Sunday, June 28, 2009

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.

Thursday, June 18, 2009

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.

Thursday, June 11, 2009

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.