QOL after Bladder Preservation

In the Red Journal:

Prospective evaluations of QOL have been lacking in the literature till recently, which is especially important in a trial of organ preservation. If the organ doesn't function properly post preservation - there is little point, and potentially can adversely affect the patient's quality of life. That is often heard as a counter argument for bladder preservation - "Sure you may preserve the bladder, but it is not going to be functional."

The GETUG has done the field a great favor by prospectively looking at this in their bladder preservation trial. Treatment was similar to the US approach - 45Gy with concurrent CDDP + 5FU, reeval with cysto, with cystectomy recommended for residual tumor, and an 18Gy boost for those without evidence of persistent/recurrent tumor. The majority reported good QOL and bladder function, and importantly with results similar to the cystectomy literature for overall survival.

Link and Abstract

Quality of Life Assessment After Concurrent Chemoradiation for Invasive Bladder Cancer: Results of a Multicenter Prospective Study (GETUG 97-015):

"Purpose: To evaluate bladder preservation and functional quality after concurrent chemoradiotherapy for muscle-invasive cancer in 53 patients included in a Phase II trial.Patient and Methods: Pelvic irradiation delivered 45Gy, followed by an 18-Gy boost. Concurrent chemotherapy with cisplatin and 5-fluorouracil by continuous infusion was performed at Weeks 1, 4, and 7 during radiotherapy. Patients initially suitable for surgery were evaluated with macroscopically complete transurethral resection after 45Gy, followed by radical cystectomy in case of incomplete response. The European Organization for Research and Treatment of Cancer quality of life questionnaire QLQ-C30, specific items on bladder function, and the Late Effects in Normal Tissues–Subjective, Objective, Management, and Analytic (LENT-SOMA) symptoms scale were used to evaluate quality of life before treatment and 6, 12, 24, and 36 months after treatment.Results: Median age was 68 years for 51 evaluable patients. Thirty-two percent of patients had T2a tumors, 46% T2b, 16% T3, and 6% T4. A visibly complete transurethral resection was possible in 66%. Median follow-up was 8 years. Bladder was preserved in 67% (95% confidence interval, 52–79%) of patients. Overall survival was 36% (95% confidence interval, 23–49%) at 8 years for all patients, and 45% (28–61%) for the 36 patients suitable for surgery. Satisfactory bladder function, according to LENT-SOMA, was reported for 100% of patients with preserved bladder and locally controlled disease 6–36 months after the beginning of treatment. Satisfactory bladder function was reported for 35% of patients before treatment and for 43%, 57%, and 29%, respectively, at 6, 18, and 36 months.Conclusions: Concurrent chemoradiation therapy allowed bladder preservation with tumor control for 67% patients at 8 years. Quality of life and quality of bladder function were satisfactory for 67% of patients."

Cardiac Atlas for RT planning

In the Red Journal:

To add to the standardization of contouring: Investigators from Michigan release an atlas for cardiac contouring. Link follows:

Development and Validation of a Heart Atlas to Study Cardiac Exposure to Radiation Following Treatment for Breast Cancer

WBRT after methotrexate for CNS lymphoma

Lancet Oncology:

A randomized trial is reported comparing MTX alone to MTX with WBRT for responders with primary CNS lymphoma. Designed as a non-inferiority trial for progression-free survival, it failed to meet it's endpoint, however, it is observed that the toxicity associated with WBRT in not insignificant. This mirrors the approach taken at Duke currently, of the selective use of WBRT after MTX, with care taken to limit exposure to those at highest risk of toxicity (particularly those >60 years of age). Of course in the non-responders, the worst toxicity is going to be progressive disease without further treatment.

Link

[Articles] High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): a phase 3, randomised, non-inferiority trial: "No significant difference in overall survival was recorded when whole brain radiotherapy was omitted from first-line chemotherapy in patients with newly diagnosed primary CNS lymphoma, but our primary hypothesis was not proven. The progression-free survival benefit afforded by whole brain radiotherapy has to be weighed against the increased risk of neurotoxicity in long-term survivors."

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.

"

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).

IORT (20Gy x 1) for early stage breast cancer

ASCO 2010:

The international TARGIT trial reports 24 month median follow up for local control, their primary endpoint. This randomized 2,231 patients to a single intraoperative treatment vs. standard WBRT. At early followup, there was no difference between the arms (0.31% for IORT and 0.29% for WBRT). There was a small and non-significant increase in wound healing issues with IORT, and the overall incidence of RTOG G3 toxicity was significantly lower in the IORT arm. While followup is clearly needed from this abstract, this data is quite provocative and the manuscript is already available showing no difference at a 4 year endpoint (published early online at the Lancet). This potentially could affect practice quite dramatically and replace APBI for the lowest risk patients...

Abstract:

Safety and efficacy of targeted intraoperative radiotherapy (TARGIT) for early breast cancer: First report of a randomized controlled trial at 10-years maximum follow-up.

NSABP B-32 confirming the safety of SNB in clinically node negative breast cancer

ASCO 2010:

This abstract is the 8 year follow up of the NSABP B-32 trial, which compared SNB (sentinel node biopsy) alone vs axillary dissection in clinically node negative patients. 5,611 patients were randomized in this trial, with the power to detect a 2% difference in DFS at 5 years. Thankfully for current practice, there was no difference between the two groups.

Primary outcome results of NSABP B-32, a randomized phase III clinical trial to compare sentinel node resection (SNR) to conventional axillary dissection (AD) in clinically node-negative breast cancer patients.

Neurocognitive effects of Partial Brain Irradiation

In the Red Journal - 9402 was a randomized trial of RT +/- PCV for AO, but one of the strengths of the trial was that prospective analysis of neurocognition was built in. What I find interesting in this report is that both arms had a stable "Brain quality of life" through the follow up period even compared to baseline (though not surprisingly this did decline in the last year of life for those who died on trial). As such little is known on the long term effects of partial brain irradiation, this observation adds significantly to our understanding of this.

Link and Abstract

Cognition and Quality of Life After Chemotherapy Plus Radiotherapy (RT) vs. RT for Pure and Mixed Anaplastic Oligodendrogliomas: Radiation Therapy Oncology Group Trial 9402: "Purpose: Radiation Therapy Oncology Group 9402 compared procarbazine, lomustine, and vincristine (PCV) chemotherapy plus radiation therapy (PCV + RT) vs. RT alone for anaplastic oligodendroglioma. Here we report longitudinal changes in cognition and quality of life, effects of patient factors and treatments on cognition, quality of life and survival, and prognostic implications of cognition and quality of life.Methods and Materials: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL). Scores were analyzed for survivors and within 5 years of death. Shared parameter models evaluated MMSE/B-QOL with survival.Results: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those who died, MMSE scores remained stable initially, whereas B-QOL slowly declined; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (p = 0.0413 for MMSE; p = 0.0016 for B-QOL) and were superior with age <50 years (p < 0.001 for MMSE; p = 0.0554 for B-QOL) and Karnofsky Performance Score (KPS) 80–100 (p < 0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV + RT (HR = 0.66, 95% CI = 0.49–0.9, p = 0.0084; HR = 0.74, 95% CI = 0.54–1.01, p = 0.0592) in models with MMSE and B-QOL. In addition, there were no differences in MMSE and B-QOL scores between arms (p = 0.4752 and p = 0.2767, respectively); higher scores predicted longer survival.Conclusion: MMSE and B-QOL scores held steady in the upper range in both arms for survivors. Younger, fitter patients had better MMSE and B-QOL and longer survival."

40Gy at 2Gy BID vs 20GY in 5Gy QD for WBRT

In the Red Journal: A randomized trial of 40Gy at 2Gy BID vs 20Gy in 5Gy fractions is reported, showing improved control with more fractionation and high total doses. How this would compare to a more standard US approach of 30Gy at 3Gy/day or 35 at 2.5Gy per day is uncertain, however it does show that these issues matter even when palliating brain metastases.

Link and Abstract:

Randomized Comparison of Whole Brain Radiotherapy, 20 Gy in Four Daily Fractions Versus 40 Gy in 20 Twice-Daily Fractions, for Brain Metastases: "Purpose: The present study compared the intracranial control rate and quality of life for two radiation fractionation schemes for cerebral metastases.Methods and Materials: A total of 113 patients with a Eastern Cooperative Oncology Group performance status <3; and stable (>2 months), absent, or concurrent presentation of extracranial disease were randomized to 40 Gy in 20 twice-daily fractions (Arm A) or 20 Gy in four daily fractions (Arm B), stratified by resection status. The European Organization for Research and Treatment of Cancer Quality of Life 30-item questionnaire was administered monthly during Year 1, bimonthly during Year 2, and then every 6 months to Year 5.Results: The patient age range was 28–83 years (mean 62). Of the 113 patients, 41 had undergone surgical resection, and 74 patients had extracranial disease (31 concurrent and 43 stable). The median survival time was 6.1 months in Arm A and 6.6 months in Arm B, and the overall 5-year survival rate was 3.5%. Intracranial progression occurred in 44% of Arm A and 64% of Arm B patients (p = .03). Salvage surgery or radiotherapy was used in 4% of Arm A patients and 21% of Arm B patients (p = .004). Death was attributed to central nervous system progression in 32% of patients in Arm A and 52% of patients in Arm B (p = .03). The toxicity was minimal, with a minor increase in short-term cutaneous reactions in Arm A. The patients’ quality of life was not impaired by the more intense treatment in Arm A.Conclusion: Intracranial disease control was improved and the quality of life was maintained with 40 Gy in 20 twice-daily fractions. This schema should be considered for better prognosis subgroups of patients with cerebral metastases."

Chemo + Hyperthermia for STS

In the Lancet Oncology - a phase III trial of chemo plus or minus hyperthermia is published resulting in a survival benefit.

Link:

[Articles] Neo-adjuvant chemotherapy alone or with regional hyperthermia for localised high-risk soft-tissue sarcoma: a randomised phase 3 multicentre study: "The optimum treatment for high-risk soft-tissue sarcoma (STS) in adults is unclear. Regional hyperthermia concentrates the action of chemotherapy within the heated tumour region. Phase 2 studies have shown that chemotherapy with regional hyperthermia improves local control compared with chemotherapy alone. We designed a parallel-group randomised controlled trial to assess the safety and efficacy of regional hyperthermia with chemotherapy."

Six fractions of RT per week for H&N

In Lancet Oncology this week a Phase III international trial comparing 5 vs 6 fractions of RT per week of H&N cancers demonstrates an improvement in local control (HR 0.63), comparable to the improvements seen with other altered fractionation, and significantly simpler than concominant boost or BID treatments.

Link below -

[Articles] Five versus six fractions of radiotherapy per week for squamous-cell carcinoma of the head and neck (IAEA-ACC study): a randomised, multicentre trial: "Several large randomised studies from western Europe and the USA have shown that accelerated fractionation of radiotherapy might be beneficial in the treatment of squamous-cell carcinoma of the head and neck (HNSCC). The aim of this study—the International Atomic Energy Agency (IAEA) ACC trial—was to determine whether accelerated fractionation could be applied in developing countries, where there are fewer therapeutic resources and where tumour burdens can be heavier."

Hypofractionated Radiotherapy for Breast Cancer: is Grade 3 an exclusion criteria

A very interesting letter to the editor in the NEJM about the Whelan Hypofractionation trial for breast cancer. In the manuscript, a subset analysis was performed suggesting that high grade cancers did worse with hypofractionation. In a letter, the investigators of the START A and B trial reanalyzed their data looking for a similar finding and found no difference, in fact the trend was for G3 cancers to do better with hypofx in their data set.

I have been shying away from hypofx in G3 patients until now, but this data will make me much more comfortable offering it to our patients.

Link:

Hypofractionated Radiotherapy for Breast Cancer:

JCO: Meta-Analysis of Concurrent Versus Sequential CTRT in NSCLC

In the JCO this week -

A meta-analysis from Auperin is published confirming a survival benefit from concurrent CTRT vs sequential chemo then RT, at the expense of acute esophageal symptoms. No surprise here, and concurrent CTRT has been the standard in our department for quite a while, however, it is good to have more data to support a new standard of care.

Link and Abstract

Meta-Analysis of Concomitant Versus Sequential Radiochemotherapy in Locally Advanced Non-Small-Cell Lung Cancer [Thoracic Oncology]: "Purpose

The previous individual patient data meta-analyses of chemotherapy in locally advanced non–small-cell lung cancer (NSCLC) showed that adding sequential or concomitant chemotherapy to radiotherapy improved survival. The NSCLC Collaborative Group performed a meta-analysis of randomized trials directly comparing concomitant versus sequential radiochemotherapy.

Methods

Systematic searches for trials were undertaken, followed by central collection, checking, and reanalysis of updated individual patient data. Results from trials were combined using the stratified log-rank test to calculate pooled hazard ratios (HRs). The primary outcome was overall survival; secondary outcomes were progression-free survival, cumulative incidences of locoregional and distant progression, and acute toxicity.

Results

Of seven eligible trials, data from six trials were received (1,205 patients, 92% of all randomly assigned patients). Median follow-up was 6 years. There was a significant benefit of concomitant radiochemotherapy on overall survival (HR, 0.84; 95% CI, 0.74 to 0.95; P = .004), with an absolute benefit of 5.7% (from 18.1% to 23.8%) at 3 years and 4.5% at 5 years. For progression-free survival, the HR was 0.90 (95% CI, 0.79 to 1.01; P = .07). Concomitant treatment decreased locoregional progression (HR, 0.77; 95% CI, 0.62 to 0.95; P = .01); its effect was not different from that of sequential treatment on distant progression (HR, 1.04; 95% CI, 0.86 to 1.25; P = .69). Concomitant radiochemotherapy increased acute esophageal toxicity (grade 3-4) from 4% to 18% with a relative risk of 4.9 (95% CI, 3.1 to 7.8; P < .001). There was no significant difference regarding acute pulmonary toxicity.

Conclusion

Concomitant radiochemotherapy, as compared with sequential radiochemotherapy, improved survival of patients with locally advanced NSCLC, primarily because of a better locoregional control, but at the cost of manageable increased acute esophageal toxicity.

"

JCO: Prognosis with Radiation Associated Sarcomas

From the JCO:

An interesting series of radiation associated soft tissue sarcomas from MSKCC, which attempts to determine if there are differences in the prognosis with a matched cohort of sporadic STS. The DSS was indeed different with an HR of 1.7(p=0.007) on MVA, however, it is significant to note that the radiation associated tumors were not given RT as often (~50% less). How this difference in treatment may have affected outcomes is uncertain, however this could certainly contribute to the difference outcomes. Regardless, it is a worthwhile subject of study, and the mansucript is worth review for the practicing radiation oncologist.

Link and Abstract:

Do Radiation-Associated Soft Tissue Sarcomas Have the Same Prognosis As Sporadic Soft Tissue Sarcomas? [Sarcomas]: "Purpose

To determine the prognostic significance of histologic type in radiation-associated soft tissue sarcomas (RASs) and determine whether RASs are associated with an inferior prognosis compared with sporadic soft tissue sarcomas (STSs).

Patients and Methods

One hundred thirty primary RASs were identified from 7,649 STS patients from 1982 to 2007. Multivariate analysis of clinicopathologic factors for disease-specific survival (DSS) was performed for RASs, and a multivariate analysis of radiation exposure was also performed for RASs and sporadic sarcomas. A matched-cohort analysis was performed for radiation-associated and sporadic malignant fibrous histiocytoma (MFH).

Results

Most RASs were high grade (83%), deep (87%), and truncal (61.5%). The median interval between radiation therapy and RAS development was 10 years (range, 1.3 to 74 years), which varied significantly by histologic type (P = .003). The 5-year DSS was 58%, and independent predictors were size > 5 cm, margin positivity, and histologic type. Multivariate analysis of histologic types of primary, high-grade radiation-associated and sporadic STSs showed that RAS was associated with a worse DSS (hazard ratio, 1.7; range, 1.1 to 2.4; P = .007). For pleomorphic MFH—the most common RAS type—the 5-year DSS was 44% versus 66% in a matched cohort of sporadic MFH patients (P = .07). DSS was significantly worse in primary RAS malignant peripheral nerve sheath tumors (MPNSTs) compared with unmatched sporadic MPNSTs (P = .001).

Conclusion

Histologic type, margin status, and tumor size are the most important independent predictors of DSS in patients with RASs. DSS in patients with primary RAS is significantly worse compared with sporadic STS independent of sarcoma histologic type."

Predictive Nomogram for Brain Metastases in Metastatic Breast Cancer

In the JCO:

Investigators from MDACC have developed a nomogram which calculates the risk of brain metastases in patients with metastatic breast cancer, validated in the current manuscript with a cohort from Canada. Risk factors are what one might expect (high grade, low age, multiple sites of metastasis, HER2 positivity). Of course this then begs the question of what to do with the information, and opens the door to discussion of a PCI trial in high risk metastatic breast cancer...

Abstract and Link

Nomogram to Predict Subsequent Brain Metastasis in Patients With Metastatic Breast Cancer [Breast Cancer]: "Purpose

Brain metastasis is usually a fatal event in patients with stage IV breast cancer. We hypothesized that its occurrence can be predicted if a clinical nomogram can be developed, thus allowing for selection of enriched patient populations for prevention trials.

Patients and Methods

Electronic medical records of patients with metastatic breast cancer were retrospectively reviewed for the period between January 2000 and February 2007 under a study approved by the institutional review board. A multivariate logistic regression analysis of selected prognostic features was done. A nomogram to predict brain metastasis was constructed and validated in a cohort of 128 patients with brain metastasis treated at the Cross Cancer Institute (Edmonton, Alberta, Canada).

Results

Of 2,136 patients with breast cancer, 362 developed subsequent brain metastasis. Age, grade, negative status of estrogen receptor and human epidermal growth factor receptor 2, number of metastatic sites (one v > one), and short disease-free survival were significantly and independently associated with subsequent brain metastasis. The nomogram showed an area under the receiver operating characteristic curve (AUC) of 0.68 (95% CI, 0.66 to 0.69) in the training set. The validation set showed a good discrimination with an AUC of 0.74 (95% CI, 0.70 to 0.79). The nomogram was well calibrated, with no significant difference between the predicted and the observed probabilities.

Conclusion

We have developed a robust tool that is able to predict subsequent brain metastasis in patients with breast cancer with nonbrain metastatic disease. Selection of an enriched patient population at high risk for brain metastasis will facilitate the design of trials aiming at its prevention.

"

CHART results in H&N cancer

An interesting article in the Red Journal about CHART in H&N cancer. Essentially this randomized trial saw no difference in disease outcomes with CHART compared to conventional fractionation, but a reduction in toxicity, as one would expect with reduced dose per fraction. Of course this CHART is a logistical challenge to many rad onc departments, and this doesn't address the larger issue of chemotherapy (see other post about RTOG 0129). I would also venture that the doses are a little low compared to the standard 70-80Gy often uses without chemo for advanced disease.

Link and Abstract:

Mature Results of a Randomized Trial of Accelerated Hyperfractionated Versus Conventional Radiotherapy in Head-and-Neck Cancer: "Purpose: To evaluate long-term late adverse events and treatment outcome of a randomized, multicenter Phase III trial of continuous, hyperfractionated, accelerated radiotherapy (CHART) compared with conventional radiotherapy (CRT) in 918 patients with advanced squamous cell carcinomas of the head and neck.Methods and Materials: Survival estimates were obtained for locoregional relapse-free survival, local relapse-free survival, overall survival, disease-specific survival, disease-free survival and for late adverse events.Results: The 10-year estimates (±1 standard error) for locoregional relapse-free survival, overall survival, disease-free survival, and disease-specific survival were 43% ± 2% for CHART and 50% ± 3% with CRT (log-rank p = 0.2); 26% ± 2% and 29% ± 3% (p = 0.4), respectively; 41% ± 2% and 46% ± 3% (p = 0.3), respectively; and 56% ± 3% and 58% ± 3% (p = 0.5), respectively. There was a small but significant reduction in the incidence of slight or worse and moderate or worse epidermal adverse events with CHART (p = 0.002 to 0.05). Severe xerostomia, laryngeal edema, and mucosal necrosis were also significantly lower with CHART (p = 0.02 to 0.05).Conclusions: Despite the reduction in total dose from 66 Gy to 54 Gy, control of locoregional disease and survival with CHART were similar to those with CRT. These findings, together with the low incidence of long-term severe adverse events, suggest that CHART is a treatment option for patients with low-risk disease and for those unable to withstand the toxicity of concurrent chemoradiotherapy."

RTOG 0129 - Accelerated concomitant boost confers no benefit if chemo is used in H&N cancers

Another abstract sees the light of day in the Red Journal:

~700 patients with stage III and IV H&N cancer were randomized to either altered fracitonation (concomitant boost) vs standard fractionation with concurrent CDDP. No differences were seen in any of the endpoints (toxicity, OS, DFS, LRC, or DM). This confirms findings from the GORTEC trial that CDDP may supersede the effect of altered fractionation in the treatment of H&N cancers. Again - the manuscript will be eagerly awaited...

Link

A Phase III Trial to Test Accelerated Versus Standard Fractionation in Combination with Concurrent Cisplatin for Head and Neck Carcinomas (RTOG 0129): Report of Efficacy and Toxicity: "A phase III trial was completed to test the efficacy-toxicity of combining cisplatin with an accelerated concomitant boost (AFX-C) versus standard fractionation (SFX) in locally advanced head and neck carcinoma (LA-HNC)."

Short Term ADT improves survival in intermediate risk prostate cancer: RTOG 94-08

The abstract for the initial results of RTOG 9408 are published in the Red Journal - ~2000 patients with T1b-2b prostate cancer were randomized to 66.6Gy +/- 4 months of ADT starting 2 months prior to RT start. 61% had GS 6 or less, about half were T1, half T2. Result demonstrated a statistically significant improvement in OS at 12years (51% vs 46%, p=0.03).

Of course one critique is that the overall RT dose is too low by todays standards, but this supports the D'Amico trial's findings and confirms potential benefit of brief ADT in intermediate and even some low risk patients. The manuscript will be eagerly awaited...

Link:

Short-term Endocrine Therapy Prior to and during Radiation Therapy Improves Overall Survival in Patients with T1b-T2b Adenocarcinoma of the Prostate and PSA ≤ 20: Initial Results of RTOG 94-08: "To test if short-term endocrine therapy prior to and during radiation therapy will improve overall survival in patients with good prognosis, locally confined, adenocarcinoma of the prostate."

NSCLC chemo meta-analysis

In the Lancet this week:

Two meta-analyses looking at the absolute benefit of chemo after surgery both with and without adjuvant radiotherapy. They found similar results in both settings with HR hovering aound 0.88 for overall survival, corresponding to a 4% absolute benefit in both groups at 5 years.

Link:

[Articles] Adjuvant chemotherapy, with or without postoperative radiotherapy, in operable non-small-cell lung cancer: two meta-analyses of individual patient data: "Many randomised controlled trials have investigated the effect of adjuvant chemotherapy in operable non-small-cell lung cancer. We undertook two comprehensive systematic reviews and meta-analyses to establish the effects of adding adjuvant chemotherapy to surgery, or to surgery plus radiotherapy."

Adding Oxaliplatin in Neoadjuvant CTRT for Rectal Cancer

From the JCO this week:

The ACCORD trial is a randomized phase III trial looking at two CTRT regimens for T3-T4 rectal tumors: 45Gy/25fx + Capecitabine vs 50Gy/25fx + Capecitabine and Oxaliplatin. It is a bit perplexing as to why the investigators decided to add a slightly different RT regimen to the randomization, as it makes the more important question (that of the addition of oxaliplatin) more difficult to evaluate. Nonetheless, their primary endpoint was pCR, and they powered the study to detect an increase from 11% in the control arm to 20% in with oxalipatin (and 5 more Gy).

Results demonstrate a non-significant difference in pCR of 13.9% in the control arm, and a 19.2% with oxaliplatin and 5 additional Gy (p=0.09). G3-4 toxicities were increased at 10.9% 45Gy + capecitabine vs 25.4% 50Gy + capox. The investigators state in their conclusions that oxaliplatin should not be used, and 50Gy with capcitabine should be explored. I would not necessarily be so quick to dismiss oxaliplatin, as the absolute difference in pCR was 5.3%, a result which might not be stasticaly significant, but may be clinical relevant, given the other interventions we pursue for a 5% benefit.

I think at the end of the day, we are left in the same position as before, with oxaliplatin being unproven but potentially worthwhile, and waiting for the NSABP-R04 trial to accrue and report (goal of 1,606 patient accrual, 2x2 randomization of capecitabine vs 5-FU and oxaliplatin vs no-oxaliplatin).

Link and abstract -

Comparison of Two Neoadjuvant Chemoradiotherapy Regimens for Locally Advanced Rectal Cancer: Results of the Phase III Trial ACCORD 12/0405-Prodige 2 [Gastrointestinal Cancer]: "Purpose

Neoadjuvant chemoradiotherapy is considered a standard approach for T3-4 M0 rectal cancer. In this situation, we compared neoadjuvant radiotherapy plus capecitabine with dose-intensified radiotherapy plus capecitabine and oxaliplatin.

Patients and Methods

We randomly assigned patients to receive 5 weeks of treatment with radiotherapy 45 Gy/25 fractions with concurrent capecitabine 800 mg/m² twice daily 5 days per week (Cap 45) or radiotherapy 50 Gy/25 fractions with capecitabine 800 mg/m² twice daily 5 days per week and oxaliplatin 50 mg/m² once weekly (Capox 50). The primary end point was complete sterilization of the operative specimen (ypCR).

Results

Five hundred ninety-eight patients were randomly assigned to receive Cap 45 (n = 299) or Capox 50 (n = 299). More preoperative grade 3 to 4 toxicity occurred in the Capox 50 group (25 v 1%; P < .001). Surgery was performed in 98% of patients in both groups. There were no differences between groups in the rate of conservative surgery (75%) or postoperative deaths at 60 days (0.3%). The ypCR rate was 13.9% with Cap 45 and 19.2% with Capox 50 (P = .09). When ypCR was combined with yp few residual cells, the rate was respectively 28.9% with Cap 45 and 39.4% with Capox 50 (P = .008). The rate of positive circumferential rectal margins (between 0 and 2 mm) was 19.3% with Cap 45 and 9.9% with Capox 50 (P = .02).

Conclusion

The benefit of oxaliplatin was not demonstrated and this drug should not be used with concurrent irradiation. Cap 50 merits investigation for T3-4 rectal cancers."

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer [Preliminary Communication]

In JAMA:

Preliminary results of RTOG-0236 with 3 year clinical endpoints are published in JAMA this week. This confirms that Timmerman's 3 fraction approach, piloted at Indiana University is applicable in a multi-center phase II trial. Local control was 91%, with an OS of 56%, which is pretty excellent considering that these are all inoperable patients from the start. Very low incidence in G3 or 4 toxicity, and no deaths - perhaps by excluding the central tumors which had resulted in most of the life threatening toxicity in the Indiana data.

Link and Abstract:

Stereotactic Body Radiation Therapy for Inoperable Early Stage Lung Cancer [Preliminary Communication]: "

Context Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management.

Objective To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer.

Design, Setting, and Patients Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non–small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 11/2 and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009.

Main Outcome Measures The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival.

Results A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported.

Conclusion Patients with inoperable non–small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.

"

SLNB for Oral Cavity Cancers

JCO: Sentinel lymph node biopsy has become a standard procedure in breast cancer and melanoma, and emerging data suggests it may be useful in other tumor sites as well (vulvar for one). The JCO this week reports on a multiinstitutional trial in early stage oral cavity tumors suggests that it may be very useful in that primary site as well.

Link and Abstract.

Sentinel Lymph Node Biopsy Accurately Stages the Regional Lymph Nodes for T1-T2 Oral Squamous Cell Carcinomas: Results of a Prospective Multi-Institutional Trial [Head and Neck Cancer]: "Purpose

The validity of sentinel lymph node biopsy (SLNB) for T1 or T2, clinically N0, oral cancer was tested by correlation of sentinel node pathologic status with that of nodes within the completion neck dissection.

Methods

This prospective, cooperative group trial involved 25 institutions over a 3-year period. One hundred forty patients with invasive oral cancers, stage T1 and T2, N0 including 95 cancers of the tongue, 26 of the floor of mouth, and 19 other oral cancers were studied. The study excluded lesions with diameter smaller than 6 mm or minimal invasion. Imaging was used to exclude nonpalpable gross nodal disease. Patients underwent injection of the lesion with ^99mTc-sulfur colloid, nuclear imaging, narrow-exposure SLNB, and completion selective neck dissection. The major end point was the negative-predictive value (NPV) of SLNB.

Results

In the 106 SLNBs, which were found to be pathologically and clinically node-negative by routine hematoxylin and eosin stain, 100 patients were found to have no other pathologically positive nodes, corresponding to a NPV of 94%. With additional sectioning and immunohistochemistry, NPV was improved to 96%. In the forty patients with proven cervical metastases, the true-positive rate was 90.2% and was superior for tongue tumors relative to floor of mouth. For T1 lesions, metastases were correctly identified in 100%.

Conclusion

For T1 or T2 N0 oral squamous cell carcinoma, SLNB with step sectioning and immunohistochemistry, performed by surgeons of mixed experience levels, correctly predicted a pathologically negative neck in 96% of patients (NPV, 96%).

"

Individualized Dose Escalation for NSCLC

JCO has an interesting article looking at individualized dose escalation depending on normal tissue constraints. This was an aggressive sequential CTRT study, which dose escalated to normal tissue tolerance depending on individual anatomy, and the toxicity/survival numbers are not bad in comparison to the standard 60-66Gy with concurrent drug.

Link and Abstract:

Mature Results of an Individualized Radiation Dose Prescription Study Based on Normal Tissue Constraints in Stages I to III Non-Small-Cell Lung Cancer [Thoracic Oncology]: "Purpose

We previously showed that individualized radiation dose escalation based on normal tissue constraints would allow safe administration of high radiation doses with low complication rate. Here, we report the mature results of a prospective, single-arm study that used this individualized tolerable dose approach.

Patients and Methods

In total, 166 patients with stage III or medically inoperable stage I to II non–small-cell lung cancer, WHO performance status 0 to 2, a forced expiratory volume at 1 second and diffusing capacity of lungs for carbon monoxide ≥ 30% were included. Patients were irradiated using an individualized prescribed total tumor dose (TTD) based on normal tissue dose constraints (mean lung dose, 19 Gy; maximal spinal cord dose, 54 Gy) up to a maximal TTD of 79.2 Gy in 1.8 Gy fractions twice daily. Only sequential chemoradiation was administered. The primary end point was overall survival (OS), and the secondary end point was toxicity according to Common Terminology Criteria of Adverse Events (CTCAE) v3.0.

Results

The median prescribed TTD was 64.8 Gy (standard deviation, ± 11.4 Gy) delivered in 25 ± 5.8 days. With a median follow-up of 31.6 months, the median OS was 21.0 months with a 1-year OS of 68.7% and a 2-year OS of 45.0%. Multivariable analysis showed that only a large gross tumor volume significantly decreased OS (P < .001). Both acute (grade 3, 21.1%; grade 4, 2.4%) and late toxicity (grade 3, 4.2%; grade 4, 1.8%) were acceptable.

Conclusion

Individualized prescribed radical radiotherapy based on normal tissue constraints with sequential chemoradiation shows survival rates that come close to results of concurrent chemoradiation schedules, with acceptable acute and late toxicity. A prospective randomized study is warranted to further investigate its efficacy.

"

PORTEC 2: VB vs WPRT for Early Endometrial Cancer

From the Lancet:

The PORTEC 2 efficacy results are published. These were previously reported at ASCO 2008, and to review, this was a randomized trial of 427 patients >= 60 years of age with IC grade 1 or 2, IB grade 3, or any age and IIA disease (excluding grade 3 with >50% myometrial invasion). After surgery they were randomized between vaginal brachytherapy (7Gy q week x 3, or 30Gy LDR) and WPRT (46Gy, 2Gy/day). Note the inclusion criteria; this excludes the IC grade 3 risk group which at the time of the trial design were at too high of a risk not to treat with WPRT. This is especially relevant as these patients had no nodal dissection.

5-year vaginal recurrence was 1.8% (95% CI 0.6—5.9) for VBT and 1.6% (0.5—4.9) for EBRT (hazard ratio [HR] 0.78, 95% CI 0.17—3.49; p=0·74). 5-year LR was 5.1% (2.8—9.6) for VBT and 2.1% (0.8—5.8) for WPRT (HR 2.08, 0.71—6.09; p=0.17); 1.5% (0.5—4.5) versus 0.5% (0.1—3.4) for isolated pelvic recurrence (HR 3·.0, 0.32—29.9; p=0.30). 5 year rate of distant metastasis was no different (8.3% [5.1—13.4] vs 5.7% [3.3—9.9]; HR 1.32, 0.63—2.74; p=0.46). 5yr OS was 84.8% (95% CI 79.3—90.3] vs 79.6% [71.2—88.0]; HR 1·17, 0·69—1·98; p=0·57, and DFS was 82.7% (76.9—88.6) vs 78.1% (69.7—86.5); HR 1.09, 0.66—1.78; p=0.74.

This, in light of the previous toxicity data presented in the JCO, they make a strong case of VBT alone in most stage I endometrial cancer.

Link:

[Articles] Vaginal brachytherapy versus pelvic external beam radiotherapy for patients with endometrial cancer of high-intermediate risk (PORTEC-2): an open-label, non-inferiority, randomised trial: "After surgery for intermediate-risk endometrial carcinoma, the vagina is the most frequent site of recurrence. This study established whether vaginal brachytherapy (VBT) is as effective as pelvic external beam radiotherapy (EBRT) in prevention of vaginal recurrence, with fewer adverse effects and improved quality of life."