Treatment recommendations for locally advanced, non-small-cell lung cancer: the influence of physician and patient factors.

PURPOSE: To determine the impact of patient age, comorbidity, and physician factors on treatment recommendations for locally advanced, unresectable non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: We surveyed radiation oncologists regarding their recommendations for treatment (chemoradiation, radiation alone, chemotherapy alone, or no therapy) for hypothetical patients with Stage IIIB NSCLC who varied by age (55 vs. 80 years) and comorbid illness (none, moderate, or severe chronic obstructive pulmonary disease [COPD]). Multinomial logistic regression was used to assess the impact of physician and practice characteristics on radiation oncologists' treatment recommendations for three scenarios with the least agreement. RESULTS: Of 214 radiation oncologists, nearly all (99%) recommended chemoradiation for a healthy 55 year old. However, there was substantial variability in recommendations for a 55 year old with severe COPD, an 80-year-old with moderate COPD, and an 80-year-old with severe COPD. Physicians seeing a lower volume of lung cancer patients were statistically less likely to recommend radiotherapy for younger or older patients with severe COPD (both p < 0.05), but the impact was modest. CONCLUSIONS: Nearly all radiation oncologists report following the evidence-based recommendation of chemoradiation for young, otherwise healthy patients with locally advanced, unresectable NSCLC, but there is substantial variability in treatment recommendations for older or sicker patients, probably related to the lack of clinical trial data for such patients. The physician and practice characteristics we examined only weakly affected treatment recommendations. Additional clinical trial data are necessary to guide recommendations for treatment of elderly patients and patients with poor pulmonary function to optimize their management.

Mucositis versus tumor control: the therapeutic index of adding chemotherapy to irradiation of head and neck cancer.

PURPOSE: To determine whether the addition of concurrent chemotherapy to radiation for head and neck cancer (HNSCC) improves the therapeutic ratio regarding tumor control vs. mucositis. METHODS AND MATERIALS: Data were taken from 14 randomized trials of radiation with or without concurrent chemotherapy for HNSCC. Mucositis-bioequivalent dose (mBED) was computed for each study using mBED = D [1 + d/(alpha/beta)] - 0.693(T - Tk)/Tp. An "S-value," relating the increase in the rate of Grade 3 (confluent) mucositis to the increase in mBED with radiation alone, was determined using data from trials of radiation alone with altered fractionation. We then determined the difference in the rate of mucositis and used the S-value to estimate the apparent difference in mBED in the chemoradiation and radiation alone arms for each trial. After accounting for differences in the radiation schedules, we estimated the mBED attributable to adding chemotherapy and compared it with previously published estimates of increases in tumor BED. RESULTS: Computed S-values ranged from 0.4 to 1.7. For S = 1, the mean increase in mBED attributable to chemotherapy was 8.3 Gy(10) (SD = 6.4). The average difference between tumor-BED and mBED was 2.8 Gy(10) (SD = 6.0). Increasing the S-value decreases the estimated increase in mBED due to chemotherapy. CONCLUSIONS: Concurrent chemotherapy improves the therapeutic index for radiation of HNSCC. Further refinements are needed in quantifying the therapeutic gain attributable to specific radiosensitizing agents in clinical trials, notably better and more consistent reporting of treatment sequelae.

Association of 11C-methionine PET uptake with site of failure after concurrent temozolomide and radiation for primary glioblastoma multiforme.

PURPOSE: To determine whether increased uptake on 11C-methionine-PET (MET-PET) imaging obtained before radiation therapy and temozolomide is associated with the site of subsequent failure in newly diagnosed glioblastoma multiforme (GBM). METHODS: Patients with primary GBM were treated on a prospective trial with dose- escalated radiation and concurrent temozolomide. As part of the study, MET-PET was obtained before treatment but was not used for target volume definition. Using automated image registration, we assessed whether the area of increased MET-PET activity (PET gross target volume [GTV]) was fully encompassed within the high-dose region and compared the patterns of failure for those with and without adequate high-dose coverage of the PET-GTV. RESULTS: Twenty-six patients were evaluated with a median follow-up of 15 months. Nineteen of 26 had appreciable (>1 cm(3)) volumes of increased MET-PET activity before treatment. Five of 19 patients had PET-GTV that was not fully encompassed within the high-dose region, and all five patients had noncentral failures. Among the 14 patients with adequately covered PET-GTV, only two had noncentral treatment failures. Three of 14 patients had no evidence of recurrence more than 1 year after radiation therapy. Inadequate PET-GTV coverage was associated with increased risk of noncentral failures. (p < 0.01). CONCLUSION: Pretreatment MET-PET appears to identify areas at highest risk for recurrence for patients with GBM. It would be reasonable to test a strategy of incorporating MET-PET into radiation treatment planning, particularly for identifying areas for conformal boost.

The impact of treatment choice for localized prostate cancer on response to phosphodiesterase inhibitors.

PURPOSE: We determined whether the impact of phosphodiesterase inhibitors on sexual function and sexual bother is different after radical prostatectomy vs radiation therapy for localized prostate cancer. MATERIALS AND METHODS: We analyzed data from 1,087 men treated for localized prostate cancer with radical prostatectomy or radiation therapy, who had at least 2 years of health related quality of life followup and who reported using a phosphodiesterase type 5 inhibitor after prostate cancer treatment. Sexual function and bother were assessed over time using the UCLA Prostate Cancer Index. Mixed model analysis was used to examine sexual function and sexual bother over time after initiation of treatment with a phosphodiesterase type 5 inhibitor. Response rates were then determined using the criterion of an increase in score of at least half the standard deviation in baseline scores, and multivariate logistic regression was used to identify predictors of improved sexual function and sexual bother in response to phosphodiesterase type 5 inhibitor use. RESULTS: Patients treated with radical prostatectomy and those who received radiation therapy had an improvement in sexual function and sexual bother after initiating phosphodiesterase type 5 inhibitor use. Response rates were similar for both types of treatment, and the only significant predictors of response to phosphodiesterase type 5 inhibitors were higher baseline (pretreatment) sexual function score and lower sexual function before phosphodiesterase type 5 inhibitor use. There was no significant change in response to phosphodiesterase type 5 inhibitors over time. CONCLUSIONS: Analysis of these data suggests that choice of treatment for localized prostate cancer is unlikely to have a significant impact on response to phosphodiesterase type 5 inhibitors should they be needed after treatment. However, patients with better pretreatment sexual function are more likely to respond to phosphodiesterase type 5 inhibitors.

Perineural invasion is a marker for pathologically advanced disease in localized prostate cancer.

PURPOSE: To determine if perineural invasion (PNI) should be included in addition to prostate-specific antigen (PSA), biopsy Gleason score, and clinical T-stage for risk-stratification of patients with localized prostate cancer. METHODS AND MATERIALS: We analyzed prostatectomy findings for 1550 patients, from a prospectively collected institutional database, to determine whether PNI was a significant predictor for upgrading of Gleason score or pathologic T3 disease after patients were stratified into low-, intermediate-, and high-risk groups (on the basis of PSA, biopsy Gleason score, and clinical T-stage). RESULTS: For the overall population, PNI was associated with a significantly increased frequency of upgrading and of pathologic T3 disease. After stratification, PNI was still associated with significantly increased odds of pathologic T3 disease within each risk group. In particular, for low-risk patients, there was a markedly increased risk of extraprostatic extension (23% vs. 7%), comparable to that of intermediate-risk patients. Among high-risk patients, PNI was associated with an increased risk of seminal vesicle invasion and lymph node involvement. Furthermore, over 80% of high-risk patients with PNI were noted to have an indication for postoperative radiation. CONCLUSIONS: Perineural invasion may be useful for risk-stratification of prostate cancer. Our data suggest that low-risk patients with PNI on biopsy may benefit from treatment typically reserved for those with intermediate-risk disease. In addition, men with high-risk disease and PNI, who are contemplating surgery, should be informed of the high likelihood of having an indication for postoperative radiation therapy.

Activity of tonically active neurons in the monkey putamen during initiation and withholding of movement.

Tonically active neurons (TANs) of the primate striatum are putative interneurons that respond to events of motivational significance, such as primary rewards, and to sensory stimuli that predict such events. Because TANs influence striatal projection neurons, TANs may play a role in the initiation and control of movement. To examine this issue, we recorded from putaminal TANs in macaque monkeys trained to make the same arm movement in two ways--in reaction to an external cue and also after a variable delay without an explicit instruction to move (self-timed movements). On other trials, the animals had to withhold movement following an external cue. The task design ensured that the three types of trials were effectively randomly interleaved, equally frequent, and similar in overall timing. Separately, we presented "playback" trials in which the same sequence of visual stimulation and reward was presented while the animals fixated without making the arm movement. We found that TAN responses were strongly affected by behavioral context. In particular, TAN responses were strikingly stronger when the animals actively withheld movements than on the corresponding playback trials, even though the stimulus sequence and reward timing were identical and no movement was made in either case. Many TANs also became active in the absence of a proximate sensory cue on self-timed movements, suggesting that TANs may reflect internal processes that are specific to self-timed movements. These results suggest that TANs may directly participate in, or monitor the motivational significance of, an animal's actions as well as external events.

Putaminal activity for simple reactions or self-timed movements.

To examine the role of basal ganglia-cortical circuits in movement initiation, we trained monkeys to make the same arm movements in two ways-in immediate reaction to a randomly timed external cue (cued movements) and also following a variable delay without an explicit initiation signal (self-timed movements). The two movement types were interleaved and balanced in overall timing to allow a direct comparison of activity before and during the movement. Posterior putaminal neurons generally had phasic, movement-related discharges that were comparable for cued and self-timed movements. On cued movements, neuronal activity increased sharply following cue onset. However, for self-timed movements, there was a slow build-up in activity that preceded the phasic discharge. This slow build-up was time-locked to movement and restricted to a narrow time window hundreds of milliseconds before movement. The difference in premovement activity between cued and self-timed trials was present before the earliest cue-onset times and was not related to any differences in the overall time-to-move between the two types of trials. These features suggest that activity evolving in the basal ganglia-cortical circuitry may drive the initiation of movements by increasing until an activity threshold is exceeded. The activity may increase abruptly in response to an external cue or gradually when the timing of movements is determined by the animals themselves rather than an external cue. In this view, small changes in activity that occur in advance of the much larger perimovement neuronal activity may be an important determinant of when movement occurs. In support of this hypothesis, we found that even for cued movements, faster reaction times were associated with slightly higher levels of activity hundreds of milliseconds before movement.