Escalated-Dose BEACOPP in the Treatment of Patients With Advanced-Stage Hodgkin's Lymphoma: 10 Years of Follow-Up of the GHSG HD9 Study [Hematologic Malignancies]

10 year HD9 results are published in this weeks JCO. To review this is a trial from the German Hodgkin Study group looking at differing chemotherapy regimens in unfavorable advanced HL. Escalated BEACOPP continues to out perform the other arms for DFS and OS, at the cost of dramatic increases in hematopoetic toxicity. One thing to keep in mind with this trial is that RT was used in 70% of these patients. Another item worth considering is the secondary malignancy rate ~6%, and this in crude numbers!

Link and Abstract
Escalated-Dose BEACOPP in the Treatment of Patients With Advanced-Stage Hodgkin's Lymphoma: 10 Years of Follow-Up of the GHSG HD9 Study [Hematologic Malignancies]: "Purpose

The HD9 trial of the German Hodgkin Study Group compared two different doses (baseline and escalated) of the bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) chemotherapy regimen in 1,196 patients with advanced-stage Hodgkin's lymphoma (HL). The previous analysis with 5 years median follow-up had indicated improved tumor control with BEACOPP escalated. Since the long-term safety and efficacy of this regimen has been debated, we report the 10-year follow-up.

Patients and Methods

Patients received one of three chemotherapy regimens: eight cycles of cyclophosphamide, vincristine, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD); eight cycles of BEACOPP baseline; or eight cycles of BEACOPP escalated.

Results

Median follow-up was 111 months. At 10 years, freedom from treatment failure (FFTF) was 64%, 70%, and 82% with OS rates of 75%, 80%, and 86% for patients treated with COPP/ABVD (arm A), BEACOPP baseline (arm B), and BEACOPP escalated (arm C), respectively (P < .001). BEACOPP escalated was significantly better than BEACOPP baseline in terms of FFTF (P < .0001) and OS (P = .0053). A total of 74 second malignancies (6.2%) were documented, including acute myeloid leukemia (0.4%, 1.5%, and 3.0%), non-Hodgkin's lymphoma (2.7%, 1.7%, and 1.0%), and solid tumors (2.7%, 3.4%, and 1.9%). The corresponding overall secondary malignancy rates were 5.7%, 6.6%, and 6.0%, respectively.

Conclusion

The 10-year follow-up of the HD9 trial demonstrates a stabilized significant improvement in long-term FFTF and OS for BEACOPP escalated in advanced-stage HL. These results challenge ABVD as standard of care for this patient population.

"

Talampanel With Standard Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma: A Multicenter Phase II Trial [Neurooncology]

Big week for RT in this weeks JCO: Interesting article looking at a novel therapeutic in GBM. Talampanel is a inhibitor of a glutamatergic excitatory pathway that GBMs seem to use for proliferation and survival. Their results with the addition of talampanel to TMZ + RT are favorable when compared to the EORTC (Stupp) trial which established the current standard of care, especially considering that the percent of methylated MGMT was lower in the current study. Phase III confirmation is planned.

Talampanel With Standard Radiation and Temozolomide in Patients With Newly Diagnosed Glioblastoma: A Multicenter Phase II Trial [Neurooncology]:
"Purpose

Recent data suggest that the glutamatergic system is important in the proliferation and migration of glioblastoma. Talampanel is a well-tolerated, oral -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker that could be beneficial in this disease.

Patients and Methods

This trial was designed to estimate overall survival in adults with newly diagnosed glioblastoma treated with talampanel in addition to standard radiation (RT) and temozolomide (TMZ). A secondary purpose was to evaluate talampanel toxicity in this setting. Talampanel was initiated with RT + TMZ and discontinued for toxicity or disease progression. Survival was compared with historical controls.

Results

Seventy-two patients were enrolled from December 2005 to July 2006. Their median age was 60 years (range, 37 to 85 years, with 17% > 70 years), median Karnofsky performance score was 90 (range, 70 to 100), and 77% had a debulking procedure. With a median follow-up time of 18 months, 55 patients (76%) have died, yielding a median survival time of 18.3 months (95% CI, 14.6 to 22.5 months). When the 60 patients who were 18 to 70 years old were compared with the European Organisation for Research and Treatment of Cancer (EORTC) RT + TMZ data, the median survival (20.3 v 14.6 months, respectively) and percentage of patients surviving at 24 months (41.7% v 26.5%, respectively; P = .02) seemed superior. The percentage of patients methylated at O⁶-methylguanine–DNA methyltransferase was lower than on the EORTC study (29% v 43%, respectively). Talampanel was well tolerated and did not increase the known hematologic or nonhematologic toxicities of TMZ.

Conclusion

Talampanel can be added to RT + TMZ without significant additional toxicity. The encouraging survival results in methylated and unmethylated patients suggest that blocking AMPA receptors may be a useful strategy in newly diagnosed glioblastoma.

"

Phase II Study of Bevacizumab With Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer: Radiation Therapy Oncology Group RTOG 0411 [Gastrointestinal Cancer]

This weeks JCO: RTOG 0411 reports out for bevacizumab + capcitabine + RT for unresectable pancreatic cancer followed by gem + bev, resulting in disappointing survival numbers. Pancreas remains a site where the field is open and in desperate need of novel therapies and approaches.


Link and Abstract:

Phase II Study of Bevacizumab With Concurrent Capecitabine and Radiation Followed by Maintenance Gemcitabine and Bevacizumab for Locally Advanced Pancreatic Cancer: Radiation Therapy Oncology Group RTOG 0411 [Gastrointestinal Cancer]:
"Purpose

The primary objective of this study was to assess the 1-year survival of patients with locally advanced, unresectable pancreatic cancer treated with the combination of bevacizumab, capecitabine, and radiation. Secondary end points were toxicity, progression-free survival (PFS), and response rate (RR).

Patients and Methods

Patients with locally advanced pancreatic cancer without duodenal invasion were treated with 50.4 Gy per 28 fractions to the gross tumor with concurrent capecitabine 825 mg/m² orally twice daily on days of radiation and bevacizumab 5 mg/kg on days 1, 15, and 29 followed by maintenance gemcitabine 1 g/m² weekly for 3 weeks and bevacizumab 5 mg/kg every 2 weeks, both in 4-week cycles until progression. Treatment plans were reviewed for quality assurance (QA).

Results

Between January 2005 and February 2006, 82 eligible patients were treated. The median and 1-year survival rates were 11.9 months (95% CI, 9.9 to 14.0 months) and 47% (95% CI, 36% to 57%). Median PFS was 8.6 months (95% CI, 6.9 to 10.5), and RR was 26%. Overall, 35.4% of patients had grade 3 or greater treatment-related gastrointestinal toxicity (22.0% during chemoradiotherapy, 13.4% during maintenance chemotherapy). Unacceptable radiotherapy protocol deviations (ie, inappropriately generous volume contoured) correlated with grade 3 or greater gastrointestinal toxicity during chemoradiotherapy (45% v 18%; adjusted odds ratio, 3.7; 95% CI, 0.98 to 14.1; P = .05).

Conclusion

The addition of bevacizumab to chemoradiotherapy followed by bevacizumab and gemcitabine resulted in a similar median survival to previous Radiation Therapy Oncology Group studies in patients with locally advanced pancreatic cancer. Prospective QA may help limit toxicity in future trials.

"

Trends in Mastectomy Rates at the Mayo Clinic Rochester: Effect of Surgical Year and Preoperative Magnetic Resonance Imaging [Breast Cancer]

This weeks JCO has a provocative article about the use of MRI in the preoperative evaluation of breast cancer. Without any clinical evidence of improved outcomes (survival, local control, etc), breast MRI has been much more utilized in the last 5 years. One effect that this manuscript clearly demonstrates is that more people are receiving mastectomies...

Link and Abstract below:

Trends in Mastectomy Rates at the Mayo Clinic Rochester: Effect of Surgical Year and Preoperative Magnetic Resonance Imaging [Breast Cancer]:
"Purpose

Recent changes have occurred in the presurgical planning for breast cancer, including the introduction of preoperative breast magnetic resonance imaging (MRI). We sought to analyze the trends in mastectomy rates and the relationship to preoperative MRI and surgical year at Mayo Clinic, Rochester, MN.

Patients and Methods

We identified 5,405 patients who underwent surgery between 1997 and 2006. Patients undergoing MRI were identified from a prospective database. Trends in mastectomy rate and the association of MRI with surgery type were analyzed. Multiple logistic regression was used to assess the effect of surgery year and MRI on surgery type, while adjusting for potential confounding variables.

Results

Mastectomy rates differed significantly across time (P < .0001), and decreased from 45% in 1997% to 31% in 2003, followed by increasing rates for 2004 to 2006. The use of MRI increased from 10% in 2003% to 23% in 2006 (P < .0001). Patients with MRI were more likely to undergo mastectomy than those without MRI (54% v 36%; P < .0001). However, mastectomy rates increased from 2004 to 2006 predominantly among patients without MRI (29% in 2003% to 41% in 2006; P < .0001). In a multivariable model, both MRI (odds ratio [OR], 1.7; P < .0001) and surgical year (compared to 2003 OR: 1.4 for 2004, 1.8 for 2005, and 1.7 for 2006; P < .0001) were independent predictors of mastectomy.

Conclusion

After a steady decline, mastectomy rates have increased in recent years with both surgery year and MRI as significant predictors for type of surgery. Further studies are needed to evaluate the role of MRI and other factors influencing surgical planning."

Late Pelvic Toxicity After Bladder-Sparing Therapy in Patients With Invasive Bladder Cancer: RTOG 89-03, 95-06, 97-06, 99-06 [Genitourinary Cancer]

In this weeks JCO there is a great article on the QOL results with the sequential RTOG Bladder preservation trials. Link and abstract below:

Late Pelvic Toxicity After Bladder-Sparing Therapy in Patients With Invasive Bladder Cancer: RTOG 89-03, 95-06, 97-06, 99-06 [Genitourinary Cancer]:
"Purpose

In selected patients with muscle-invasive bladder cancer, combined-modality therapy (transurethral resection bladder tumor [TURBT], radiation therapy, chemotherapy) with salvage cystectomy, if necessary, can achieve survival rates similar to radical cystectomy. We investigated late pelvic toxicity after chemoradiotherapy for patients treated on prospective protocols.

Patients and Methods

Between 1990 and 2002, 285 eligible patients enrolled on four prospective protocols (Radiation Therapy Oncology Group [RTOG] 8903, 9506, 9706, 9906) and 157 underwent combined-modality therapy, surviving ≥ 2 years from start of treatment with their bladder intact. Rates of late genitourinary (GU) and GI toxicity were assessed using the RTOG Late Radiation Morbidity Schema, with worst toxicity grade (scale 0 to 5) occurring ≥ 180 days after start of consolidation therapy reported for each patient. Persistence of toxicity was defined as grade 3+ toxicity not decreasing by at least one grade. Logistic and Cox regression analyses were performed to evaluate relationship between clinical characteristics, frequency, and time to late grade 3+ pelvic toxicity. Covariates included age, sex, stage, presence of carcinoma in situ, completeness of TURBT, and protocol.

Results

Median follow-up was 5.4 years (range, 2.0 to 13.2 years). Seven percent of patients experienced late grade 3+ pelvic toxicity: 5.7% GU and 1.9% GI. In only one of nine patients did a grade 3+ GU toxicity persist. Notably there were no late grade 4 toxicities and no treatment-related deaths. None of the clinical variables studied predicted for late grade 3+ pelvic toxicity.

Conclusion

Rates of significant late pelvic toxicity for patients completing combined-modality therapy for invasive bladder cancer and retaining their native bladder are low."

Kennedy's GBM treatment

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

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. "

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:

nature: Antioxidant and oncogene rescue of metabolic defects caused by loss of matrix attachment

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. "

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

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

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

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."

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.

"

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.

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.

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.

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.

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: