Howard D. Thames

Direct evidence that prostate tumors show high sensitivity to fractionation (low α/β ratio), similar to late-responding normal tissue

Abstract Purpose : A direct approach to the question of whether prostate tumors have an atypically high sensitivity to fractionation (low α/β ratio), more typical of the surrounding late-responding normal tissue. Methods and Materials : Earlier estimates of α/β for prostate cancer have relied on comparing results from external beam radiotherapy (EBRT) and brachytherapy, an approach with significant pitfalls due to the many differences between the treatments. To circumvent this, we analyze recent data from a single EBRT + high-dose-rate (HDR) brachytherapy protocol, in which the brachytherapy was given in either 2 or 3 implants, and at various doses. For the analysis, standard models of tumor cure based on Poisson statistics were used in conjunction with the linear-quadratic formalism. Biochemical control at 3 years was the clinical endpoint. Patients were matched between the 3 HDR vs. 2 HDR implants by clinical stage, pretreatment prostate-specific antigen (PSA), Gleason score, length of follow-up, and age. Results : The estimated value of α/β from the current analysis of 1.2 Gy (95% CI: 0.03, 4.1 Gy) is consistent with previous estimates for prostate tumor control. This α/β value is considerably less than typical values for tumors (≥8 Gy), and more comparable to values in surrounding late-responding normal tissues. Conclusions : This analysis provides strong supporting evidence that α/β values for prostate tumor control are atypically low, as indicated by previous analyses and radiobiological considerations. If true, hypofractionation or HDR regimens for prostate radiotherapy (with appropriate doses) should produce tumor control and late sequelae that are at least as good or even better than currently achieved, with the added possibility that early sequelae may be reduced.

Accelerated fractionation vs hyperfractionation: Rationales for several treatments per day

Treatment with several doses per day offers the prospect of a significant therapeutic gain using readily available low LET beams. These regimens can be classified as either accelerated fractionation or hyperfractionation according to their rationales. With accelerated fractionation a conventional number of dose fractions is delivered in a significantly shortened overall treatment time in order to reduce the opportunity for tumor cell regeneration during treatment. With hyperfractionation, on the other hand, a large number of significantly reduced dose fractions is used to give a greater total dose in a conventional overall treatment time. The rationale for this strategy is threefold: 1) increased opportunity for tumor cell redistribution and reoxygenation between dose fractions: 2) a possibly lower oxygen enhancement ratio with small incremental doses; and 3) different sparing of late reacting normal tissues with small dose fractions. A review of the published clinical experience with multiple fractions per day treatment reveals few studies of either pure accelerated fractionation or hyperfractionation since both are limited by acute normal tissue reactions. This has led to a variety of hybrid regimens, some of which have no clear rationale. The choice between accelerated fractionation and hyperfractionation is determined by the regenerative capability of tumor clonogens during treatment. A method of selection based on potential doubling times is presented.

Time-dose factors in radiotherapy: a review of the human data

The values for alpha/beta (fractionation sensitivity, or recovery capacity) for early and late reactions in human normal tissues are consistent with results from experimental animals. For breast treatments direct analysis indicates that for early reactions alpha/beta is in the range 7 to 11 Gy, while for late effects it is in the range 2 to 4 Gy. Data on recovery kinetics in human tissues is limited but these indicate that recovery may be slower in humans than in rodents. For early skin reactions the halftime of recovery is about 1 h, while for late telangiectasia it is more than 3 h. alpha/beta values for human tumors are more variable than in rodents: some are high (head and neck, lung, skin, cervix) and similar to those for early reacting normal tissues. Others are low, including melanomas, where alpha/beta was estimated at 0.6 (-1.1, 2.5) Gy, and liposarcomas, where direct analysis of cases surveyed from the literature suggested that alpha/beta = 0.4 (-1.4, 5.4) Gy. Repopulation kinetics is faster in the mucosa of the soft palate and faucial pillars (1.8 Gy/day) than in head and neck tumors (up to 1 Gy/day).

Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: Implications for postoperative irradiation

PURPOSE The objective of this study was to determine locoregional recurrence (LRR) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation. PATIENTS AND METHODS A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospective trials. Median follow-up time was 116 months. Rates of isolated and total LRR (+/- distant metastasis) were calculated by Kaplan-Meier analysis. RESULTS The 10-year actuarial rates of isolated LRR were 4%, 10%, 21%, and 22% for patients with zero, one to three, four to nine, or >/= 10 involved nodes, respectively (P <.0001). Chest wall (68%) and supraclavicular nodes (41%) were the most common sites of LRR. T stage (P <.001), tumor size (P <.001), and >/= 2-mm extranodal extension (P <.001) were also predictive of LRR. Separate analysis was performed for patients with T1 or T2 primary disease and one to three involved nodes (n = 404). Those with fewer than 10 nodes examined were at increased risk of LRR compared with those with >/= 10 nodes examined (24% v 11%; P =.02). Patients with tumor size greater than 4.0 cm or extranodal extension >/= 2 mm experienced rates of isolated LRR in excess of 20%. Each of these factors continued to significantly predict for LRR in multivariate analysis by Cox logistic regression. CONCLUSION Patients with tumors >/= 4 cm or at least four involved nodes experience LRR rates in excess of 20% and should be offered adjuvant irradiation. Additionally, patients with one to three involved nodes and large tumors, extranodal extension >/= 2 mm, or inadequate axillary dissections experience high rates of LRR and may benefit from postmastectomy irradiation.

Repair capacity and kinetics of human skin during fractionated radiotherapy: erythema, desquamation, and telangiectasia after 3 and 5 year's follow-up

Prospective clinical fractionation studies on acute and late reactions in skin have been going on since 1972 at the Radiotherapy Department in Gothenburg. The clinical assay consisted of breast cancer patients irradiated postoperatively to the internal mammary nodes from unilateral or bilateral fields exposed to various dose schedules. 750 fields in 450 patients have been analysed. Schedules with 1, 2 or 5 fractions per week and 2 or 3 fractions per day were evaluated with erythema, desquamation and telangiectasia as endpoints. For some schedules a dose-response relationship was established in a limited dose range, but often there was only one dose group per schedule. These data are suited to analysis by the method of direct analysis of quantal response. This was used in the present analysis, along with the linear quadratic (LQ) model and its generalization, the incomplete repair (IR) model. The repair capacity was similar for erythema and desquamation, with alpha/beta ratios between 7.5 and 11.2 Gy. Unexpectedly, there was more significant time factor during radiotherapy courses up to 6 weeks for erythema and desquamation, but the repair capacity was changed after 4 weeks for both endpoints, and alpha/beta increased to between 18.3 and 34.5 Gy. The repair capacity for late telangiectasia differed significantly from that for erythema and desquamation, with alpha/beta values between 2.8 and 4.3 Gy. There was a significant time factor for telangiectasia with characteristic doubling time of about 16 days, when an exponential function for time was used. Concerning the repair kinetics in skin, there were insufficient data to obtain precise estimates, but there was a suggestion of two components of repair. This was inferred from higher-than-predicted recovery with 15-min intervals, when the data were fitted with the monoexponential model. The monoexponential fit gave t1/2 between 1.1 and 1.3 h for acute effects and 3.5 h for late effects. Recovery after 15-min fractionation intervals, if it resulted from a fast repair component, would be consistent with a half-time of 0.3-0.4 h. The time factor and the relative long half-time for repair for late effects have important implications for multiple-fraction-per-day treatment, and imply that interfraction intervals of 4 h or less, as commonly used, will be insufficient. Instead, intervals of 6 h or longer are recommended. Using accelerated fractionation with a significant reduction in overall treatment time a dose reduction is still necessary to take into account the time factor for late effects.(ABSTRACT TRUNCATED AT 400 WORDS)

A new isoeffect curve for change in dose per fraction

A method is proposed for using survival curve parameters for calculating the change in total dose necessary to achieve an equal response in a tissue when the dose per fraction is varied. The method uses the ratio alpha/beta of the coefficients of the linear quadratic survival formula and accounts only for the effect of repair of cellular injury. Absolute values for alpha and beta are not required. The isoeffect curves vary for different tissues. A dose adjustment to account for differences in the regeneration of surviving cells that might result from changing a treatment regimen must be made separately and will also vary from tissue to tissue. Examples of the use of the curves are given. At present, the curves, particularly those for late effects, are uncertain and caution should be observed in using them until they are defined more accurately with additional data.

Breast Conservation After Neoadjuvant Chemotherapy: The M.D. Anderson Cancer Center Experience

PURPOSE To determine patterns of local-regional recurrence (LRR) and ipsilateral breast tumor recurrence (IBTR) among patients treated with breast conservation therapy after neoadjuvant chemotherapy. PATIENTS AND METHODS Between 1987 and 2000, 340 cases of breast cancer were treated with neoadjuvant chemotherapy followed by conservative surgery and radiation therapy. Clinical stage at diagnosis (according to the 2003 American Joint Committee on Cancer system) was I in 4%, II in 58%, and III in 38% of patients. Only 4% had positive surgical margins. RESULTS At a median follow-up period of 60 months (range, 10 to 180 months), 29 patients had developed LRR, 16 of which were IBTRs. Five-year actuarial rates of IBTR-free and LRR-free survival were 95% and 91%, respectively. Variables that positively correlated with IBTR and LRR were clinical N2 or N3 disease, pathologic residual tumor larger than 2 cm, a multifocal pattern of residual disease, and lymphovascular space invasion in the specimen. The presence of any one of these factors was associated with 5-year actuarial IBTR-free and LRR-free survival rates of 87% to 91% and 77% to 84%, respectively. Initial T category (T1-2 v T3-4) correlated with LRR but did not correlate with IBTR (5-year IBTR-free rates of 96% v 92%, respectively, P =.19). CONCLUSION Breast conservation therapy after neoadjuvant chemotherapy results in acceptably low rates of LRR and IBTR in appropriately selected patients, even those with T3 or T4 disease. Advanced nodal involvement at diagnosis, residual tumor larger than 2 cm, multifocal residual disease, and lymphovascular space invasion predict higher rates of LRR and IBTR.

Long-term multi-institutional analysis of stage T1-T2 prostate cancer treated with radiotherapy in the PSA era.

PURPOSE To report the long-term outcome for patients with Stage T1-T2 adenocarcinoma of the prostate definitively irradiated in the prostate-specific antigen (PSA) era. METHODS AND MATERIALS Nine institutions combined data on 4839 patients with Stage T1b, T1c, and T2 adenocarcinoma of the prostate who had a pretreatment PSA level and had received >or=60 Gy as definitive external beam radiotherapy. No patient had hormonal therapy before treatment failure. The median follow-up was 6.3 years. The end point for outcome analysis was PSA disease-free survival at 5 and 8 years after therapy using the American Society for Therapeutic Radiology and Oncology (ASTRO) failure definition. RESULTS The PSA disease-free survival rate for the entire group of patients was 59% at 5 years and 53% at 8 years after treatment. For patients who had received >or=70 Gy, these percentages were 61% and 55%. Of the 4839 patients, 1582 had failure by the PSA criteria, 416 had local failure, and 329 had distant failure. The greatest risk of failure was at 1.5-3.5 years after treatment. The failure rate was 3.5-4.5% annually after 5 years, except in patients with Gleason score 8-10 tumors for whom it was 6%. In multivariate analysis for biochemical failure, pretreatment PSA, Gleason score, radiation dose, tumor stage, and treatment year were all significant prognostic factors. The length of follow-up and the effect of backdating as required by the ASTRO failure definition also significantly affected the outcome results. Dose effects were most significant in the intermediate-risk group and to a lesser degree in the high-risk group. No dose effect was seen at 70 or 72 Gy in the low-risk group. CONCLUSION As follow-up lengthens and outcome data accumulate in the PSA era, we continue to evaluate the efficacy and durability of radiotherapy as definitive therapy for early-stage prostate cancer. Similar studies with higher doses and more contemporary techniques will be necessary to explore more fully the potential of this therapeutic modality.

Accelerated Fractionation in the Radiation Treatment of Head and Neck Cancer—A Critical Comparison of Different Strategies

There is strong clinical and radiobiological evidence that protraction of overall treatment time has an adverse influence on the radiocurability of certain human tumors. Overall treatment time can be reduced without recourse to large dose fractions by the use of accelerated fractionation, but in patients with head and neck cancer acute mucosal reactions limit the extent to which treatment can be accelerated. Three different prototypical schedules for accelerated fractionation have been devised to avoid exceeding acute mucosal tolerance. Type A consists of an intensive short course in which the overall duration of treatment is markedly decreased with a corresponding substantial reduction of total dose; type B achieves a modest decrease in overall time without reduction of total dose by using a split-course technique; type C also achieves a modest decrease in overall time without reduction of total dose by means of the concomitant boost technique. A hybrid schedule combining features of types B and C allows additional shortening of overall treatment time without reduction of total dose. Available radiobiological and clinical data suggest that schedules of types B or C which do not compromise total dose are generally preferable to those of type A in which there is a trade-off between total dose and overall time. For a given total dose and overall time, a continuous treatment of type C is likely to produce more cell kill than a split-course of type B, although the latter will be better tolerated. Because of the increased acute toxicity associated with all schedules of accelerated fractionation, rational selection of patients for such treatment is important. New techniques to measure the potential doubling time of human tumors in vivo offer this prospect.

Influence of technologic advances on outcomes in patients with unresectable, locally advanced non-small-cell lung cancer receiving concomitant chemoradiotherapy.

PURPOSE In 2004, our institution began using four-dimensional computed tomography (4DCT) simulation and then intensity-modulated radiotherapy (IMRT) (4DCT/IMRT) instead of three-dimensional conformal radiotherapy (3DCRT) for the standard treatment of non-small-cell lung cancer (NSCLC). This retrospective study compares disease outcomes and toxicity in patients treated with concomitant chemotherapy and either 4DCT/IMRT or 3DCRT. METHODS AND MATERIALS A total of 496 NSCLC patients have been treated at M. D. Anderson Cancer Center between 1999 and 2006 with concomitant chemoradiotherapy. Among these, 318 were treated with CT/3DCRT and 91 with 4DCT/IMRT. Both groups received a median dose of 63 Gy. Disease end points were locoregional progression (LRP), distant metastasis (DM), and overall survival (OS). Disease covariates were gross tumor volume (GTV), nodal status, and histology. The toxicity end point was Grade >or=3 radiation pneumonitis; toxicity covariates were GTV, smoking status, and dosimetric factors. Data were analyzed using Cox proportional hazards models. RESULTS Mean follow-up times in the 4DCT/IMRT and CT/3DCRT groups were 1.3 (range, 0.1-3.2) and 2.1 (range, 0.1-7.9) years, respectively. The hazard ratios for 4DCT/IMRT were <1 for all disease end points; the difference was significant only for OS. The toxicity rate was significantly lower in the IMRT/4DCT group than in the CT/3DCRT group. V20 was significantly higher in the 3DCRT group and was a significant factor in determining toxicity. Freedom from DM was nearly identical in both groups. CONCLUSIONS Treatment with 4DCT/IMRT was at least as good as that with 3DCRT in terms of the rates of freedom from LRP and DM. There was a significant reduction in toxicity and a significant improvement in OS.