204 I. J. Radiation Oncology 0 Biology l Physics Volume 31. Number I, 1995

Fig. 1. Patient’s cellulitis developed one year after radiation. It was limited to the radiation field and the immediate adjacent area.

IN RESPONSE TO RESCIGNO ET AL.

To the Editor: There may be treatment implications forthcoming from the recent report entitled, “Breast Cellulitis after Conservative Surgery

and Radiotherapy” by Rescigno et al. (1). In 1989, a 67-year-old diabetic female presented with a breast mass.

Lumpectomy revealed a 4.5-cm infiltrating ductal carcinoma. Nineteen lymph nodes were negative for cancer. The incisions healed well.

Systemic treatment consisted of tamoxifen. Breast radiation included the delivery of 47 Gy in fractionated therapy by tangents using Cobalt beam and an Iridium boost to the tumor bed of 16 Gy.

One year later, the patient was admitted to the hospital with fever of 102” F and warmth, redness, and tenderness limited to the irradiated left breast and adjacent skin (Figure I). She was treated with systemic antibiotics (oxacillin, I g every 6 h) for cellulitis of the breast. She had no prior infectious complications either prior to or after this episode.

Blood cultures were positive for strep agalactae. This bacterium is associated with diabetics (2). The patient’s signs and symptoms resolved completely. There was no evidence of breast cancer recurrence--locally or distantly-upon reevaluation.

It was postulated that because of the greater radiation surface dose delivered by Cobalt compared to linear accelerator, especially in a woman with a large breast, that the cellulitis observed may have been connected to diabetes-related vascular changes exacerbated by those vascular effects associated with radiation therapy. The relationship is strongly suggestive because of limited area of infectious involvement to the irradiated site.

The interim of 1 year between lumpectomy and cellulitis would suggest it was not related to the surgical procedure.

In our institution, patients receiving postlumpectomy radiation are not treated on a cobalt machine. Diabetics are scrutinized to minimize skin dose because of this observed infectious complication.

GILBERT S. LEDERMAN, M.D.

Dept. of Radiation Oncology Staten Island University Hospital Staten Island, NY

I. Rescigno, J.; McCormick, B.; Brown, A. E.; Myskowski, P. L. Breast cellulitis after conservative surgery and radiotherapy. Int. J. Radiat. Oncol. Biol. Physics 29:163, 1; 1994.

2. Opal, S. M.; Cross, A.; Palmer, M.; Almazan R. Group B strepto-

coccal sepsis in adults and infants. Arch. Intern. Med. 148:641-645; 1988.

FURTHER CHARACTERIZATION OF POSTRADIOTHERAPY CELLULITIS

AND EFFORTS AT PREVENTION

To the Editor: We thank Olivotto et al. and Dr. Ledennan for sharing their experiences with patients who developed cellulitis or persistent er- ythema after conservative surgery and radiotherapy for breast cancer.

The similarities with our group of patients with regard to clinical findings is striking. Dr. Lederman’s case illustrates a potential high-risk group for the development of cellulitis-those patients who have vascular compromise prior to any radiotherapy. Although treatment with 6-MV photons, as suggested by Dr. Lederman, would reduce the surface dose, this may not be effective in preventing cellulitis since most of our patients were treated with 6-MV photons.

In response to Olivotto et al., we agree that radiation may have pri- marily been responsible for the findings in those patients whom we clas- sified as having chronic persistent cellulitis, although we retained the term “cellulitis” because in some cases we saw minor initial responses to antibiotic therapy. A recent article by Winkelmann et al. (1) sheds some light on the chronic reaction that they termed “pseudoscleroder- matous panniculitis” based on a careful pathological review of skin biop- sies from three of their four patients who presented with a similar clinical picture. In addition to the more typical changes, including hyperkeratotic epidermis, hyalinized blood vessels, endothelial hyperplasia, and alter- ations in fibroblast morphology, they report diffuse lymphocytic inflam- mation and focal plasmacytosis involving the dermis and fat, distinct from a sclerodermatous reaction or simple fat necrosis. Of note, similar to our patients with chronic erythema, their four cases involved worsening radiotherapy (RT)-induced erythema l-6 months after radiotherapy and improvement with the use of topical steroids and wet dressings. Those cases of erythema due to infection, including Dr. Lederman’s, occur more variably in time with patients at risk years after therapy. Our present policy is to obtain skin cultures from all patients. I f the skin remains erythematous after a 4-week trial of antibiotic therapy (e.g., dicloxacillin 500 mg q.i.d. or erythromycin for penicillin-allergic patients), a skin biopsy is performed and topical steroid therapy is initiated.

We agree that effective strategies to prevent post-RT cellulitis/erythema are needed. Bacterial causes may be prevented more easily than the chronic cases. Meticulous hemostasis at surgery, as suggested by Olivotto et al. is prudent and may be preventative. Level III axillary dissection should be avoided if lower level disease is minimal or absent. Diagnosis of patients with early signs of postoperative infection and prompt ad- ministration of antibiotics may prevent future post-RT relapses. Perhaps absorbable suture material may contribute to the risk.

We disagree with the proposal of Olivotto et al. that some high-risk patients may be spared radiation. Withholding radiation therapy in pa- tients at risk for post-RT persistent erythema would, of course, be as- sociated with a high risk of local recurrence. The attendant influence of local recurrence on cosmesis and possibly on the risk of distant metastasis is unacceptable. Until ongoing trials establish which favorable patient subsets, if any, can be observed, we recommend RT to nearly all patients after local excision (except those with certain active collagen vascular diseases). Further characterization of persistent post-RT erythema may provide clues to effective treatment and prevention short of abandoning the local treatment strategies that we presently rely on to safely conserve the breast.

JOHN RESCIGNO, M.D.

BERYL MCCORMICK, M.D.

Department of Radiation Oncology Memorial Sloan-Kettering Cancer Center 1275 York Ave. New York, NY 10021

Winkelmann, R. K.; Gordon, L. G.; Quimby, S. R.; Connolly, S. M. Pseudosclerodermatous panniculitis after irradiation: An un- usual complication of megavoltage treatment of breast carcinoma. Mayo Clin. Proc. 68:122-127; 1993.

NEUTRON THERAPY IN PROSTATE CANCER-IS THE THERAPEUTIC RATIO IMPROVED?

To The Editor: The article “Photon vs. Fast Neutron External Beam Radiotherapy in the Treatment of Locally Advanced Prostate Cancer: Results of a Randomized Prospective Trial” by Russell et al. (3) reports a significantly higher local control rate in patients treated with neutrons, without any corresponding improvement in survival.

The authors ascribe the lack of a demonstrable survival advantage to the relatively short follow-up of the study. Three articles are quoted ( 1, 2,4), where an association has been demonstrated between local control, the subsequent risk of development of distant metastases, and ultimate

Correspondence 205

survival. The inference is that with mom follow-up, the better load control now observed in the neutron-treated patients will be reflected in improved survival. However, in each of the cited papers, the difference between patients who were locally controlled or recurrent was clearly apparent at 5 years. Conversely, the present study, with a median follow-up of 68 months, shows virtually identical rates of both cancer-specific survival and freedom from distant me&tams. This being the case, it is unlikely that the survival of patients treated with neutrons will improve relative to that of patients treated with photons in the near future. It is also unclear whether the higher overall incidence of an elevated prostate spe- cific antigen (PSA) in patients treated with photons has any implication for their ultimate prognosis because the PSA elevation may simply reflect the higher local recurrence rate in the photon-treated group. For the PSA information to have independent prognostic value, data on patients free of locally recurrent tumor need to be considered.

We agree with the authors that the incidence of neutron-induced rectal complications in this study was correlated with the use of a multileaf collimator at The University of Washington facility. Other factors, how- ever, appear to have contributed to the higher complication rate seen with neutrons, because at the M.D. Anderson Cancer Center, small reo tang&u fields without special collimation or customized blocking were used for both photon and neutron treatments. The neutron beam is physically inferior to high energy photons for the treatment of pelvic tumors, mainly because it has a lesser depth dose and a wider penumbra. This inevitably leads to a worse dose distribution with neutrons, regardless of beam-shaping capability. To what extent this deficiency of the neutron dose distribution contributed to the complications is difficult to tell. What is apparent in hindsight is that the dose specified for neutron therapy was too high, certainly for the M.D. Anderson and the University of California Los Angeles beams.

Much as we would like it to be true, we cannot agree with the con- cluding statement in the paper: “Fast neutron radiation therapy is sig- nificantly more effective than external beam photon radiation therapy in the treatment of locally advanced prostate cancer.” Survival and tox- icity, not just local control, have to be considered in the evaluation of treatment effectiveness, and by these measures, one might reasonably conclude that the therapeutic ratio achieved with fast neutron therapy was actually inferior to the result with photons. A future analysis will be necessary to resolve these important issues.

LESTER J. PETERS, M.D. Professor and Head Division of Radiotherapy M.D. Anderson Cancer Center

GUNAR K. ZAGARS, M.D. Professor of Radiotherapy Department of Radiotherapy M.D. Anderson Cancer Center

Fuks, Z.; Leibel, S. A.; Wallner, K. E.; Begg, C. B.; Fair, W. R.; Anderson, L. L.; Hilaris, B. S.; Whitmore, W. F. The eff& of local control on metastatic dissemination in carcinoma of the prostate: Long-term results in patients treated with “‘1 implantation. Int. J. Radiat. Oncol. Biol. Phys. 21(3):537-547; 1991. Kuban, D. A.; El-Mahdi, A. M.; Schellhammer, P. F. Prognosis in patients with local recurrence after definitive irradiation for prostatic carcinoma. Cancer 63:2421-2425; 1989. Russell, K. J.; Caplan, R. J.; Laramore, G. E.; Bumison, C. M.; Maor, M. H.; Taylor, M. E.; Zink, S.; Davis, L. W.; Griffin, T. W. Photon versus fast neutron external beam radiotherapy in the tmat- ment of locally advanced prostate cancer: Results of a randomized prospective trial. Int. J. Radiat. Oncol. Biol. Phys. 28:47-54; 1994. Zagars, G. K.; von Eschenbach, A. C.; Ayala, A. G.; Schultheiss, T. E.; Sherman, N. E. The influence of local control on metastatic dissemination of prostate cancer treated by external beam mega- voltage radiation therapy. Cancer 68~2370-2377; 199 1.

THE IMPORTANCE OF INCOMPLETE REPAIR, INTERFRACI’ION INTERVAL, AND FRACTIONAL DOSE

To the Editor: The authors, K. A. Mason et al., (I) presented a very interesting and important study, “Comparison of Continuous and Pulsed

Low Dose Rate Brachytherapy: Biological Equivalence in Viva.” This in vivo data shows that the incomplete repair model proposed by P. Nilsson et al. (2) quite accurately predicts the response of tumor and/or acutely responding tissue to irradiation. The indication that functional biological equivalence for an acutely responding tissue can be achieved with pulse dose rate higher than the upper limit of 3 Gy/h may have significant impact in the practice of brachytherapy. After reading this article, there are a few thoughts that we would like to ask the authors to comment on to improve our understanding of this subject.

How important is the quadratic component’s contribution to the biological effect of cell survival? In relation to the linear component, the magnitude of repairable damage from irradiation, the quadratic component, varies with the LX/@ ratio and the dose delivered per fraction. As in the model derived by P. Nilsson et al., the biological effect, E, may be written as:

E = a(m) + ,%.x2- C(n, p, z, At) (Es. 1)

where n = number of fractions or pulses x = dose per fraction r = exposure time of each fraction p = repair constant C = a function corrects for both repair during the irradiation and

incomplete repair between fractions At = interhaction interval

Table 1 shows the magnitude and relative proportion of the qua- dratic and linear terms for C = 1.0 (complete repair) and o/t!3 = 10 Gy, (Y = 0.23 Gy-’ vs. a’/#I’ = 2 Gy, a’ = 0.05 Gy-‘.

This simple calculation demonstrates that the importance of predicted cell survival from the quadratic term depends on the dose delivered per fraction as shown in Eq. I. The incomplete repair correction factor, C, modifies the degree of damage caused by xr for each fraction. The impact of C or cell survival may or may not be significant. From Table 1, it seems that even with 20% difference in C, the dose per fraction would still be the dominant factor over AC on survival. The dose per fraction chosen in this study, 0.7 Gy per pulse, belongs to the range of low dose par ii-action. The clinically used dose per pulse for high dose rate brachytherapy is much higher. The effect of interfraction interval At: As shown by P. Nilsson et al. the intertiion interval Al is an important factor in the repairing process. If the repetitive period between initiation of two consecutive exposures is T, (T = r + At), the importance of At may easily be observed by the following analysis. Using Nilsson’s data with mod- ification, the correction factor,. C, is shown in Fig. 1, as a function of 7, At, and t1/2, which is the repair half-time. An isoperiod curve is drawn on top of the curves published by Nilsson et al. for n = 3 fractions.

Figure la shows the isoperiod curve for T = 2t1/2. The correction factor varies within a narrow range, less than 20% in this case, with a

Table 1. The relative biological effectiveness of quadratic vs. linear component for each exposure

aI/3 = 10 a/p = 2 a = 0.23 a = 0.05

x=3Gy x=0.7Gv x=3Gv x=0.7Gv

CXX 0.69 0.161 0.15 0.035 b2 0.207 0.01127 0.225 0.01225

0.07 0.35 (7%) (35%)

BX’ *AC- - ax 8.7% 1.3% 30% 5.2%

*AC = 20%

* AC is the amount of variation of correction factor due to partial repair. The example above is the percent changes of /3x2/ ox as a result of 20% variation of C.