Experience with Hodgkin's Disease in a Radiotherapy Department at an Indian Hospital

R Kaul, M Gairola, S Gupta, BK Mohanti
Department of Radiotherapy,
Institute of Rotary Cancer Hospital,
All India Institute of Medical Sciences, New Delhi-110029, India

Introduction

The radiosensitivity of Hodgkin's lymphoma (Hodgkin's disease; HD) was discovered by Gilbert in 19391 a milestone in the development of curative treatment for HD. Gilbert found that high dose radiotherapy to the area of involvement and contiguous nodal sites improved survival.¹ Incorporat-ing Gilbert's principle, Peters found that cure of HD was possible for patients who received only radiotherapy as a sole treatment modality.²

During the past 2 decades, many trials have shown that combined modality protocols confer improved disease-free survival. In recent years, the prescribed radiotherapy dose has shifted to low dose treatment in combination with chemotherapy. The overall survival (OS) found in 1960 was 40% and in the late 1980s was 75%. Currently, the OS has risen to 95%. This improvement is basically due to refined diagnostic criteria, improved staging techniques, and advances in radiotherapy techniques and chemotherapy schedules.

The objective of our study was to evaluate our experience of treating HD at the department of radiotherapy at the All India Institute of Medical Sciences, India.

Materials and Methods

A retrospective review was conducted in 172 patients with HD treated with definitive radiotherapy and chemotherapy from 1985 to 1995. All patients underwent clinical staging procedures, including chest radiograph, computed tomography of the chest and abdomen if needed, bone marrow biopsy for patients with stages III and IV disease and high-risk patients, and blood chemistry tests. The disease of each patient was staged according to the Ann Arbor staging system. The histology was classified according to Rye's classification. Radiotherapy field and doses varied in our study depending on the disease status, patients' general condition, Karnofsky performance score (KPS), and chemotherapy regimen.

The standard mantle field included all lymph nodes below the mandible and above the diaphragm. Extended mantle included mantle, splenic pedicle, and para-aortic field. Minimantle included bilateral cervical, supraclavicular, and axillary lymph nodes. Inverted Y fields included the inguinal, femoral, pelvic, and para-aortic nodal area. The involved field included diseased nodal sites and first echleon nodal drainage. The energy used was 4 MV, 6 MV, and cobalt 60. The radiotherapy doses delivered were 25 Gy/15# to 45 Gy/25# depending on the state of disease, KPS, and chemotherapy regimen. Chemotherapy was given to patients with symptoms of fever, night sweats, loss of weight, and to all patients with disease above stage I. The most frequently used chemotherapy regimens were COPP (cyclophosphamide, vincristine, procarbazine, prednisone), ABVD (adriamycin, bleomycin, vinblastine, DTIC), or the latest hybrid regimens.

Results

Of 172 patients, 120 were male and 52 female. The stages at which the patients presented are listed in table 1. The histological classification is given in table 2. The various radiotherapy schedules and fields used are shown in table 3. The overall survival of the patient population was 76% at 5 years and relapse-free survival was 61%. Relapse-free survival was analysed with regard to various prognostic factors but only the stage and number of nodes involved were found to be significant.

Table 1. Distribution of Stages at Presentation

Table 2. Distribution of Histological Classification (Ryes')

Salvage therapy in the form of radiotherapy was given to 13 patients to alleviate symptoms of pain and respiratory distress. Salvage chemotherapy was given to 36 patients, and 4 patients received both treatment modalities as palliative therapy. No data is available for 10 patients. Analysis of the cause of death revealed that 20 patients died due to HD and 30 died of intercurrent disease. The remainder received radiotherapy and/or chemotherapy with curative intent.

Pattern of Failure

20 patients had in-field recurrence, 5 had marginal miss either due to the block used in portals or the involved area received less than the prescribed radiotherapy dose. 20 recurrences were documented outside of the initial nodal involvement area. Pelvic failure was only seen in 3 patients with supra diaphragmatic disease. Two patients had bone marrow relapse.

Complications

The most commonly found acute complications were pneumonitis and Lhermitte's phenomenon, and the long-term complications were hypothyroidism in 6 patients, second malignancies in 2, bowel symptoms in 4, oesophageal symptoms in 3, dental problems in 2, and sepsis in 6.

Discussion

The prognosis for HD has improved dramatically in the past 3 decades, mainly due to the emergence of new, improved radiation therapy techniques and effective multi-agent chemotherapy. However, salvage radiotherapy can only be given in a palliative setting, and is not curative. Our survival results are inferior to those quoted by western countries. The possible reasons for this are our socio-demographic profile, illiteracy, long distances from patients' homes to the referral hospitals, and poor primary health service infrastructure. For these reasons, patients are not followed up and our survival data worsens.

A pattern of care survey performed from 1973 to 1983 had reported that the poor outcome was related to the use of limited field radiation, source skin distance < 80 cm with cobalt 60, and absence of meticulous simulations.³ Kinzie et al. demonstrated in 1973 that the outcome of treatment was directly related to the adequacy of the portal margins.³ In 1983, a pattern of care survey revealed that the outcome of treatment had improved due to better techniques, use of a linear accelerator, better simulations, and improved patient selection. These results have particular importance since they represent national averages across a broad spectrum of treatment facilities. The data suggest that an 85% cure rate for early stage HD can be achieved with radiation alone.

Table 3. Radiotherapy Prescription Given in This Study

Substantial data document increased normal tissue damage in HD with increasing daily and total doses of radiation. The probability of musculoskeletal hypoplasia in children was noted at 35-40 Gy and the incidence of pericarditis was higher at 30 Gy in patients who did not have a subcarinal block. The probability of subclinical hypothyroidism appears to be dose related, with a rate of 44% after doses of > 30 Gy compared with 27% after doses of 30 Gy.⁴ Abdominal injury was high in the pattern of care study after doses of > 35 Gy.⁵ Some data suggest that the incidence of a second malignancy increases with doses > 30-40 Gy.⁶

Fletcher and Shukovsky concluded that the dose response curve was sigmoid in shape with little additional local control achieved with doses > 30 Gy.⁷ Two multi-centre studies analysing similar data from a number of sources differ in conclusion about dose and in-field recurrence. The first analysis found evidence of 98% in-field disease control for subclinical disease, tumours < 6 cm, and tumours > 6 cm with doses of 32.4 Gy, 36.9 Gy, and 37.4 Gy, respectively.⁷ The second analysis found no evidence of disease control with doses > 32.5 Gy.⁸ A randomised trial has now demonstrated no difference in subclinical disease control for doses of 30 and 40 Gy and the optimal dose may be in the range of 25-30 Gy. This difference in dose relating to disease control at < 35 Gy or > 35 Gy is consistent with the concept of a sigmoid dose response curve by Fletcher and Shukovsky.⁷ This study suggests that the relevant dose range in the steep part of the dose response curve and follow-up plateau may vary with tumour volume. The plateau after the steep part for small volume is 30 Gy, for subclinical disease < 30 Gy, and for large volume > 35 Gy. The addition of chemotherapy affects the entire dose response curve, at least in moderate volume disease. Numerous reports show the increase in toxicity is greater at 35 Gy and suggest there is a clinically relevant separation between the dose response curves for tumour control probability and normal tissue tolerance that decreases with increased volume, providing a rationale for the optimal dose.

Conclusion

Our data reflect the results of doses in the range of 30-35 Gy for the involved area, tumour < 6 cm, and 25-30 Gy for areas at risk. Patients at poor risk or with bulky disease are best treated by radiotherapy in conjunction with chemotherapy.

References

1. Gilbert R. Radiotherapy in Hodgkin's Disease. Am J Radiol 1939; 41:198-241.

2. Peters MV, Middlemiss K. A study of Hodgkin's disease treated by radiation. Am J Radiol 1958; 79:114-121.

3. Kinzie JJ, Hanks GE, Maclean CJ, et al. PCS: Hodgkin's disease relapse rate and adequacy of portals. Cancer 1983; 52:2223-2226.

4. Hoppe RT, Hanol A, Hanke SG, et al. The management of bulky mediastinal Hodgkin disease. Hematol Oncol Clin N Am 1989; 3:265-276.

5. Hoppe RT, Coleman CN, Cou RS, et al. The management of stage I-II HD with RT or combined modality. Stanford experience. Blood 1982; 59:455-465.

6. Rodriguez MA, Fuller LM, Zimmerman SO, et al. Hodgkin's disease: study of treatment intensities and incidences of second malignancies. Ann Oncol 1993; 4:25-131.

7. Fletcher GH, Shukovsky LJ. The interplay of radiocurability and tolerance in RT and human cancer. J Radio Electrol 1975; 56:383-400.

8. Dutcher J, Wierke PH. Combined modality treatment of Hodgkin disease confined to nodal areas. Dev Oncol 1985; 32:37.