Local control of carcinoma of the tonsil by radiation therapy: An analysis of patterns of fractionation in nine institutions

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx: Tumor dose-response and repopulation

Objective. To determine the most effective irradiation regimen (total dose and dose per fraction) for hypofractionated treatment for prostate carcinomas according the TCP/NTCP radiobiological criteria.Material and methods. Using the tomographic information of five patients with low-risk prostate adenocarcinoma as an example, the authors devised dosimetric radiation therapy plans using the volumetric modulated arc therapy (VMAT) procedure. They considered the range of total doses of 33.5 to 38 Gy administered in 4 and 5 fractions. Based on the equivalent uniform dose concept proposed by A. Niemierko and on the computed differential dose volume histograms, the investigators modeled local tumor control probability (TCP) values, by taking into account the uncertainties of main radiobiological parameters, and estimated normal tissue complication probabilities (NTCP) for the anterior rectal wall as the organ most at risk of irradiation. An effective dosimetric plan was selected according to the UTCP criterion and the probability of complication-free tumor control, i.e. TCP (1 – NTCP).Results. The results of modeling the UTCP criterion show that with a higher total dose, the TCP value increases and so does the NTCP value, therefore the optimal radiation therapy plans are to irradiate with a total dose of 34 Gy over 4 fractions or with a dose of 36–37 Gy over 5 fractions. The difference between the fractionation regimens is that the UTCP value is achieved with a higher TCP value over 4 fractions and with a lower load on the rectal wall over 5 fractions.Conclusion. The choice of a specific fractionation regimen should be determined from the calculated values of differential dose volume histograms for each patient, as well as from radiobiological criteria, such as TCP, NTCP and UTCP.

Effective beam directions using radiobiologically optimized IMRT of node positive breast cancer

Clinical studies in the hypofractionated stereotactic body radiotherapy (SBRT) have shown a reduction in the probability of local tumor control with increasing initial tumor volume. In our earlier work, we obtained and tested an analytical dependence of the tumor control probability (TCP) on the total and hypoxic tumor volumes using conventional radiotherapy model with the linear-quadratic (LQ) cell survival. In this work, this approach is further refined and tested against clinical observations for hypofractionated radiotherapy treatment schedules. Compared to radiotherapy with conventional fractionation schedules, simulations of hypofractionated radiotherapy may require different models for cell survival and the oxygen enhancement ratio (OER). Our TCP simulations in hypofractionated radiotherapy are based on the LQ model and the universal survival curve (USC) developed for the high doses used in SBRT. The predicted trends in local control as a function of the initial tumor volume were evaluated in SBRT for non-small cell lung cancer (NSCLC). Our results show that both LQ and USC based models cannot describe the TCP reduction for larger tumor volumes observed in the clinical studies if the tumor is considered completely oxygenated. The TCP calculations are in agreement with the clinical data if the subpopulation of radio-resistant hypoxic cells is considered with the volume that increases as initial tumor volume increases. There are two conclusions which follow from our simulations. First, the extent of hypoxia is likely a primary reason of the TCP reduction with increasing the initial tumor volume in SBRT for NSCLC. Second, the LQ model can be an acceptable approximation for the TCP calculations in hypofractionated radiotherapy if the tumor response is defined primarily by the hypoxic fraction. The larger value of OER in the hypofractionated radiotherapy compared to the conventional radiotherapy effectively extends the applicability of the LQ model to larger doses.

One hundred sixteen patients with stage III carcinoma of the breast were treated by primary radiation therapy. The 5-year actuarial survival and relapse-free survival were 25% and 22%, respectively. The 5-year actuarial probability of local tumor control for the entire group was 64%. In patients undergoing an excisional biopsy and an interstitial implant of the primary tumor area, local control was 100%. In patients who had either an excisional biopsy or an implant, the 5-year actuarial probability of local control was 77% and 76%, respectively. In contrast, in patients having neither an excisional biopsy nor an implant, local control was only 41%. In patients receiving a total dose of greater than 6000 rad, from external beam treatment or from external beam plus an interstitial implant, the local control was 78% compared to 39% in patients receiving a total dose of less than 6000 rad. Forty-one patients received some form of adjuvant therapy. Both local control and relapse-free survival were improved in patients receiving chemotherapy as the sole adjuvant and in patients receiving chemotherapy combined with an endocrine ablative procedure. However, patients treated with only an endocrine ablative procedure had no improvement in survival nor in local control. These results indicate that primary radiation therapy can provide local control in a high proportion of patients with stage III carcinoma of the breast and suggest that chemotherapy is effective in improving both local control and survival in these patients.

Results of treating stage III carcinoma of the breast by primary radiation therapy

Purpose: Many protocols have been applied on Stereotactic Body Radio Therapy (SBRT) and Stereotactic Radio Surgery (SRS) for lung cancers. This work is to investigate the effect of patient variation on tumor control probabilities (TCP) for SBRT, SRS as well as standard fractionated radio therapy for lung cancer treatment. Method and Materials: Linear-quadratic (LQ) model was used in our TCP analysis. Three different protocols were investigated with the same parameters for LQ model: 1 fraction with 22 Gy total dose, 4 fractions with 48 Gy total dose and 33 fractions with 6600 Gy total dose. The dose inhomogeneity was assumed with a Gaussian distribution with a deviation of σdose. The patient's variation of radio-sensitivity for a population was added assuming Gaussian distributions for LQ parameters αand β with σα and σβ, respectively. Results: Although dose inhomogeneity's existence requires high total dose to achieve the same TCP, for most clinic cases, the dose increase is very limited and TCP could be evaluated base on single prescribed dose for these plans. Patient's variation σα has more impact on 33 fractions IMRT treatment, the total dose needs to increase by 15%, 19% and 26% to maintain 95% TCP in SRS, SBRT and IMRT when σα increases from 0.0 to 0.2. At the same time, Patient's variation σβ has more impact on SRS, the total dose needs to increase by 17%, 12% and 5% to keep 95% TCP in SRS, SBRT and IMRT while patient variation σβ increases from 0.0 to 0.2. Conclusion: Lung SRS and SBRT provide better tumor control for lung cancer than standard IMRT. However, patient variation should be considered when SRS and SBRT are designed for lung cancer treatment. SRS and SBRT also may lead to more lung complications.

To improve the effectiveness and efficiency in radiation therapy, various treatment modalities and fractionation schemes have been introduced and combined for cancer treatment. Biological effective dose (BED) and equivalent dose in 2Gy fraction (EQD2) are used to evaluate and compare different modalities and fractionations and also used to determine dose prescriptions for new radiation schemes. BED and EQD2 are functions of α/β and the accuracy of α/β value is essential. A single α/β value of 10Gy has been used for cervical cancer in clinical practice. However, our previous study first found that cervical cancer has a broad range of α/β values across in vitro studies that follow a right-skewed log-normal distribution. If patient populations follow such a distribution, it may have potential impact on radiation therapy for cervical cancer. To investigate the impact of variation in the α/β of cervical cancer on the expected EQD2 associated with clinical outcome for cervix cancer patients treated with radiation therapy and how that variance could influence the determination of alternate fractionation schemes. A right-skewed log-normal distribution of experimentally derived α/β values was applied to a reference tumor control probability (TCP) curve generated from cervical cancer patients treated with radiation, and a population of patients following that distribution were simulated using Monte Carlo sampling. An alternate equation for equivalent dose in 2Gy fractions (EQD2) was derived that considered variance in α/β and was used to generate new values and associated TCP curves that could be plotted on a common EQD2 axis. Convolution curves of TCP and normal tissue complication probability (NTCP) were generated to determine the potential shift in optimal dose and probability of risk-free local control (RFLC). Theoretical treatment failure rates were generated to evaluate changes in rates of treatment outcomes. Variation in α/β obtained from published experimental results produced potential losses in TCP of up to 24% in the range of clinical interest. RFLC curves predicted an optimal treatment dose of 95Gy EQD2 when applying our most probable α/β of 4.25Gy, 10Gy higher than that predicted by the reference curve. The α/β distribution saw a decrease in RFLC of 17%. To achieve a TCP of 90%, possible HDR fractionation schemes ranged from 56Gy in 14 fractions to 32Gy in 2 fractions, with the associated increase in normal tissue dose ranging from 11 to 16Gy EQD2. The distribution of cervical cancer α/β values derived from experimental results produced significant changes in tumor control when applied to a reference TCP curve. TCP decreased with both the average and most probable α/β values. It is suggested that variance and heterogeneity in α/β be more explicitly incorporated to account for those patients that do deviate from the assumed constant value, especially in the case of evaluating different radiation schemes.

1. Assuming a precise dose delivery and a biologically homogeneous tumour cell population, it is possible to express the tumour control probability (TCP) in terms of a random cell kill (Poisson statistics). After a standard 60 Gy course of multifraction irradiation with a fraction size of 2 Gy, the TCP depends on the initial number of tumour clonogens, the SF2 (surviving fraction after 2 Gy which is a measure of intrinsic radiosensitivity), the degree of proliferation during the interfraction intervals and the number of fractions (i.e. the total dose). 2. A typical dose-response curve for tumour control has a sigmold-shape with a threshold. The steepness of the curve can be described in terms of the normalized dose response gradient γ defined as the per cent increase in the TCP per 1% increase in dose. The TCP curve has a maximum steepness between TCP values of 20 and 70%. The idealized curve is much steeper than most clinically observed TCP curves which have a median γ -value of 3.0. The reduced steepness of the clinical curve is attributed to: (a) uncertainties in dose delivery, and (b) biological heterogeneities. 3. Dosimetric uncertainties can result from random and systematic errors. The combined effect results in a reduced TCP and flattening of the TCP curve to a degree that depends on the standard deviation of the mean dose within the treated volume. Narrow variations of the dose distribution do not reduce the TCP seriously if the mean dose is used for dose prescription. In the case of wide variations, the minimum dose should be chosen. The precision required for dose delivery depends on the response gradient. If γ ≤ 3, the standard deviation should not exceed 5% of the mean dose but this should be reduced to 3% if γ exceeds 3. 4. The reduced control probability associated with an increased tumour volume is attributed to (a) increased number of clonogens, (b) increased hypoxia, and (c) appearance of radioresistant cell variants. The latter two factors play an increasing role in the large volume range. 5. The complication-free tumour control probability can be defined in terms of a utility function represented by the product of the TCP and the probability of escaping serious complications. Both dosimetric errors and biological heterogeneity result in a reduced utility function. This emphasizes the importance of dosimetric precision. Predictive assays may identify the radioresistant subpopulation whose poor response may diminish the overall curability rate of a clinically defined group of tumours.

Purpose: Evaluation of the expected effectiveness of radiation therapy based on models of the local tumor control probability (Tumor Control Probability – TCP) for the head-neck cancer. 
 Material and methods: The study used data from 11 patients with locally advanced head-neck cancer (larynx, oropharynx, and oral cavity). For each patient two dosimetric treatment plans have been prepared: SIB-VMAT (70 Gy per tumor, 50 Gy per lymph nodes, 25 fractions) and SEQ-VMAT (70 Gy per tumor, 50 Gy per lymph nodes, 35 fractions). The developed plans were analyzed using A. Niemierko's TCP model with parameters obtained by B. Maciejewski (TCD50 = 70.26 Gy with a 49-day total treatment time), taking into account the dose–volume histograms and the total treatment time.
 Results: The developed plans ensured a high level of coverage (98–98 %) of the Clinical treatment volume (CTV) in all but one patient. The average TCP SIB-VMAT is 99.9 % due to the very short total treatment time. The average TCP for SEQ-VMAT is 61.0%. For one patient, both SIB-VMAT and SEQ-VMAT showed zero expected efficacy due to 95–95 % CTV coverage.
 Conclusion: The use of TCP model allows analyzing personalized treatment plans for patients and developing adaptive treatment regimens with an increase in the total dose, dose per fraction, and a decrease in the total treatment time.

Dose fractionation and regeneration in radiotherapy for cancer of the oral cavity and oropharynx. Part 2. Normal tissue responses: acute and late effects

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy

Dose, volume, and tumor control prediction in primary radiotherapy of non-small-cell lung cancer

Objective.To develop a mechanistic extension of the Poisonnian linear quadratic (LQ) tumor control probability (TCP) formulation by incorporating tumor volume and cell sensitivity inter-patient variations which can be applied to a cohort of patients.Approach.A novel closed-form expression for TCP was derived from first principles, incorporating inter-individual variations in tumor volume and cell sensitivity within the LQ model of tumor control. Furthermore, an exponential time dependence of local control (LC) in terms of TCP was introduced. The proposed model was fitted to 22 datasets of early-stage non-small cell lung cancer (NSCLC), encompassing various dose regimes, tumor volumes, treatment duration and outcome values over different follow-up periods. A log-likelihood algorithm was employed for the fitting process.Main results.The fit of the population TCP model, which adopts tumor volume and cell radiosensitivities uniformly distributed, resulted in a cell sensitivity value ofα¯U=0.37 [0.13-0.47]Gy-1, its corresponding bandwidthΔα= 0.37 [0.04-0.42] Gy-1,β =0. 015 [0.009-0.039] Gy-2, the characteristic time at which LC reaches TCP,t1/2= 19.6 [7.3-90.8] months, and the cell population doubling timeTd= 2.0 [0.2 4.9] days. The parametersα¯U,Δα andβwere found to be significant (p< 0.05), whilet1/2andTdproved non-statistically significant for the model under Wald test. This model describes data from 1675 lesions and offers a better fit compared to alternative approaches incorporating Gaussian or log-normal radiosensitivity distributions.Significance.A closed form of TCP population model was derived by including cell sensitivity and tumor size heterogeneities. A relation between TCP and LC was established by modeling LC as an exponential function of follow-up time. The derived TCP population model facilitates direct application to clinical datasets and was tested against NSCLC clinical data. Individual TCP can be estimated from the radiobiological parameters of the population.

Curative Radiotherapy for Stage I Non-small Cell Lung Cancer: Is There Evidence for Further Dose Escalation?