Hyperbaric oxygen in radiation therapy

HYPERBARIC OXYGEN IN RADIATION THERAPY JOHN R. GLASSBURN, MD,* LUTHER W. BRADY, MD,+ AND HENRY P. PLENK, MD, M S ~

The importance of oxygen with low LET radiations has been established beyond any doubt in many different systems, both plant and animal. While some studies, especially head and neck tumors, are impressive, it has not been demonstrated unequivocally that radiation under hyperbaric conditions is superior to well fractionated, well conceived, conventional radiotherapy. Any resulting gain in survival from the addition of hyperbaric oxygen will be limited, especially with more advanced stages of disease. Well controlled studies, especially with earlier stage disease, are still necessary. It would be worth- while to undertake such trials, especially with tumors of the head and neck constituting the most promising site of study, as others have noted: since even a 5% to 10% improvement in survival would mean many lives saved. Continued trials with hyperbaric oxygen, oxygen in other forms, neutrons and other particles, and radiation sensitizing drugs are all justified in an attempt to overcame the oxygen effect on human tumors.

Cancer 39:751-765, 1977.

HE USE OF HYPERBARIC OXYGEN TO DE- T crease anoxia in human tumors and to increase their radiosensitivity has been under clinical investigation for over 20 years. Gray and his colleagues" in 1953, first suggested the possible clinical use of oxygen when they published their results relating to the effect of oxygen as a factor in radiotherapy in a mouse Ehrlich ascites tumor and subsequently in other tumor systems. They demonstrated that the effect of oxygen on the response of the tumor to a given dose of radiation was greater than that on skin and hair. They postulated, therefore, that a substantial therapeutic gain could be achieved in the effec- tiveness of radiation with oxygen breathing.

However, many observations relating to the effect of oxygen in radiation therapy preceded this work. Hahn" in 1904, reported that local application of ice water during radiation reduced skin reaction. Hol thu~en '~ in 1921, found

Presented at the American Cancer Society National Con- ference on Radiation Oncology: Present Status and Future Potential, May 27-29, 1976, San Francisco, California.

From the Department of Radiation Therapy and Nuclear Medicine, Hahnemann Medical College and Hospital, Philadelphia.

* Associate Professor. ' American Cancer Society Professor of Clinical Oncology

and Professor and Chairman. Director, Radiation Center, L.D.S. Hospital; Clinical

Professor of Radiology, University of Utah, Salt Lake City. Address for reprints: John R. Glassburn, MD, Depart-

ment of Radiation Therapy and Nuclear Medicine, The Hahnemann Medical College and Hospital, 230 North Broad Street, Philadelphia, PA 19102.

Received for publication November 19, 1976.

that the radiation dose required to prevent As- caris eggs from hatching was three times as great in an aerobic environment as compared to air. Several i n v e ~ t i g a t o r ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ in the 1920s and the 1930s, noted that reducing blood supply to an irradiated area decreases the amount of radiation damage produced. Other in- vestigators68*28,22 confirmed the effect of anoxia in providing some degree of radiation protection to animals given whole body irradiation.

Early clinical observations also indicated that patients with marked anemia or poor circulation responded badly to radiotherapy" and this has been confirmed by more recent clinical re- p o r t ~ ~ ~ ~ ~ ~ ~ in patients with carcinoma of the cervix. Hill and his colleagues,'' using a mouse experimental model, demonstrated that the fraction of hypoxic cells in the tumors of anemic mice was twice as large as that in normal controls and stated, moreover, that anemia could reduce local control of tumor by 20%.

In a classic observation, Hultborn" reported that in patients irradiated preoperatively for carcinoma of the rectum the portion of the tumor which showed damage first was the region with the best blood supply. H e theorized that this selective damage was on the basis of better vas- cularization and increased proliferation of the cells in this area due to a higher oxygen concentration.

Thomlinson and Gray" demonstrated histo- logically that tumors tend to grow in solid mas- ses or cords which are not penetrated by capil- laries. They demonstrated that no tumor cord

751

752 CANCER February Supplement 1977 Vol. 39

more than 200 pm in radius was without central necrosis and no central necrosis was found in any tumor cord less than 160 pm in radius. Numerous animal studies were subsequently undertaken to attempt to define the proportion of hypoxic cells in various tumor

Estimates of the percentage of anoxic cells in these various models range from 1 % to greater than 50% depending on the tumor system investigated.

Cater and Silver' reported in 1960 on the polarographic measurements of oxygen tensions in tumors before and after radiotherapy with their results favoring the use of hyperbaric oxygen. Evans and Naylor,'? using the same method, demonstrated wide variations in the oxygen tension of human tumors. Breathing oxygen at four atmospheres produced an increase in oxygen tension at all tumor sites studied.

Thoday and Readg0 demonstrated that the effect of x-rays on broad bean roots was rapidly and dramatically changed by varying the oxygen concentration and that full radiosensitivity occurred after exposure to oxygen of about one minute, g'A8S.79 They also were the first to show that changes in oxygen tension post-radiation had no effect on radiosensitivity.

The first report of the use of oxygen in treating human tumors was by Hultborn and Forss- berg4' in 1954. They irradiated four patients with skin tumors with half of each tumor being irradiated in air at atmospheric pressure and the other half with the patient breathing oxygen at atmospheric pressure. They demonstrated an enhanced radiation effect in the portion of the tumor treated in oxygen. This was followed in 1955 by the report of Churchill-Davidson and his colleagues" who irradiated eight patients with a variety of tumors with half of each tumor being irradiated under hyperbaric conditions and half in air. In seven of the eight cases, biopsy specimens of the tumor were found to have more damage in the portion of the tumor irradiated under hyperbaric conditions.

Wildermuth, in 1964,"' summed up the radiobiologic basis of hyperbaric oxygen in radiation therapy as being due to four factors. First, anoxia results from cancer overgrowth. Second, anoxic cells are relatively radio-resistant. Third, anoxia is overcome by hybaroxia. Finally, hybaroxia does not increase radiosensitivity of normal tissues. This last fact is not completely true as shown by subsequent clinical experience that will be documented in the results of the trials to the present time.

For those interested in a complete review of the historical aspects of the effect of oxygen in

77,102,42,44.88.61

radiation therapy, we recommend the excellent and complete articles by Churchill-Davidson" and Wooton."' Much of the early work of the relationship between oxygen and radiosensitivity has also been reviewed by Patt.

COMPLICATIONS AND SIDE EFFECTS OF HYPERBARIC OXYGEN THERAPY

Effects on Normal Tissues

It was discovered rather early in the course of clinical trials that there were some normal human tissues which also experienced increased damage when irradiated in the presence of hyperbaric oxygen. Churchill-Davidson'o.8 had to reduce the dose when laryngeal cartilage was included in the irradiated area to avoid unacceptable complication of cartilage necrosis. He noted no apparent increase in damage to cartilage in other sites.

VandenBrenk and his colleagues loo analyzed a group of 357 patients receiving radiation therapy under hyperbaric conditions in an attempt to compare the incidence of radiation myelitis in this group to other reports of central nervous system damage following radiation in air. The authors concluded that the incidence of myelitis in hyperbaric oxygen appeared to be higher than in air but that a conclusive statement could not be made from this group. Churchill-David- son' in analyzing his cases could find no increase in incidents of radiation myelitis compared to other series reported for conventional radiotherapy.

Coy and Dolman," however, reported an incidence of 18% of myelitis at 9 months in a small group of patients treated in hyperbaric oxygen with 3600 rads in eight fractions over a 4-week period. A comparable group of patients treated in air failed to develop this complication; they concluded that hyperbaric oxygen indeed did increase the incidence of radiation myelitis.

Howard-Flanders and Wright" reported an increased radiosensitivity of growing cartilage in oxygen as compared to air in C57 black mice; however, no increased risk of bone necrosis in the presence of hyperbaric oxygen has been observed to date in rather extensive clinical experi- e nce .

Withers and Scott113 evaluated the effect of oxygen on the skin of a mouse and found increased sensitivity of the skin to the effects of radiation under hyperbaric oxygen conditions. The ratio of the damage under hyperbaric conditions to the damage produced with the radiation in air increased as the dose of radiation increased. VandenBrenk'? found that skin dam-

No. 2 HYPERBARIC OXYGEN IN RADIATION THERAPY Glassburn et a l . 753

age produced under hyperbaric conditions was increased at all dose levels. Again, the differential in damage between the air and the hyperbaric group was dependent on the dose fractionation. This work was also confirmed by the observations of Moss and Haddysz working with Sprague-Dawley rats.

Mucosal reactions also may be increased under hyperbaric conditions and difficulty in ob- taining healing of mucosal defects caused by massive tumor destruction has been encountered.'

Increased bowel damage is another potential complication when radiation is given under hyperbaric conditions. Johnson and Walton, " in a group of patients treated for advanced carcinoma of the cervix, noted a 16% incidence of serious bowel complications in the hyperbaric group compared to a 6% complication rate in the control group. We encountered similar prob- lems in patients treated for carcinoma of the cervix to such a degree that a dose reduction was necessary. 2 4 9 3 3 Bates".' reports on treatment for carcinoma of the cervix also confirm these observations. In the recent randomized trial conducted by the Radiation Therapy Oncology Group in the United States, an increased incidence of radiation bowel damage resulted in some deaths. More attention to limiting the dose from intracavitary radiation reduced complications significantly.

Two other papers are of special interest in relation to bowel sensitivity under hyperbaric conditions: Wiernik and Perrins"' evaluated the radiosensitivity of normal human rectal mucosa to irradiation in patients treated in air and oxygen by measuring the cellular content of serial biopsies from the rectum. These patients received ten fractions of 425 rads on a twice- weekly basis over 5 weeks. No quantitative difference in cellular damage following irradiation in hyperbaric oxygen could be demonstrated. No difference in acute bowel damage under hyperbaric oxygen or air, but an increase in late bowel damage, was observed by Johnson, et al." in rats treated with high pressure oxygen.

The weight of evidence suggests that hyperbaric oxygen when given to the pelvis does increase the incidence of serious bowel complications and in some cases has led to increased morbidity and mortality.

Effect of Oxygen on Distant Metastatic Disease

Johnsons1 was one of the first investigators to suspect a possible effect of hyperbaric oxygen on distant metastatic disease.

In his initial non-randomized series of patients treated for gynecologic tumors, 25% of the patients in the hyperbaric group were dead with metastatic disease, whereas, only 5% of the control group died from distant metastases during the first 6 months. In spite of an apparent increase in the incidence of metastases with hyperbaric oxygen, on a 5-year follow-up in the Stage I11 group 53% of patients treated with hyperbaric oxygen-as opposed to 18.7% of patients treated in air-were alive and free of disease. For Stage IV these figures were 25% for hyperbaric oxygen and 0% for air.66

Cade and McEwan,' in a controlled trial of patients treated for cancer of the bladder, noted twice as many patients who died of metastatic disease in the hyperbaric oxygen group as in the control air group. Wildermuth"' also felt from his observations that more patients treated under hyperbaric conditions demonstrated metastatic disease.

Several biologic experiments have demonstrated that increased oxygen tension may en- hance the development of neoplasms produced by carcinogenic stimuli due to radiation or

The initial observations by Johnson" relating to the possible increase in metastases led to numerous animal experiments. Dettmer et al." investigated the effect of oxygen on enhancing the growth of radiation-induced mammary tumors. They found that the high-pressure oxygen increased the incidence of tumors and decreased the time of development of the primary lesions; however, the bulk of the experimental evidence available at this time weighs against hyperbaric oxygen having any significant effect on development of distant metastases. Feder et aPO in a C3H mouse system could not demonstrate that hyperbaric oxygen increased the growth rate of distant metastases from locally implanted neoplasms. Evans" investigated a squamous-type skin cancer in C B A mice irradiated in hyperbaric oxygen and found a 14% distant metastatic rate in air and a 20% rate in oxygen. This difference was not significant and could be explained on other bases. Kluft and B~erema , '~ again using mice, demonstrated a slower development of tumor growth in animals receiving intermittent high pressure oxygen. Ackerman' investigated the "take" of tumor cells injected into Sprague- Dawley rats under conditions of hyperbaric oxygen at two atmospheres pressure in air. He was unable to demonstrate any difference in the frequency of the "take" or the size of the tumors which developed. Other investigators have also been unable to demonstrate an adverse effect of

chemicals. 71,70.40,41,16

754 CANCER February Supplement 1977 VOl. 39

hyperbaric oxygen on metastases6'@ in animal systems.

A review of the clinical work to date also supports the contention that no increase in the frequency of distant metastases or its rate of development can be demonstrated under hyperbaric conditions. Churchill-Davidson" in a non- randomized series of patients demonstrated that 26% of the patients treated in hyperbaric oxygen and 30% of a comparable air group demonstrated distant metastases. Henk3' in his randomized series of patients with tumors of the head and neck could demonstrate no difference in the incidence of metastases between the hyperbaric and air groups; however, in his patients with metastases, the control rate of the primary tumor was twice as great in hyperbaric oxygen as in air.

Johnson, 62 analyzing the incidence of distant metastases in a collected series of patients from a number of institutions, also could find no difference between patients treated in air or oxygen. Interestingly, VandenBrank" and his co-investigators, in evaluating the progression and development of metastatic lesions in patients receiving high-pressure oxygen for tumors of the head and neck, found a significant decrease in the incidence of distant spread in the high-pressure oxygen group, an observation which they concluded was due to improved control of the primary tumor. Certainly, the weight of evidence at the present time suggests that hyperbaric oxygen does not have a significant effect on increasing the incidence or growth rate of metastatic disease.

Complications Related to Direct Effect of Oxygen

Otic barotrauma is an obvious risk when using oxygen under pressure. Watson and Ba- nerjeelo7 found that this complication occurred quite frequently with accumulation of fluid in the middle ear and hemorrhages in the tym- panic membranes. These complications, however, usually resolved spontaneously and, in most cases, cause little or no symptoms. Rounthwaite and Banerjee" evaluated 57 patients who underwent over 1300 compres- sions; only one of this group required myringotomy. Thirty-nine of the patients, however, had some findings which resolved such as hem- orrhage, serous otitis, and transient hearing loss. Wildermuth"' found otalgia to be the most frequent complication in his first 100 patients. Fifty-four of the patients had symptoms and two required myringotomy. A skilled operator of the

chamber can reduce the incidence of barotrauma significantly.

Toxicity to the central nervous system" is also a danger for patients subjected to high-pressure oxygen with convulsions resulting from the direct toxic action of oxygen on the brain. Church- ill-Davidson" reported an incidence of four convulsions in 900 exposures in patients conscious during pressurization and one convulsion in an anesthetized patient. Watson and Banerjee"' had an incidence of two convulsions in a total of 107 patients who had undergone multiple com- pressions. In both of these cases, factors were present which might have stimulated their occurrence. VandenBrenk" reported an incidence of 0.3% convulsions in 3200 high-pressure oxygen exposures under anesthesia in 780 patients. A similarly low incidence has been experienced by other centers in unanesthetized patients.

Lastly, the risk of an explosive decompression was recognized from the inception of research with high-pressure oxygen; measures were in- corporated by all investigators in this field to minimize this possibility. One case of the explosive decompressionDa has been reported in the literature which resulted in injuries to the per- sonnel and patient, but no deaths. This occurred with a new prototype of machine which is no longer on the market.

Most of the complications encountered in treating patients under hyperbaric conditions were due to lack of experience and can now be avoided. Some increase in risks would be acceptable with demonstrated therapeutic gain.

PHYSIOLOGIC ASPECTS OF HYPERBARIC OXYGEN TREATMENT

Dose Fractionation

One of the most frequently encountered variables in the trials with hyperbaric oxygen has been the size of the dose and number of fractions employed. Since most conventional radiation therapy is given at the rate of 200 rads per treatment fraction on a five-day-week basis, the most obvious course was to add hyperbaric oxygen in hopes of demonstrating increasing tumor control and survivals. Suit and his coworkersa7 reported in 1967 on experiments with a D B A mouse mammary carcinoma that the effect of high-pressure oxygen in improving the results of radiation was dependent on the dose fraction schedule employed.

Withers and Scott"' produced a curve which exhibits the changing oxygen enhancement ratio with dose under anoxia, air and hyperbaric oxygen from skin of mice.

No. 2 HYPERBARIC OXYGEN IN RADIATION THERAPY Glassburn et al. 755

RCvksz and Littbrand" also conclude that no single value for oxygen enhancement ratio (0 E R) can define the modifying effect on survival and the relative sensitivity of anoxic and oxic populations will vary with the radiation dose delivered. Nias" demonstrated increased 0 E R with size of fraction in anoxia and air with 300-kV x-rays.

The change in the 0 E R in hyperbaric oxygen is more graphically demonstrated in Fig. 1 derived from experiments with Chinese hamster cells by Revtsz and Littbrand.81 It can be seen that in the first 150 to 200 rad the two curves are practically superimposed and it is only after we approach 400-500 rad that the curves divide significantly. When we plot the size of the indi: vidual fraction used in various unconventional treatment schemes with high-pressure oxygen in human trials, we find that the 0 E R of a 400- rad fraction is approximately 2.07, and of a 725- fraction is approximately 2.3.

also pointed out that the oxygen enhancement ratio was best improved by large fractional doses since the differential destruction between aerobic and anoxic cells occurs on the slope rather than the shoulder of the cell survival curve. Doses in the range of 500 to 700 rads are felt to be most effective to take advantage of the oxygen enhancement ratio in an tn vitro however, larger doses increase damage to the vasculature of both the tumor and the normal tissues included in the treatment field." This may result in unacceptable normal tissue damage and has the potential of causing tumor anoxia due to damage to the tumor vasculature.

RCvCsz in his work with fractionation regimens in combination with oxygen treatment concluded that hyperbaric oxygen is of therapeutic value only if used with large doses of radiation per fraction. Plenk747','6 and Di~che" '*~~ have stressed this point repeatedly on the basis of their own clinical experience, re- views of other clinical reports, and the radiobiologic data available.

Pressurization and Soaking Time Most investigators have chosen to treat

patients in hyperbaric oxygen at three atmospheres of pressure as this was found to be prac- tical in the unanesthetized patient and was un- likely to be complicated by barotraumati~~' effects. Good agreement exists regarding the "soaking" time necessary for optimal oxygenation of the tumor to 10 mm Hg minimum. Wooton115 found that 7 ?4 minutes was sufficient to reach this level although the time to reach

Rubin et

equilibrium throughout the tumor mass would be 22.5 minutes. Suit and Maeda,'"in work with a mouse mammary carcinoma, found that hyperbaric oxygen at four atmospheres of pressure for 15 minutes was quite effective in decreasing anoxia in small tumors and of intermediate ef- fectiveness for tumors containing grossly ne- crotic areas. Froese" also investigated the many variables affecting tumor oxygenation and soaking time. Most clinical investigators have con- sidered a minimum soaking time of 15 minutes to be adequate.

RESULTS OF CLINICAL TRIALS

Four tumor sites have been intensively investigated over the past 20 years, namely, head and neck, bronchus, bladder and uterine cervix. We will review briefly the results of the trials related to each of these areas as the success and experience with hyperbaric oxygen does vary from site to site.

Carcinoma of the Cervix Advanced carcinoma of the uterine cervix has

been investigated by at least 10 different groups using various fractionation schemes both with

"Oh OER 161

0.1 -

5 5 O.O1:

i :

0.001 1

o.Ooo1-

500 1WO 1503 2M)O 2500 3000

r m e (RI

FIG. 1. Oxygen enhancement ratio in oxically and anoxi- cally irradiated Chinese hamster cells. (Courtesy of RCvtsz and Littbrand)"


and without radium. Bates and Churchill-Da- vidson2' reported a group of 43 patients with Stage 11-B and I11 carcinoma of the cervix treated in hyperbaric oxygen delivering 3600 rads in six fractions over 18 days. Thirty-eight of these patients were Stage 111 and the survival at 5 years was 36% in this group. A significant incidence (five of 43 patients) of bowel necrosis was encountered in their series. The authors felt that a radium insertion was not necessary to achieve good results and their survival figure at 5 years is comparable to many of the conventional treatment programs reported in the literature.

A different approach was taken by Dische'* who investigated in a randomized trial a conventional fractionation program with a radium insertion in both the air and oxygen groups for Stage 11, I11 and IV-A cervical carcinomas. The one-year survival results favored the oxygen group; however, in the small number of patients followed for 5 years, the survival in the air group was superior, although no statistical significance could be demonstrated. Pelvic failures tended to occur earlier in the air group but again equal- ized at 5 years. Some increase in bowel morbidity was also noted with the addition of high- pressure oxygen. Local failure occurred in 15% in the oxygen group and in 42% of the air group in Stage I1 and I11 patients.

A similar conventional fractionation schedule was used by Watson et al."in a randomized trial delivering 4250 rads in 20 fractions and with each group also having a radium placement. No significant improvement was obtained with the addition of hyperbaric oxygen, although the results favored the hyperbaric group.

Johnson and Walton" also used conventional fractionation schedules but delivered higher doses with the patients receiving 5500 to 6500 rads in 27 to 32 fractions. Some of the patients also had radium placements. Again, the authors felt that the hyperbaric group had slightly improved results and that the failure to demonstrate a significant gain in tumor control was probably due to the oxygen vasoconstrictive effect at conventional doses.

Another study of considerable interest is that reported by Ward et a1.'06, utilizing 10 fractions of external radiation in air or hyperbaric oxygen and three insertions with the Cathetron for Stage 11-B and 111 carcinoma of the cervix. At the time of their preliminary report, 45 patients had been entered into this study with the air group having the best results.

Two other studies must be mentioned. Fletcher et a1." reported the results of a rando-

mized trial from M. D. Anderson Hospital of Stage I through IV-A carcinoma of the uterine cervix. This is by far the largest trial reported to the present time for this site and it includes 109 patients treated in the hyperbaric oxygen chamber and 125 patients treated in air. Treatment techniques were identical; conventional frac- tionations were used in both groups. The results in the air group appeared to be slightly better than those of the group treated in oxygen although the difference was not significant. The complication rate was similar in both groups.

I n the initial randomized trial conducted at Hahnemann utilizing conventional fractionation regimens, we were unable to demonstrate any improvement in survivals in the hyperbaric group due partially to an increased complication

Over the past several years, we have been participating in the national randomized trial." The patients treated in oxygen received 400 rads times ten over a 5-week period, plus a radium insertion, and the control group was treated with conventional fractionation plus radium. No difference in survival has been demonstrated to the present time and the study was discontinued because of increased bowel complications which led to severe morbidity and to one fatality. Limiting the intracavitary dose to 2000 rads to Point A has reduced complications significantly.

The ~ t ~ d i e ~ ~ ' ~ ' ~ ~ ~ ' ~ ' relating to treatment of carcinoma of the cervix with hyperbaric oxygen are summarized briefly in Table 1. No group has demonstrated to the present time that survival of patients with carcinoma of the cervix can be increased by the addition of hyperbaric oxygen although some of these failures can be ascribed to a poor choice of fractionation schedules. The complication rate in the experience of our group and in the experience of others has been significantly increased. The results of ongoing trials with shorter fractionation schedules will deter- mine the feasibility of further studies.

Carcinoma of the Lung Fewer trials are available to investigate the

efficacy of hyperbaric oxygen in the treatment of carcinoma of the lung. Randomized trials were reported by Cade and McEwan in 1968' and by Brown and Plenk." Both the oxygen and the control groups in Cade and McEwan's series received 6000 rads in forty fractions over an 8- week period with no significant difference between the two groups. I n 1968, their treatment program was therefore changed to a total of 3600 rads in 3 weeks with 600 rads per fraction


being delivered on a twice-weekly basis. As of 1972, their 3-year survival appeared better in the hyperbaric group." In Brown's and Plenk's small randomized series, the 1-year survival of the hyperbaric group was 65% compared to 22% for the air group, but this difference disappeared after 2 years.

Four other non-randomized series are noted in Table 2, all of which involved only small numbers of patients but did use more appropri- ate fractionation schedules. Plenk et al.1'916 reported the Salt Lake City experience with non- randomized groups. Forty-four patients were treated in hyperbaric oxygen with a 12-month survival of 44% and 24-month survival of 10%.

matched series of control patients had a 1-year survival of 5% and no survivors at 2 years.

VandenBrenk et al." and Wildermuth"* also reported on small numbers of patients and felt that patients treated in oxygen fared better than those treated in air although no significant difference could be documented.

Radiation therapy under any conditions for carcinoma of the lung is going to fail in the vast majority of patients because of widespread dis- semination of the disease process. It would be difficult to influence the long-term survival significantly with the addition of hyperbaric oxygen but this does not rule out better local control and better short-term survivals.

Ninety-seven patients were treated in air and had a 12-month survival of 28% and a 24-month Carcinoma of the Urinary Bladder survival of 8%. Most of the patients treated in air were treated in a period prior to start of hyperbaric oxygen therapy.

Churchill-Davidson" used six fractions of 600 rads each and achieved a 1-year survival of 23%, and a 2-year survival of 14% for this group. A

A significant amount of clinical experience has also been gained with the use of hyperbaric oxygen in carcinoma of the urinary bladder (Table 3). Cade and McEwan' reported the results of a randomized trial with 20 patients in each group using conventional fraction schedules delivering

TABLE 1. Trials in Carcinoma Cervix

#Pts. #Pts. Total Results Authors Randomized HPO Air dose Fx. time Sig favor

Churchill- No 43 - 3600 6 18-19 - H PO Davidson days

1. Bates&

2. Dische Yes 37 40 5500 27 5 % No Air + radium weeks

3. Watson Yes 62 63 4250 20 4 No HPO + radium weeks

4. Johnson & No 46 25 5500-6500 27- 6 No HPO Walton f radium 32 weeks

5. Ward e t a / . Yes 23 22 3150 10 29 No Air i- cathetron days

6. Lindberg & Yes 109 125 4000-6500 20- 4-8 No Air Fletcher + radium 36 weeks

7. Glassburn Yes 17 23 5000-6000 20- 6 N o Same et al. + radium 30 weeks

8. Glassburn Yes 13 20 6000air 30 5-6 No Same 4000 0, 10 weeks + radium

9. Watson& No 16 - 5000 25 5 Air Banerjee weeks

10. Tobin& Yes 7 7 daily dose fx's Vermund ?

No Air

11. Wiernik & Yes 13 19 4250 10 31 No HPO Perrins f radium days

758 CANCER Februaty Supplement 1977 Vol. 39

TABLE 2. Carcinoma of the Lung

#Pts. #Pts. Results Author Randomized HPO air Total dose Fx. Time Sig favor

1. Cade& Yes 25 24 6OOOrads 40 8 N o Same McEwan weeks

2. Plenk & No 44 - 4800 rads 12 32-42 No HPO Card days

3. Churchill- No 21 - 3500-3750 6 18 N o HPO Davidson e ta l . rads days

4. VandenBrenk N o 21 - 2400 rads 3 21 No HPO e t a l . days

days 3000 rads 6 17

5. Wildermuth No 22 - Dose not specified N o HPO

6000 rads in 40 fractions over 8 weeks. N o significant difference could be demonstrated although the air group had slightly better results. Wiernik and Perrins log reported a small randomized group of patients treated with 4250 rads in ten fractions over 31 days. The mean survival to death in the oxygen group was 400 days and of the air group was 327 days but no significant difference could be demonstrated in this small group.

Van den Brenkg6 reported a series of 43 non-

randomized patients treated with short fractionation schedules. He felt this group did better than comparable groups treated in air. A small randomized trial was reported with eight patients in each group with the air group receiving 3300 rads in four fractions in 22 days and the oxygen group receiving 3000 rads in four fractions over the same period. The author felt there was a significant difference in favor of hyperbaric oxygen.

Dische" reported the results for 67 patients

TABLE 3. Carcinoma Bladder

#Pts. #Pts. Results Author Randomized HPO Air Total dose Fx Time Sig favor

1. Cade & Yes 20 20 6000 rads 40 8 No Air McEwan weeks

2. Wiernik & Yes 8 13 4250 rads 10 31 No HPO Perrins days

3. VandenBrenk Yes 8 8 3300rads 4 17 Yes HPO air days

0 2 days

days

days

3000 rads 4 17

VandenBrenk No 43 - 3000 rads 3 21 - HPO

3000 rads 6 17

4. Dische Yes 34 33 * 6OOOrads 30 42 No Air days

days 4725 rads 15 33

5. Plenk Yes 19 21 4800 rads 12 4-6 Yes H PO 0 2 weeks

air 30 weeks 6000 rads 24- 6

6 . Jaffe & No 27 - 5000 rads 37 50 Air Kagan days

* A portion of both the air and 0, group were treated with each fractionation scheme.


treated with two different fractionation schemes and could demonstrate no benefit by the addi-

Brenk are encouraging and further work in this area may be indicated.

tion of hyperbaric oxygen. Plenk'' reported the results with 40 patients

randomized to oxygen and air with the oxygen group receiving 4800 rads in 12 fractions over 32 days and the air group receiving 6000 rads in 24 to 30 fractions over 42 elapsed days. The author concluded that, although a statistically significant difference at any one point could not be demonstrated, a comparison of the total curves by means of regression analysis of the logarithm of the proportion surviving vs time did demonstrate a significant improvement in favor of the oxygen series.

Certainly, the reports of Plenk and van den

Carcinoma of the Head and Neck The most convincing study to date is that

presented by Henk at the Fifth International Hyperbaric Congress in Vancouver, B. C . in August of 1973." It is not only distinguished by the large number, 277 patients, but also by the thoroughness of the analysis of the material and the several control studies comparing different fractionation techniques (Table 4).

Survival rates in high-pressure oxygen and air for a 5-year period are 45.3 and 36.8%, respectively, representing a 20% improvement with high-pressure oxygen over air which still is not

TABLE 4. Carcinoma of the Head & Neck

#Pts. #Pts. Results Author Randomized HPO air Total dose Fx Time Sig favor

1. Henk

Henk

Henk

2. Plenk

3. VandenBrenk

VandenB renk

4. Churchill- Davidson

5. Shigematsu

6. Chang ef al.

7. Sealy

8. Tobin& Vermund

Yes 143 152

Yes 22 16

Yes 14 13

No 111 -

No 162 -

Yes 17 12

No 102 -

Yes 21 21

Yes 26 25

No 33 -

Yes 9 8

3500-4500 rads

4150-4500 rads Ox 6300 rads

air

4150 rads

6300 rads 0 1

air

2900 rads 3600 rads 4800 rads

Multiple fx. schemes

2900 rads

3100 rads 0 1

air

3600 rads

4000-5000 rads 6000-7000 rads

4200 rads air

3600 rads 0 2

6000-6600 rads air 4500 rads

200 radsjfx.

10

10

30

10

30

4 6

12

4

4

6

8-10

8-10

7

6

30

9

total

3 weeks

3

6 weeks

weeks

3

6 weeks

weeks

18-22 days

21 days 21 days

19 days

4- 5 weeks

3 % weeks

3 weeks

6 weeks 4 M

weeks

dose?

No

No

No

No

No

No

No

No

No

No

No

HPO

HPO

HPO

HPO

H PO

H PO

HPO

HPO

HPO

Same

Same

760 CANCER February Supplement 1977 Val. 39

TABLE 5. Hyperbaria in Head and Neck Cancer: Survival in a 10 Fraction Trial (38)

(Courtesy of J. M. Henk and Simon Fraser University)

TABLE 7. 'Salvage', Surgery for Recurrent of Residual Local Disease

(Courtesy J. M . Henk and Simon Fraser University)

Survival rates Years after

start of OHP' Air* radiotherapy N L N L

1 125 71.5% 152 63.3% 2 82 56.8% 93 51.1% 3 56 48.0% 66 44.5% 4 40 45.3% 49 39.6% 5 30 45.3% 32 36.8%

N = No. of patients at risk at beginning of interval L = Proportion of patients alive at end of interval. * Difference not significant (p > .05) OHP-air

quite at a statistically significant level. (Table 5); however, analyzing recurrence-free status (tumor control probability) this difference at 5 years is very significant, P < 0.001 : HPO 54.6%, air 28% (Table 6).

The answer lies in the vast difference in the number of patients requiring salvage surgery for recurrent or residual local disease (Table 7). While 14 of 125 (11%) patients with HPO required surgery, 42 of 152 air patients (28%) had this procedure performed for local failure.

While primary control probability at 3 years is 40% in HPO and 33% in air in the most advanced lesions, a very significant difference of 76% and 39% is observed in the less advanced lesions (Table 8).

Henk points out that in the presence of a 46% anticipated incidence of distant metastases ac- cording to O'Brien, '' a totally effective local treatment would not be expected to improve the survival rate more than about 17% above that of the control group in this trial.

In order to answer the question whether or

TABLE 6. Hyperbaria in Head and Neck Cancer: Recurrence-free rate in 10 Fraction Trial (38)

(Courtesy of J. M. Henk and Simon Fraser University) ~

Recurrence-Free Rates (tumor control probability)

Years after start of OHP' AIR*

radiotherapy N L N L

1 125 62.6% 152 39.1% 2 67 57.2% 57 34.0% 3 50 54.6% 43 31.4% 4 38 54.6% 32 30.0% 5 30 54.6% 20 28.0%

N = No. of patients at risk at beginning of interval. L = Proportion of patients remaining free of local disease

* Difference significant, p < 0.001 OHP-air

at end of interval.

OH P AIR

No. of operations performed 14 4 2 p < 0 . 0 1

Unsuccessful 10 20 - Successful* 4 22p < 0.01

*i.e. patient free of tumour to date

not 10 fractions in air represent optimal treatment for the control group, a current Cardiff trial compares 10 fractions in HPO in 22 days with 30 fractions in 42 days in air, giving 6300 rad or an N S D of 1850 ret. Preliminary results already demonstrate a decided advantage in favor of the oxygen group. Another fractionation trial comparing 10 fractions and 30 fractions in air reveals almost identical results in the two groups.

Henk, therefore, has demonstrated beyond doubt that their 1 0-fraction treatment produces results comparable in every way to conventional methods used by other centers and that by comparison treatment with HPO produced a decided advantage over air when used in the short fractionation scheme employed a t Cardiff.

Preliminary results of a second trial" dealing with carcinoma of the larynx, with the hyperbaric group being treated in ten fractions over 3 weeks to a total of 4150 rads, compared to an air group receiving 6300 rads in 30 fractions, con- tinues to show a significant difference in local tumor control at last report.

Plenk7' reported the Salt Lake City experience in treating 111 consecutive cases of head and neck cancers in a non-randomized trial, dating back to the beginning of his oxygen experience. Several different fractionation schemes were used and the author felt that the results were at least comparable with those obtained by other methods of treatment, in spite of the fact that some of the treatment schedules employed with earlier patients were later recognized as in- adequate.

Advantages were cited as being of less tissue reaction, shorter treatment time and less ex-

TABLE 8. Primary Tumor Control Probability (Courtesy .J. M. Henk and Simon Fraser University)

Most Advanced Less Advanced

Years OHP AIR OHP A1 R

1 52% 42% 78% 49% 2 45% 35% 76% 42% 3 40% 33% 76% 39%


pense with HPO. Van den Brenke6 and Church- ill-Davidson" have also reported on large numbers of patients treated in hyperbaric oxygen for head and neck tumors. Both authors concluded that treatment in hyperbaric oxygen was superior to that in air and the complications for treating this are quite acceptable.

Shigematsu*' and his co-workers reported a group of 42 patients randomized to treatment in air or HPO with tumors of the maxillary sinus. The air group received 6000-7000 rad in 8 to 10 fractions over 4-5 weeks and the oxygen group 4000-5000 rad in 8-10 fractions over the same period. The recurrence-free rate was found to be better in the HPO at 1 year (47% vs 31%) as was the crude survival rate (63% vs 56%) although no significant difference could be demonstrated.

Chang, Conley and Herbert' treated 26 patients with hyperbaric oxygen, six times 600 rad in 3 weeks, and used two air control groups: 12 patients treated with seven times 600 rad in 3 weeks, and thirteen patients treated with 220 rad times thirty in 6 weeks. Five-year survivals were 38% in the HPO group and 25 and 22%, respectively, in the two control groups. The seven and 30-fraction groups in air gave surpris- ingly similar results.

The primary tumor control of the TsT4 lesions over 6 months was 65% in the HPO group and 48% in the combined control groups. Even with less than optimal radiation dose to the cervical lymph nodes because of planned combined radiation and surgery, the clearance rate of the nodes in H P 0 was 42% compared to 33% in the combined air groups.

Sealy el al.*' reviewed a series of 51 patients with cancer of the nasopharynx treated by chance in either oxygen or air. The results sug- gest that there may be an advantage from HPO as shown by death rate between 1-2 years, the 2- year survival rate and the local recurrence rate. This area seems to be the most fruitful site for further clinical investigation with hyperbaric oxygen for several reasons: 1) The data summarized in Table 4 indicate that oxygen will improve not only local tumor control but also survival rates. 2) It is an area in which tumors, even if locally advanced, usually do not dissemi- nate throughout the body until later in the course of the disease process; therefore, in most instances, all of the patients' active disease, even in the more advanced cases, will be encom- passed by the radiation fields. 3) The risk to neighboring normal tissues such as bowel does not exist and the spinal cord can be protected at

TABLE 9. Survival

(Courtesy A. H. W. Nias and Simon Fraser University)

OER for HeLa Cells at Different Levels of

Dose Dose under

level (rads) (rads) O E R

60 200 200 1.00 45 250 325 1.30 35 300 425 1.42 20 400 625 1.56 10 500 950 1.90 3 650 1450 2.23 1 800 1900 2.37 0.3 1000 2400 2.40

Survival in air hypoxia

safe tolerance levels. 4) All of the treatment can be given safely by external radiation under hyperbaric oxygen and the need for interstitial im- plants has been virtually eliminated.

Trials of Other Sites Some experience has also been gained with

the use of HPO in treating other sites. Church- ill-Davidson" treated eight patients with gliomas, delivering 3500 to 3750 rads in six fractions over 18 days, and was unable to demonstrate sterilization of tumor in any of the patients. Watson and Banerjee"' reported a 1- year survival for thirty patients with gliomas treated in hyperbaric oxygen of 43%. They compared this group of patients to a group of 944 patients treated in air with similar fractionation schemes of which 51.5% survived one year. Analysis of the first 28 randomized patients in the L D S Hospital experience7' treated with equal techniques in air and hyperbaric oxygen, i e, 12 X 400 rad in 32 days, reveals no significant difference in the two groups.

Chang7 reported preliminary results of a randomized trial utilizing various dose fraction- ations with 38 patients treated in hyperbaric oxygen and 42 patients treated in air. Although no significant difference could be demonstrated between the two groups, better control and survival was obtained in hyperbaric oxygen.

VandenBrenk and colleagues'o' evaluated the efficacy of hyperbaric oxygen in the treatment of sarcomas of bone and soft tissue and reported good tumor regression and frequent sterilization of the primary tumors.

Dische and Senanayake*' treated 22 patients with carcinoma of the colon and rectum in hyperbaric oxygen at two atmospheres of pressure with six fractions over 17 to 20 days, delivering a tumor dose minimum ranging from 2590 rads to 3490 rads. Eighteen of the patients completed

762 CANCER February Supplement 1977 VOl. 39

treatment. Of 15 patients in whom tumors could be palpated, eight had complete regression and seven partial regression of the tumor bulk. Com- plete symptomatic relief was obtained in 10 patients and partial relief in seven. These results certainly seem to be superior to most reports dealing with this problem. Favorable results have also been obtained in treating patients with salivary gland tumors with excellent control in hyperbaric oxygen.‘’

DISCUSSION Over the past 23 years, many clinical trials

have taken place to try to define the role of hyperbaric oxygen in improving control rates and survival when used in conjunction with radiation therapy in the treatment of malignant disease. There is no question that the basic radiobiologic data accumulated over many years confirms the importance of the oxygen effect. Why, then, is it that after many clinical trials and hundreds of treated patients, that a therapeutic gain with the addition of high-pressure oxygen to radiation has not been clearly demonstrated?

(1) The first reason may be the poor choice of patient material for these trials. As with any new mode of therapy, the most advanced patients or the patients for whom no satisfactory mode of therapy is available are utilized. In many of the studies mentioned, better local control of advanced disease was obtained but survival figures were not significantly changed due to death from distant disease. Certainly, patients with advanced carcinoma of the lung will rarely be cured by local therapy of any sort and assessment should be of local control rather than survival only.

(2) Many of the trials have also been un- controlled for a variety of reasons. Some investigators were so impressed with initial pilot studies they felt controls were not necessary or even unethical. In some, the population available for study was too small to allow sufficient data accumulation in a controlled study over a reasonable period of time. (3) Some programs were developed before the biologic data on the optimal dose frac-

tionation in high-pressure oxygen were available. It was reasonable under the cir- cumstances to make the addition of hyperbaric oxygen the only variable; however, when poor results were obtained under these conditions, many programs were abandoned. A consensus is developing now that no significant gain in therapeutic ratio can be expected by the addition of oxygen without a change in the fractionation scheme.

(4) Another problem encountered by investigators in this field has been an increase in normal tissue reaction, which is detailed in a previous section. O n a theoretical basis, the sensitivity of normally oxygenated cells should not be increased by the addition of oxygen; however, our own experience and that of others indicates that increased normal tissue damage does occur and in some tissues such as bowel and spinal cord has led to increased morbidity and complications, obviating the improved tumor control. ( 5 ) The main value of randomized studies is not in the use of identical techniques in air and oxygen but to decide whether the optimal techniques in oxygen will bring forth improvement over optimal techniques in air.

Hyperbaric techniques have helped to re-eval- uate conventional time-dose schedules and ra- diobiologists are pointing out directions in which such investigations may go. Though hyperbaric oxygen has not brought about the strik- ing enhancement of radiation effects observed in the laboratory, the more recent results with shorter fractionation schedules are much more encouraging. Results may improve if we learn to make optimal use of the method.

In view of the fact that so many patients with advanced disease die of their metastases, we may have to be satisfied with 10 to 20% improve- ments in survival even if the rate of local control should approach perfection. Inclusion of earlier stages may produce more significant differences. Larger, well controlled series followed over longer periods of time will be necessary to produce statistically significant results in many sites.

REFERENCES

1. Ackerman, N. B.: The effects of hyperbaric oxygen on the “take” of metastatic tumors in the liver and lungs. Fourth International Congress on Hyperbaric Medicine, Program Abstract, Sapporo, Japan, 1969; p. 62.

2. Bates, T. D.: The treatment of stage 3 carcinoma of the cervix by external radiotherapy and high-pressure oxygen. Br. J . Radio/. 42:266-69, 1969.

3. Bates, T. D., and Churchill-Davidson, I . : Hyperbaric

No. 2 HYPERBARIC OXYGEN IN RADIATION THERAPY Glassburn et a/ . 763

oxygen combined with radiotherapy for carcinoma of the cervix. Br. J . Radtol. 47:511-512, 1974.

4. Cade, I. S. and McEwan, J. 8 . : Megavoltage radiotherapy in hyperbaric oxygen. A controlled trial. Cancer 20:8 17-21, 1967.

5. Cater, D. B., and Silver, I. A.: Quantitative Measure- ments of Oxygen Tension in Normal Tissues and in Tumors of Patients before and after Radiotherapy. Acta Radiol 53:233-256, 1960.

6. Chang, C. H., Conley, J. J. and Herbert, C.: Radio- therapy of advanced carcinoma of the oropharyngeal region under hyperbaric oxygenation. A m . J . Roentgenol. 117:509-515, 1973.

7. Chang, C. H., Pool, J. L.: Radiotherapy of glioblas- toma multiforme under hyperbaric oxygenation: A prospec- tive study. Presented at the American Cancer Society Brain Tumor Symposium, Atlanta, George, February 1976.

8. Churchill-Davidson, I . : Long-term effects of hyperbaric oxygen and irradiation on non-neoplastic tissues. Front. Radint. Ther. Onrol. 1 :134-140, Karger, Basel/New York, 1968.

9. Churchill-Davidson, I: The Oxygen Effect in Radio- therapy-Historical Review. Front. Radial. Ther, Onrol. 1 :1-15, Karger, Basel/New York, 1968.

10. Churchill-Davidson, I . , Foster, C. A., Wiernik, G., et al.: The place of oxygen in radiotherapy. Br. J. Radiol. 39:321-331, 1966.

11. Church-Davidson, I . , Metters, J. S., Foster, C. A., Bates, T. D.: The management of cervical lymph node metastases by hyperbaric oxygen and radiotherapy. Clin. Ra- dio/. 24:498-501, 1973.

12. Churchill-Davidson, I., Sanger, C., Thomlinson, R. H.: High-pressure oxygen and radiotherapy. Lancrl I : 1091 - 1094, 1955.

13. Coy, P., and Dolman, C. L.: Radiation myelopathy in relation to oxygen level. Br. 3. Radiol. 44:705-707, 1971.

14. Crabtree, H. G., and Cramer, W.: The action of radium on cancer cells. 11. Some factors determining the susceptibility of cancer cells to radium. Eleventh Sci Rep Cancer Res, Fd. London, Taylor and Frances, 1934; pp. 89- 101.

15. Dettmer, C . M., Kramer, S., Gottlieb, S. F., Aponte, G . E. : Carcinogenic properties of increased oxygen tensions. I . Effects on radiation-induced mammary tumors. J . Notl . Cuncei Inst. 41 :751-756, 1968.

16. DiPaolo. J . A.: Influence of altered atmospheric oxygen on urethane-induced pulmonary tumors in mice. J . .Natl. Cancer Inst. 23535-540, 1959.

17. Dische, S.: The hyperbaric oxygen chamber in the radiotherapy of carcinoma of the bladder. Br. 3. Radiol. 46:13-17, 1973.

18. Dische, S.: The hyperbaric oxygen chamber in the radiotherapy of carcinoma of the uterine cervix. Br.3. Radiol. 47:99-107, 1974.

19. Dische, S.: Hyperbaric oxygen in radiotherapy, 1973. Presented at the International Congress of Radiology in Madrid, Spain, October 1973.

20. Dische, S.: Clinical trials with hyperbaric oxygen in radiotherapy. Oncology 1970 III:308-312. Diagnosis and Management of Cancer: General Considerations. Pro- ceedings of the Xth International Cancer Congress. Year- book Medical Publishers, 1971.

21. Dische, S., and Senanayake, F.: Radiotherapy using Hyperbaric Oxygen in the Palliation of Carcinoma of Colon and Rectum. Qin. Radiol. 23:512-518, 1972.

22. Dowdy, A. H., Bennett, L. R., and Chastain, S. M.: Protective action of anoxic anoxia against total body roent- gen irradiation of mammals. Radiologv 55:879-885, 1950.

23. DuSault, L. A.: Application of oxygen factor to clinical radiotherapy. Radiology 100:675-678, 1971.

24. Emery, H. W., Lucas, B. G . B., and Williams, A. G.: Technique of irradiation of conscious patients under increased oxygen pressure. Lancet 1 :248-250, 1960.

25. Evans, J. C.: Metastasis following radiotherapy in hyperbaric oxygen. Radiology 93: 1155-1 157, 1969.

26. Evans, J . C. and Bergsjo, P.: The influence of anemia on the results of radiotherapy in carcinoma of the cervix. Radiology 84:?09-717, 1965.

27. Evans, N. T. S. and Naylor, P. F. D.: The effect of oxygen, breathing and radiotherapy upon the tissue oxygen tension of some human tumors. Br. 3. Radiol. 36:418-425, 1963.

28. Evans, T. C., Goodrich, J. P., and Slaughter, J. C. : Temperature and radiosensitivity of skin of newborn rats. IV. Effects of decreased circulation and breathing during radiation. Radiology 38:201-206, 1942.

29. Faust, D. S., Brady, L. W., Kazem, I., Germon, P. A,: Hybaroxia and radiation therapy in carcinoma of the cervix. (Stage 111 and IV): A clinical trial. Fourth International Hyperbaric Congress Proceedings, 1969; pp 410-414.

30. Feder, B. H., Stein, J. J., Smith, T. K. et al.: The effect of hyperbaric oxygen on pulmonary metastases in C8h mice. R a d i d q y 90:1181-1184, 1968.

31. Fletcher, G. H., Lindberg, R. D., Caderao, J., Whar- ton, T.: The preliminary results of randomized trial of patients with late stage cancer of the uterine cervix using hyperbaric tank or atmospheric oxygen. Presented at Ameri- can Radium Society, May 1975. Cancer 39.

32. Froese, G.: The factors affecting tumour oxygenation. Fronl. Radiot. Ther. Oncol. 1 :16-26, Karger, Basel/New York, 1968.

33. Glassburn, J. R., Damskcr, J . I., Brady, L. W.. et al.: Hyperbaric oxygen and radiation in the treatment of advanced cervical cancer. Fifth International Hyperbaric Con- gress Proceedings. 11 313-819, Simon Fraser University, 1974.

34. Glassburn, J. R. and Brady, I.. W.: Unpublished data.

35. Gray, L. H. : Radiobiologic basis of oxygen as a modifying factor in radiation therapy. Am. J . Radiol. 85:803-815, 1961.

36. Gray, L. H., Conger, A. D., Ebert, M., Hornsey, S., Scott, 0. C. A.: The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br. J . Radiol. 26:638-648, 1953.

37. Hahn, R. : Einen Beitrag zur Rontgentherapie. Fortsrhr Geb Rdntgenstr. .Vuklearmed. 8: 120, 1904.

38. Henk, J. M.: Overcoming the oxygen effect: Hyper- baric oxygen or protracted fractionation. Fifth International Hyperbaric Congress Proceedings, Simon Fraser University. II:794-801, 1974.

39. Henk, J. M.: The influence of oxygen and hypoxia on laryngeal cancer management. Laryngoscop 85:1134-1144, 1975.

40. Heston, W. E., and Pratt, A. W.: Increase in induced pulmonary tumors in mice associated with exposure to high concentrations of oxygen. Proc Soc Exp Riof Med 92:451-454, 1956.

41. Heston, W. E., and Pratt, A. W.: Effect ofconcentra- tion of Oxygen on Occurrence of Pulmonary Tumors in Strain A Mice. J Nat’l Cancer Inst 22:70?-717, 1959.

42. Hewitt, H. B.: The effect on cell survival of inhalation of oxygen under high pressure during irradiation in rtvo of a solid mouse sarcoma. Br. J . Radiol. 39:19-24, 1966.

43. Hewitt, H. B., and Sakamoto, K.: The comparative survival of clonogenic cells of a murine epithelioma after irradiation in mice breathing air, oxygen and carbon dioxide or hyperbaric oxygen. Br. J . Radiol. 44:457-463, 1971.

44. Hill, R. P., Bush, R. S., Yeung, P.: The effect of anaemia on the fraction of hypoxic cells in an experimental

https://www.researchgate.net/publication/9759501_Quantitative_Measurements_of_Oxygen_Tension_in_Normal_Tissues_and_in_the_Tumors_of_Patients_Before_and_After_Radiotherapy?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0




https://www.researchgate.net/publication/236366277_Long-term_effects_of_hyperbaric_oxygen_and_irradiation_on_non-neoplastic_tissues_Front?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0




https://www.researchgate.net/publication/18207536_Megavoltage_Radiotherapy_in_Hyperbaric_Oxygen-a_Controlled_Trial?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0



https://www.researchgate.net/publication/18595425_Radiotherapy_of_Advanced_Carcinoma_of_the_Oropharyngeal_Region_Under_Hyperbaric_Oxygenation?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0




https://www.researchgate.net/publication/236361240_The_Oxygen_Effect_in_Radiotherapy-Historical_Review?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0

https://www.researchgate.net/publication/236361240_The_Oxygen_Effect_in_Radiotherapy-Historical_Review?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0

https://www.researchgate.net/publication/18545333_The_management_of_cervical_lymph_node_metastases_by_hyperbaric_oxygen_and_radiotherapy?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0










tumor. Br. 3. Radiof. 44:299-304, 1971. 45. Holthusen, H.: Beitrage zur Biologie der Strahlenwir-

kung. Untersuchungen an Askarideneiern. Pfliiegers Arch. 187:1, 1921.

46. Howard-Flanders, P., and Wright, E. A.: Effect of oxygen on the radiosensitivity of Rrowing bone and a pos- . - sibl; danger in the use of oxygen during rabiotherapy. . N h r e 175:428-429. 1955.

47. Hultborn, K. A, : Cancer of the colon and rectum. Acta C.’hir. Scand. [Suppf] 172:143-155, 1952.

48. Hultborn, K. A., and Forssberg, A, : Irradiation of skin tumours during pure oxygen inhalation. ‘4rla Radio/., Slockh. 42:475-484, 1954.

49. Jaffe, H. L. and Kagan, A. R. : Daily Hybaroxic Ra- diotherapy. Am. 3. Radio/. 158-162, 1972.

50. Johnson, R. E., Kagan, A. R. , Bryant, T. L.: Hyper- baric oxygen effect on experimental tumor growth. Radiology 88:775-777, 1967.

51 . Johnson, R. J . R.: Gynecological cancer treated with cobalt under hyperbaric conditions: Front. Radiat. 7 h e 7 Oncol. I:149-155. Karger, Basel/New York, 1968.

52. Johnson, R. J. R . : Results of randomized trials. Fifth International Hyperbaric Congress Proceedings. Simon Fra- ser University. 11:837, 1974.

53. Johnson, R. J. R., and Walton, R. J.: Sequential study on the effect of the addition of hyperbaric oxygen on the five-year survival rates of carcinoma of the cervix treated with conventional fractional radiation. Am. 3. Rocntgmol. 120:lll-117, 1974.

54. Johnson, R. J. R. , Wiseman, N. , Hog, G. R.: Radi- ation-induced bowel damage in rats treated under conditions of air or hyperbaric oxygen. Clin. Radioi. 23:106-109, 1972.

55. Johnson, R. J. R.: Personal Communication, ,January 1970.

56. Jolly, J.: Action des Rayons X sur les Cellules. Modi- fications de la Radio-sensibilit6 par Ligature des Con- nexions Vasculaires. C‘. R. .Soc. B i d . (Paris) 91:351-354, 1924.

57. Kluft, 0. and Boerema, I.: Hyperbaric oxygen in experimental cancer in mice: Clinical application of hyperbaric oxygen. New York, Elsevier Publishing Company,

58. Lacassagne, A.: Chute de la Sensibilite aux Rayons X Chez la Souris Nouveau-nCe en etat D’AsphyxiC. C. R. A m d . Sci. (Paris) 215:231-232, 1942.

59. McCredie, J. A,, Inch, W. R., Kruuv, J., Watson, T. A.: Effects hyperbaric oxygen on growth and metastases of the C,HBA tumor in the mouse. Cancer 19:1537-1542, 1966.

60. McEwan, J . : Hyperbaric oxygen as an adjuvant to megavoltage radiotherapy. Rr. 3. Radiol. 45:395, 1972.

61. Milne, N., Hill, R. P., Bush, R. S.: Factors affecting hypoxic K H T tumor cells in mice breathing O,, O1 + CO,, or hyperbaric oxygen with or without anesthesia. Radiology 106:663-671, 1973.

62. Moss, W. T. , and Haddy, F. J.: The relationship between oxygen tension of inhaled gas and the severity of acute radiation pneumonitis. Radiology 75:55-58, 1960.

63. Mottram, J. C.: O n the skin reactions to radium exposure and their avoidance in therapy; An experimental investigation. Br. 3. Radio/. 29:174-180, 1924.

64. Mottram, J. C. : A factor of importance in the radiosensitivity of tumors. Br. 3. Radiof. 9:606-614, 1936.

65. Mottram, J. C., and Eidinow, A.: O n the effect of anaemia on the reactions of the skin and of tumors to radium exposure. Br. 3. Surg. 19:481-487, 1932.

66. Nias, A. H. W.: The oxygen enhancement ratio of mammalian cells under different irradiation conditions.

1964; pp: 126-136.

Fifth International Hyperbaric Congress Proceedings, Van- couver, B. C., Canada. II:650-659, 1974.

67. O’Brien, P. H. , Carlson, R., Steubner, E. A,: Distant metastases in epidermoid cell carcinoma of the head and neck. C.hncrr 27:304-307, 1971.

68. Parker, R . G., and Wooton, P.: Physiological evaluation of patients subjected to hyperbaric radiation therapy. Fronl. Rndia f . 7ht -7 . ORCO/. 1:llO-118. Kargcr, Basel/New York, 1968.

69. Patt, H. M.: Protective mechanisms in ionizing radiation injury. Physzof. Reo. 33:35-76, 1953.

70. Plaine, H. L.: The effects of oxygen and hydrogen peroxide on the action of a specific gene and on tumor induct ion in drosophila melanogas ter. C ; e n e h 40: 268- 280, 1955.

71. Plaine, H. L. and Glass, G.: The effect of oxygen upon the induction by x-rays of melanotic tumors in drosophila melanogaster. Cancer Res. 12:829-833, 1952.

72. Plenk, H . P.: Hyperbaric radiation therapy in head and neck malignancies; an evaluation of time-dose schules and review of 11 1 cases. Fifth International Hyperbaric Con- gress Proceedings, Simon Fraser University. 829-836, 1974.

73. Plenk, H . P.: Hyperbaric radiation therapy. Prelimi- nary results of a randomized study of cancer of the urinary bladder and review of the oxygen Experience. Am. ,7. Roenlge- nol. 114:152-157, 1972.

74. Plenk, H. P.: Hyperbaric oxygen radiation therapy: Time-dose schedules and present status. I n Fraction Size in Radiobiology and Radiotherapy. T. Sugahara, L. RCvCsz, and 0. C. A. Scott, Eds.: Tokyo, Igaku Shoin, Ltd, Balti- more, The Williams and Wilkins Company, 1974.

75. Plenk, H . P. and Card, R. Y . : Hybaroxic radiation therapy. A review of two years’ experience with 167 patients. .Am. .7. Rnetilgcnof. 99:900-914, 1967.

76. Plenk, H. P.: Present status of hyperbaric radiation therapy. Refresher Course delivered at the RSNA, 1974; monograph privately published by author.

77. Powers, W. E., and Tolmach, L. J.: A multi-component x-ray survival curve for mouse lymphosarcoma cells irradiated in uirm. Ahinturr (London) 197:710-711, 1963.

78. Powers, W. E., and Tolmach, L . J . : Demonstration of an anoxic component in mouse tumor cell population by in wtw assay of survival following irradiation. Radiology 83:328-335, 1964.

79. Read, J.: The effect of ionizing radiation on the broad bean root. Part X. Br. .7. Radiof. 25:89-99 and 154-160, 1952.

80. RCvCsz, L: Clinical trials with a dynamic fractionation regime in combination with oxygen treatment. Theo- retical basis and preliminary results. Fifth International Hy- perbaric Conference, Simon Fraser University, 1974, 782-793.

81. RCvCsz, L. and Littbrand, B.: Variation of the oxygen enchancement ratio at different x-ray dose levels and its possible significance. In Advances in Radiation Research Biology and Medicine, vol. 3. J. F. Duplan and A. Chapiro, Eds. London, Gordon and Breach, 1974; pp. 1215-1224.

82. Rounthwaite, F. J., and Banerjee, P.: Hyperbaric oxygen radiotherapy and the need for preliminary myringotomy. Larngosrope 78:2153-2159, 1968.

83. Rubin, P., Poulter, C. A., Quick, R. S.: Changing perspectives in oxygen breathing and radiation therapy. Am. .7. Roenfgenol. 105:665-681, 1969.

84. Sealy, R. , Helman, P., Greenstein, A,, Shepstone, B.: T h e treatment of locally advanced cancer of the head and neck with intra-arterial cytotoxics, cobalt and hyperbaric oxygen therapy. Cancer 34:497-500, 1974.

85. Sealy, R. , Berry, R. J., Ryall, R . D. H . , Miller,

No. 2 HYPERBARIC OXYGEN IN RADIATION THERAPY Glassburn el al. 765

E. E. D., Sellars, S. L.: The treatment of carcinoma of the nasopharynx in hyperbaric oxygen: An outside assessment. Submitted for publication to Radiation Oncology.

86. Shigematsu, Y., Fuchihata, H., Makino, T., and In- oue: Radiotherapy with reduced fraction in head and neck cancer, with special reference to hyperbaric oxygen radiotherapy in maxillary sinus carcinoma (a controlled study). In Fraction Size in Radiobiology and Radiotherapy, Ed T. Sugahara, L. Rkvksz, and 0. C. A. Scott, Eds. Igaku Shoin Ltd. Tokyo; Baltimore, The Williams and Wilkins Com- pany, 1974; pp. 180-187.

87. Suit, H., Lindberg, R., Suchato, C., Ozenne, A.: Radiation dose fractionation and high-pressure oxygen in radiotherapy of the D B A mouse mammary carcinoma. Am. J . Roentgenol. 99:895-899, 1967.

88. Suit, H., and Maeda, M.: Oxygen effect factor and tumor volume in the C,H mouse mammary carcinoma. Am. .7. Roentgenol. 96:177-182, 1966.

89. Thoday, J. M., and Read, J.: Effect of oxygen on the frequency of chromosome aberrations produced by x-Rays. .Vature (London) 160:608, 1947.

90. Thoday, J. M., and Read, J.: Effect of oxygen on the frequency of chromosome aberrations produced by alpha rays. Nature (London) 163:133-134, 1949.

91. Thomlinson, R. H.: The oxygen effect in mammals. Br. J . Cancer 14:555-576, 1960.

92. Thomlinson, R. H., and Gray, L. H.: The histological structure of some human lung cancers and the possible implications for radiotherapy. Br.J. Cancer 9:539-549, 1955.

93. Tobin, D. A,: Explosive decompression in a hyperbaric oxygen chamber. Am. 3. Roentg. 622:624, 1971.

94. Tobin, D. A. and Vermund, H.: A randomized study of hyperbaric oxygen as an adjunct to regularly fractionated radiation therapy for clinical treatment of advanced neoplastic disease. A m . J . Roentgenol. 111:613-621, 1971.

95. van den Brenk, H. A. S.: Hyperbaric oxygen in radiation therapy: Investigation of dose-effect relationships in tumor response and tissue damage. A m . J . Roentgenol. 102:s-26, 1968.

96. van den Brenk, H. A. S.: Increased radiosensitivity of skin in humans irradiated in 4 ATA oxygen pressure. Front Radial. 7 h e r Oncol. I : 141-148, Karger, Basel/New York, 1968.

97. van den Brenk, H. A. S., Kerr, R. C., Richter, W., Papworth, M. P.: Enhancement of radiosensitivity of skin of patients by high-pressure oxygen. Br. 3. Radiol. 383357464, 1965.

98. van den Brenk, H. A . S., Madigan, J. P., Kerr, R. C.: An analysis of the progression and development of metastases in patients receiving x-radiation in hyperbaric oxygen. Clin. Radiol. 18:54-61. 1967.

99. van den Brenk, H. A. S., Madigan, J. P., Kerr, R. C.: Experience in Melbourne with use of hyperbaric oxygen combined with megavoltage radiation in 614 cases of advanced malignant disease. Fronl. Radiat. Ther. Oncol. I:162-174, Karger, Basel/New York, 1968.

100. van den Brenk, H. A. S., Richter, W., Hurley, R. H.:

Radiosensitivity of the human oxygenated cervical spinal cord based on analysis of 357 cases receiving 4-MeV X-rays in Hyperbaric Oxygen. Br. .3. Radiol. 41:205-214, 1968.

101. van den Brenk, H. A. S., Kerr, R. C., Madigan, J. P., Cass, N. M., Richter, W.: Results from tourniquet anoxia and hyperbaric oxygen techniques combined with megavoltage treatment of sarcomas of bone and soft tissues. Am. 3. Rorntgmol. 96:760-776, 1966.

102. Van Putten, L. M., and Kallman, R. F.: Oxygen- ation of a transplantable tumor during fractionated radiation therapy. 3. Null. Cancer Instit. 40:441-451, 1968.

103. Van Putten, L. M., and Kallman, R. F.: Effects of pre-irradiation on the ratio of oxygenated and anoxic cells in a transplanted mouse tumor. Front. Radial. Ther Oncol. I:27-37, Karger, Basel/New York, 1968.

104. Vigario, G., Kurohara, S. S., George, F. W.: Associ- ation of hemoglobin levels before and during radiotherapy with prognosis in uterine cervix cavity. Radiology 106:649-652, 1973.

105. Ward, A. J., Stubbs, B., Dixon, B.: Carcinoma of the cervix: Establishment of a hyperbaric oxygen trial associated with the use of the cathetron. Br. J . Radiol. 47:319-325, 1974.

106. Watson, E. R., Morris, S., Halnan, K. E.: Hyper- baric oxygen and radiotherapy in advanced carcinoma of the cervix. I n Gynecologic Cancer, T. J. Deeley, Ed. New York, Appleton Century Crofts, 1971; pp. 53-60.

107. Watson, T. A., and Banerjee, P.: Clinical experience with hyperbaric oxygen in radiotherapy. J . Can. Assoc. R a -

108. Wiernik, G., and Perrins, D.: The radiosensitivity of normal human rectal mucosa to irradiation in hyperbaric oxygen. Br. 3. Radiol. 45:737-744, 1972.

109. Wiernik, G., and Perrins, D. J. D.: Hyperbaric oxygen and radiotherapy in advanced carcinoma of the cervix and bladder. Fifth International Hyperbaric Congress Pro- ceedings, Vancouver, B. C . II:820-829, 1974.

110. Wildermuth, 0.: Hybaroxic radiation therapy in cancer management. Radiology 82:767-777, 1964.

111. Wildermuth, 0.: The present status of hybaroxic radiotherapy: A perspective view from five years’ clinical experience. Rad (,‘lfniG5 of.North ‘4m. VII :345-351, 1969.

112. Wildermuth, 0:: The Seattle experience with hybaroxic radiotherapy. Front. Radiat. Ther. Oncol. I : 175-182, Karger, Basel/New York, 1968.

113. Withers, H. R. and Scott, 0.: The oxygen effect in normal tissues. Br. .J. Radiol. 37:720, 1964.

114. Withers, H..R., and Scott, 0. C. A.: British Empire Cancer Campaign Report, 1964, 233.

115. Wooton, P.: An approach to the determination of individual patient soaking times in hyperbaric oxygen radiation therapy. In Frontiers of Radiation Therapy and On- cology, Proceedings of the First Annual San Francisco Can- cer Symposium. S. Karger, Basel/New York, 1968. I:90-97.

116. Wooton, P: Oxygen as a radiotherapeutic adjuvant. Prog. Radia. Ther. II:94-113. Grune and Stratton, 1962.

dlfJ/. 20:132-137, 1969.

https://www.researchgate.net/publication/5740715_Effect_of_oxygen_on_frequency_of_chromosome_aberrations_produced_by_alpha-rays?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0




https://www.researchgate.net/publication/240049613_Effect_of_Pre-irradiation_on_the_Ratio_on_Oxygenated_and_Anoxic_Cells_in_a_Transplanted_Mouse_Tumor?el=1_x_8&enrichId=rgreq-c811bd13306fccfe467af7fe0323a4bb-XXX&enrichSource=Y292ZXJQYWdlOzIyODE3NDI1O0FTOjE2MzQzOTI4MDQwMjQzNkAxNDE1OTc4MzY5NTU0







Date post:	04-Dec-2023
Category:	Documents
Upload:	independent
View:	0 times
Download:	0 times

Hyperbaric oxygen in radiation therapy

Documents