Adjuvant Chemotherapy for NSCLC, updates on two influential trials

JCO this week: Two of the more influencial trials on adjuvant chemotherapy for resected NSCLC are updated, the JBR-10 and the IALT studies. The JBR-10 study continues to show a survival benefit out to almost 10 years, though the stage IBs seemed not to benefit. The IALT study continued to demonstrate a DFS benefit, but the OS figures had slipped to non-significance.

Links and abstracts:

Randomized Phase III Trial of Vinorelbine Plus Cisplatin Compared With Observation in Completely Resected Stage IB and II Non-Small-Cell Lung Cancer: Updated Survival Analysis of JBR-10 [Thoracic Oncology]: "Purpose

Adjuvant cisplatin-based chemotherapy (ACT) is now an accepted standard for completely resected stage II and III A non–small-cell lung cancer (NSCLC). Long-term follow-up is important to document persistent benefit and late toxicity. We report here updated overall survival (OS) and disease-specific survival (DSS) data.

Patients and Methods

Patients with completely resected stage IB (T2N0, n = 219) or II (T1-2N1, n = 263) NSCLC were randomly assigned to receive 4 cycles of vinorelbine/cisplatin or observation. All efficacy analyses were performed on an intention-to-treat basis.

Results

Median follow-up was 9.3 years (range, 5.8 to 13.8; 33 lost to follow-up); there were 271 deaths in 482 randomly assigned patients. ACT continues to show a benefit (hazard ratio [HR], 0.78; 95% CI, 0.61 to 0.99; P = .04). There was a trend for interaction with disease stage (P = .09; HR for stage II, 0.68; 95% CI, 0.5 to 0.92; P = .01; stage IB, HR, 1.03; 95% CI, 0.7 to 1.52; P = .87). ACT resulted in significantly prolonged DSS (HR, 0.73; 95% CI, 0.55 to 0.97; P = .03). Observation was associated with significantly higher risk of death from lung cancer (P = .02), with no difference in rates of death from other causes or second primary malignancies between the arms.

Conclusion

Prolonged follow-up of patients from the JBR.10 trial continues to show a benefit in survival for adjuvant chemotherapy. This benefit appears to be confined to N1 patients. There was no increase in death from other causes in the chemotherapy arm."

Long-Term Results of the International Adjuvant Lung Cancer Trial Evaluating Adjuvant Cisplatin-Based Chemotherapy in Resected Lung Cancer [Thoracic Oncology]

Purpose

Based on 5-year or shorter-term follow-up data in recent randomized trials, adjuvant cisplatin-based chemotherapy is now generally recommended after complete surgical resection for patients with non–small-cell lung cancer (NSCLC). We evaluated the results of the International Adjuvant Lung Cancer Trial study with three additional years of follow-up.

Patients and Methods

Patients with completely resected NSCLC were randomly assigned to three or four cycles of cisplatin-based chemotherapy or to observation. Cox models were used to evaluate treatment effect according to follow-up duration.

Results

The trial included 1,867 patients with a median follow-up of 7.5 years. Results showed a beneficial effect of adjuvant chemotherapy on overall survival (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.02; P = .10) and on disease-free survival (HR, 0.88; 95% CI, 0.78 to 0.98; P = .02). However, there was a significant difference between the results of overall survival before and after 5 years of follow-up (HR, 0.86; 95% CI, 0.76 to 0.97; P = .01 v HR, 1.45; 95% CI, 1.02 to 2.07; P = .04) with P = .006 for interaction. Similar results were observed for disease-free survival. The analysis of non-lung cancer deaths for the whole period showed an HR of 1.34 (95% CI, 0.99 to 1.81; P = .06).

Conclusion

These results confirm the significant efficacy of adjuvant chemotherapy at 5 years. The difference in results beyond 5 years of follow-up underscores the need for the long-term follow-up of other adjuvant lung cancer trials and for a better identification of patients deriving long-term benefit from adjuvant chemotherapy.

Results in stage I, II LPHD

A retrospective study from Dana-Farber reports on outcomes from LPHD (lymphocyte predominant Hodgkin's disease). They report excellent 10yr results with limited field RT. Chemotherapy alone resulted in poor PFS, however most were salvaged. Larger fields did not appear to improve results.

Link and Abstract:

Early-Stage, Lymphocyte-Predominant Hodgkin's Lymphoma: Patient Outcomes From a Large, Single-Institution Series With Long Follow-Up [Hematologic Malignancies]: "Purpose

The optimal treatment for early-stage, lymphocyte-predominant Hodgkin's lymphoma (LPHL) is not well defined. Treatment has become less aggressive over time in an attempt to reduce iatrogenic complications, such as cardiac mortality and second cancers, but long-term efficacy is unclear. We present the long-term outcome of patients treated at a single institution.

Patients and Methods

The study population includes 113 patients with stage I or II LPHL treated between 1970 and 2005. Pathologic diagnosis for all patients was confirmed using standard criteria. Ninety-three patients received radiation therapy (RT) alone, 13 received RT with chemotherapy, and seven received chemotherapy alone. Among patients treated with RT, 25 received limited-field, 35 received regional-field, and 46 received extended-field RT.

Results

Median follow-up was 136 months. Ten-year progression-free survival (PFS) rates were 85% (stage I) and 61% (stage II); overall survival (OS) rates were 94% and 97% for stages I and II, respectively. PFS and OS did not differ among patients who received limited-field, regional-field, or extended-field RT. In contrast, six of seven patients who received chemotherapy alone without RT developed early disease progression and required salvage treatment. Multivariable analysis adjusting for extent of RT, clinical stage, sex, and use of chemotherapy confirmed that the extent of RT was not significantly associated with PFS (P = .67) or OS (P = .99). The addition of chemotherapy to RT did not improve PFS or OS compared with RT alone.

Conclusion

RT alone leads to sustained disease control and high long-term survival rates in patients with early-stage LPHL. This study supports the use of limited-field RT alone to treat this disease."

Active surveillance for Low risk Prostate Cancer

JCO this week:

A single arm study from Canada suggests that active surveillance is a reasonable option in low risk ACP. Though 50% of those that did undergo radical treatment ended up having PSA failure, it was only 13% of the overall cohort. That said the follow up remains a little short at just under seven years; I would like to see 10-15 year data reported due to the fact that often prostate cancer death occurs much later than detection or biochemical failure.

Link and Abstract

Clinical Results of Long-Term Follow-Up of a Large, Active Surveillance Cohort With Localized Prostate Cancer [Genitourinary Cancer]: "Purpose

We assessed the outcome of a watchful-waiting protocol with selective delayed intervention by using clinical prostate-specific antigen (PSA), or histologic progression as treatment indications for clinically localized prostate cancer.

Patients and Methods

This was a prospective, single-arm, cohort study. Patients were managed with an initial expectant approach. Definitive intervention was offered to those patients with a PSA doubling time of less than 3 years, Gleason score progression (to 4 + 3 or greater), or unequivocal clinical progression. Survival analysis and Cox proportional hazard model were applied to the data.

Results

A total of 450 patients have been observed with active surveillance. Median follow-up was 6.8 years (range, 1 to 13 years). Overall survival was 78.6%. The 10-year prostate cancer actuarial survival was 97.2%. Overall, 30% of patients have been reclassified as higher risk and have been offered definitive therapy. Of 117 patients treated radically, the PSA failure rate was 50%, which was 13% of the total cohort. PSA doubling time of 3 years or less was associated with an 8.5-times higher risk of biochemical failure after definitive treatment compared with a doubling time of more than 3 years (P < .0001). The hazard ratio for nonprostate cancer to prostate cancer mortality was 18.6 at 10 years.

Conclusion

We observed a low rate of prostate cancer mortality. Among the patients who were reclassified as higher risk and who were treated, PSA failure was relatively common. Other-cause mortality accounted for almost all of the deaths. Additional studies are warranted to improve the identification of patients who harbor more aggressive disease despite favorable clinical parameters at diagnosis."

Induction Cetuximab, Paclitaxel and Carboplatin in H&N cancers

JCO this week: MD Anderson reports the results of a Phase II combining cetuximab, paclitaxel and carboplatin before definitive surgery, radiation or chemoradiation. Interesting results, but obviously the overall question of whether induction is the best approach remains up in the air. Abstract and link:

Induction Chemotherapy and Cetuximab for Locally Advanced Squamous Cell Carcinoma of the Head and Neck: Results From a Phase II Prospective Trial [Head and Neck Cancer]: "Purpose

To determine the potential efficacy of combining cetuximab with chemotherapy in patients with advanced nodal disease, we conducted a phase II trial with induction chemotherapy (ICT) consisting of six weekly cycles of paclitaxel 135 mg/m² and carboplatin (area under the curve = 2) with cetuximab 400 mg/m² in week 1 and then 250 mg/m² (PCC).

Patients and Methods

Forty-seven previously untreated patients (41 with oropharynx primaries; 33 men, 14 women; median age, 53 years; performance status of 0 or 1) with squamous cell carcinoma of the head and neck (SCCHN; T1-4, N2b/c/3) were treated and evaluated for clinical and radiographic response. After ICT, patients underwent risk-based local therapy, which consisted of either radiation, concomitant chemoradiotherapy, or surgery, based on tumor stage and site at diagnosis.

Results

After induction PCC, nine patients (19%) achieved a complete response, and 36 patients (77%) achieved a partial response. The most common grade 3 or 4 toxicity was skin rash (45%), followed by neutropenia (21%) without fever. At a median follow-up time of 33 months, locoregional or systemic disease progression was observed in six patients. The 3-year progression-free survival (PFS) and overall survival (OS) rates were 87% (95% CI, 78% to 97%) and 91% (95% CI, 84% to 99%), respectively. Human papillomavirus (HPV) 16, found in 12 (46%) of 26 biopsies, was associated with improved PFS (P = .012) and OS (P = .046).

Conclusion

ICT with weekly PCC followed by risk-based local therapy seems to be feasible, effective, and well tolerated. PFS is promising, and this sequential treatment strategy should be further investigated. Patients with HPV-positive tumors have an excellent prognosis."

soy and breast cancer survival.

For those that Had Tofurky for Thanksgiving Dinner like me:

from JAMA - abstract and link

Soy Food Intake and Breast Cancer Survival [Original Contribution]: "

Context Soy foods are rich in isoflavones, a major group of phytoestrogens that have been hypothesized to reduce the risk of breast cancer. However, the estrogen-like effect of isoflavones and the potential interaction between isoflavones and tamoxifen have led to concern about soy food consumption among breast cancer patients.

Objective To evaluate the association of soy food intake after diagnosis of breast cancer with total mortality and cancer recurrence.

Design, Setting, and Participants The Shanghai Breast Cancer Survival Study, a large, population-based cohort study of 5042 female breast cancer survivors in China. Women aged 20 to 75 years with diagnoses between March 2002 and April 2006 were recruited and followed up through June 2009. Information on cancer diagnosis and treatment, lifestyle exposures after cancer diagnosis, and disease progression was collected at approximately 6 months after cancer diagnosis and was reassessed at 3 follow-up interviews conducted at 18, 36, and 60 months after diagnosis. Annual record linkage with the Shanghai Vital Statistics Registry database was carried out to obtain survival information for participants who were lost to follow-up. Medical charts were reviewed to verify disease and treatment information.

Main Outcome Measures Total mortality and breast cancer recurrence or breast cancer–related deaths. Cox regression analysis was carried out with adjustment for known clinical predictors and other lifestyle factors. Soy food intake was treated as a time-dependent variable.

Results During the median follow-up of 3.9 years (range, 0.5-6.2 years), 444 deaths and 534 recurrences or breast cancer–related deaths were documented in 5033 surgically treated breast cancer patients. Soy food intake, as measured by either soy protein or soy isoflavone intake, was inversely associated with mortality and recurrence. The hazard ratio associated with the highest quartile of soy protein intake was 0.71 (95% confidence interval [CI], 0.54-0.92) for total mortality and 0.68 (95% CI, 0.54-0.87) for recurrence compared with the lowest quartile of intake. The multivariate-adjusted 4-year mortality rates were 10.3% and 7.4%, and the 4-year recurrence rates were 11.2% and 8.0%, respectively, for women in the lowest and highest quartiles of soy protein intake. The inverse association was evident among women with either estrogen receptor–positive or –negative breast cancer and was present in both users and nonusers of tamoxifen.

Conclusion Among women with breast cancer, soy food consumption was significantly associated with decreased risk of death and recurrence.

"

RT first or Chemo first in Anaplastic Glioma

In the JCO this week:

Randomized data in different sequences of RT and Chemo in anaplastic Chemo. The bottom line from my take is that there is no significant difference in outcome, but toxicity is worse with chemo first. It is puzzling then that the conclusions of the paper state "These data may allow recommending chemotherapy as first-line treatment of patients with anaplastic gliomas, including patients with AA." That seems a bit at odds with the data presented - i.e. when you have two arms with equivalent therapeutic outcome, toxicity should drive the treatment decision, clearly favoring RT. It was also designed as a superiority trial for chemotherapy first, not a non-inferiority trial, so really it surely doesn't prove that chemo is as effective as RT either.

Link and astract:

NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma With Procarbazine, Lomustine, and Vincristine or Temozolomide [Neurooncology]: "Purpose

The standard of care for anaplastic gliomas is surgery followed by radiotherapy. The NOA-04 phase III trial compared efficacy and safety of radiotherapy followed by chemotherapy at progression with the reverse sequence in patients with newly diagnosed anaplastic gliomas.

Patients and Methods

Patients (N = 318) were randomly assigned 2:1:1 (A:B1:B2) to receive conventional radiotherapy (arm A); procarbazine, lomustine (CCNU), and vincristine (PCV; arm B1); or temozolomide (arm B2) at diagnosis. At occurrence of unacceptable toxicity or disease progression, patients in arm A were treated with PCV or temozolomide (1:1 random assignment), whereas patients in arms B1 or B2 received radiotherapy. The primary end point was time to treatment failure (TTF), defined as progression after radiotherapy and one chemotherapy in either sequence.

Results

Patient characteristics in the intention-to-treat population (n = 274) were balanced between arms. All histologic diagnoses were centrally confirmed. Median TTF (hazard ratio [HR] = 1.2; 95% CI, 0.8 to 1.8), progression-free survival (PFS; HR = 1.0; 95% CI, 0.7 to 1.3, and overall survival (HR = 1.2; 95% CI, 0.8 to 1.9) were similar for arms A and B1/B2. Extent of resection was an important prognosticator. Anaplastic oligodendrogliomas and oligoastrocytomas share the same, better prognosis than anaplastic astrocytomas. Hypermethylation of the O⁶-methylguanine DNA-methyltransferase (MGMT) promoter (HR = 0.59; 95% CI, 0.36 to 1.0), mutations of the isocitrate dehydrogenase (IDH1) gene (HR = 0.48; 95% CI, 0.29 to 0.77), and oligodendroglial histology (HR = 0.33; 95% CI, 0.2 to 0.55) reduced the risk of progression. Hypermethylation of the MGMT promoter was associated with prolonged PFS in the chemotherapy and radiotherapy arm.

Conclusion

Initial radiotherapy or chemotherapy achieved comparable results in patients with anaplastic gliomas. IDH1 mutations are a novel positive prognostic factor in anaplastic gliomas, with a favorable impact stronger than that of 1p/19q codeletion or MGMT promoter methylation."

Preoperative Chemotherapy Versus Preoperative Chemoradiotherapy for Stage III (N2) Non–Small-Cell Lung Cancer

From the Red Journal: Shameless self and departmental promotion below

Link and Abstract

Preoperative Chemotherapy Versus Preoperative Chemoradiotherapy for Stage III (N2) Non–Small-Cell Lung Cancer: "Purpose: To compare preoperative chemotherapy (ChT) and preoperative chemoradiotherapy (ChT-RT) in operable Stage III non–small-cell lung cancer.Methods and Materials: This retrospective study analyzed all patients with pathologically confirmed Stage III (N2) non–small-cell lung cancer who initiated preoperative ChT or ChT-RT at Duke University between 1995 and 2006. Mediastinal pathologic complete response (pCR) rates were compared using a chi-square test. The actuarial overall survival, disease-free survival, and local control were estimated using the Kaplan-Meier method and compared using the log–rank test. Multivariate Cox regression analysis was also performed.Results: A total of 101 patients who initiated preoperative therapy with planned resection were identified. The median follow-up was 20 months for all patients and 38 months for survivors. The mediastinal lymph nodes were reassessed after preoperative therapy in 88 patients (87%). Within this group, a mediastinal pCR was achieved in 35% after preoperative ChT vs. 65% after preoperative ChT-RT (p = 0.01). Resection was performed in 69% after ChT and 84% after ChT-RT (p = 0.1). For all patients, the overall survival, disease-free survival, and local control rate at 3 years was 40%, 27%, and 66%, respectively. No statistically significant differences were found in the clinical endpoints between the ChT and ChT-RT subgroups. On multivariate analysis, a mediastinal pCR was associated with improved disease-free survival (p = 0.03) and local control (p = 0.03), but not overall survival (p = 0.86).Conclusion: Preoperative ChT-RT was associated with higher mediastinal pCR rates but not improved survival."

Roles of Radiation Dose and Chemotherapy in the Etiology of Stomach Cancer as a Second Malignancy

From the Red Journal: An interesting report of secondary cancers due to RT... this time stomach adenocarcinomas, not something that I usually think of.

Link and Abstract

Roles of Radiation Dose and Chemotherapy in the Etiology of Stomach Cancer as a Second Malignancy: "Purpose: To evaluate the roles of radiation dose, chemotherapy, and other factors in the etiology of stomach cancer in long-term survivors of testicular cancer or Hodgkin lymphoma.Methods and Materials: We conducted a cohort study in 5,142 survivors of testicular cancer or Hodgkin lymphoma treated in the Netherlands between 1965 and 1995. In a nested case–control study, detailed information on treatment, smoking, gastrointestinal diseases, and family history was collected for 42 patients with stomach cancer and 126 matched controls. For each subject, the mean radiation dose to the stomach was estimated. Relative risks (RRs) of stomach cancer and the radiation-related excess relative risk (ERR) per gray were calculated by conditional logistic regression analysis.Results: The risk of stomach cancer was 3.4-fold increased compared with the general population. The risk increased with increasing mean stomach dose (p for trend, <0.001), at an ERR of 0.84 per Gy (95% confidence interval [CI], 0.12–15.6). Mean stomach doses of more than 20 Gy were associated with a RR of 9.9 (95% CI, 3.2–31.2) compared with doses below 11 Gy. The risk was 1.8-fold (95% CI, 0.8–4.4) increased after chemotherapy and 5.4-fold (95% CI, 1.2–23.9) increased after high doses of procarbazine (≥13,000 mg) vs. <10,000 mg. The RR of smoking more than 10 cigarettes per day vs. no smoking was 1.6 (95% CI, 0.6–4.2).Conclusions: Stomach cancer risk is strongly radiation dose dependent. The role of chemotherapy, particularly of procarbazine and related agents, needs further study, because of the relatively small numbers of chemotherapy-treated subjects."

Toxicity of Three-Dimensional Conformal Radiotherapy for Accelerated Partial Breast Irradiation

From the Red Journal: EBRT based PBRT may not be the best solution...

Link and Abstract

Toxicity of Three-Dimensional Conformal Radiotherapy for Accelerated Partial Breast Irradiation: "Purpose: To assess the incidence and severity of late normal tissue toxicity using three-dimensional conformal radiotherapy to deliver accelerated partial breast irradiation.Methods and Materials: A total of 60 patients were treated with three-dimensional conformal radiotherapy for accelerated partial breast irradiation. Treatment planning and delivery were in strict accordance with the technique and specified dose–volume constraints of the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol. Late toxicity was evaluated according to the Radiation Therapy Oncology Group grading schema. The cosmetic outcome was scored using the Harvard criteria. Univariate logistic regression analysis was performed to evaluate the correlation of dosimetric variables with outcome.Results: At a median follow-up of 15 months, moderate-to-severe late toxicity developed in 10% of patients. The most pronounced late toxicity was subcutaneous fibrosis: 25% Grade 2-4 and 8.3% Grade 3-4. The modified planning tumor volume/whole breast volume ratio, ratio of the volume of breast tissue receiving 5%, 20%, 50%, and 80% of the prescription dose to the whole breast volume, and maximal dose within the breast correlated with the development of fibrosis (p = .10, p = .03, p = .04, p = .06, p = .09, and p = .046, respectively). The overall cosmetic outcome was good to excellent in 81.7%, fair in 11.7%, and poor in 6.7%. The presence of subcutaneous fibrosis, modified planning tumor volume/whole breast volume ratio, ratio of the volume of breast tissue receiving 5% and 20% of the prescription dose to the whole breast volume, and pathologic specimen volume correlated with the risk of a fair/poor cosmetic outcome (p < .001, p = .02, p = .05, p = .04, p = .01, respectively).Conclusion: The three-dimensional conformal radiotherapy technique for accelerated partial breast irradiation as specified in the National Surgical Adjuvant Breast and Bowel Project B-39/Radiation Therapy Oncology Group 0413 protocol resulted in a remarkably high rate of moderate-to-severe late normal tissue effects, despite the relatively brief follow-up period. The toxic events correlated clearly with several dose–volume parameters."

Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244 [Hematologic Malignancies]

This week's JCO:

For Advanced HD, a randomized trial from the UK reports on the relative efficacy of Stanford V vs ABVD. The short answer - both are ok, just different toxicities. Most of the patients received RT in both arms, however usage was higher with Stanford V. This is due to the fact that mid trial, patients in CR after ABVD did not recieve RT, whereas RT is an integral part of the Stanford V regimen.

Link and Abstract:

Randomized Comparison of the Stanford V Regimen and ABVD in the Treatment of Advanced Hodgkin's Lymphoma: United Kingdom National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244 [Hematologic Malignancies]: "Purpose

This multicenter, prospective, randomized controlled trial compared the efficacy and toxicity of two chemotherapy regimens in advanced Hodgkin's lymphoma (HL): the weekly alternating Stanford V and the standard, twice-weekly regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).

Patients and Methods

Patients had stage IIB, III, or IV disease or had stages I to IIA disease with bulky disease or other adverse features. Radiotherapy was administered in both arms to sites of previous bulk (> 5 cm) and to splenic deposits, although this was omitted in the latter part of the trial for patients achieving complete remission (CR) in the ABVD arm. A total of 520 patients were randomly assigned and were assessed for the primary outcome measure of progression-free survival (PFS). Five hundred patients received protocol treatment, and radiotherapy was administered to 73% in the Stanford V arm and to 53% in the ABVD arm.

Results

The overall response rates after completion of all treatment were 91% for Stanford V and 92% for ABVD. During a median follow-up of 4.3 years, there was no evidence of a difference in projected 5-year PFS and overall survival (OS) rates (76% and 90%, respectively, for ABVD; 74% and 92%, respectively, for Stanford V). More pulmonary toxicity was reported for ABVD, whereas other toxicities were more frequent with Stanford V.

Conclusion

In a large, randomized trial, the efficacies of Stanford V and ABVD were comparable when given in combination with appropriate radiotherapy.

"

Local Excision Alone Without Irradiation for Ductal Carcinoma In Situ of the Breast: A Trial of the Eastern Cooperative Oncology Group [Breast Cancer]

This weeks JCO:

A very interesting article on lumpectomy alone in selected DCIS patients is reported from ECOG and the NCTG. This was a phase II trial of lumpectomy alone small (<2.5cm)>3mm). The five year results meet their goals in the low-intermediate grade group with 6.1% ipsilateral events, however was unacceptably high in the high grade group. These two cohorts were planned from the start to be analyzed separately.

The only comment that I would have is that I will like to see the 10 year data when it is available, as the failure curves in the manuscript look like they are begining to jump after the currently reported endpoint.

Of course, the real test of lumpectomy alone in selected DCIS will be the randomized RTOG trial 98-04 which will be maturing with the next few years.

Link and Abstract:

Local Excision Alone Without Irradiation for Ductal Carcinoma In Situ of the Breast: A Trial of the Eastern Cooperative Oncology Group [Breast Cancer]: "Purpose

To determine the risk of ipsilateral breast events in patients with ductal carcinoma in situ (DCIS) treated with local excision without irradiation.

Patients and Methods

Patients with either low- or intermediate-grade DCIS measuring 2.5 cm or smaller, or high-grade DCIS measuring 1 cm or smaller who had microscopic margin widths of 3 mm or wider and no residual calcifications on postoperative mammograms were eligible for a prospective trial conducted from 1997 to 2002 by the Eastern Cooperative Oncology Group and North Central Cancer Treatment Group. Patients entered in 2000 and later could take tamoxifen if they wished. Median age at last surgery for the entire population was 60 years (range, 28 to 88 years), and median tumor sizes in the two strata were 6 mm and 5 mm, respectively.

Results

With a median follow-up of 6.2 years, the 5-year rate of ipsilateral breast events in the 565 eligible patients in the low/intermediate grade stratum was 6.1% (95% CI, 4.1% to 8.2%). With a median follow-up of 6.7 years, this incidence for the 105 eligible patients in the high-grade stratum was 15.3% (95% CI, 8.2% to 22.5%).

Conclusion

Rigorously evaluated and selected patients with low- to intermediate-grade DCIS with margins 3 mm or wider had an acceptably low rate of ipsilateral breast events at 5 years after excision without irradiation. Patients with high-grade lesions had a much higher rate, suggesting that excision alone is inadequate treatment. Further follow-up is necessary to document long-term results.

"

Relationship Between Potentially Modifiable Lifestyle Factors and Risk of Second Primary Contralateral Breast Cancer Among Women Diagnosed With Estrogen Receptor-Positive Invasive Breast Cancer [Breast Cancer]

From this weeks JCO:

Nothing surprising in this retrospective study, but it lends more weight to the idea of promoting healthy lifestyles in cancer survivors. This is definitely useful to answer a question that we often hear from our patients :"what can I do to prevent another cancer?"

Link and Abstract

Relationship Between Potentially Modifiable Lifestyle Factors and Risk of Second Primary Contralateral Breast Cancer Among Women Diagnosed With Estrogen Receptor-Positive Invasive Breast Cancer [Breast Cancer]: "Purpose

An outcome of considerable concern among breast cancer survivors is the development of second primary breast cancer. However, evidence regarding how potentially modifiable lifestyle factors modulate second breast cancer risk is limited. We evaluated the relationships between obesity, alcohol consumption, and smoking on risk of second primary invasive contralateral breast cancer among breast cancer survivors.

Methods

Utilizing a population-based nested case-control study design, we enrolled 365 patients diagnosed with an estrogen receptor–positive (ER+) first primary invasive breast cancer and a second primary contralateral invasive breast cancer, and 726 matched controls diagnosed with only an ER+ first primary invasive breast cancer. Obesity, alcohol use, and smoking data were ascertained from medical record reviews and participant interviews. Using conditional logistic regression we evaluated associations between these three exposures and second primary contralateral breast cancer risk.

Results

Obesity, consumption of ≥ 7 alcoholic beverages per week, and current smoking were all positively related to risk of contralateral breast cancer (odds ratio [OR], 1.4; 95% CI, 1.0 to 2.1; OR, 1.9; 95% CI, 1.1 to 3.2; and OR, 2.2; 95% CI, 1.2 to 4.0, respectively). Compared with women who consumed fewer than seven alcoholic beverages per week and were never or former smokers, women who consumed ≥ 7 drinks per week and were current smokers had a 7.2-fold (95% CI, 1.9 to 26.5) elevated risk of contralateral breast cancer.

Conclusion

Our population-based study adds to the limited available literature and suggests that obesity, smoking, and alcohol consumption influence contralateral breast cancer risk, affording breast cancer survivors three means of potentially reducing this risk."

Preoperative Multimodality Therapy Improves Disease-Free Survival in Patients With Carcinoma of the Rectum: NSABP R-03 [Gastrointestinal Cancer]

JCO this week: the NSABP R03 is published. A preop vs postop CTRT trial for rectal cancer, similar to the practice defining German trial. Unfortunately underpowered, it nonetheless demonstrates a DFS benefit. How to interpret this benefit in the light of no difference in LC is slightly more problematic, especially comparing to the larger German trial.

Link and Abstract:

Preoperative Multimodality Therapy Improves Disease-Free Survival in Patients With Carcinoma of the Rectum: NSABP R-03 [Gastrointestinal Cancer]: "Purpose

Although chemoradiotherapy plus resection is considered standard treatment for operable rectal carcinoma, the optimal time to administer this therapy is not clear. The NSABP R-03 (National Surgical Adjuvant Breast and Bowel Project R-03) trial compared neoadjuvant versus adjuvant chemoradiotherapy in the treatment of locally advanced rectal carcinoma.

Patients and Methods

Patients with clinical T3 or T4 or node-positive rectal cancer were randomly assigned to preoperative or postoperative chemoradiotherapy. Chemotherapy consisted of fluorouracil and leucovorin with 45 Gy in 25 fractions with a 5.40-Gy boost within the original margins of treatment. In the preoperative group, surgery was performed within 8 weeks after completion of radiotherapy. In the postoperative group, chemotherapy began after recovery from surgery but no later than 4 weeks after surgery. The primary end points were disease-free survival (DFS) and overall survival (OS).

Results

From August 1993 to June 1999, 267 patients were randomly assigned to NSABP R-03. The intended sample size was 900 patients. Excluding 11 ineligible and two eligible patients without follow-up data, the analysis used data on 123 patients randomly assigned to preoperative and 131 to postoperative chemoradiotherapy. Surviving patients were observed for a median of 8.4 years. The 5-year DFS for preoperative patients was 64.7% v 53.4% for postoperative patients (P = .011). The 5-year OS for preoperative patients was 74.5% v 65.6% for postoperative patients (P = .065). A complete pathologic response was achieved in 15% of preoperative patients. No preoperative patient with a complete pathologic response has had a recurrence.

Conclusion

Preoperative chemoradiotherapy, compared with postoperative chemoradiotherapy, significantly improved DFS and showed a trend toward improved OS.

"

[Articles] Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial

Presented at ASTRO last year as a plenary, the MDA randomized trial of SRS alone vs SRS + WBRT is published in Lancet Oncology. This is an interesting trial, as it had a neurocognitive primary endpoint, which is one of the larger concerns with WBRT. This trial certainly adds to the data on the neurocognitive effects of WBRT, however, one can't help but focus on the survival difference between the arms. I would venture that the data presented in the paper, especially the lack of any differences in neurologic deaths and the lack of any difference in the larger RTOG and Japanese trials, that this is not a treatment effect. Then the question remains, what did cause this, and could it have influenced the primary endpoint? Another point that I will add to this is the trial was stopped due to a 4 month evaluation of memory, as opposed to a later time point. I would suggest that this may be too early of a measurement time for the long term effects of WBRT.

Nonetheless, this trial does support the use of SRS alone in this population and the prospective nature of the neurocognitive evaluation is to be applauded.

Link:

[Articles] Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial: "It is unclear whether the benefit of adding whole-brain radiation therapy (WBRT) to stereotactic radiosurgery (SRS) for the control of brain-tumours outweighs the potential neurocognitive risks. We proposed that the learning and memory functions of patients who undergo SRS plus WBRT are worse than those of patients who undergo SRS alone. We did a randomised controlled trial to test our prediction."

History of Health Insurance in the US

This American Life had an entertaining show on Health Insurance in the US a few weeks ago. Worth a listen.

Link

Someone Else's Money

Use of Axillary Deodorant and Effect on Acute Skin Toxicity During Radiotherapy for Breast Cancer: A Prospective Randomized Noninferiority Trial

From the Red Journal:

This seems like a silly randomized trial, but it adds information to a question that comes up in clinic all the time: Can I wear deodorant while getting RT? Answer: yes per this trial, but aluminum containing antiperspirants are not tested. I like that they added a less sweating end point with a statistically significant result!

Link and abstract:

Use of Axillary Deodorant and Effect on Acute Skin Toxicity During Radiotherapy for Breast Cancer: A Prospective Randomized Noninferiority Trial: "Purpose: To prospectively determine the effect of deodorant use on acute skin toxicity and quality of life during breast radiotherapy (RT).Methods and Materials: Before breast RT, 84 patients were randomly assigned to the deodorant group (n = 40) or the no-deodorant group (n = 44). The patients were stratified by axillary RT and previous chemotherapy. Toxicity evaluations were always performed by the principal investigator, who was unaware of the group assignment, at the end of RT and 2 weeks after completion using the Radiation Therapy Oncology Group acute skin toxicity criteria. Symptoms of acute skin toxicity (i.e., discomfort, pain, pruritus, sweating) and quality of life were self-evaluated. For each criterion, the point estimate of rate difference with the 95% one-sided upper confidence limit was computed. To claim noninferiority owing to deodorant use, the 95% one-sided upper confidence limit had to be lower than the noninferiority margin, fixed to 12.8%.Results: In the deodorant vs. no-deodorant groups, Grade 2 axillary radiodermatitis occurred in 23% vs. 30%, respectively, satisfying the statistical criteria for noninferiority (p = .019). Grade 2 breast radiodermatitis occurred in 30% vs. 34% of the deodorant vs. no-deodorant groups, respectively, also satisfying the statistical criteria for noninferiority (p = .049). Similar results were observed for the self-reported evaluations. The deodorant group reported less sweating (18% vs. 39%, p = .032). No Grade 3 or 4 radiodermatitis was observed.Conclusion: According to our noninferiority margin definition, the occurrence of skin toxicity and its related symptoms were statistically equivalent in both groups. No evidence was found to prohibit deodorant use (notwithstanding the use of an antiperspirant with aluminum) during RT for breast cancer."

Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort [Genitourinary Cancer]

JCO this week:
An interesting report from the Health Professionals Follow-up Study looking at those who "deferred treatment" for prostate cancer. They find no difference in rates of death or clinical metastases with those that pursued this approach, though 49% had been treated by 7.7 years.

This is clearly an important piece of information in the debate over prostate cancer screening and treatment decisions. However, to poke a few holes:
1. This is a study of professionals who may not represent a larger population.
2. There is no data on how many men needed long term or indefinite hormone ablation, which may well have been different between the approaches.
3. The death and metastasis rate may not have matured yet due to the well known indolent nature of this disease.
4. The hazard ratio on the multivariate analysis is informative in how broad it is (0.61- 1.75). Thus there could have been up to a 75% increase in the metastasis or death rate in the deferred treatment cohort, and the result would have remained non-significant.

That said, we obviously treat many if not a majority of prostate cancers without affecting a man's life span or QOL except in the negative with treatment related events. The next step is to better identify those in whom we can forgoe any therapy with minimal risks of progression.

Link and Abstract:

Prospective Study of Determinants and Outcomes of Deferred Treatment or Watchful Waiting Among Men With Prostate Cancer in a Nationwide Cohort [Genitourinary Cancer]: "Purpose

To examine consequences of deferred treatment (DT) as initial management of prostate cancer (PCa) in a contemporary, prospective cohort of American men diagnosed with PCa.

Participants and Methods

We evaluated deferred treatment for PCa in the Health Professionals Follow-up Study, a prospective study of 51,529 men. Cox proportional hazards models were used to calculate hazard ratios (HRs) for time to eventual treatment among men who deferred treatment for more than 1 year after diagnosis. HRs for time to metastasis or death as a result of PCa were compared between patients who deferred treatment and those who underwent immediate treatment within 1 year of diagnosis.

Results

From among 3,331 cohort participants diagnosed with PCa from 1986 to 2007, 342 (10.3%) initially deferred treatment. Of these, 174 (51%) remained untreated throughout follow-up (mean 7.7 years); the remainder were treated an average of 3.9 years after diagnosis. Factors associated with progression to treatment among DT patients included younger age, higher clinical stage, higher Gleason score, and higher prostate-specific antigen at diagnosis. We observed similar rates for development of metastases (n = 20 and n = 199; 7.2 v 8.1 per 1,000 person-years; P = .68) and death as a result of PCa (n = 8 and n = 80; 2.4 v 2.6 per 1,000 person-years; P = .99) for DT and immediate treatment, respectively.

Conclusion

In this nationwide cohort, more than half the men who opted for DT remained without treatment for 7.7 years after diagnosis. Older men and men with lesser cancer severity at diagnosis were more likely to remain untreated. PCa mortality did not differ between DT and active treatment patients."

Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial [Breast Cancer]

JCO this week: Presented two ASTROs ago, a reanalysis of the EORTC boost trial is now published using centralized path review.

Perhaps one of the interesting conclusions was that margin status did not influence local control. Does this mean that we should not re-excise women that have positive margins, and proceed directly to radiotherapy? One must remember that the entry criteria to this trial was negative margins, therefore all of the positive margins discovered on central path review were presumably missed on the initial interpretation. One might also then assume that these are therefore relatively small regions of margin positivity, and thus very different from patients with known positive margins up front. This should be taken into account when interpreting the results.

Link and Abstract:

Impact of Pathological Characteristics on Local Relapse After Breast-Conserving Therapy: A Subgroup Analysis of the EORTC Boost Versus No Boost Trial [Breast Cancer]: "Purpose

To investigate the long-term impact of pathologic characteristics and an extra boost dose of 16 Gy on local relapse, for stage I and II invasive breast cancer patients treated with breast conserving therapy (BCT).

Patients and Methods

In the European Organisation for Research and Treatment of Cancer boost versus no boost trial, after whole breast irradiation, patients with microscopically complete excision of invasive tumor, were randomly assigned to receive or not an extra boost dose of 16 Gy. For a subset of 1,616 patients central pathology review was performed.

Results

The 10-year cumulative risk of local breast cancer relapse as a first event was not significantly influenced if the margin was scored negative, close or positive for invasive tumor or ductal carcinoma in situ according to central pathology review (log-rank P = .45 and P = .57, respectively). In multivariate analysis, high-grade invasive ductal carcinoma was associated with an increased risk of local relapse (P = .026; hazard ratio [HR], 1.67), as was age younger than 50 years (P < .0001; HR, 2.38). The boost dose of 16 Gy significantly reduced the local relapse rate (P = .0006; HR, 0.47). For patients younger than 50 years old and in patients with high grade invasive ductal carcinoma, the boost dose reduced the local relapse from 19.4% to 11.4% (P = .0046; HR, 0.51) and from 18.9% to 8.6% (P = .01; HR, 0.42), respectively.

Conclusion

Young age and high-grade invasive ductal cancer were the most important risk factors for local relapse, while margin status had no significant influence. A boost dose of 16 Gy significantly reduced the negative effects of both young age and high-grade invasive cancer.

"

Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy

JAMA this week: more on Robotic Surgery for Prostate Cancer. The short on this retrospective study looking the robotic assisted laparoscopic prostatectomy - fewer blood transfusions, 1 day less in the hospital, increased incontinence and erectile dysfunction, same efficacy for cancer. The increased adverse event profile is a bit of a surprise here, and may cool some jets with this technique.

Of course, like any surgery, individual technique and skill probably matter, and this was a broad group from the SEER database. An individual surgeons results may be different that the broader group, and there is a significant learning curve on this procedure. Toxicity is also a notoriously hard thing to pin down in uncontrolled studies, and patients may have very different expectations going into a robotic procedure compared to an open.

Link and Abstract:

ORIGINAL CONTRIBUTION: Comparative Effectiveness of Minimally Invasive vs Open Radical Prostatectomy: "

Context Minimally invasive radical prostatectomy (MIRP) has diffused rapidly despite limited data on outcomes and greater costs compared with open retropubic radical prostatectomy (RRP).

Objective To determine the comparative effectiveness of MIRP vs RRP.

Design, Setting, and Patients Population-based observational cohort study using US Surveillance, Epidemiology, and End Results Medicare linked data from 2003 through 2007. We identified men with prostate cancer who underwent MIRP (n = 1938) vs RRP (n = 6899).

Main Outcome Measures We compared postoperative 30-day complications, anastomotic stricture 31 to 365 days postoperatively, long-term incontinence and erectile dysfunction more than 18 months postoperatively, and postoperative use of additional cancer therapies, a surrogate for cancer control.

Results Among men undergoing prostatectomy, use of MIRP increased from 9.2% (95% confidence interval [CI], 8.1%-10.5%) in 2003 to 43.2% (95% CI, 39.6%-46.9%) in 2006-2007. Men undergoing MIRP vs RRP were more likely to be recorded as Asian (6.1% vs 3.2%), less likely to be recorded as black (6.2% vs 7.8%) or Hispanic (5.6% vs 7.9%), and more likely to live in areas with at least 90% high school graduation rates (50.2% vs 41.0%) and with median incomes of at least $60 000 (35.8% vs 21.5%) (all P < .001). In propensity score–adjusted analyses, MIRP vs RRP was associated with shorter length of stay (median, 2.0 vs 3.0 days; P<.001) and lower rates of blood transfusions (2.7% vs 20.8%; P < .001), postoperative respiratory complications (4.3% vs 6.6%; P = .004), miscellaneous surgical complications (4.3% vs 5.6%; P = .03), and anastomotic stricture (5.8% vs 14.0%; P < .001). However, MIRP vs RRP was associated with an increased risk of genitourinary complications (4.7% vs 2.1%; P = .001) and diagnoses of incontinence (15.9 vs 12.2 per 100 person-years; P = .02) and erectile dysfunction (26.8 vs 19.2 per 100 person-years; P = .009). Rates of use of additional cancer therapies did not differ by surgical procedure (8.2 vs 6.9 per 100 person-years; P = .35).

Conclusion Men undergoing MIRP vs RRP experienced shorter length of stay, fewer respiratory and miscellaneous surgical complications and strictures, and similar postoperative use of additional cancer therapies but experienced more genitourinary complications, incontinence, and erectile dysfunction.

"

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial

From the Lancet this week:

More bad news from the WHI - Women had a trend (NS) towards more NSCLC diagnoses in the HRT arm, and statistically significant worse survival from lung cancer. Of course this is post-hoc, and should be treated as hypothesis generating more than definitive evidence. Regardless, enthusiasm for HRT has been sufficiently curbed.

Link:

Oestrogen plus progestin and lung cancer in postmenopausal women (Women's Health Initiative trial): a post-hoc analysis of a randomised controlled trial: "In the post-intervention period of the Women's Health Initiative (WHI) trial, women assigned to treatment with oestrogen plus progestin had a higher risk of cancer than did those assigned to placebo. Results also suggested that the combined hormone therapy might increase mortality from lung cancer. To assess whether such an association exists, we undertook a post-hoc analysis of lung cancers diagnosed in the trial over the entire follow-up period."

Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer [Breast Cancer]

In interesting contrast to a prior study from the NEJM earlier this year, this weeks JCO has another retrospective study looking at isolated tumor cells and micromets in SLN biopsies from women with breast cancer. In this study, there was no difference in outcome for patients with isolated tumor cells or micromets (<2mm). Do I detect the need for a randomized trial?

Abstract and Link from the JCO


Impact of Micrometastases in the Sentinel Node of Patients With Invasive Breast Cancer [Breast Cancer]:
"Purpose

Lymph node metastases are the most significant prognostic indicator for patients with breast cancer. Sentinel node biopsy (SNB) has led to an increase in the detection of micrometastases in the sentinel node (SN). This prospective study was designed to determine the survival impact of micrometastases in SNs of patients with invasive breast cancer. This study is based on the new sixth edition of the American Joint Committee on Cancer (AJCC) staging criteria.

Patients and Methods

Between January 1, 1992 and April 30, 1999, 790 patients entered this prospective study at the John Wayne Cancer Institute. The SN was examined first by hematoxylin and eosin (HE), and if the SN was negative with HE, then immunohistochemical staining was performed. The patients were then divided into four groups based on AJCC nodal staging: pN0(i–), no evidence of tumor (n = 486); pN0(i+), tumor deposit ≤ 0.2 mm (n = 84); pN1mi, tumor deposit more than 0.2 mm but ≤ 2 mm (n = 54), and pN1, tumor deposit more than 2 mm (n = 166). Disease-free survival (DFS) and overall survival (OS) were estimated using the Kaplan-Meier method. The log-rank test was used to determine differences in DFS and OS of patients from different groups.

Results

At a median follow-up of 72.5 months, the size of SN metastases was a significant predictor of DFS and OS.

Conclusion

Patients with micrometastatic tumor deposits, pN0(i+) or pN1mi, do not seem to have a worse 8-year DFS or OS compared with SN-negative patients. As expected, there was a significant decrease in 8-year DFS and OS in patients with pN1 disease in the SN.

"

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

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

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

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

Patients and Methods

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

Results

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

Conclusion

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

"

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

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

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

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

Patients and Methods

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

Results

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

Conclusion

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

"

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

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


Link and Abstract:

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

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

Patients and Methods

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

Results

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

Conclusion

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

"

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

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

Link and Abstract below:

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

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

Patients and Methods

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

Results

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

Conclusion

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

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

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

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

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

Patients and Methods

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

Results

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

Conclusion

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

Kennedy's GBM treatment

Regardless of your political persuasion, Ted Kennedy was a force in the Senate, and shaped much of the current dialogue on health care reform (in addition to many other issues over his long political career). As his treatment involved surgery at Duke and proton therapy in Boston, it may be of interest to read media reports of his treatment course:

Link to CNN article

Exposure to Low-Dose Ionizing Radiation from Medical Imaging Procedures

Very interesting article on the use of medical imaging and the resulting dose in a broad population sample in this weeks NEJM.

Link:
Exposure to Low-Dose Ionizing Radiation from Medical Imaging Procedures: "The use of medical imaging procedures has been increasing, and this study estimated the exposure of U.S. patients to low-dose ionizing radiation from these procedures. The exposure was substantial, largely because of radiation from computed tomography and nuclear imaging. The highest average effective dose was attributable to myocardial perfusion imaging, and most imaging occurred in outpatient settings. These data indicate that the use of imaging can result in high radiation doses. "

Antioxidants and Cancer: More Caution

This week's nature has a very interesting article on a potential pro-survival effect of antioxidants on metastatic cells. This stems from the observation that cells that loose attachment to the extracellular matrix (ECM), have increased levels of reactive oxygen species (ROS) intracellularly, leading to a reduced atp levels. In this model, these defects were reversed by the application of antioxidants (NAC or a vitamin E derivative).

Of course we have been telling patients for years not to take large amounts of antioxidants during radiation therapy due to the potential reversal of the oxygen dependent indirect effect of RT. This however is a much broader cautionary tale, albiet without any direct human clinical data at this time...

Link:

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

Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer

Banner day for oncology in this weeks NEJM:

The BIG 1-98 trial comparing different hormonal manipulations for the adjuvant treatment of postmenopausal women have finally reported on the "switching" arms of the trial. This trial has previously reported that the tamoxifen only arm was inferior to the letrozole arm, however there were those that believed that a switch between tamoxifen and letrozole would be beneficial. That has not been born out in these results, with the tamoxifen early arm demonstrating more early recurrences than the other arms.

Link:

Letrozole Therapy Alone or in Sequence with Tamoxifen in Women with Breast Cancer: "This study of adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive early breast cancer showed that disease-free survival was similar after 5 years of treatment with letrozole alone, 2 years of treatment with letrozole followed by 3 years with tamoxifen, or 2 years of treatment with tamoxifen followed by 3 years with letrozole. Five years of letrozole monotherapy may be superior to 5 years of tamoxifen monotherapy. "

Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer

The NEJM this week has an article directly relevant to patients receiving long term androgen deprivation with radiation therapy for high risk prostate cancer. In this phase III trial, patients undergoing androgen deprivation were randomized to receive denosumab, a monoclonal antibody targeting the NFKB ligand. The intervention resulted in improved bone density, and perhaps more importantly, resulted in decreased vertebral fractures, all at no significant observed toxicities.

This joins a number of randomized trials conducted by Dr. Smith and others on similar agents (see table below). What remains to be seen is what the best intervention is, both in terms of efficacy and cost.



Link:

Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer

Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

NEJM has two interesting articles on EGFR recepter mutations and response to targeted treatments. The first of these demonstrates the incidence of EGRF mutations in the NSCLC population, and highlights the known associated demographic characteristics: non or light female smokers with adenocarcinoma. The study also demonstrates increased benefit to erolotinib, a TKI targeting the receptor.

Screening for Epidermal Growth Factor Receptor Mutations in Lung Cancer

Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma

This weeks NEJM has a quite striking phase III trial comparing a gefitinib to a carbo-taxol in a carefully selected cohort: non or light smokers from east asia with adenocarcinoma of the lung. This subset has been previously described as having an excellent response to treatment, but the very positive results of this trial prove a very significant benefit to disease free survival, and also demonstrate that the benefit in this subpopulation is related to EGFR mutation status.

Gefitinib or Carboplatin-Paclitaxel in Pulmonary Adenocarcinoma

Weight Lifting in Women with Breast-Cancer-Related Lymphedema

From the NEJM this week: An interesting randomized trial looking at lymphedema after breast cancer treatment, and challenging some of the paradigms of prevention.

Weight Lifting in Women with Breast-Cancer-Related Lymphedema: "Weight lifting has generally been discouraged for women with breast-cancer-related lymphedema because of concern that it might worsen the lymphedema. In this randomized trial involving breast-cancer survivors with lymphedema, women undergoing a 1-year weight-lifting program were no more likely than controls to have increased arm swelling, had greater improvement in the severity of lymphedema symptoms and strength, and had a lower incidence of confirmed exacerbations of lymphedema."

Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer

From the NEJM this week: One of the first studies showing that micromets are clinically significant (in a large retrospective series).

Micrometastases or Isolated Tumor Cells and the Outcome of Breast Cancer: "This study involving women with early-stage breast cancer showed an association between the presence of isolated tumor cells or micrometastases in sentinel or axillary lymph nodes and the 5-year rate of disease-free survival. Women with such findings in these lymph nodes who received systemic adjuvant therapy had an improved outcome.

"

Endometrial Cancer: Vaginal Brachytherapy vs Whole Pelvis

In this weeks JCO, the first results of the PORTEC 2 trial are published.

In this randomized trial, 427 patients >= 60 years of age with IC grade 1 or 2, IB grade 3, or any age and IIA disease (excluding grade 3 with >50% myometrial invasion, were randomized between vaginal brachytherapy (7Gy q week x 3, or 30Gy LDR) and WPRT (46Gy, 2Gy/day). Note the inclusion criteria; this excludes the IC grade 3 risk group which at the time of the trial design were at too high of a risk not to treat with WPRT.

This is a QOL report, and not surprisingly, VBT comes out on top, particularly with GI toxicities, which let to better social functioning as well.

This is gratifying, as it proves that less is more as far as the adverse events are concerned. Of course, more importantly what is the efficacy data.

This was presented at ASCO 2008. At 3-years vaginal relapse occurred 0.9% in the VBT arm and 2.0% after EBRT (p=0.97), 3-year pelvic relapse was 3.6% and 0.7% (p=0.03), respectively. 3 year distant relapse was 6.4% in the VBT group and 6.0% in the EBRT group (NS). No difference in 3-year OS (90.4% vs. 90.8% p=0.55) and RFS (89.5% vs. 89.1% p=0.38).

So now it's time to step back to the primary study endpoint, which was vaginal relapse, and unfortunately the stats section is a little vague here, probably because this is a QOL report not the clinical results. What it clear is that this was not designed as a non-inferiority trial for pelvic relapse, which to be honest, is what it probably should have been. If you are trying to say that vaginal brachytherapy is safe and as effective as WPRT, then the endpoint should be either pelvic relapse, distant relapse or overall survival. The pelvic relapses were actually significantly worse with VBT, thought the absolute difference was small (~3%). What is important about this is that these patients are essentially unsalvageable, which may eventually show in the OS numbers (though I wouldn't hold my breath due to the power of the study and competing causes of death in this patient population).

That stated, clearly VBT is an option for these patients, and this study, with relatively minor flaws in comparison to others supports the approach.

Bevacizumab for NF2 associated AN

An interesting article yesterday at NEJM, in which investigators at MGH gave bevacizumab to 10 patients with NF2 associated acoustic neuromas (vestibular schwannomas). 9/10 had reduction in tumor size after administration and 4/7 evaluable for changes in hearing had an improvement. Very interesting data, and may be useful in large tumors that would be difficult to treat with either surgery or RT.

SBRT for NSCLC

In this weeks JCO there is an interesting article from investigators in Sweden and Norway reporting a phase II trial of 15Gy x 3 for T1 and T2, medically inoperable NSCLC. Of import, the dose was prescribed to the 67% IDL, meaning that the dose to the center of many of these tumors was much higher.

57 patients were enrolled, the majority were T1 (70%). 3 year OS was 60%, but perhaps more importantly, given their comorbidities, the CSS was 88%. 3 year LC was 92%. 16 patients experienced grade 3 toxicity (28%), and there was one patient with grade 4 dyspnea. No grade 5 toxicities were seen.



This lends even greater support to the practice, and is a great improvement over the prior standard of 70Gy to a postage stamp field to those that are not healthy enough for lobectomy. The next step of course is to look at this in the medically operable patient... stay tuned to ongoing clinical trials on this subject.

PET-CT for NSCLC

The NEJM this week has in interesting randomized trial on the utility of PET-CT in the preoperative workup of NSCLC.

Investigators from Denmark randomized 189 patients to receive either PET-CT or conventional CT as preoperative staging for NSCLC. Mediastinoscopy was performed in most patients in both arms(94%). After PET–CT, 38/98 patients were classified as having inoperable NSCLC compared to 18/91 patients in the CT arm. 60/98 in the PET–CT arm and 73/91 in the CT arm underwent thoracotomy (p=0.004). 21/60 surgeries in the PET–CT arm and 38/73 in the CT arm were futile (i.e. posiitive mediastinum, distant disease,p=0.05). Survival and number of curative surgeries were no different between the arms.

While it has been long known that PET added significantly to the sensitivity and specificity of lung cancer staging, this is the first study to demonstrate that it results in clinically meaningful results. A reduction in the number of unnecessary thoracotomies would represent a reduction in the cost of treating NSCLC, both financially and in terms of the morbidity and mortality of the procedure itself.

Cranial RT necessary for high risk ALL?

In this weeks NEJM there is an interesting article looking at the role of RT (or lack thereof) in preventing CNS relapse in newly diagnoses ALL.

This was a single arm trial which eliminated RT from the treatment protocol in all patients with newly diagnoses ALL. 498 were enrolled, however only 71 would have recieved prophylactic cranial irradiation (PCI) off protocol. These 71 were compared with 56 historical controls who did recieve PCI. Treatment intensity was risk based. "Triple intrathecal" therapy was used (consisting of MTX, cytarabine and hydrocoritsone).

5-yr EFS in 498 was 85.6% (95% CI, 79.9-91.3) and 5yr OS was 93.5% (95% CI, 89.8-97.2). 5yr isolated CNS relapse 2.7% (95% CI, 1.1-4.3), any CNS relapse was 3.9% (95% CI, 1.9-5.9). The 71 who did not have PCI had longer continuous complete remission than the 56 historical controls (P=0.04). Only one patient in the cohort that would have had PCI failed in the CNS.

CNS leukemia (CNS-3 status) or a traumatic LP with blasts and ≥1% residual disease after 6 weeks of remission induction had poorer EFS. CNS relapse risks included t(1;19), CNS involvement at diagnosis, and T-cell ALL. The authors however do not reccomend PCI in this cohort, as 90% of these patients would have recieved PCI unecessarily.

What the authors do not report (as it is not yet available) is on the long term neurocognitive and developemental consequences of intense intrathecal chemotherapy. The conclusions are predicated upon the assumption that this treatment will be an improvement over PCI (which may not be unreasonable), however only long term and in depth follow up will demonstrate this.

Dose response for AVMS

In re to chart rounds today, there was question about the dose response to SRS for AVMs. Flickinger published an excellent report in the red journal, 1996 addressing this issue.

Below is the dose response curve from their study:

Induction vs Concurrent chemotherapy in Head and Neck Cancer

In the green journal today there is an update of the Pignon Meta-analysis for radiation and chemotherapy.

87 trials with 16,485 patients. With chemotherapy in addition to radiotherapy, HR for death was 0.88 (p less than 0.0001) with an absolute reduction of mortality of4.5% at 5 year. There was an interaction (p less than 0.0001) in chemotherapy timing, i.e. adjuvant, induction or concomitant. Concomitant chemotherapy was superior to induction chemotherapy, with HR 0.81 (p less than 0.0001) absolute reduction of 6.5% at 5 years. Chemo was also of less utility with older patients (p = 0.003, test for trend).

Thus more fuel for the induction vs. concurrent debate. One must point out though that the Posner trial however used induction and concurrent chemotherapy, thus a comparison of optimal induction with concurrent treatment vs. optimal concurrent chemoradiotherapy remains unanswered...

Developing a Genomic Signature for Epirthelial Mesenchymal Tranrsition

KH presents on Developing a Genomic Signature for Epithelial Mesenchymal Transition (EMT)

Background in the Potti lab. NEJM 2006; 355:570.
Gene expression patterns were examined in a Cohort of Duke patients with early stage NSCLC, then validated in two independent cohorts (CALGB, ACOSOG). 133 genes in the developed signature (k-ras, MDR upregulation, and down regulation of tumor suppression). Strong predictions of recurrence and survival.

Currently the lab is working wuth a 52 gene signature for radiation sensitivity which was developed initially at the University of Chicago. Resistant clones were selected from a cell line that was serially irradiated and the gene signature differentiates between the resistant selected clones and the initial sensitive cell line. The Potti lab has confirmed this in previously unirradiated cell lines, and has predictive value in predicting radiation response in vitro.

This signature is then clinically tested in samples from patients with head and neck cancer and in group with rectal cancer. Accuracy for response to RT was on the order of 75% for association with pCR in the rectal cancer patients, and (?radiographic) response in the Head and Neck patients.

A current direction is integrating mircoRNAs into the gene chips, which requires no additional technology, just different probes.

Switching gears to EMT.

Epithelial Mesenchymal Transition (EMT) occurs in normal embyogenesis. It is also implicated in Lung and Kidney fibrosis, and possibly radiation resistance. Perhaps most intriguingly, EMT is also implicated in the invasion and metastasis process of carcinomas (and an MET [mesenchymal to epithelial tranisition] process then occurs after establishement of a distant colony).

E Cadherin and multiple other pathways (including the Hedgehog pathway) regulate this process. Coculturing with myofibroblasts release Hh(hedgehog) into the microenvironment, and this has been shown to produce EMT in cholangiocytes.

Plan will be two develop an EMT model in NSCLC lines via either coculturing with myofibroblasts or transfection with adenovirus vectors carrying Hh DNA, then developing a gene signature for this process.

EORTC: 6 months vs 3 years Androgen Deprivation for Prostate Cancer

NEJM this week has published the EORTC 6 months vs 3 years of ADT trial.

This was a trial of 1113 men with T2c-T3, or pN1 prostate cancer, with 970 randomized to 6 months of ADT (starting with RT), vs 3 years ADT. RT was 50Gy WPRT with a 20Gy boost. The trial was a non-inferiority trial between the two regimens.

Median f/u was 6.4 years, and an interim analysis for futility crossed it's boundary. HR for death in the 6 month arm was 1.42 (p=0.65 for non-inferiority); 5 year OS was 84.8% in the 3 year arm vs 81.0% in the 6 month arm. DFS and BRFS were also both worse in the 6 month arm (SS). They have a number of nice QOL measures in the paper, showing decreased sexual function, increased insomnia and hot flashes in the 3 year arm, but the global QOL was similar between the arms.

There was also no difference in fatal cardiac events.

So conclusions: 6 months of ADT is "not non-inferior" to 3 years. This is a little different than saying 3 years is better than 6 months, but at the end of the day, it's hard to justify 6 months alone, in patients that would have entered on this trial.

However, that last statement is worth looking at: these T2c, T3a and T3b patients are a distinct and very small subset of high risk disease in the US in 2009. Many of the patients that we treat today are high risk because of high Gleason Grade rather than high T stage. The optimal treatment for this group is an unknown.

Comparing to the 92-02 results, which had a similar patient population, they showed a DFS and BRFS improvement, but only improved survival in the high grade sub-group. No data on subgroup analysis for this trial, but plan on seeing it in the next year or so in the JCO or similar...

MALT lymphoma

JP presents on MALT lymphoma.

68 yo with chronic nasal congestion. Sinus and chest CT revealed a R orbital mass (incidental finding). Biopsy obtained revealing an atypical lymphoid infiltrate, CD20+, monoclonal B-cell population. PET ct was positive in the R orbit alone. IEA MALT lymphoma of the orbit.

On exam conjuctival erythema noted with injected sclera, no other abnormalities.

Marginal Zone Lymphoma includes MALTs, Nodal marginal B-cell lymphoma (monocytoid lymphoma), Primary splenic marginal zone lymphoma.

3rd most common NHL (after DLBCL and FL). 7-8% of B-cell lymphomas. Most commonly occur in the stomach, and account for 50% of gastric lymphomas (the other half are DLBCLs).

Named due to subsite of origin within a lymph node/aggregate. Germinal center in the middle, mantle zone surrounding that, then the marginal zone surrounding that. Marginal zone residents are more mature lymphocytes.

Orbital subsite include the lacrimal gland, conjunctiva, retrobulbar region. Occaisionally the is bilateral presentations. (Technically this is a stage IV presentation, but biologically this would behave much more like a stage II).

Sjogren's syndrome associated with salivary gland MALT.

Infectious associations.
H. pylori has a large association with gastric MALT (92% of gastric MALTs show this).
C. psittaci associated with ocular adnexal MALT (80% of ocular adnexal MALTs from Italian work, though this is controversial in the US data).
C. jejuni and small intestine MALTs.
B. bordoferria and skin MALTs.

MALT B-cells are CD20+, CD21+, CD35+, IgM+

Gastric MALTs are initially treated with PPI, clarithromycin, amoxicillin, with a 50-80% response rate.

t11:18 (26-40% penetrance) trisomy 3, trisomy 18, all predict for antibiotic resistance. Occaisionally one also sees t14:18 (usually seen in follicular lyphoma).

Wundisch JCO 2005: 120 H pylori + with IAE gastric MALT, treated with H pylori eradication. 96/120 achieved CR with antiobiotic therapy, 24/120 went on to secondary treatment. With median f/u 6.3 years, continuous complete response in 77, histologic residual disease in 16 (all went into a CR with observation alone), 3 relapsed. contributions. 5 yr CCR rates were 71%. 5 yr OS was 90% in all patients, only 2 died of lymphoma (both transformed). 27% of CR patients showed an ongoing B-cell monoclonality.

Checter JCO 1998. MSKCC n=51 treated to 30Gy median dose, CR 96%, FFTF 4yr 89%, OS 4 yr, 83%, CSS 4 yr 100%.
Vrieling, Rad Onc 2008. Netherlands n=115 40 Gy median CR 96%, CaSS 10yr 94%.

Italian phase II. Ferreri JNCI 2006. 27 OAL (12 relapsed), 3 week course of doxycycline 100mg bid x 3 weeks. 41% positive for C. psittaci. FFS 3yr 66%. CR was 22%. Authors conclusion were that antiobiotics were promising, though certainly this is nowhere near the responses in gastric MALT to triple therapy.

Tsang IJROBP 2001. PMH. 70pts with MALT. Doses were 25-30Gy range. CR to RT was 96%. 5yr OS 96%. 5yr DFS 76% (only 69% in sites other than stomach and thyroid). LC with RT was 60/62 (crude). Failures tend to be in other regions were MALT occurs. Tsang JCO 2003 - (different patients?) with 5.1 yr median f/u, same results.

Bolek IJROBP 1999. UF. 38pt with 8.3 yr median f/u. All orbital lymphomas. Many had 20Gy or less, median dose 25Gy. In field local control 100%. In low grade tumors DFS at 5yrs was around 60%, worse for high grade tumors.

Pfeffer IJROBP 2004. 23 pts treated, 12 with partial orbital volumes, 11 with full orbit. No reccurences in the whole orbit. 4 recurrences (33%) in patients treated with partial orbital treatments. Therefore treat the region not the GTV alone with margin.

Treated with a wedge pair to the entire R orbit to 24Gy in 2Gy/fraction.

Potential Late Effects - Cataracts with this dose are extremely common. Dry eye may be common, but severity should be limited with <30Gy. Keratoconjunctivitis, corneal ulceration, retinitis, etc would be rare.

Management of Breast Cancer in the BRCA positive population

Patrick (MSII) presents on the Management of BRCA positive patients.

Case: 30 yo AAF with a mass in the UIQ of the R breast. Maternal aunt with Breast CA at 44, also paternal grandmother with breast cancer and ovarian cancer at 86.

Biopsy: Poorly differentiated 1.3cm cancer. Triple negative. Lumpectomy and SLNB negative. (T1N0M0 triple negative). BRCA1 positive.

BRCA1: 17q21 activated by DNA damage. Interacts with CHK1 and CHK2
BRCA2: 13q12 regulates cell cycle, promotes S/G2 arrest

BRCA mutations in 1%
Enriched in the Ashkenazi Jewish population (Icelandic, Swedish, Hungarian populations as well).

Criteria for testing: Early breast cancer <=50. Two primaries in a single individual or close relative. Breast and ovarian primaries. Family member with male breast cancer.

Testing costs 300-3000$ depending on the extent of the test.

BRCA1 BRCA2
Breast Cancer 65-85% 45-85%
Ovarian Cancer 37-62% 11-23%
high grade low grade
triple negative er/pr + her2-
medullary

Early Screening. Self Breast exams at 18, clinical exams at 25. Mammograms and MRI testing at 25 or 10 years before the youngest age a relative was diagnosed with breast cancer.

Breast MRI Kriege NEJM 351:427. 1909 high risk patients (358 BRCA carriers), MRI sensitivity 80%, spec 90%, Mammo sens 33%, spec 95%.

Warner JAMA. 236 carriers. MRI sens 77%, spec 95.4%. Also looked at mammo, U/S, and CBE.

Meijers NEJM 2001;345:159. 139 carriers, 76 underwent prophylactic mastectomy, the rest choosing surveillance. With f/u of 3 years. 0/76 cancers in the mastectomy group. 8/63 in the the surveillance group, p=0.003. 5yr incidence in the surveillance group was 17%.

PROSE JCO 2004 22:1055. 90% reduction in breast cancer in carriers. In patients who also had a BSO, there was a 95% reduction.

Kauff: Prospective prophylactic bilateral salpingo-oophorectomy (BSO), HR of 0.25 for the development of ovarian or breast cancers.

Eisen: JCO 23:7491 - BSO conferred a 46-56% reduction in breast cancers. Benefit was greater if performed before 40 years of age.

Domcheck Lancet Onc 7:233. 426 with some getting BSO, some observation (prospective cohort). Overall Survival HR was 0.24 (SS) with BSO.

Pierce 160 BRCA carriers undergoing BCT. Incidence of contralateral cancers was in carriers 39%, vs 7% controls, p<0.001 at 15years. Pierce also reports in the JCO 2000, that there was no clear survival detriment to breast consevation (BCT) in carriers (though follow up was only 5 years).

Case resolution: Pt consuled about prophylactic mastectomy, BCT, prophylactic BSO, and TC chemotherapy. Pt elected to pursue BCT with close followup, with BSO after child bearing in complete (preferably before age 40).

Oncoanatomy: Mediastinum

AC presents the resident portion of the Oncoanatomy module on the Mediastinum

Anterior, middle and posterior mediastinal compartments have no intrinsic discriminating planes, however the division is useful for differential diagnosis. Primarily the middle compartment contains the heart, great vessels and airways, the anterior and posterior compartments are simply in front of or behind these structures.

Anterior Compartment
Contents include Internal mammary vessels, thymus, fat pad.
DDx for masses: 4Ts - Thymic lesions, Thyroid, Teratoma, (Terrible) Lymphoma PMBCL or Lymphoblastic lymphoma

Primary mediastinal b-cell lymphoma - variant of DLBCL. R-CHOP often used. Consolidative RT is often used. Outcomes may be more favorable than other variants of DLBCL. Peak age in the 30s and 40s.

Lymphoblastic Lymphoma: Pre B or C cells, blurred line between this and lyphoblastic lymphoma. Male predominance, peak incidence in 2nd and 3rd decades. Thymic origin CD7+, CD5+, CD2+. Mediastinal involvement in 60-70%. Treated along leukemic protocols (VPDC). Role of RT is unclear. In T-cell cases, CNS prophylaxis is indicated (intrathecal MTX +/- cranial RT).

Middle Mediastinum: Great vessels, Heart, Trachea and Airways.
Primarily metastasis or lyphoma.

Posterior Mediastinum: Esophagus, Lymph nodes, Fat, Sympathetic chains, the Azygous vein, Thoracic duct.
DDx: Neurogenic tumors, esophageal tumors, aortic lesions.

Hodgkin Lymphoma. Historically treated with RT alone with a 5yr survival of approximately 30%.

Mantle field: superior edge is at the mastoid tips, inferior at T9-10 spaces, lateral borders include the axillary nodal regions. Custom blocking is used for bilateral lungs, and humeral heads, shaped to include the bilateral hila. Lanrynx block is placed around 20Gy.

JAMA 2003;290:2831 (Hull) - 415pts with HL treated with RT or CTRT, with 80% recieving mantle fields. 10% developed CAD by 20 years. 6% had valvular dysfunction at 22yrs.

RT + doxorubicin. Myrehaug, Leukemia Lymphoma 49:1486. Doxorubicin seems to have a supra additive effect on cardiac toxicity with an HR for cardiac morbidity of 2.77 vs HR 1.82 with RT alone.

Monitoring Response to Thermodox using Optical Spectroscopy

Greg Palmer Ph.D. present his post-doc work in Dr. Dewhirst's Lab:

Optical spectoscopy involves measuring the reflectance, and fluorescence of tissue, and looking to provide structural and functional information. This is a non-invasive, near real-time, non-destructive measurement.

Three properties are measured: absorbance, scattering, and fluorescence.

Measurable Quantities:
Hb concentrations and saturation
NAD, NADPH
Collagen
Amino Acids
Extrinsic Fluorecence (doxorubicin and other drugs or contrast agents)
Size and density of scattering centers (collagen structure)

Depth may be done up to 5cm when utilizing infrared wavelengths (though with shorter wavelengths, we may be limited to millimeters).

Measurement within 10% can be arrived at via monte carlo model fit for hemoglobin concentrations. PO2 can thereby also be estimated. This contrasts to BOLD imaging which only measures relative change.

Note that the measurements are volume averaged, thus less sensitive to positition than an ependorf electrode.

Thermodox is doxorubicin encapsulated within a thermally sensitive liposome. This is given in combination with regional hyperthermia for directed chemotherapy delivery. As doxorubicin is fluorescent (593nm), measurements with optical spectroscopy can estimate in real time, regional drug concentrations may be estimated.

Concentrations as estimated by optical spectroscopy and correlated to HPLC assay as reference resulted in excellent correlation r=0.9, p=1e-20.

Hb saturation and concetration both are seen to increase after hyperthermia. In the setting of liposomal doxorubin, these do not increase, which may be a result of doxorubicin's direct affect on vasculature. One can see a dramatic increase in doxorubicin after application of hyperthermia to liposomal doxorubicin, much greater than free dox +HT, or free dox alone.

Ongoing clinical work is progressing in Head and Neck, Breast, and Cervical Cancer... stay tuned.