy group. 8/63 in the the surveillance group, p=0.003. 5yr incidence in the surveillance group was 17%.
PROSE JCO 2004 22:1055. 90% reduction in breast cancer in carriers. In patients who also had a BSO, there was a 95% reduction.
Kauff: Prospective prophylactic bilateral salpingo-oophorectomy (BSO), HR of 0.25 for the development of ovarian or breast cancers.
Eisen: JCO 23:7491 - BSO conferred a 46-56% reduction in breast cancers. Benefit was greater if performed before 40 years of age.
Domcheck Lancet Onc 7:233. 426 with some getting BSO, some observation (prospective cohort). Overall Survival HR was 0.24 (SS) with BSO.
Pierce 160 BRCA carriers undergoing BCT. Incidence of contralateral cancers was in carriers 39%, vs 7% controls, p<0.001 at 15years. Pierce also reports in the JCO 2000, that there was no clear survival detriment to breast consevation (BCT) in carriers (though follow up was only 5 years).
Case resolution: Pt consuled about prophylactic mastectomy, BCT, prophylactic BSO, and TC chemotherapy. Pt elected to pursue BCT with close followup, with BSO after child bearing in complete (preferably before age 40).
Case: 30 yo AAF with a mass in the UIQ of the R breast. Maternal aunt with Breast CA at 44, also paternal grandmother with breast cancer and ovarian cancer at 86.
Biopsy: Poorly differentiated 1.3cm cancer. Triple negative. Lumpectomy and SLNB negative. (T1N0M0 triple negative). BRCA1 positive.
BRCA1: 17q21 activated by DNA damage. Interacts with CHK1 and CHK2
BRCA2: 13q12 regulates cell cycle, promotes S/G2 arrest
BRCA mutations in 1%
Enriched in the Ashkenazi Jewish population (Icelandic, Swedish, Hungarian populations as well).
Criteria for testing: Early breast cancer <=50. Two primaries in a single individual or close relative. Breast and ovarian primaries. Family member with male breast cancer.
Testing costs 300-3000$ depending on the extent of the test.
BRCA1 BRCA2
Breast Cancer 65-85% 45-85%
Ovarian Cancer 37-62% 11-23%
high grade low grade
triple negative er/pr + her2-
medullary
Early Screening. Self Breast exams at 18, clinical exams at 25. Mammograms and MRI testing at 25 or 10 years before the youngest age a relative was diagnosed with breast cancer.
Breast MRI Kriege NEJM 351:427. 1909 high risk patients (358 BRCA carriers), MRI sensitivity 80%, spec 90%, Mammo sens 33%, spec 95%.
Warner JAMA. 236 carriers. MRI sens 77%, spec 95.4%. Also looked at mammo, U/S, and CBE.
Meijers NEJM 2001;345:159. 139 carriers, 76 underwent prophylactic mastectomy, the rest choosing surveillance. With f/u of 3 years. 0/76 cancers in the mastectomy group. 8/63 in the the surveillance group, p=0.003. 5yr incidence in the surveillance group was 17%.
PROSE JCO 2004 22:1055. 90% reduction in breast cancer in carriers. In patients who also had a BSO, there was a 95% reduction.
Kauff: Prospective prophylactic bilateral salpingo-oophorectomy (BSO), HR of 0.25 for the development of ovarian or breast cancers.
Eisen: JCO 23:7491 - BSO conferred a 46-56% reduction in breast cancers. Benefit was greater if performed before 40 years of age.
Domcheck Lancet Onc 7:233. 426 with some getting BSO, some observation (prospective cohort). Overall Survival HR was 0.24 (SS) with BSO.
Pierce 160 BRCA carriers undergoing BCT. Incidence of contralateral cancers was in carriers 39%, vs 7% controls, p<0.001 at 15years. Pierce also reports in the JCO 2000, that there was no clear survival detriment to breast consevation (BCT) in carriers (though follow up was only 5 years).
Case resolution: Pt consuled about prophylactic mastectomy, BCT, prophylactic BSO, and TC chemotherapy. Pt elected to pursue BCT with close followup, with BSO after child bearing in complete (preferably before age 40).
Subscribe to:
Posts (Atom)
