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.

"

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.

"

JCO: Gefitinib integration into CTRT for H&N cancer

JCO this week:

An interesting phase II looking at the integration of gefitinib (an EGFR TKI), with concurrent chemoradiotherapy. The overall approach is different than what many centers would call standard treatment with induction carbo/paclitaxel, followed by 5FU, HU, and gefinitib with BID RT, then continuing gefitinib afterwards. The results however are good in comparison to historical controls, and it will be very interesting to see how integration of EGFR inhibition in ongoing phase III trials will fair when result mature over the next ~5 years.

Link and abstract

Epidermal Growth Factor Receptor Inhibitor Gefitinib Added to Chemoradiotherapy in Locally Advanced Head and Neck Cancer [Head and Neck Cancer]: "Purpose

Assess efficacy and toxicity of gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, added to, and in maintenance after, concurrent chemoradiotherapy (CCRT) in locally advanced head and neck cancer (LA-HNC) and correlate outcomes with EGFR gene copy number alterations.

Patients and Methods

Patients with stage III to IV LA-HNC received two cycles of carboplatin/paclitaxel induction chemotherapy (IC) followed by split-course CCRT with fluorouracil, hydroxyurea, twice daily radiotherapy (FHX), and gefitinib (250 mg daily) followed by continued gefitinib for 2 years total. The primary end point was complete response (CR) rate after CCRT. EGFR gene copy number was assessed by fluorescent in situ hybridization.

Results

Sixty-nine patients (66 with stage IV disease, 37 with oropharynx primary tumors, and 67 with performance status 0 to 1) were enrolled with a median age of 55 years. Predominant grade 3 or 4 toxicities during IC and CCRT were neutropenia (n = 20) and in-field mucositis (n = 59) and dermatitis (n = 23), respectively. CR rate after CCRT was 90%. After median follow-up of 3.5 years, 4-year overall, progression-free, and disease-specific survival rates were 74%, 72%, and 89%, respectively. To date, one patient has developed a second primary tumor in the aerodigestive tract. In 31 patients with available tissue, high EGFR gene copy number was associated with worse overall survival (P = .02).

Conclusion

Gefitinib can be administered with FHX and as maintenance therapy for at least 2 years, demonstrating CR and survival rates that compare favorably with prior experience. High EGFR gene copy number may be associated with poor outcome in patients with LA-HNC treated with this regimen.

"

RT protocol compliance and outcome for H&N cancer

JCO: In addition to reporting out the negative results of tirapazamine, the TROG investigators reported on those with protocol violations, and found at SS worse over all survival (HR = 2!) and local control. i.e. - expertise does matter, at least for H&N RT.

Link and Abstract:

Critical Impact of Radiotherapy Protocol Compliance and Quality in the Treatment of Advanced Head and Neck Cancer: Results From TROG 02.02 [Head and Neck Cancer]: "Purpose

To report the impact of radiotherapy quality on outcome in a large international phase III trial evaluating radiotherapy with concurrent cisplatin plus tirapazamine for advanced head and neck cancer.

Patients and Methods

The protocol required interventional review of radiotherapy plans by the Quality Assurance Review Center (QARC). All plans and radiotherapy documentation underwent post-treatment review by the Trial Management Committee (TMC) for protocol compliance. Secondary review of noncompliant plans for predicted impact on tumor control was performed. Factors associated with poor protocol compliance were studied, and outcome data were analyzed in relation to protocol compliance and radiotherapy quality.

Results

At TMC review, 25.4% of the patients had noncompliant plans but none in which QARC-recommended changes had been made. At secondary review, 47% of noncompliant plans (12% overall) had deficiencies with a predicted major adverse impact on tumor control. Major deficiencies were unrelated to tumor subsite or to T or N stage (if N+), but were highly correlated with number of patients enrolled at the treatment center (< five patients, 29.8%; ≥ 20 patients, 5.4%; P < .001). In patients who received at least 60 Gy, those with major deficiencies in their treatment plans (n = 87) had a markedly inferior outcome compared with those whose treatment was initially protocol compliant (n = 502): –2 years overall survival, 50% v 70%; hazard ratio (HR), 1.99; P < .001; and 2 years freedom from locoregional failure, 54% v 78%; HR, 2.37; P < .001, respectively.

Conclusion

These results demonstrate the critical importance of radiotherapy quality on outcome of chemoradiotherapy in head and neck cancer. Centers treating only a few patients are the major source of quality problems.

"

Tirapazamine for H&N cancer

JCO: A phase three trial looking at the addition of tipazamine (a selective hypoxic cytotoxin) is reported in JCO this week. Unfortunately there were no significant differences.

Link and Abstract:

Tirapazamine, Cisplatin, and Radiation Versus Cisplatin and Radiation for Advanced Squamous Cell Carcinoma of the Head and Neck (TROG 02.02, HeadSTART): A Phase III Trial of the Trans-Tasman Radiation Oncology Group [Head and Neck Cancer]: "Purpose

Promising results in a randomized phase II trial with the hypoxic cytotoxin tirapazamine (TPZ) combined with cisplatin (CIS) and radiation led to this phase III trial.

Patients and Methods

Patients with previously untreated stage III or IV (excluding T1-2N1 and M1) squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx were randomly assigned to receive definitive radiotherapy (70 Gy in 7 weeks) concurrently with either CIS (100 mg/m²) on day 1 of weeks 1, 4, and 7 or CIS (75 mg/m²) plus TPZ (290 mg/m²/d) on day 1 of weeks 1, 4, and 7 and TPZ alone (160 mg/m²/d) on days 1, 3, and 5 of weeks 2 and 3 (TPZ/CIS). The primary end point was overall survival (OS). The planned sample size was 850, estimated to result in 334 deaths, which would provide 90% power to detect a difference in 2-year survival rates of 60% v 70% for CIS versus TPZ/CIS, respectively (hazard ratio = 0.69).

Results

Eight hundred sixty-one patients were accrued from 89 sites in 16 countries. In an intent-to-treat analysis, the 2-year OS rates were 65.7% for CIS and 66.2% for TPZ/CIS (TPZ/CIS – CIS: 95% CI, –5.9% to 6.9%). There were no significant differences in failure-free survival, time to locoregional failure, or quality of life as measured by Functional Assessment of Cancer Therapy–Head and Neck.

Conclusions

We found no evidence that the addition of TPZ to chemoradiotherapy, in patients with advanced head and neck cancer not selected for the presence of hypoxia, improves OS.

"

HPV and H&N cancer

NEJM:

The RTOG 0129 protocol of altered fractionation with chemo vs. standard fractionation with chemo in head and neck cancers is a negative trial, however, published in the NEJM this week is the results of the trial broken down by prognostic factor. Unsurprisingly HPV plays a large role in oropharynx cancers, and clearly needs to be taken into account when designing future trials.

Link:

Human Papillomavirus and Survival of Patients with Oropharyngeal Cancer

ASCO 2010: Sequential Chemo then RT vs concurrent CTRT in Cervical Cancer

ASCO 2010:

A phase III trial of induction carboplatin and paclitaxel followed by WPRT and brachy compared to standard concurrent chemoradiotherapy followed by brachy in cervical cancer. They find no significant difference in OS or PFS, but trends favored induction treatment. The toxicity profiles also favored the sequential (experimental) arm.

So what's not to like? Well, as Dr. Eifel stated in her excellent discussion of the data, multiple trials of induction treatment prior to the concurrent CDDP era were negative for benefit, perhaps due to accelerated repopulation. This is a small trial, and occurs in the setting of multiple large randomized trials demonstrating a dramatic benefit to concurrent cddp and radiation. Her conclusion in the discussion were that large international trials should be designed to confirm the use of either induction or adjuvant chemotherapy, and especially before abandoning concurrent cisplatin.

Link:

Randomized phase III adjuvant study in high-risk cervical cancer: Simultaneous radiochemotherapy with cisplatin (S-RC) versus systemic paclitaxel and carboplatin followed by percutaneous radiation (PC-R): A NOGGO-AGO-Intergroup Study.

TMZ alone or RT alone for elderly patients with GBM

ASCO 2010:

Two similarly sized and designed trials are reported which randomized patients >65 in the NOA-08 and >60 Malmstrom abstract to temozolomide vs RT alone and came to different conclusions. In the NOA-08 trial TMZ alone was not non-inferior (i.e. it was worse) than RT - which is the current standard. In the Malmstrom abstract they looked at conventional RT(60Gy in 2Gy/day) vs a hypofractionated regimen vs TMZ, and found no difference (even the trend was against RT). The TMZ was also different between the trials (1week on and off in the NOA trial vs d1-5 Q28 in the Malmstrom abstract). Regardless of which treatment paradigm was pursued, the outcome comparisons are poor no matter what, and better treatment stratagies should be explored.

Addendum - The abstract discussion was lively, primarily focused on the Malmstrom piece. There were some concerns that this trial had a poorer prognosis group which may not have benefited by 60Gy in 2Gy/fx.

Dr. Grossman discussed the trial - and pointed out that in the Stupp EORTC trial, there is a subgroup analysis in those >60 years of age - which seem to have a benefit in the tail of the curve with combined TMZ/RT. Therefore in a good PS patient, between 60-70yrs, combined treatment is the standard in this group. He also points out that MGMT status also matters in elderly patients (Gerstner). And lastly, the control arm of the Stupp trial (RT alone) between years of 60-70 performed much better than any of the arms of these two trials, suggesting that patient selection is driving a lot of these differences.

Links:

NOA-08 randomized phase III trial of 1-week-on/1-week-off temozolomide versus involved-field radiotherapy in elderly (older than age 65) patients with newly diagnosed anaplastic astrocytoma or glioblastoma (Methusalem).

Glioblastoma (GBM) in elderly patients: A randomized phase III trial comparing survival in patients treated with 6-week radiotherapy (RT) versus hypofractionated RT over 2 weeks versus temozolomide single-agent chemotherapy (TMZ).