Monday, September 20, 2010

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]


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 (BEACOPPbaseline) + 30 Gy of IFRT; or four cycles of BEACOPPbaseline + 20 Gy of IFRT.


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%. BEACOPPbaseline 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 BEACOPPbaseline 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 BEACOPPbaseline, 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.


Moderate dose escalation using BEACOPPbaseline 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


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).


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.


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


Tuesday, September 14, 2010

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


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 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."

Wednesday, September 1, 2010

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.


[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.