P duce a major symptom complex pose a challenging. Palliative Treatment of Advanced Cancer Using Multiple Nonconjluent Pencil Beam Radiation

Transcription

1 Palliative Treatment of Advanced Cancer Using Multiple Nonconjluent Pencil Beam Radiation A Pilot Study Mohammed Mohiuddin, MD, Danny Lee Curtis, MD, William T. Grizos, MD, and Lydia Komarnicky, MD In the era of orthovoltage radiation, multiple nonconfluent pencil beam radiation (GRID) therapy was utilized to minimize superficial normal tissue damage while delivering tumorcidal doses at specified depths in tissues. The success of GRID therapy was based on the fact that small volumes of tissues could tolerate high doses of radiation. Since the development of megavoltage radiation and skin sparing, GRID therapy has been abandoned. In a pilot study, the authors adapted the principles of GRID therapy to megavoltage photon beams to treat patients with massive tumors or recurrent tumors after tolerance doses of radiation. Twentytwo patients have been entered in the study. All patients were symptomatic and had exhaustive conventional surgery, chemotherapy, and radiotherapy approaches to treatment. A 5050 GRID (open to closed areas) was utilized, and a prescribed dose of 000 to 500 cgy to the open areas was given using a single photon field. In four patients, a second GRID treated was delivered at a split course interval of 4 weeks. The followup in these patients ranges from month to 8 months. The results of treatment have been remarkable with 0 of patients achieving dramatic relief of severe symptoms, and several patients showing significant objective regression. No acute effects have been observed, including those patients having large volumes of the abdomen irradiated. No unusual skin or subcutaneous early or late damage has been observed in followup. Cancer 66:48,990. ATIENTS WITH MASSIVE or bulky tumors that pro P duce a major symptom complex pose a challenging problem for the oncologist. Although local tumor control may today be an unrealistic goal, even the palliation of symptoms with our conventional treatment approaches have a limited probability of success because of the large size of these tumors and/or unfavorable histologic types. A majority of these patients have already been treated with maximum surgery and convention tolerance doses of chemotherapy and radiotherapy. Innovative new approaches are, therefore, required for Presented in part at the 7st Annual Meeting of the American Radium Society, St. Thomas, US Virgin Islands, April 5 9, 990. From the Department of Radiation Oncology and Nuclear Medicine, Thomas Jefferson University Hospital, Philadelphia. Address for reprints: Mohammed Mohiuddin, MD, Department of Radiation Oncology, Thomas Jefferson University Hospital, 05 Walnut Street, Philadelphia, PA Accepted for publication March 0, 990. effective delivery of higher radiation doses. Our experience in the 960s with orthovoltage radiation indicated that high cumulative radiation doses (>,000 rad) could be delivered using spatially fractionated (GRID) radiation therapy' with acceptable normal tissue tolerance. We therefore modified the use of this orthovoltage technique and developed a multiple nonconfluent pencil beam radiation (GRID) approach with megavoltage radiation to treat these special categories of patients, that is, those who had either been treated to tolerance with conventional radiation or who had massive tumor bulk that was unlikely to benefit from conventional therapies. Materials and Methods From 985 to 988, patients have been entered onto this study. These included nine patients with sarcomas, six patients with recurrent gastrointestinal cancer, three with massive liver metastases, and four patients with mis 4

2 No. TREATMENT OF CANCER USING GRID * Mohiuddin et al. 5 cellaneous tumors. All patients presented with significant symptoms and most had exhausted conventional surgery, chemotherapy, and radiotherapy approaches to their treatment (Table ). A 5050 GRID (open to closed areas) was utilized, and patients were treated on a Phillips Linac 755 megavoltage unit with photon energy of 6 mev. A sourcetoskin distance of 00 cm was maintained for all treatments. Single unopposed fields were used in all cases. In four cases the GRID treatment was repeated at a 4 week interval. Maximum field sizes of the GRID were 5 X 5 cm; and where the tumor field extended beyond this, the GRID fields were matched on the skin. Tumor doses were prescribed to maximum dosage (DMax) in the open areas of the GRID. The GRID itself was constructed in the workshop of the Department of Radiation Oncology at Thomas Jefferson University Hospital (Philadelphia). It was made as follows. Two 6.35mm thick Lucite plates (Rohm & Haas Co., Philadelphia, PA) were aligned in parallel 6.4 cm apart by four aluminum spacers bolted at the corners of the Lucite. Each plate contained 4 holes which were arranged in a triangular lattice so that there was a 50% open and 50% blocked area (5HVL) over a total 5 cm X 5 cm field. The corresponding holes were spaced on the front and back plate in such a way as to take into account the divergence of 6meV photon beams at the specified source diaphragm distance of 66 cm. Stainless steel tubing, 0.8 mm thick, with an inside diameter of 7.9 mm was inserted through the holes. Then, 58 C Cerrobend alloy (Acme Alloys, Philadelphia, PA) was poured to fill in all space between the stainless steel tubes. The GRID is shown in Figure. It would be classified as a hexagonal array sieve as described by Loevinger. The radiation dose distribution using our GRID with MV photons was described by Mitev and S~ntharalingham.~ doses delivered ranged from 000 cgy to 500 cgy. Six patients had previously received prior radiation to = 5000 cgy. The size of tumors treated ranged from 6 X 5 cm to 5 X 5 cm, and the average dimension of TABLE. Distribution of Patients FIG.. The Jefferson Hexaboard Array GRID that fits into the alloy tray of the linear accelerator. the fields treated was 4 X 4 cm. Fourteen patients were given additional externalbeam radiation together with the GRID. Followup in these patients ranges from to 8 months. Patients were analyzed for relief of symptoms, subjective and objective response, and acute and late tissue effects. No attempt was made to correlate with survival as this essentially was a palliative mode of treatment. Results All patients in this study were carefully followed to assess acute and late normal tissue effects (Table ) and to observe responses to treatment. The acute tolerance of the patients was exceptionally good with only one of patients developing skin erythema. In this patient who was treated for massive hepatomegaly, two appositional GRID fields were matched on the anterior abdominal wall with a total irradiated area of 30 X 5 cm. The erythema developed within 5 minutes of the GRID treatment and lasted for 4 hours. There was no pruritus, and the erythema subsided spontaneously. No other patients have manifested skin reactions in the acute or subacute phases. No subcutaneous fibrosis has been observed. Osteosarcoma Liposarcoma Leiom yosarcoma Colorectal CA Liver Squamous (vagina) Renal cell CA Melanoma Adeno CA (prostate) No. of Prior Concurrent patients XRT XRT TABLE. Complications Acute toxicity Nausea /* (7%) Diarrhea / (7%) Erythema / (5%) Hematologic 0 (0%) Neurologic 0 (0%) Late toxicity Small bowel / (8%) Tissue necrosis 0/ (0%) Lymphedema 0 (0%) Neurologic 0/ (0%) CA: carcinoma: XRT: radiation therapy; Adeno CA adenocarcinoma. * Twelve patients received abdominal fields.

3 6 CANCER July 990 Vol. 66 TABLE 3. Response Rate as a Function of the Four Most Common Symptoms response Symptoms no. CR(%) PR(%) CR+ PR NR(%) Pain 9 5(6) (67) 89% (7) Edema 3 3(00) 00% Bleeding 4 4jlOO) 00% Mass effect 5 4 (80) 80% CR: complete response; PR: partial response; NR: no response. Of patients that underwent GRID treatment over an abdominal field, two patients developed diarrhea that was mild and controlled by medication. One patient developed a transient small bowel obstruction which was treated by surgical lysis and is now 7 months posttreatment for a recurrent rectal cancer. This patient had received a total of 7000 cgy radiation to the presacral space and was thereafter boosted with the GRID field for an additional 000 cgy. Of these patients, nausea and vomiting were reported in two patients who underwent GRID treatment to their liver. No untoward late effects have been observed to date. The longest surviving patient has been followed for 8 months, and received two GRID treatments delivered over the brachial plexus and shoulder area for a recurrent sarcoma after 7000cGy conventional treatment. She had marked improvement with complete resolution of symptoms of a frozen shoulder. No subsequent nerve damage or skin changes have been observed. Clinical responses were observed in 0 patients and are shown in Table 3. Pain was the primary reason for treatment in 9 patients and was relieved totally in five (6%) and partially in I (67%) patients. Massive leg edema was partially relieved in three of three patients. Clinical responses as a function of histology are shown in Table 4 and were seen primarily in patients treated FIG.. Massive retropentoneal liposarcoma of the left psoas origin (pretreatment). with the GRID treatment plus externalbeam radiation to doses of 5000 cgy. Two of six patients with osteogenic sarcoma and two of six patients with rectal cancer obtained complete resolution of symptom complexes due to bulky tumor as measured on radiographic studies and confirmed on clinical evaluation. Two of four patients with miscellaneous tumors, (one with melanoma and one patient with squamous cell carcinoma of the vagina) also had complete resolution of disease for an overall complete response (CR) rate of 7% (6/). Partial responses (PR) were observed in 4 other patients (64%), and two patients had no subjective or objective regression of disease or symptom complex. The overall response rate was 0 of (9 %). Grade and no Grade 4 toxicity was observed, comparing well with conventional therapy. TABLE 4. Clinical Response Rate as a Function of Histologic Type response No. of Histologic type patients CR (%) PR (%) CR + PR (%) NR (%) Osteosarcoma 6 (33) 4 (67) 6 (00) Liposarcoma (50) l(50) I(50) Leiom yosarcoma l(00) (00) Colorectal 6 (33) 4 (67) 6 (00) Liver ( ) 3 (67) (67) l(33) Miscellaneous* 4 (40) (50) 4 (00) 6 (7) 4 (64) 0 (9) (9) CR: complete response; PR partial response; NR: no response. * Includes squamous cell carcinoma vagina, renal cell carcinoma, melanoma, and adenocarcinoma prostate.

4 No. TREATMENT OF CANCER USING GRID Mohiuddin et al. 7 FIG. 3. Massive retroperitoneal liposarcoma of left psoas origin (posttreatment). Discussion Nonconfluent multiple pencil beam radiation therapy (GRID), or spatially fractionated radiation (as opposed to dose/time fractionation) is a technique that has been utilized in the treatment of cancer as far back as 909. First, Kohler4 in Germany, and then Liberson in the United States ( 933), independently described irradiation through a perforated screen (k., irradiation with multiple small pencil beams that are interrupted with regularly spaced blocked areas like a screen or sieve ). Orthovoltage ( KVP) xrays were the only available means of radiation therapy in the first half of this century. The lack of skin sparing and poor depth doses initiated the development of innovative techniques to treat large, deeply seated tumors to high doses without prohibitive damage to the overlying structures. The GRID approach was then used to treat these cancers including head and neck, lung, esophagus, and pelvis.6* Extensive clinical experience with the GRID approach indicated that small nonconfluent (less < cm in diameter) areas of the skin and subcutaneous tissues could tolerate radiation doses in the range of,000 to 0,000 rad without necessarily producing significant acute or late normal tissue damage. 3l0 Therefore, the clinical basis of using the GRID with orthovoltage radiation was to minimize radiation effect in the superficial tissues while taking advantage of the side and back scatter properties of the lowenergy radiation to deliver a more homogenous dose at depth in tissues. However, after the development of megavoltage radiation with its better depth dose distribution and skinspar ing properties, the use of GRID fields as a means for improved physical dose delivery became obsolete. Yet, the radiobiologic principles that enable spatially fractionated high doses to be given have not received much attention except in brachytherapy applications. Even here, most attention has been given to low activity sources delivering low dose rates over prolonged treatment times. More recently, remote afterloading, highdose rate brachytherapy applicators have been developed. They have again shown that spatially fractionated radiation allows safe delivery of higher doses without exceeding normal tissue tolerance. lo We have adapted these same principles for use with megavoltage radiation as a method for delivering high integral doses of radiation. The nonuniform distribution of radiation with alternating highdose and lowdose regions seems to allow for the delivery of these higher integral doses. We have used this premise and delivered megavoltage radiation in multiple nonconfluent pencil beams (GRID) as an externalbeam simulation of remote high activity afterloading systems. Our initial experience with the patients treated in this study is unique. All of these patients were considered to have advanced disease unlikely to be helped with any form of conventional therapy. The overall tolerance of our patients, in spite of the large fraction sizes given, was extremely good and clearly could not have been obtained with openfield radiation to similar dose fractions and field sizes. Of patients, 8 patients had no acute side effects, three patients had minimal effects and only two patients treated for massive liver disease showed any significant nausea or vomiting. None of the patients have developed any longterm complications. This includes patients who had the GRID treatment given to the abdomen and/or the pelvis, and only one of these patients developed any signs of small bowel obstruction. Response to treatment was impressive and far exceeded all expectations from the initial goals of therapy. Clinical responses (palliation of symptoms and objective regression) was observed in 0 of patients (9%) with six of (7%) having complete relief of their symptom complex. Figures and 3 represent pretreatment and posttreatment responses after treatment in a patient with massive liposarcoma involving the left psoas and retroperitoneum. Several of the patients had short survivals due to other areas of progressive disease. Thus their followup was only to 3 months, but 4 patients have been followed from 3 to 8 months, and three of these patients are alive greater than year. The duration of response has been durable. Our treatment technique should not be confused with the hemibody technique used to palliate large more diffuse metastatic disease (i.e., bone metastases). The GRID is rather an attempt to focus in on large bulky soft tissue

5 8 CANCER July 990 Vol. 66 tumors that have not, or will likely not, respond to our usual treatment approaches. However, the response rates of hemibody do parallel ours, as reported by the Radiation Therapy Oncology Group, with 0% CR and a 66% PR rates, but hemibody treatment was associated with 0% lifethreatening toxicities whereas our GRID treatment had none. Thus, both may have a unique place in our arsenal against advanced cancer. In summary, the adaptation of spatially fractionated radiation to megavoltage photon beams has allowed us to add a new dimension to the care and support of patients with massive or bulky tumors, and of patients who have exhausted conventional modalities of treatment. At the same time, it is an exciting new concept to explore in the treatment of locally advanced cancers where conventional approaches to treatment have met with less than spectacular success. It has significantly improved the quality of life of patients without adding the burdens of acute toxicity and f or tissue damage. REFERENCES I. Jolles B. Further Considerations in xray sieve therapy. Br JRadiol 954; Loevinger R. GRID Therapy VII: I. Physical Part. Monograph 960, pp Mitev G, Suntharalingham N. Semiempirical calculation of dose distributions for high energy photon beam Grid therapy (Abstr). Med Phys 986; 3: Kohler H. Rontgentiefen Therapie mit Massendosen. MMW 909; 56: Liberson F. Value of multiperforated screen in deep xray therapy. Radiology 933; 0: Marks H. New approach to roentgen therapy with use of GRID Preliminary report. JMt Sinai Hosp 950; 7: Marks H. Clinical experience with irradiation through a GRID. Radiology 95; 58: Hams W. Recent clinical experience with the GRID in the xray treatment of advanced cancer. Radiology 95; 58: Jolles B. The study of connectivetissue reaction to radiation: The sieve or chess method. Br J Cancer 949; Vahrson H, Rautive G, eds. High Dose Rate Afterloading in Treatment of Uterus, Breast, and Rectum. Proceedings of an International Symposium, Giessen, 986. Munich, Vienna and Baltimore; Urban and Schwarzenberg, 988.