Time-dose Factors Research Articles

Tolerance of the Brachial Plexus to High-Dose Reirradiation

To study the tolerance of the brachial plexus to high doses of radiation exceeding historically accepted limits by analyzing human subjects treated with reirradiation for recurrent tumors of the head and neck. Data from 43 patients who were confirmed to have received overlapping dose to the brachial plexus after review of radiation treatment plans from the initial and reirradiation courses were used to model the tolerance of this normal tissue structure. A standardized instrument for symptoms of neuropathy believed to be related to brachial plexus injury was utilized to screen for toxicity. Cumulative dose was calculated by fusing the initial dose distributions onto the reirradiation plan, thereby creating a composite plan via deformable image registration. The median elapsed time from the initial course of radiation therapy to reirradiation was 24months (range, 3-144months). The dominant complaints among patients with symptoms were ipsilateral pain (54%), numbness/tingling (31%), and motor weakness and/or difficulty with manual dexterity (15%). The cumulative maximum dose (Dmax) received by the brachial plexus ranged from 60.5Gy to 150.1Gy (median, 95.0Gy). The cumulative mean (Dmean) dose ranged from 20.2Gy to 111.5Gy (median, 63.8Gy). The 1-year freedom from brachial plexus-related neuropathy was 67% and 86% for subjects with a cumulative Dmax greater than and less than 95.0Gy, respectively (P=.05). The 1-year complication-free rate was 66% and 87%, for those reirradiated within and after 2years from the initial course, respectively (P=.06). The development of brachial plexus-related symptoms was less than expected owing to repair kinetics and to the relatively short survival of the subject population. Time-dose factors were demonstrated to be predictive of complications.

Altered-fractionated radiotherapy in locally advanced head and neck cancer

To revisit the biologic rationale, the clinical methodology, the outcome and perspectives of altered fractionation in head and neck oncology. Various prospective trials and meta-analyses clearly underline the major benefit patients with locally advanced disease draw from hyperfractionation and the need for an adequate selection of time-dose factors to optimize therapeutic index for accelerated regimens. In addition, the advent of high-precision techniques such as intensity-modulated radiation therapy is bound to favor the development of more intensive regimens of irradiation in the management of locally advanced head and neck squamous cell carcinomas. Altered fractionation, both as stand-alone strategy or as part of approaches combining radiation to systemic treatments, is offering a lot of opportunities to the radiation oncologist. Its role is likely to gain ground in all high-risk patients not amenable to systemic treatments, or for whom the high toxicity of chemotherapy is not justified, in case, for instance, of intermediate-risk disease.

Radiation recall dermatitis with gatifloxacin: A review of literature

Radiation recall dermatitis (RRD) is a hypersensitivity skin reaction at the previously irradiated site after the administration of certain pharmacologic agent, which recovers on stopping the medication. RRD is a well-recognized phenomenon with the use of chemotherapeutic agents; however, only a few cases have been reported with noncytotoxic antibiotics, despite their common use in patients with cancer. We report here a case of RRD with the use of gatifloxacin and describe the time dose factors of radiation exposure, characteristics of skin reactions, management and response and our reasons to label this case as RRD. We also discuss published work regarding proposed mechanisms, histological features, radiation dose threshold and response to rechallange with the RRD-triggering drug. If RRD is to be characterized unequivocally, all the potential areas of confusion must be clarified like radiosensitization, nonhealing of acute reactions and skin-related adverse effects of the RRD-triggering drug. With the same objective, we further discussed radiosensitization and photosensitizing potential of fluoroquinolones. Gatifloxacin, although devoid of photosensitivity reactions, may cause idiosyncratic hypersensitivity reaction to cause RRD and should be considered as a potential cause of RRD. Given the potential severity of the reaction and increasing use of gatifloxacin, it is important to be aware of this phenomenon.

Treatment of early and moderately advanced vocal cord carcinoma with 6-MV X-rays

Purpose: Whereas there are many reports regarding treatment of early vocal cord cancer with cobalt 60 or 2–4-MV X-rays, there are still few reports on the results of treatment with 6-MV X-rays. Theoretically, 6-MV X-rays result in greater underdosage of tumor at the air-tissue interface and at the anterior commissure. This paper analyzes the results of irradiation of early and moderately advanced squamous cell carcinoma of the true vocal cord treated exclusively with 6-MV X-rays in a community hospital. The literature pertinent to the issue is reviewed. Methods and Materials: Eighty-three patients with Tis, T1, T2, or T3 squamous cell carcinoma of the true vocal cord were treated with curative intent at Bethesda Memorial Hospital in Boynton Beach, Florida between April 1986 and April 1998. The dose schedules most commonly used were 63 Gy in 28 fractions (2.25 Gy per fraction once a day) for T1 tumors or 74.40 Gy in 62 fractions (1.2 Gy per fraction twice a day) for T2 and T3 tumors. All patients have minimum 2-year follow-up; 63 (76%) have 5-year minimum follow-up. Results: Local control was achieved in 6 of 6 Tis, 53 of 54 (98%) T1, 8 of 8 T2, and 6 of 6 T3 lesions. No complications were encountered. Conclusions: A recent literature review indicates that the treatment of early vocal cord cancer with 6-MV X-rays remains controversial. The dose schedules used in the present paper produced a high rate of local control, a finding that is consistent with reports of other investigators who used dose schedules similar to those used in the present series. However, several other investigators have reported significantly lower rates of local control for T1 or T2 glottic cancer treated with 6-MV X-rays when compared to results obtained with cobalt 60 or 4 MV at their own institution. The latter institutions used lower total doses and/or lower dose per fraction than those institutions reporting high rates of local control with 6 MV. Data from the literature, as well as our own data, are consistent with the following hypotheses: ( 1) the lower rates of local control reported by several institutions when using 6 MV compared with cobalt or 2–4 MV, using the same radiation dose schedules for each beam energy, indicate that underdosage of mucosal surfaces in the laryngeal air cavity may be a clinically important phenomenon, and ( 2) time-dose factors, although certainly important for lower energy beams, may be even more important when using 6 MV.

Radiation retinopathy after external-beam irradiation: analysis of time-dose factors

Purpose : To investigate the risk of radiation-induced retinopathy according to total radiation dose and fraction size, based on both retrospective and prospectively collected data. Methods and Materials : Between October 1964 and May 1989, 68 retinae in 64 patients received fractionated external-beam irradiation during the treatment of primary extracranial head and neck tumors. All patients had a minimum of 3 years of ophthalmologic follow-up (range, 3 to 26 years; mean, 9 years; median, 8 years). Results : Twenty-seven eyes in 26 patients developed radiation retinopathy resulting in visual acuity of 20/200 or worse. The mean and median times to the onset of symptoms attributable to retinal ischemia were 2.8 and 2.5 years, respectively. Fourteen of the injured eyes developed rubeosis iridis and/or neovascular glaucoma. Radiation retinopathy was not observed at doses below 45 Gy, but increased steadily in incidence at doses >- 45 Gy. In the range of doses between 45 and 55 Gy, there was an increased risk of injury among patients who received doses per fraction of ≥ 1.9 Gy ( p = .09). There was also a trend toward increased risk of injury among patients who received chemotherapy (two of two vs. four of ten in the 45–51 Gy range; p = .23). The lowest dose associated with retinopathy was 45 Gy delivered to a diabetic patient by twice-a-day fractionation. The data did not suggest an increased risk of radiation retinopathy with increasing age. Conclusion : The current study suggests the importance of total dose as well as dose per fraction, and adds support to a small body of literature suggesting that patients with diabetes mellitus or who receive chemotherapy are at increased risk of injury. A sigmoid dose-response curve is constructed from our current data and data from the literature.

Radiation optic neuropathy after megavoltage external-beam irradiation: analysis of time-dose factors

Purpose : To investigate the risk of radiation-induced optic neuropathy according to total radiotherapy dose and fraction size, based on both retrospective and prospectively collected data. Methods and Mateirials : Between October 1964 and May 1989, 215 optic nerves in 131 patients received fractionated external-beam irradiation during the treatment of primary extracranial head and neck tumors. All patients had a minimum of 3 years of ophthalmologic follow-up (range, 3 to 21 years). The clinical end point was visual acuity of 20 100 or worse as a result of optic nerve injury. Results : Anterior ischemic optic neuropathy developed in five nerves (at mean and median times of 32 and 30 months, respectively, and a range of 2–4 years). Retrobulbar optic neuropathy developed in 12 nerves (at mean and median times of 47 and 28 months, respectively, and a range of 1–14 years). No injuries were observed in 106 optic nerves that received a total dose of < 59 Gy. Among nerves that received doses of ≥ 60 Gy, the dose per fraction was more important than the total dose in producing optic neuropathy. The 15-year actuarial risk of optic neuropathy after doses of ≥ 60 Gy was 11% when treatment was administered in fraction sizes of < 1.9 Gy, compared with 47%, when given in fraction sizes of ≥ 1.9 Gy. The data also suggest an increased risk of optic nerve injury with increasing age. Conclusion : As there is no effective treatment of radiation-induced optic neuropathy, efforts should be directed at its prevention by minimizing the total dose, paying attention to the dose per fraction to the nerve, and using reduced-field techniques where appropriate to limit the volume of tissues that receive high-dose irradiation.

Predictive role of tdf values in late rectal recto-sigmoid complications in irradiation treatment of cervix cancer

Radiation-induced late rectal and recto-sigmoid complications for different doses per fraction were analyzed retrospectively in 203 cases of Stage IIIB carcinoma of the uterine cervix. The patients were treated with a combination of external irradiation and a single intracavitary insertion during January 1979 to December 1983. The external irradiation was randomised to deliver by four different fractionation regimens having dose per fraction of 2 Gy, 3 Gy, 4 Gy and 5.4 Gy. The doses for various fractionations were matched with the daily regimen using the time-dose factors (TDF) model. A single intracavitary insertion delivered a dose of 22 to 24 Gy to point A using Fletcher-Suit applicator. All patients had a minimum follow-up of 30 months. Thirty nine cases of late radiation induced rectal and recto-sigmoid complications were observed. The complication rate of 8.2% for daily treatment regimen delivering 2 Gy per fraction was increased to 33.3% for once weekly treatment regimen delivering 5.4 Gy per fraction ( p = 0.041). Despite similar Time-Dose Factors (TDF) values in four different treatment regimens, the complication rate increased significantly in the once weekly regimen. The analysis suggest that the Time-Dose Factors (TDF) values do not predict correctly the late normal tissue reactions for different dose fractionation schedules.

The predictive role of bioeffect dose models in radiation-induced late effects in glottic cancers

Late radiation-induced laryngeal oedema for different doses per fraction was analyzed in 208 cases with squamous cell carcinoma of the vocal cord. The series comprised 156 cases with T1N0M0 and 52 cases with T 2N 0M 0 lesions. Radical radiotherapy was given with three different regimens delivering 3.33 Gy, 2.5 Gy, and 2.25 Gy per fraction. There were 52 cases of late radiation-induced laryngeal oedema. A strong correlation ( p < 0.015) between the dose per fraction and the risk of the late complication in the vocal cord has been demonstrated. The analysis suggests that the empirical models like Nominal Standard Dose (NSD) or Time-Dose Factors (TDF) do not predict correctly the late normal tissue reactions for different dose fractionations. The analysis with extrapolated response dose (ERD) values of the linear-quadratic (L-Q) model also fail to correlate with the late complications ( p > 0.5). Care should be exercized when using these bioeffect dose models to calculate regimens iso-effective for late damage, even when modest changes in fraction size from 2 to 3 Gy are contemplated.

Time-dose factors in positive neck nodes treated with irradiation only

This article describes an analysis of time-dose and clinical factors which affect the 2 year rate of control of cervical node metastases from squamous cell carcinoma of the head and neck following external beam radiotherapy in a series of 140 patients. We find that node diameter and normalized total dose are the most important factors, and that overall treatment time is not statistically significant.

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

The values for α/β (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 α/β 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. α/β 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 α/β was estimated at 0.6 ( - 1.1, 2.5) Gy, and liposarcomas, where direct analysis of cases surveyed from the literature suggested that α/β = 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).

Radiation therapy in the treatment of cervical Cancer: The university of Chicago/Michael reese hospital experience

A retrospective analysis was conducted on 307 patients referred for radiation therapy at The University of Chicago and Michael Reese Hospital between 1971 and 1986. Median follow-up was 6.4 years. Treatment techniques varied during the time of the study. Actuarial disease-free survivals were 78%, 64%, 55%, 33%, 41%, and 60% for stage IB, IIA, IIB, IIIA, IIIB, and IVA, respectively. Stage, size of the cervical lesion, and hemoglobin level during treatment were prognostic factors. Treatment technique as well as time dose factors were analyzed with respect to survival, failures, and complications.

Fractionation Parameters for Human Tissues and Tumors

Time-dose factors such as fractionation sensitivity (alpha/beta) can sometimes be estimated from clinical data, when there is a wide variation in dose, fraction size, treatment time, etc. This report summarizes estimates of fractionation parameters derived from clinical results. Consistent with the animal data, alpha/beta is higher for acutely responding than for late-responding normal tissues. While many human tumors seem to be characterized by high alpha/beta values, there are exceptions (e.g. melanomas). Repair kinetics may be slower in human than in rodent skin and mucosa, but there are no hard and fast estimates of the repair halftime. Regeneration in head and neck tumors is equivalent to a daily dose of 1 Gy or less, while in the mucosa it is equivalent to approximately 1.8 Gy/day.

Time-dose relationships for local tumor control and complications following irradiation of squamous cell carcinoma of the base of tongue.

Between October 1964 and September 1981, 114 previously untreated patients with squamous cell carcinoma of the base of the tongue were treated with curative intent by a radical course of irradiation at the University of Florida. With a minimum 2-year follow-up, local control was achieved in 78, 65, 76, and 17% of T1, T2, T3, and T4 lesions, respectively. Control results could be correlated with time-dose factors and treatment techniques. No patient required mandibulectomy for osteoradionecrosis following radiation therapy. Complications of bone and soft tissue could not be related to time-dose factors.

Elective neck irradiation for squamous cell carcinoma of the head and neck: analysis of time-dose factors and causes of failure.

This is an analysis of 190 patients who were treated with radiation therapy alone at the University of Florida, between October 1964 and December 1982, for T1-4 N0 squamous cell carcinoma of the head and neck; in all patients, the primary lesion was permanently controlled and the neck was evaluable for at least 2 years following radiation therapy. The control of neck node disease is analyzed as a function of elective neck irradiation, the dose of radiation delivered to the first-echelon lymph nodes, and the likelihood that occult disease was present in the neck prior to treatment.

Analysis of time-dose factors in clinically positive neck nodes treated with irradiation alone in squamous cell carcinoma of the head and neck

This is a retrospective analysis of time-dose factors in 139 patients with 238 evaluable clinically positive lymph nodes treated with external beam radiation therapy alone to the primary lesion and neck for squamous cell carcinoma of the head and neck at the University of Florida from October 1964 through April 1980. Lymph node control by lymph node size was 8 8 (100%) for <1.0 cm, 51 62 (82%) for 1.0 cm, 68 82 (83%) for 1.5–2.0 cm, 24 40 (60%) for 2.5–3.0 cm, 24 38 (63%) for 3.5–6.0 cm, and 0 8 (0%) for ≧7.0 cm. Lymph node control was also influenced by dose, overall treatment time, and fractionation schedule; these factors were interrelated and appeared to increase in importance as the size of the lymph node increased.

An analysis of the role of radiotherapy alone and in combination with chemotherapy and surgery in the management of advanced breast carcinoma.

One hundred-eight consecutive patients with Stage III breast carcinoma received radiotherapy as the primary method of treatment. Of these, 53 had prior chemotherapy and 47 had a postirradiation mastectomy as planned adjunct modalities. The overall actuarial survival probability is 40 +/- 6% at five years and 14 +/- 6% at ten years. The corresponding probabilities of freedom from metastases are 27 +/- 5% and 14 +/- 5%, while those of local control are 58 +/- 8% and 52 +/- 8% respectively. The patients receiving chemotherapy show both increased five and ten year probabilities of metastatic control of 38 +/- 7% and 22 +/- 8% and also a five and ten year local control rate of 73 +/- 8%. The patients with additional mastectomy exhibit an improved five year local control rate of 80 +/- 8% but the probability of remaining free from metastatic disease is unaltered being 31 +/- 7% at five and 12 +/- 7% at ten years. The 23 patients receiving chemotherapy prior to radiotherapy, without a subsequent mastectomy have the highest metastatic control of 41 +/- 12% at five years. In this group, eight patients treated with time-dose factors (TDFs) of over 80 have had only one local failure with a preliminary five year local control probability of 80 +/- 18% and metastases-free rate of 58 +/- 19%. Based on these results recommendations are made for minimum tumor doses of 6000 rad and adjuvant chemotherapy. This should be delivered before radiotherapy, since with this sequence of treatment both local control and survival are improved.

Treatment of Skin Carcinoma of the Face and Neck-Reply

In Reply.— It appears that Dr Lindsay has misconceptions about radiation therapy in the treatment of any form of cancer, and more particularly, in the treatment of carcinomas of the skin. There are great differences in the manner in which radiotherapy may be administered; such differences affect not only the choosing of the proper equipment and filtration, but also especially affect the time-dose factors. Judgment of results cannot be made on the assumption that any practice is comparable with another. If one were to base one's judgment on Dr Lindsay's experience, one would have to agree with him. What we have presented is evidence that skillful irradiation, using filtered radiations adequately fractionated over several weeks of daily irradiation, results not only in easy and constant control of carcinomas, but, in addition, in the best conservative and aesthetic results. That Dr Lindsay has not been privileged to observe these possibilities is

Analysis of time-dose factors in squamous cell carcinoma of the oral tongue and floor of mouth treated with radiation therapy alone

This is a retrospective analysis of 147 patients with squamous cell carcinoma of the oral tongue and floor of mouth who were treated with radical radiation therapy at the University of Florida between October 1964 and December 1977. Control of the primary lesion was analyzed in respect to total dose, time, treatment modality, and split vs. continuous course therapy. There is an increase in local control of T2 lesions of the oral tongue with treatment by radium alone or radium and less than 3000 rad external beam irradiation as compared to radium and 3000 rad or more external beam (p = 0.02) and in T3 lesions of the floor of mouth with treatment by radium and 3000 rad or more external beam as compared to external beam alone (p = 0.11). Analysis of time-dose factors reveals an increase in local control with increasing dose over shorter periods of time in T3 lesions of the floor of mouth and T2–3 lesions of the oral tongue. Whereas dose appears to be important in all of these groups, overall treatment time appears to influence local control more in oral tongue lesions than in floor of mouth lesions.

Late reactions and complications in patients treated with high energy neutrons p (66MeV) Be(49MeV)

Eight of 22 patients who were followed for a year or more after neutron doses in excess of 20 Gy slowed significant late reactions. Late reactions were also observed in 6 of 20 patients who were treated with a neutron boost of 7.5 Gy following 50 Gy of photons for intraoral cancer, and in 5 of 9 ‘mixed beam’ patients who received 9 to 11 neutron Gy with 45 to 50 photon Gy concurrently over a seven week treatment period. Nine of 20 patients who were treated with curative doses of neutrons following recurrence after radical photon therapy had excessively severe late effects. In the neutron only group, a tentative isoeffect line (dose versus fractions) for cutaneous fibrosis could be drawn with an origin at 20 Gy and a slope of 0.04. A time-dose factors analysis of the whole series suggested that a TDF of 120 (±10) defined the threshold for severe stromal fibrosis and associated complications.

Postoperative irradiation for squamous cell carcinomas of the head and neck: analysis of time-dose factors related to control above the clavicles

The combination of radical surgery followed by postoperative irradiation is commonly employed in the treatment of advanced head and neck cancers. However, there has been little in the literature concerning the dose required to prevent recurrence after operation. A retrospective analysis of 71 patients with squamous cell carcinoma of the oral cavity, oropharynx, pyriform sinus, supraglottic larynx, and glottic larynx who were treated by surgery and postoperative irradiation attempted to define the time-dose relationship required to prevent recurrence. The failure rate above the clavicles decreased with increasing dose up to 7000 rad. The effect on control of positive surgical margins, bone and cartilage invasion, neck staging, perineural extension, perinodal extension, and split-course technique was reviewed; both positive surgical margins and split-course technique were found to be associated with a decrease in local control at every dose level below 6500 rad. The complications of combined therapy were found to be independent of dose. From these analyses, dose recommendations for various clinical situations are made, as well as recommendations for adjustments in radiation techniques to take advantage of the predictable sites of recurrence.