the "Bolla" trial of long term ADT updated

Lancet Oncology:

The "Bolla" trial of Long Term ADT for prostate cancer is updated, with the DFS and OS benefit confirmed out to 10 years. What is also reassuring in this update is that the cardiovascular mortality was not increased with LHRH agonists.

Link:

[Articles] External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study: "In patients with prostate cancer with high metastatic risk, immediate androgen suppression with an LHRH agonist given during and for 3 years after external irradiation improves 10-year disease-free and overall survival without increasing late cardiovascular toxicity."

HPV subtypes for cervical cancer worldwide

Lancet Oncology:

A large report of the prevalence of HPV subtypes causing cervical cancer is published, again confirming HPV 16, 18, 31, and 33 as the primary actors. Interestingly, it also highlights HPV 45, and the prevalence of HPV in cervical adenocarcinomas.

Link:

[Articles] Human papillomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study: "To our knowledge, this study is the largest assessment of HPV genotypes to date. HPV types 16, 18, 31, 33, 35, 45, 52, and 58 should be given priority when the cross-protective effects of current vaccines are assessed, and for formulation of recommendations for the use of second-generation polyvalent HPV vaccines. Our results also suggest that type-specific high-risk HPV-DNA-based screening tests and protocols should focus on HPV types 16, 18, and 45."

PET response in treatment of Esophageal cancer

JCO this week:

An interesting retrospective series from Wake Forest examines the potential role of PET in prediction and prognosis in Esophageal cancer. In this series, outcomes of patients treated with trimodality therapy (CT, RT, and surgery) did reasonably well regardless of PET response, but in the definitive CTRT group, PET-CR predicted a large difference in survival and local control. The question now is whether PET can be used to select patients that would benefit from surgery, after completing a course of CTRT, which could potentially spare up to a 1/3 of patient a potentially morbid intervention.

Link and Abstract:

Outcomes of Patients With Esophageal Cancer Staged With [18F]Fluorodeoxyglucose Positron Emission Tomography (FDG-PET): Can Postchemoradiotherapy FDG-PET Predict the Utility of Resection? [Gastrointestinal Cancer]: "Purpose

To determine whether [¹⁸F]fluorodeoxyglucose positron emission tomography (FDG-PET) can delineate patients with esophageal cancer who may not benefit from esophagectomy after chemoradiotherapy.
Patients and Methods

We reviewed records of 163 patients with histologically confirmed stage I to IVA esophageal cancer receiving chemoradiotherapy with or without resection with curative intent. All patients received surgical evaluation. Initial and postchemoradiotherapy FDG-PET scans and prognostic/treatment variables were analyzed. FDG-PET complete response (PET-CR) after chemoradiotherapy was defined as standardized uptake value ≤ 3.
Results

Eighty-eight patients received trimodality therapy and 75 received chemoradiotherapy. Surgery was deferred primarily due to medical inoperability or unresectable/metastatic disease after chemoradiotherapy. A total of 105 patients were evaluable for postchemoradiotherapy FDG-PET response. Thirty-one percent achieved a PET-CR. PET-CR predicted for improved outcomes for chemoradiotherapy (2-year overall survival, 71% v 11%, P < .01; 2-year freedom from local failure [LFF], 75% v 28%, P < .01), but not trimodality therapy. On multivariate analysis of patients treated with chemoradiotherapy, PET-CR is the strongest independent prognostic variable (survival hazard ratio [HR], 9.82, P < .01; LFF HR, 14.13, P < .01). PET-CR predicted for improved outcomes regardless of histology, although patients with adenocarcinoma achieved a PET-CR less often.
Conclusion

Patients treated with trimodality therapy found no benefit with PET-CR, likely because FDG-PET residual disease was resected. Definitive chemoradiotherapy patients achieving PET-CR had excellent outcomes equivalent to trimodality therapy despite poorer baseline characteristics. Patients who achieve a PET-CR may not benefit from added resection given their excellent outcomes without resection. These results should be validated in a prospective trial of FDG-PET–directed therapy for esophageal cancer.
"

JCO: Gem+RT vs Gem alone in Pancreatic CA

In JCO:

Pancreatic cancer continues to be a difficult tumor to treat, where even the largest recent advances (EGRF inhibition, Gemcitabine) provide very modest benefit at best. Gemcitabine + RT was a subject of some excitement due to the radiosensitizing properties of the drug, but unfortunately in many centers it was found to also sensitize to normal tissue as well. Thus the US approach has been Gem alone, and RT + 5FU or capecitabine if used at all.

The study at hand is at once great in terms of concept by looking at Gem alone vs Gem concurrently with RT , but unfortunately limited by it's scope. As a randomized phase II, little can be concluded, asside from the fact that the toxicities as less than otherwise expected in the concurrent arm. There is not however evidence of a large therapeutic benefit with the approach, thus I feel that, as before, this is a disease in desperate need of a breakthrough.

Link and Abstract

Adjuvant Gemcitabine Alone Versus Gemcitabine-Based Chemoradiotherapy After Curative Resection for Pancreatic Cancer: A Randomized EORTC-40013-22012/FFCD-9203/GERCOR Phase II Study [Gastrointestinal Cancer]: "Purpose

The role of adjuvant chemoradiotherapy (CRT) in resectable pancreatic cancer is still debated. This randomized phase II intergroup study explores the feasibility and tolerability of a gemcitabine-based CRT regimen after R0 resection of pancreatic head cancer.

Patients and Methods

Within 8 weeks after surgery, patients were randomly assigned to receive either four cycles of gemcitabine (control arm) or gemcitabine for two cycles followed by weekly gemcitabine with concurrent radiation (50.4 Gy; CRT arm). The primary objective was to exclude a < 60% treatment completion and a > 40% rate of grade 4 hematologic or GI toxicity in the CRT arm with type I and II errors of 10%. Secondary end points were late toxicity, disease-free survival (DFS), and overall survival (OS).

Results

Between September 2004 and January 2007, 90 patients were randomly assigned (45:45). Patient characteristics were similar in both arms. Treatment was completed per protocol by 86.7% and 73.3% (80% CI, 63.1% to 81.9%; 95% CI, 58.1% to 85.4%) in the control and CRT arms, respectively, and grade 4 toxicity was 0% and 4.7% (two of 43; 80% CI, 1.2% to 11.9%), respectively. In the CRT arm, three patients experienced grade 3–related late toxicity. Median DFS was 12 months in the CRT arm and 11 months in the control arm. Median OS was 24 months in both arms. First local recurrence was less frequent in the CRT arm (11% v 24%).

Conclusion

Adjuvant gemcitabine-based CRT is feasible, well-tolerated, and not deleterious; adding this treatment to full-dose adjuvant gemcitabine after resection of pancreatic cancer should be evaluated in a phase III trial.

"

Angiosarcoma

Lancet Oncology -

An interesting review article on angiosarcoma in the Lancet Oncology this week: these difficult tumors often involve the radiation oncologist, either as a long term complication of prior therapy (classically breast radiation), or as treatment.

Link

[Review] Angiosarcoma: "Angiosarcomas are rare soft-tissue sarcomas of endothelial cell origin that have a poor prognosis. They can arise anywhere in the body, most commonly presenting as cutaneous disease in elderly white men, involving the head and neck and particularly the scalp. They can be caused by therapeutic radiation or chronic lymphoedema and hence secondary breast angiosarcomas are an important subgroup. Recent work has sought to establish the molecular biology of angiosarcomas and identify specific targets for treatment."

NSABP B-32 - Sentinel Node Study published for OS

In the Lancet Oncology,

Though already common practice, the NSABP B-32 trial randomizing breast cancer patients to sentinel lymph node mapping vs a full axillary dissection is published revealing no difference in any clinical endpoint. This is good news as it already has become standard practice in most US centers. Another thing to keep in mind about this is that there is a 5-15% false negative rate of the procedure, which has clearly not translated into a meaningful difference in outcomes in this trial.

Link:

[Articles] Sentinel-lymph-node resection compared with conventional axillary-lymph-node dissection in clinically node-negative patients with breast cancer: overall survival findings from the NSABP B-32 randomised phase 3 trial: "Overall survival, disease-free survival, and regional control were statistically equivalent between groups. When the SLN is negative, SLN surgery alone with no further ALND is an appropriate, safe, and effective therapy for breast cancer patients with clinically negative lymph nodes."

Cabazitaxel for Prostate CA

Lancet:

Interesting phase III trial reported in Lancet this week: the study population was of patient with castrate resistant, metastatic prostate cancer, progressing after docetaxel. They were randomized to mitoxantrone vs. a novel taxane cabazitaxel. Toxicity was higher with cabazitaxel, but there was an improvement in both progression free and overall survival. As rad oncs are occaisionally the primary oncologists that prostate cancer patients see, this is a signficant advance worthy of our notice.

Link:

[Articles] Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial: "Prostate cancer is the second most common cause of cancer death in men in the USA and the third most common cause of death in developed countries. For patients with metastatic prostate cancer, androgen deprivation therapy improves symptoms, but patients invariably develop progressive disease. On the basis of an improvement in survival compared with mitoxantrone plus prednisone in patients with metastatic castration-resistant prostate cancer, docetaxel in combination with prednisone is standard first-line chemotherapy in this setting. No treatment has been approved by the US Food and Drug Administration, however, for patients whose disease progresses after docetaxel treatment. Mitoxantrone is often administered because of its favourable effects on quality-of-life outcomes. However, no intervention improves survival in this disease setting."

Radiation Proctitis

Image of Radiation Proctitis in the NEJM:

One thing I find a little concerning about this is that in the caption, it is implied that they biopsied the lesion to establish the diagnosis of proctitis. We never recommend this unless these is concern of cancer, as any injury to previously irradiated tissue, especially tissue already demonstrating late effect, can have unintended complications. Having seen fistulas formed after biopsy in similar cases, I would recommend treated clinically based on the history and appearance from the colonoscopy.

Radiation Proctitis: "New England Journal of Medicine, Volume 363, Issue 12, Page 1163, September 2010."

Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial [Hematologic Malignancies]

JCO:

The results of HD11 are published (after having been available online for the last month). HD11 was a counterpart to the HD10 study which looked at early favorable Hodgkin's disease. HD11 was the unfavorable early stage patients, defined as the presence of any of the following: large medistinal mass (greater than 1/3 of the maximum thoracic diameter), extranodal disease, involvement with less than 2 nodal areas, and an elevated ESR (less than 50mm for IA and IIA, and less than 30mm for IB and IIB).
This was a 2x2 trial, looking at escalating chemotherapy (comparing the standard ABVD to BEACOPP), and de-escalating RT (30Gy to 20Gy). Unfortunately, the answer was not clear cut, with both of the comparisons being negative (i.e. BEACOPP was not superior to ABVD, and 20Gy was not "non-inferior" to 30Gy). Of course the temptation is to the look at each of the four arms individually - in which it was observed that the escalation of BEACOPP may conterbalance the descalation of 20Gy, but in the end, one must look on this as a unplanned subgroup analysis.

At the end of the day what are we left with from HD10 and HD11? In favorable patients, a new standard of 20Gy and 2 cycles of ABVD is established, but in unfavorable disease ABVD x4 with 30GY IFRT still stands.

Link and Abstract:

Intensified Chemotherapy and Dose-Reduced Involved-Field Radiotherapy in Patients With Early Unfavorable Hodgkin's Lymphoma: Final Analysis of the German Hodgkin Study Group HD11 Trial [Hematologic Malignancies]: "Purpose

Combined-modality treatment consisting of four to six cycles of chemotherapy followed by involved-field radiotherapy (IFRT) is the standard of care for patients with early unfavorable Hodgkin's lymphoma (HL). It is unclear whether treatment results can be improved with more intensive chemotherapy and which radiation dose needs to be applied.

Patients and Methods

Patients age 16 to 75 years with newly diagnosed early unfavorable HL were randomly assigned in a 2 x 2 factorial design to one of the following treatment arms: four cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) + 30 Gy of IFRT; four cycles of ABVD + 20 Gy of IFRT; four cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP_baseline) + 30 Gy of IFRT; or four cycles of BEACOPP_baseline + 20 Gy of IFRT.

Results

With a total of 1,395 patients included, the freedom from treatment failure (FFTF) at 5 years was 85.0%, overall survival was 94.5%, and progression-free survival was 86.0%. BEACOPP_baseline was more effective than ABVD when followed by 20 Gy of IFRT (5-year FFTF difference, 5.7%; 95% CI, 0.1% to 11.3%). However, there was no difference between BEACOPP_baseline and ABVD when followed by 30 Gy of IFRT (5-year FFTF difference, 1.6%; 95% CI, –3.6% to 6.9%). Similar results were observed for the radiotherapy question; after four cycles of BEACOPP_baseline, 20 Gy was not inferior to 30 Gy (5-year FFTF difference, –0.8%; 95% CI, –5.8% to 4.2%), whereas inferiority of 20 Gy cannot be excluded after four cycles of ABVD (5-year FFTF difference, –4.7%; 95% CI, –10.3% to 0.8%). Treatment-related toxicity occurred more often in the arms with more intensive therapy.

Conclusion

Moderate dose escalation using BEACOPP_baseline did not significantly improve outcome in early unfavorable HL. Four cycles of ABVD should be followed by 30 Gy of IFRT.

RT after RCHOP for DLBCL

JCO:

This week a retrospective study from MDACC examined the effects of RT after RCHOP in DLBCL, demostrating an association with improved OS and DFS. Unfortunately, the samples are biased towards RT, with the lower stages receiving RT more frequently. The authors attempt to correct for this with MVA and a matched pair analysis, with the benefits being maintained, though of interest, the results of the advanced stage alone is not presented in the article. In the end, there is only so much that can be done to fully account for the selection bias.

Nonetheless, this article supports consolidative RT after R-CHOP, which is not a small issue given the advantage that R-CHOP demonstrates over CHOP alone (the randomized data supporting RT is in the pre-rituximab era).

Link and Abstract:

Benefit of Consolidative Radiation Therapy in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP Chemotherapy [Radiation Oncology]: "Purpose

The current standard therapy for patients with diffuse large B-cell lymphoma (DLBCL) is rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). The role of consolidative radiation therapy (RT) in the setting of R-CHOP chemotherapy is not well reported. This retrospective analysis is an attempt to clarify this role.

Patients and Methods

Subjects were 469 patients with histologically confirmed DLBCL treated between January 2001 and December 2007. Variables including age, sex, Ann Arbor disease stage, bulky disease status, standardized uptake values (SUVs) on positron emission tomography (PET), International Prognostic Index (IPI), and Ki67 staining (proliferation).

Results

Of 469 patients, 190 (40.5%) had stage I or II disease and 279 (59.5%) had stage III or IV disease, 327 (70%) had at least six cycles of R-CHOP, and 142 (30.2%) had involved-field RT (dose, 30 to 39.6 Gy) after complete response to chemotherapy. Median follow-up was 36 months (range, 8 to 85 months). Multivariate analysis showed that RT (P < .0001), IPI score (P = .001), response to therapy (P = .001), use of six to eight cycles of R-CHOP (P < .001), and combined presence (P = .006) or absence (P = .025) of high Ki67, high PET SUV, and bulky disease influenced overall survival (OS) and progression-free survival (PFS). Matched-pair analyses of patients who received six to eight cycles of R-CHOP with stage I or II disease (44 pairs) and all stages (74 pairs) indicated that RT improved OS (hazard ratio [HR], 0.52 and 0.29, respectively) and PFS (HR, 0.45 and 0.24, respectively) compared with no RT.

Conclusion

This study showed significant improvements in OS and PFS among patients who received consolidation RT after R-CHOP chemotherapy for DLBCL.

"

Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection: A Randomized Controlled Trial [Original Contribution]

JAMA:

The ESPAC-3 trial is published, which compared 5FU vs Gemcitabine in resected pancreatic cancer. Unfortunately, this negative trial only seems to move pancreatic cancer back a step to 5FU alone as a standard. To put this in the larger context: there are two competing paradigms for the treatment of resected pancreatic cancer, the US approach of RT + Gem based on RTOG data, and the European approach of chemotherapy alone, generally Gem based on the CONKO trial (which showed a benefit of Gem over observation). The current trial suggests that 5FU alone is as good (or bad depending on your perspective). Regardless, new therapies continue to be desperately needed for this disease.

Link and Abstract:

Adjuvant Chemotherapy With Fluorouracil Plus Folinic Acid vs Gemcitabine Following Pancreatic Cancer Resection: A Randomized Controlled Trial [Original Contribution]: "

Context Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer.

Objective To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer.

Design, Setting, and Patients The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up.

Interventions Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m², intravenous bolus injection, followed by fluorouracil, 425 mg/m² intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m² intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months.

Main Outcome Measures Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life.

Results Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (²₁ = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.

Conclusion Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer.

Trial Registration clinicaltrials.gov Identifier: NCT00058201

"

SRS in the Brainstem

Red Journal:

Retrospective series from the Cleveland Clinic looking at results with SRS to brainstem lesions. They have pretty reasonable results for an area of the CNS which has bee quite anxiety provoking in the past. They do allow for a dose reduction to lesions here, and recommend the following doses compared to RTOG 90-05: for lesions less than 2cm 18Gy, 2-3cm 15Gy, 3-4cm 12Gy

Link and Abstract

Stereotactic Radiosurgery for Single Brainstem Metastases: The Cleveland Clinic Experience: "Purpose: To assess the imaging and clinical outcomes of patients with single brainstem metastases treated with stereotactic radiosurgery (SRS).Materials and Methods: We retrospectively reviewed the data from patients with single brainstem metastases treated with SRS. Locoregional control and survival were calculated using the Kaplan-Meier method. Prognostic factors were assessed using a Cox proportional hazards model.Results: Between 1997 and 2007, 43 patients with single brainstem metastases were treated with SRS. The median age at treatment was 59 years, the median Karnofsky performance status was 80, and the median follow-up was 5.3 months. The median dose was 15 Gy (range, 9.6–24), and the median conformality and heterogeneity index was 1.7 and 1.9, respectively. The median survival was 5.8 months from the procedure date. Of the 33 patient with post-treatment imaging available, a complete radiographic response was achieved in 2 (4.7%), a partial response in 8 (18.6%), and stable disease in 23 (53.5%). The 1-year actuarial rate of local control, distant brain control, and overall survival was 85%, 38.3%, and 31.5%, respectively. Of the 43 patients, 8 (19%) died within 2 months of undergoing SRS, and 15 (36%) died within 3 months. On multivariate analysis, greater performance status (hazard ratio [HR], 0.95, p = .004), score index for radiosurgery (HR, 0.7; p = .004), graded prognostic assessment score (HR, 0.48; p = .003), and smaller tumor volume (HR, 1.23, p = .002) were associated with improved survival. No Grade 3 or 4 toxicities were observed.Conclusion: The results of our study have shown that SRS is a safe and effective local therapy for patients with brainstem metastases."

Nodal treatment for Breast Cancer after pCR in Nodes

Red Journal:

An interesting article from France is published examining the potential value of lymph node irradiation (LNI) in patients achieving pCR after neoadjuvant chemotherapy, finding no differences in outcome if nodes were prophylactically covered. While this is an interesting observation, and useful data to have, one must note that the majority of patients in this retrospective study were cN0, and moreover that there was a predominance of cN0 patients in the no LNI cohort. And additional observation is that there were no cN2 patients in the no LNI cohort, nor were any patients with pathologic documentation of disease pre treatment. Even with a multivariate analysis, I am uncertain that these factors could be appropriately controlled for to come to a meaningful conclusion in cN1 but pN0 patients (a common clinical problem).

Link and Abstract:

Is Regional Lymph Node Irradiation Necessary in Stage II to III Breast Cancer Patients With Negative Pathologic Node Status After Neoadjuvant Chemotherapy?: "Purpose: Neoadjuvant chemotherapy (NAC) generally induces significant changes in the pathologic extent of disease. This potential down-staging challenges the standard indications of adjuvant radiation therapy. We assessed the utility of lymph node irradiation (LNI) in breast cancer (BC) patients with pathologic N0 status (pN0) after NAC and breast-conserving surgery (BCS).Methods and Materials: Among 1,054 BC patients treated with NAC in our institution between 1990 and 2004, 248 patients with clinical N0 or N1 to N2 lymph node status at diagnosis had pN0 status after NAC and BCS. Cox regression analysis was used to identify factors influencing locoregional recurrence–free survival (LRR-FS), disease-free survival (DFS), and overall survival (OS).Results: All 248 patients underwent breast irradiation, and 158 patients (63.7%) also received LNI. With a median follow-up of 88 months, the 5-year LRR-FS and OS rates were respectively 89.4% and 88.7% with LNI and 86.2% and 92% without LNI (no significant difference). Survival was poorer among patients who did not have a pathologic complete primary tumor response (hazard ratio, 3.05; 95% confidence interval, 1.17–7.99) and in patients with N1 to N2 clinical status at diagnosis (hazard ratio = 2.24; 95% confidence interval, 1.15–4.36). LNI did not significantly affect survival.Conclusions: Relative to combined breast and local lymph node irradiation, isolated breast irradiation does not appear to be associated with a higher risk of locoregional relapse or death among cN0 to cN2 breast cancer patients with pN0 status after NAC. These results need to be confirmed in a prospective study."

implications of pCR in Rectal Cancer

Lancet Oncology:

A meta-analysis is published today in Lancet Oncology, which explores the prognostic implications of a pathologic complete response. Many of us use this as a surrogate for the relative effectiveness of neoadjuvant treatment regimens, and while single trial and institution data has supported this, the manuscript at hand takes broader look at the prognostic implications, and confirms what has already become a standard endpoint for evaluating rectal cancer treatment.

Link:

[Articles] Long-term outcome in patients with a pathological complete response after chemoradiation for rectal cancer: a pooled analysis of individual patient data: "Locally advanced rectal cancer is usually treated with preoperative chemoradiation. After chemoradiation and surgery, 15–27% of the patients have no residual viable tumour at pathological examination, a pathological complete response (pCR). This study established whether patients with pCR have better long-term outcome than do those without pCR."

BSO for BRCA 1 and 2 carriers

In JAMA this week:

An interesting study of prospectively followed patients with BRCA1 and 2, looking at outcomes with prophylactic mastectomy and salpingo-oophorectomy. While mastectomy did provide some protection against future breast cancers, the benefits of the BSO were much more striking, with risk reductions in breast and ovarian cancer specific survival, as well as an overall survival benefit.

Now clearly, there are other factors that influence a woman's choice to undergo either mastectomy or BSO, and one can easily imagine confounders in patient selection. However, given those limitations, this is strong support for these risk reduction strategies.

Link and Abstract:

Association of Risk-Reducing Surgery in BRCA1 or BRCA2 Mutation Carriers With Cancer Risk and Mortality [Original Contribution]: "

Context Mastectomy and salpingo-oophorectomy are widely used by carriers of BRCA1 or BRCA2 mutations to reduce their risks of breast and ovarian cancer.

Objective To estimate risk and mortality reduction stratified by mutation and prior cancer status.

Design, Setting, and Participants Prospective, multicenter cohort study of 2482 women with BRCA1 or BRCA2 mutations ascertained between 1974 and 2008. The study was conducted at 22 clinical and research genetics centers in Europe and North America to assess the relationship of risk-reducing mastectomy or salpingo-oophorectomy with cancer outcomes. The women were followed up until the end of 2009.

Main Outcomes Measures Breast and ovarian cancer risk, cancer-specific mortality, and overall mortality.

Results No breast cancers were diagnosed in the 247 women with risk-reducing mastectomy compared with 98 women of 1372 diagnosed with breast cancer who did not have risk-reducing mastectomy. Compared with women who did not undergo risk-reducing salpingo-oophorectomy, women who underwent salpingo-oophorectomy had a lower risk of ovarian cancer, including those with prior breast cancer (6% vs 1%, respectively; hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.04-0.59) and those without prior breast cancer (6% vs 2%; HR, 0.28 [95% CI, 0.12-0.69]), and a lower risk of first diagnosis of breast cancer in BRCA1 mutation carriers (20% vs 14%; HR, 0.63 [95% CI, 0.41-0.96]) and BRCA2 mutation carriers (23% vs 7%; HR, 0.36 [95% CI, 0.16-0.82]). Compared with women who did not undergo risk-reducing salpingo-oophorectomy, undergoing salpingo-oophorectomy was associated with lower all-cause mortality (10% vs 3%; HR, 0.40 [95% CI, 0.26-0.61]), breast cancer–specific mortality (6% vs 2%; HR, 0.44 [95% CI, 0.26-0.76]), and ovarian cancer–specific mortality (3% vs 0.4%; HR, 0.21 [95% CI, 0.06-0.80]).

Conclusions Among a cohort of women with BRCA1 and BRCA2 mutations, the use of risk-reducing mastectomy was associated with a lower risk of breast cancer; risk-reducing salpingo-oophorectomy was associated with a lower risk of ovarian cancer, first diagnosis of breast cancer, all-cause mortality, breast cancer–specific mortality, and ovarian cancer–specific mortality.

"

HD10 published: 20Gy and 2 cycles ABVD

in the NEJM:

HD10 is published after a series of abstracts, all reaching the same conclusion: reduced intensity treatment is effective in early stage, favorable Hodgkin's lymphoma. This was a 2x2 non-inferiority trial looking at 30Gy vs 20Gy IFRT and 2 vs 4 cycles of ABVD; and no differences were noted in any clinical endpoint in the 1370 patients enrolled. The tempting comparison of 20Gy and 2 cycles vs 30Gy and 4 cycles is not a valid comparison in this trial due to the 2x2 design, but as a post-hoc analysis the authors did do this, demonstrating no difference in the most intense treatment and the least intense treatment (with HR 1.07 0.65-1.77, and an absolute difference of 1.6% at 5yr FFTF).

I think this now becomes the standard of care in these patients; however - one must be careful to differentiate between favorable and unfavorable early stage HD. Unfortunately, this quite important piece of information was delegated to an online only supplement. To sum up: those with any risk factor were excluded. This includes: large medistinal mass (>= 1/3 of the maximum thoracic diameter), extranodal disease, involvement with >2 nodal areas, and an elevated ESR (>=50mm for IA and IIA, and >=30mm for IB and IIB). Clinicians must be mindful of this when deintensifying treatment.

Link to the article.

Reduced Treatment Intensity in Patients with Early-Stage Hodgkin's Lymphoma: "New England Journal of Medicine, Volume 363, Issue 7, Page 640-652, August 2010. "

PSA screening for Prostate Cancer

In the Lancet Oncology this week:

The results of a PSA screening trial is published from Sweden. 20,000 men were randomized between PSA screening every two years vs. no screening. With 14 years follow up, the number of men diagnosed with prostate cancer was 12.7% in the screened vs 8.4% in the non-screened populace. This translated to a HR of 1.64 (1.5-1.8 95% CI) for prostate cancer diagnosis. More importantly the HR for death of prostate cancer was 0.44 with screening (0.28-0.68 95% CI), though no difference was seen in overall survival. The number needed to screen (NNS) was 293, and the number needed to treat (NNT) was 12 to prevent one prostate cancer death. Not surprisingly the majority of the benefit was seen over 10 years out.

This is a higher reduction in risk than that seen in two prior studies (the ERSPC and the PLCO studies), so there is some conflicting data on this subject to be aware of (the ERSPC tiral was positive, but to a lesser degree, and the PLCO study was negative). The authors present a rationale for why the results were more pronounced in this study in their discussion.

full text via science direct here

[Articles] Mortality results from the Göteborg randomised population-based prostate-cancer screening trial: "Prostate cancer is one of the leading causes of death from malignant disease among men in the developed world. One strategy to decrease the risk of death from this disease is screening with prostate-specific antigen (PSA); however, the extent of benefit and harm with such screening is under continuous debate."

Matched Pair Analysis Comparing Surgery Followed By Radiotherapy and Radiotherapy Alone for Metastatic Spinal Cord Compression [Palliative and Supportive Care]

In the JCO this week:

A retrospective international series, calls into question the results of the Patchell Study of decompressive surgery before RT in spinal cord compression. The Patchell study demostrated a significant benefit in terms of recovery of amulation in addition to other neurologic endpoints, as well as survival. This study matched pairs of 1:2 for surgery + RT and RT alone, and, in short, found no differences. The authors of this JCO article conclude that the population in the randomized trial was very selected, and that perhaps, in a broader population the question should be subject to another randomized trial.

I don't know how much enthusiasm there would be to run such a trial again, and at least in our experience, surgery is reserved for the most selected population, mostly likely to benefit (single tumors, controlled primaries, etc.). Additionally, like the Patchell study, laminectomies (which make up a fair portion of the retrospective study) are not routinely recommended, as direct decompressions are a superior surgery in these situation.

Nonetheless, this is an interesting article looking at a common situation that has little randomized data to guide treatment.

Link and Abstract

Matched Pair Analysis Comparing Surgery Followed By Radiotherapy and Radiotherapy Alone for Metastatic Spinal Cord Compression [Palliative and Supportive Care]: "Purpose

The appropriate treatment for MSCC is controversial. A small randomized trial showed that decompressive surgery followed by radiotherapy was superior to radiotherapy alone. That study was limited to highly selected patients. Additional studies comparing surgery plus radiotherapy to radiotherapy could better clarify the role of surgery.

Methods

Data from 108 patients receiving surgery plus radiotherapy were matched to 216 patients (1:2) receiving radiotherapy alone. Groups were matched for 11 potential prognostic factors and compared for post-treatment motor function, ambulatory status, regaining ambulatory status, local control, and survival. Subgroup analyses were performed for patients receiving adequate surgery (direct decompressive surgery plus stabilization of involved vertebrae), patients receiving laminectomy, patients with solid tumors, patients with solid tumors receiving adequate surgery, and patients with solid tumors receiving laminectomy.

Results

Improvement of motor function occurred in 27% of patients after surgery plus radiotherapy and 26% after radiotherapy alone (P = .92). Post-treatment ambulatory rates were 69% after surgery plus radiotherapy and 68% after radiotherapy alone (P = .99). Of the nonambulatory patients, 30% and 26%, respectively, (P = .86) regained ambulatory status after treatment. One-year local control rates were 90% after surgery plus radiotherapy and 91% after radiotherapy alone (P = .48). One-year overall survival rates were 47% and 40%, respectively (P = .50). The subgroup analyses did not show significant differences between both groups. Surgery-related complications occurred in 11% of patients.

Conclusion

In this study, the outcomes of the end points evaluated after radiotherapy alone appeared similar to those of surgery plus radiotherapy. A new randomized trial comparing both treatments is justified.

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Lancet: IORT for Breast - the TARGIT-A trial

In the Lancet

Previously available online and presented at ASCO, the TARGIT-A trial is published in Lancet today. To briefly recap - this multinational randomized trial looked at conventional fracitonation vs 20Gy in a single treatment intraoperatively. 4 year data shows similar local control, with potentially slightly less toxicity, and clearly less time and resources devoted. While the time points evaluated are still too early to replace the standard of care in all patients, in selected patients, this approach is potentially very attractive.

Link:

[Articles] Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial: "After breast-conserving surgery, 90% of local recurrences occur within the index quadrant despite the presence of multicentric cancers elsewhere in the breast. Thus, restriction of radiation therapy to the tumour bed during surgery might be adequate for selected patients. We compared targeted intraoperative radiotherapy with the conventional policy of whole breast external beam radiotherapy."

JCO: RT for advanced HD and unfavorable early HD

This weeks JCO:

A very compelling analysis is presented looking at non-randomized results with consolidation RT after chemotherapy in a prospective chemo trial for advanced stage and early unfavorable Hodgkin Disease. Despite the fact that the RT group had more "bulky" disease and more incomplete responders, a benefit was seen across the board for PFS and OS, with HRs for all subgroups <= to 0.5. Also interestingly they looked at dose (see figure 5), showing no compelling dose response beyond 30Gy.

Link and Abstract

Consolidation Radiotherapy in Patients With Advanced Hodgkin's Lymphoma: Survival Data From the UKLG LY09 Randomized Controlled Trial (ISRCTN97144519) [Hematologic Malignancies]: "Purpose

This study analyzed the outcomes of nonrandomized consolidation radiotherapy (RT) given after chemotherapy in the initial treatment of advanced Hodgkin's lymphoma (HL). The results were collected prospectively within a randomized controlled trial of induction chemotherapy.

Patients and Methods

Patients were randomly assigned between doxorubicin, bleomycin, vinblastine, and dacarbazine and one of two prespecified multidrug regimens. At least six cycles of chemotherapy were planned, with up to eight for patients showing slower response. Involved-field RT was recommended for incomplete response to chemotherapy or bulk disease at presentation. The primary outcome measure was progression-free survival (PFS), landmarked from the end of chemotherapy.

Results

Among 807 patients randomly assigned, 702 achieved objective response. Postchemotherapy RT for consolidation was reported in 300 (43%). With median follow-up of 6.9 years, 161 PFS events and 83 deaths were reported. Baseline characteristics showed more patients with bulk disease having RT (190 [63%] v 111 [28%]) and only partial response after chemotherapy (150 [50%] v 36 [9%]). Other baseline characteristics were similar. PFS was superior for patients having RT (hazard ratio [HR], 0.43; 95% CI, 0.30 to 0.60) with 5-year PFS 71% without RT, 86% with RT. A similar advantage was seen for overall survival (HR, 0.47; 95% CI, 0.29 to 0.77). There was no evidence of heterogeneity of treatment effect across subgroups.

Conclusion

Patients who received consolidation RT apparently had better outcomes, consistently across all prognostic groups which persisted in multivariate analysis. This suggests that RT contributes significantly to the cure rate for advanced HL, although patient selection for combined modality treatment requires better definition in prospective trials.

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