OF HODGKINíS DISEASE

SUMMARY *

Flow chart *

BACKGROUND *

PROTOCOL *

CASE RECORD FORMS *

This protocol includes early stages, i.e. stages I and II without B-symptoms, of adult (18-70 years) patients with Hodgkin's disease (HD). Basically, most patients will be treated with a limited, risk adapted number of chemotherapy courses followed by involved-field radiotherapy without any staging laparotomy.

Separate guidelines are given for supradiaphragmatic and infradiaphragmatic presentations.

Separate guidelines are also given for lymphocytic predominance (LP) histology and for the other histologies, lymphocyte-rich classical HD (LR-CHD, previously usually included among LP-HD which now only includes the nodular paragranuloma), nodular sclerosis (NS) and mixed cellularity (MC). Lymphocytic depletion (LD) is not included - if they occur, they are recommended to be treated as advanced HD.

In the major group of patients, supradiaphragmatic LR-CHD, NS and MC histologies, separate guidelines are given for patients without any risk factor and with one or several risk factors. In these patients, risk factors are (note that other risk factors are used in other subgroups):

• bulky disease
• three or more lymph node regions involved
• erythrocyte sedimentation rate (ESR) ³ 50 mm

Although this protocol gives a clear description of the recommended treatment, it is important to remember that other factors may also be of importance for the choice of therapy in an individual patient.

Treatment for patients without any risk factor is two courses of an antracycline containing regiment (preferably ABVD or alternatively MOPP/ABV) followed by involved field radiotherapy (IF-RT, 30 Gy) unless a considerable residual mass is remaining after the chemotherapy. In those instances, the dose should be increased to 35 Gy to the residual mass and for patients with risk factors, four courses of chemotherapy followed by IF-RT.

Patients with LP-HD in stage IA, the most common presentation in LP-HD, without any risk factors are recommended to be treated with RT alone.

The patients will be prospectively registered and continuously followed in order to be able to evaluate the principles also in the long run. All patients in these stages with HD in the Nordic countries, i.e. also patients not treated according to the recommendations, should be registered.

Flow chart

With modern radiotherapy and chemotherapy together with appropriate staging, approximately 75% of all young patients with Hodgkinís disease (HD) are cured of their disease . These results are particularly favourable in those stages where the disease is limited to one side of the diaphragm, or stages I + II, particularly if no B-symptoms are present. Today it can be expected that more than 90% of these patients will be long term disease-free survivors.

Traditionally, patients in the early stages have been treated with radiotherapy alone . It was early noticed that the number of recurrences became less when larger radiation fields were used compared to when only involved areas were treated. These results have also been seen in a number of randomized trials. Long term overall survival has, however, not been significantly improved in these trials, since salvage chemotherapy after radiation failure is usually very effective . During the late 70ís and early 1980ís, it was recognised that certain patients, even if the disease was anatomically limited, i.e. stages I + II, had high recurrence rates after radiation alone. For example, patients having B-symptoms, those with bulky disease and those with several involved sites recurred more frequently, sometimes by more than 50% even if extended-field radiation was given . Also histologic subtype (MC higher than NS histology), and the level of certain laboratory values have indicated higher recurrence rates. Most of these prognostic factors are correlated with, and ultimately reflect, the patientís total tumour burden .

It was also early recognized that combinations of radiotherapy and chemotherapy resulted in a significantly reduced number of failures. None of the studies have, however, shown that overall survival is superior in the initially combined treatment group, since the results with salvage chemotherapy after radiotherapy are good. This was clearly substantiated in an overview where individual data of 1688 patients in 13 trials of radiotherapy with or without chemotherapy were reviewed . The risk of recurrence was halved after the addition of chemotherapy, but overall survival was not significantly improved.

The results indicate that in early stages, only about 10% of the patients are expected to die from HD. Results from large co-operative groups after prolonged follow-up indicate, however, that long-term survival is not so favourable. These and other studies have shown an increased risk of late, sometimes fatal complications, above all secondary malignancies and cardiac toxicity . The magnitude of these fatal complications are still poorly known, although certain reports indicate that they may be large and that within a 20-30 year period, more patients with early stage HD will die from complications than from HD .

Patients in early stages without risk factors have, with few exceptions usually been treated with irradiation alone in the Nordic countries . Most patients have been treated with the mantle technique. At certain centres, some patients have got radiation also to the paraaortic regions (STNI) whereas at other centres, selected patients have got even less extensive radiotherapy (mini-mantle). After an adequate clinical staging procedure, i.e. without staging laparatomy and splenectomy, it can be expected that about 20% of these patients will recur. This figure is, however, dependent upon selection criteria. Most of the recurrences appear in the abdomen. If staging laparatomy with splenectomy is done prior to the treatment, it is likely that recurrence rate is slightly lower, or about 10%. It is also likely that the recurrence risk is lower if the patients are treated with STNI rather than mantle. Independently of primary treatment very few patients will die from HD since, as mentioned above, chemotherapy after failure is usually very effective.

It has generally been accepted that certain subgroups of patients initially require treatment with both chemotherapy and radiotherapy in order to keep the proportion of patients recurring at a sufficiently low level. The combined treatment has then usually consisted of a full course of chemotherapy, i.e. about 6 months of treatment, preceded or usually followed by radiotherapy. In certain studies, particularly from the Nordic countries, the chemotherapy has been limited in the number of courses .

Between 10 - 15% of early stage HD are primarily localized below the diaphragm. As a group, infradiaphragmatic HD patients are generally slightly older and more often men, and bulky disease and MC are more frequently seen than in supradiaphragmatic HD. This appears to be particularly true for those with an abdominal as opposed to inguinal presentation. Some groups have reported that the prognosis for infradiaphragmatic HD is worse than supradiaphragmatic HD, but most groups tend to agree that, stage by stage, the prognosis is the same .

Using modern staging and treatment principles, histologic subgroup has lost its prognostic relevance . The natural course of the disease differs, however, between the subgroups. This appears to be particularly true for LP-HD. During the latest years, an international collaborative group, in which several Nordic groups participated, has collected a large number of cases originally classified as LP-HD and made a thorough clinico-pathologic investigation. Applying strict morphologic criteria, approximately 3% of all HD cases constitute a distinct group of 'true' LP-HD. This group was previously often designated nodular paragranuloma. It can be separated from the other classical HD subgroups NS and MC and from a group now designated lymphocyte-rich classical HD (LR-CHD) constituting about one third of the cases originally classified as LP-HD. It is also distinct from low-grade follicular NHL although several common features exist. Due to particular clinical features like indolent presentation, slow time to progression and delayed time to relapse, there is now international consensus that treatment of LP-HD (nodular paragranuloma) should be separated from the other 'classical HD' subgroups. There is also one report indicating that MOPP-like regimens may be more effective than ABVD-like regimens in LP-HD .

With 5-10 year overall survival figures approaching or exceeding 90% in early stages of HD, it is unlikely that further improvements in treatment results will be achieved. Since it has been clearly recognised that both the acute and long-term toxicity after these treatments are substantial, there is a need not to over-treat too many patients. In the light of the excellent results, and the knowledge that certain patients can be rendered long-term disease-free survivors with less treatment than previously given, a need to reduce treatment intensity, without compromizing the anti-tumour effect is necessary. Above all, it appears necessary to particularly reduce the amount of treatment that, with the present knowledge, may cause late toxicity.

The very favourable treatment results together with the fact that the relevant endpoints to study sometimes do not occur until after several decades have complicated the design of new trials. A working group with representatives from all countries (except Iceland) made suggestions for trials that have been discussed during more than one year. It was then recognized that the total number of eligible patients in the Nordic countries is rather limited. For example, if a protocol in patients without risk factors suggesting randomization between mantle (in some presentations less than mantle) and two chemotherapy courses (ABVD or MOPP/ABV) + IF-RT had been accepted by all centres, a completion time of at least five years would have been required in order to reach sufficient power to exclude meaningful differences. Co-operations with other groups internationally would then be necessary. During early 1998, such co-operations were also extensively looked for.

a) A prospective study protocol defining treatment strategies in subgroups of patients, in principal one group without and one group with risk factors. Complete registration, possible in the Nordic countries, will enable valid conclusions about short-term and long-term outcome.

b) In patients without risk factors, it was possible for a centre covering a defined population to join either a UK, an EORTC and a GHSG protocol (see flow sheet).

c) In patients with risk factors, it was likewize possible to join either an EORTC protocol or a GHSG protocol.

Some of the treatment arms in the European trials adhered to the interest of several Nordic centres, and some were, in fact, identical to the Nordic principles, but it turned out not to be realistic to get general acceptance for either of the protocols. Therefore, the working group, after national consultations has decided to create a Nordic protocol. The protocol recommendations are to treat all patients except certain LP-HD with a limited, risk-adapted number of chemotherapy courses followed by radiotherapy. The radiotherapy should be given only against macroscopically known disease at presentation.

This protocol includes patients living in the Nordic countries with

1. Stages I + II A

2. Between 18 and 70 years of age.

3. Histologically proven HD, LP, NS, LR-CHD and MC histology

4. No previous treatment

All patients fulfilling the above mentioned criteria should be centrally registered using separate sheets. This registration will first occur in each country and then jointly at the Regional Oncological Centre in Uppsala. The Case Record Forms are included.

Mandatory investigations

1. Biopsy to confirm the diagnosis of HD and subsequent central review.
2. History, full physical examination, height and weight.
3. Ear, nose and throat inspection. Biopsies only in case of suspect changes.
4. Laboratory investigations.

• Haemoglobin, leukocytes including differential white cell count and trombocytes
• Erythrocyte sedimentation rate (ESR)
• Electrolytes, S-Albumin, S-Creatinine, S-Urate, Serum hepatic enzymes including S-Bilirubin, S-ALP, S-ASAT (optional), S-ALAT, and S-LDH.

1. Chest x-ray.
2. CT (MRT) scan of chest, abdomen and pelvis. The CT (MRT) scan should always include primarily involved site (s), i.e. often also the neck region. The axillae should also be investigated. More enlarged lymph nodes than those palpable will be detected. Needle biopsies should be performed when unclear findings are detected.
3. Ultrasonography of abdomen. It is required that two abdominal investigations should be performed and found to be without evidence of HD. See . Note that needle biopsies should be performed with the aid of CT or ultrasonography in case any unclear finding is seen .
4. See also page 11 under evaluation of late effects.

Optional investigations

1. Bone marrow aspirate/trephine biopsy.
2. Isotope bone scanning if there is bone pain or elevated S-ALP.
3. Other abdominal investigations like lymphangiography and liver and spleen isotope scanning.
4. Test for HIV (this is recommended to be done in all cases).
5. Gallium scintigraphy.

Other investigations

1. Odontologic investigation with adequate prophylactic advice and treatment of a poor dental status is recommended to be done in all patients and not only in those where radiotherapy towards the oral cavity will be performed.
1. Pneumococcus vaccination (optional).
1. Cryopreservation of semen.

It is not completely known whether male fertility will be preserved after two courses of MOPP/ABV. The risk of infertility should thus be discussed with the patient and cryopreservation offered. If the preservation of fertility is essential, ABVD should be the preferred treatment.

Bulky disease is defined as, either a mediastinal mass ³ 0.33 of the internal thoracic diameter measured at the level of the TH 5-6 interspace on a PA chest x-ray and/or a mediastinal and/or hilar mass exceeding 10 cm in the largest diameter on a CT-scan of the chest, or a peripheral or abdominal lymph node conglomerate exceeding 10 cm in the largest diameter.

Patient entry is on the basis of local histology performed by a hematopathologist. When the patient is registered, representative blocks or unstained sections will be requested by the trial offices in each country for central histology review. The practical details of this will be further discussed.

Supradiaphragmal classical HD (LR-CHD, NS, MC)

1. Bulky disease (for definition, see above)
1. Three or more involved sites
1. ESR ³ 50 mm

Two courses of chemotherapy, either ABVD or MOPP/ABV (see below) followed by involved field radiation. The involved field radiation is given to primarily involved sites with margins (see examples). The dose should be 1.76 Gy x 17 = 30 Gy to the entire volume. If the response to the chemotherapy is poor (less than PR of peripheral sites), two more courses could be given. Further, if residual tumour is present prior to the start of radiotherapy, the dose can be increased to 35 Gy (3 more fractions) to the site of the residual tumour with a margin of 3 cm.

Four courses of chemotherapy, either ABVD or MOPP/ABV followed by involved field radiation as above. Additional two courses, or an alternate regimen, could be given if the response is poor.

It should be noted that patients with B-symptoms are not included in the protocol. It is recommended that patients in stage I B are treated in the same way as patients in stages I + II A with risk factors, i.e., as described above with four courses of chemotherapy followed by involved field radiation. Alternatively, they may be treated as advanced stage HD. Patients with stage II B should be treated as advanced stage HD (stages III-IV).

1. Bulky disease (for definition, see above)
1. Central/pelvic location
1. Stage II
1. ESR ³ 50 mm

Two courses of chemotherapy, either ABVD or MOPP/ABV followed by involved field radiation. The involved field radiation is given to primarily involved sites with margins (see examples). The dose should be 1.76 Gy x 17 = 30 Gy to the entire volume (35 Gy if residual tumour is present prior to the start of radiotherapy).

Four courses of chemotherapy, either ABVD or MOPP/ABV followed by involved field radiation as above.

1. Bulky disease
1. Two lymph node regions that are not adjacent to each other
1. More than two lymph node regions
1. ESR ³ 50 mm

Involved field radiotherapy to 30 Gy alone.

Two or four courses of chemotherapy, preferably MOPP/ABV or MOPP alone followed by involved field radiotherapy to 30 Gy. Two courses are given if the only risk factor is number 2, whereas four courses are recommended if any of the other risk factors are present.

For all patients, remission status will be assessed after two (and four) chemotherapy courses, i.e. prior to the radiotherapy, and one month after the completion of all treatment. Physical examination will be combined with a repeat CT scan to determine a response category:

• Complete response (CR). Normalization of previously abnormal investigations
• Complete response unconfirmed (CR(u)). Minimal residual abnormality on chest x-ray/CT scan .
• Partial response (PR). A reduction of at least 50% and no new lesions.
• Progression. 25% increase in the product of two orthogonal diameter measurement of any lesion or the development of new lesions.
• No change. A response intermediate between progression and partial response.

Following completion of all treatment, patients will be seen after one month and then three monthly in years 1 and 2, four monthly in year 3, six monthly in years 4 and 5, annually between 5 and 10 years and every other year there after (see below for women irradiated to parts of the breasts before 30 years of age). At each follow-up visit, patients should be examined for evidence of recurrent disease and blood should be drawn for a full blood count and ESR. Any symptoms of concern should be investigated appropriately.

One year after the end of treatment, primarily positive investigations should be repeated. This often means a CT investigation of the chest. In addition, an abdominal investigation, CT or ultrasonography is recommended one year after treatment.

Since long-term freedom from late effects is an important endpoint in the protocol, it is recommended that patients are investigated prior to any therapy in order to obtain a baseline value and not just during long-term follow-up.

• Heart

Electrocardiogram (ECG) and echocardiogram/Doppler prior to treatment, after 5 years and then every 3^rd year unless symptoms indicate other investigations. A myocardial scintigraphy is recommended in case of precardial pain/distress.

• Lungs

Spirometri prior to treatment, after 5 years and then every 3^rd year. If spirometry shows abnormal signs or the patient has lung symptoms lung scintigraphy is recommended to reveal ventilation and/or perfusion abnormalities.

• Testis/ovary

In males (except LP without risk factors), tests for sperm function prior to and 3 - 6 months after the end of treatment, and in case of oligo/azoospermia, then once a year if the patient agree. In females, careful menstruation anamnesis prior to and after treatment. In women with a premature menopause a liberal policy for hormone substitution should be applied. Hormonal analyses (FSH, LH and testosterone/oestrogen) prior to and after treatment and then yearly. If normal levels are seen for 2 years, no further tests are indicated.

• Thyroid

Serum-TSH should be controlled yearly in all patients irradiated against the thyroid, even if the patient has no clinical hypothyroid symptoms. Appropriate substitution should be given if S-TSH increases.

• Second malignancy

No firm recommendations when to start mammography in patients irradiated towards the breasts can presently be given. Patients included in the protocol will, unless firm knowledge will appear, be followed accordingly:

Patients irradiated towards any parts of the breasts before 30 years of age should be examined yearly beginning10 years after irradiation. At every clinical control, a careful palpation of the breasts should be done. Mammography will be performed in patients above 30 years. If the mammography is difficult to evaluate, add an ultrasonography and then follow the patient with ultrasonography. In women below 30 years of age, ultrasonography (or MRT) will be performed.

Relapse should be confirmed histologically whenever possible. Treatment of relapse should preferentially be with a standard doxorubicin containing chemotherapy combination. A "limited" relapse outside previously irradiated areas could occasionally be treated with radiotherapy alone, particularly if the recurrence occurs late (beyond 2 years). Otherwise, it is not possible to clearly define relapse treatment since this may change during the study period and follow-up.

Chemotherapy

The chemotherapy combination is permissive, but should be a "modern" doxorubicin containing regimen. Two combinations, ABVD and MOPP/ABV can primarily be recommended. It is possible that ABVD has the most favourable toxicity profile in these groups of patients, and therefore will be preferred by most centres.

The most optimal regimen to be used in early stages prior to radiation is not known. In advanced stages, several recent trials have added new knowledge about anti-tumour effects and to some extent also about late effects.

It is the opinion by the working group that a regimen with high activity in advanced HD should be used also in the early stages, provided its adverse effects are not too excessive. A schematic illustration of the antitumour activity based upon randomized trials in advanced stage HD is shown in Table 1. Based upon the most recent GHSG trial, it is likely that BEACOPP (escalated superior to basic) has the best antitumour effect. The use of BEACOPP in early and intermediate stages outside a randomized trial is, however, not recommended because of an unfavourable toxicity profile (concerns about a high risk of MDS/AML). The slightly inferior regimens in advanced HD, e.g., ChlVPP, EBVP and VAPEC-B have less acute and potentially also late toxicity than the standard regimens, but whether this outweighs their less antitumour activity is not known. Of the standard regimens, ABVD will be preferred by most researchers, but in combination with mediastinal radiotherapy, concerns about late lung- and heart toxicity can be expressed. However, using MOPP-ABV hybrid (MOPP/ABVD is not recommended since it contains both alcylating agents, procarbazine and dacarbazine), concerns about late AML/MDS can likewize be expressed. It is possible that these two regimens are equally good, but that either one can be preferred in individual patients.

Standard ABVD

MOPP/ABVD

MOPP ABV-hybrid

Better BEACOPP

BEACOPP esc

Inferior MOPP (ChlVPP)

EBVP

VAPEC-B

Unproven Stanford V

PVACE-BOP

In this protocol, ABVD and MOPP/ABV are both recommended as standard regimens. In LP-HD, MOPP/ABV is the preferred treatment (or occasionally MOPP alone, but the scientific support for this recommendation is very weak).

It is important that the radiotherapist sees all patients before the start of chemotherapy so that he/she can be fully aware of the initial extent of disease documented on clinical examination and CT scanning. It is particularly important to review CT images of the axilla to ensure that nodes have not gone unreported at this site. With the exception of a nodal mass within the chest that has shrank, the target volume for involved field radiotherapy is the initial extent of disease.

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In patients with early stage HD without risk factors, two chemotherapy courses are given, and in patients with risk factors, four courses. An evaluation of tumour response clinically and with appropriate radiologic technique (CT in most instances) should be done after the second course prior to the start of radiotherapy in patients without risk factors and prior to the third course and after the fourth course prior to the radiotherapy in those with risk factors.

If a patient has no response (SD) to the two or four chemotherapy courses or progresses during the treatment, the treatment strategy must be reconsidered, since the chances that these patients will be cured by additional involved-field radiotherapy may not be very high. The treatment of these patients must be individualized depending upon a number of factors (e.g. change of tumour size, extent of disease, tolerability to the treatment). Alternatives may be additional courses of another regimen, extended-field radiotherapy or high-dose treatment with stem cell support.

The myelosuppressive drugs (Mustine, Procarbazine, Doxorubicin, Vinblastine and Dacarbazine) will be given at full dose and on time if the neutrophil count is > 1 x 10⁹/l and the platelet count is > 50 x 10⁹/l. If less than these values, treatment should be delayed by one week and then restarted at full dose. If the interval cannot be kept intact, growth factor support from day 4 or 3 days after the last chemotherapy is recommended. Dose reductions should be avoided, unless severe or life threatening adverse effects occurred.

The relatively non-myelosuppressive drugs will be given at full dosage irrespective of the blood counts.

Following chemotherapy, radiotherapy should be commenced between 21 and 28 days of the last chemotherapy injection.

All patients should be treated with megavoltage equipment using up-to-date techniques. This means for example that all beams should be treated each day, and adequate compensation filters to compensate for inhomogeneities in tissues should be used. All treatments should be dose planned in at least one representative section (2D). Full 3D planning is desirable but not mandatory in all patients.

Classically, irradiation has been given to 40 Gy . Later studies have, however, shown that this dose is unnecessarily high, and have failed to demonstrate any dose response relationship at doses higher than about 35 Gy . Certain centres have also traditionally treated patients to a dose of 35 Gy with excellent control rates . Other studies have shown that for subclinical disease, a dose of 30 Gy is sufficient .

In this protocol the recommended dose to the internal target volume (ITV, NACP recommendations (Acta Oncol, vol 36, suppl 10, 1997) see below) is 30 Gy to primarily involved-sites after chemotherapy (2 or 4 courses) is given. If there is a residual mass after the chemotherapy prior to the radiotherapy, the dose may, at the discretion of the treating physicians, be increased to 35 Gy to the residual disease. The dose should be prescribed in a representative point in the planned section (volume). If a 3D planning is performed, this usually corresponds to the average dose in the ITV (or planning target volume, PTV).

If radiotherapy, usually mantle irradiation, is given without prior chemotherapy to patients with classical HD outside the protocol, the recommended dose is 35 Gy to primarily involved sites and 30 Gy to primarily non-involved sites.

Involved field radiotherapy means treating the anatomical extent of detectable masses of HD as determined prior to treatment with chemotherapy. The only exceptions to this are if a nodal mass within the chest or within the abdomen at the level of the kidneys has shrunk after chemotherapy. Then the lateral margins can be applied to the residual abnormality. This will permit reduction of the heart and lung radiation, and spare the kidneys or at least reduce the irradiated volume.

The initial extent of disease should be determined, preferably by the radiotherapist, who should see both the patient and the CT scans and other relevant information before the commencement of chemotherapy. It is particularly important to review CT images of the axillae to ensure that nodes have not gone unreported at this site.

To avoid delays, radiotherapy will need to be planned during or just after the last planned chemotherapy course.

There is no intention to treat a whole Ann Arbor lymph node region when it is only partly involved by macroscopic disease.

A 3-cm margin beyond the initially macroscopically involved sites is recommended for the clinical target volume (CTV), except in the mediastinum and/or lung hili where a margin of 1 cm laterally of the remaining expansiveness should be applied. However, the margins of 3 cm beyond the initially macroscopically involved site(s) should be practised cranially and caudally also in the mediastinum. An internal margin including physiological changes such as organ motions should be added around the CTV and an ITV is defined by the outer border of the anatomically adjusted internal margin of the CTV. This ITV corresponds approximately to the PTV as defined in ICRU Report 50 (1993). In order to allow for penumbra and day to day variations in set up, this means that the margins between primarily involved nodes and beam limits will be approximately 4 ñ 4.5 cm except laterally in the mediastinum/lung hili or paraaortally at the kidney level where it will be about 2 cm. At the level of the kidneys, the beams shall at least include the transverse processes of the lumbar vertebrae.

If a boost treatment up to a total dose of 35 Gy is given to residual disease prior to the start of the radiotherapy, the same margins should be used. Thus, in this case, the original detectable mass plus a margin of 3 cm constitutes the initial CTV treated to a dose of 30 Gy and the residual tumour plus the same margin constitutes the CTV treated with an additional 5 Gy.

As far as possible continuous beams should be applied. Since one of the aims with this programme is to reduce the radiotherapy, deviation from this principle should be made if large uninvolved volumes will be irradiated.

In a woman with bilateral inguinal involvement, this principle will mean that both ovaries will be irradiated. Modifications or omittance of the irradiation should then be discussed.

A series of examples of recommended radiotherapy fields are provided in figures.

 

 

CASE RECORD FORMS

Registration

Treatment

Follow-up