Let's talk about a groundbreaking advancement in the treatment of advanced-stage classical Hodgkin lymphoma (cHL). This cancer, a type of germinal center B-cell cancer, has unique challenges due to its aggressive nature and the intensive treatments required. But here's the good news: recent decades have seen a remarkable improvement in prognosis, with a 5-year survival rate now exceeding 80%. This progress is largely thanks to advancements in chemoimmunotherapy and radiotherapy.
The journey of treatment for cHL has come a long way since the early 20th century when radiotherapy (RT) was the primary modality. While RT was effective for early-stage disease, it fell short for advanced stages and came with significant long-term side effects. This led to the development of new treatment regimens, such as MOPP, which was thought to cure nearly half of terminal patients. However, MOPP had its own complications, including a high risk of secondary malignancies, prompting the search for better alternatives.
Enter ABVD and BEACOPP, two treatment regimens that gained prominence in the 1970s and 1980s. ABVD, a combination of doxorubicin, bleomycin, vinblastine, and dacarbazine, was found to be less toxic than MOPP and just as effective in inducing complete remission. BEACOPP, a more aggressive regimen, was developed later and showed superior results in advanced-stage cHL, with a 10-year freedom from treatment failure (FFTF) of 82% compared to 64% for COPP/ABVD.
But it's not just about the treatment regimens; the introduction of functional imaging, specifically fluorodeoxyglucose-PET (FDG-PET), has been a game-changer. Interim PET, performed after just two cycles of chemotherapy (PET2), has proven to be an excellent predictor of treatment response. A negative PET2 result, indicating a Deauville score of 1 to 3, is associated with significantly improved outcomes compared to a positive PET2 result (Deauville 4-5). For instance, in the RATHL trial, patients with negative PET2 had a 3-year progression-free survival (PFS) rate of 85.7%, while those with positive PET2 had a rate of only 67.5%.
The prognostic value of PET2 has been validated in numerous randomized trials and has become a cornerstone of treatment strategies for advanced-stage cHL. By identifying patients who will respond well to standard therapy and those who require more aggressive treatment, PET2 allows for a more personalized approach. This PET-adapted approach is based on risk stratification, where low-risk patients with negative PET2 can have their treatment de-escalated to minimize long-term toxicities, while high-risk patients with positive PET2 can be considered for intensified treatment to improve outcomes.
For example, the HD12 study aimed to reduce the number of EB cycles from 8 to 4, along with omitting RT, which was given to 70% of patients in the HD9 study. While this reduction in chemotherapy dose did not significantly reduce toxicity, it did result in a slight decrease in efficacy. On the other hand, the HD15 study found that 6EB was more effective and less toxic than 8EB, and limited RT to PET-positive residual lesions larger than 2.5 cm. Similarly, the HD18 trial showed that de-escalating treatment to 4 cycles for patients with negative PET2 did not compromise results, with a 5-year PFS of 92.2%.
While some studies, like the GHSG studies, reported benefits in both PFS and overall survival (OS) with EB compared to ABVD, others did not find an OS benefit and even questioned the PFS benefit, highlighting the toxicity concerns associated with EB. This led to the development of new treatment strategies, including the use of novel agents like brentuximab vedotin and immunotherapy.
The ECHELON-1 trial, for instance, showed that substituting bleomycin with brentuximab vedotin (BV-AVD) improved 3-year PFS to 83.1% compared to 76.0% for ABVD. The HD21 trial introduced BrECADD, a modified BEACOPP regimen incorporating brentuximab vedotin, which was found to be safer and more effective than BEACOPP, with a 4-year PFS of 94.3% compared to 90.9% for BEACOPP. The SWOG1826 trial further supported the use of immunotherapy, finding that nivolumab-based treatment (N-AVD) resulted in a 2-year PFS of 92% compared to 83% with BV-AVD.
PET-adapted therapy has revolutionized the treatment of advanced-stage cHL by allowing for personalized treatment approaches. For patients with an excellent initial response (PET2 negative), treatment can be de-escalated to reduce adverse effects while still achieving high survival rates. Conversely, for those with a poor initial response (PET2 positive), intensifying treatment can lead to better disease control and survival benefits. Trials like RATHL, AHL2011, and HD18 have provided strong evidence for this approach, but there are still challenges, such as relapse and the accuracy of PET scans.
The future of PET-adapted therapy lies in combining PET2 imaging with other biomarkers like TARC, CD68, CD163, and IL-10 to more accurately identify high-risk patients. Additionally, the development of new treatments and the continued exploration of immunotherapy offer hope for further improving outcomes in PET2-positive patients. Long-term follow-up is also crucial to ensure that reducing treatment intensity does not compromise long-term survival or increase the risk of secondary malignancies.
In conclusion, PET-adapted therapy has significantly improved the management of advanced-stage Hodgkin lymphoma by tailoring treatment to individual patient needs. While challenges remain, the progress made in recent years offers a promising outlook for patients with this disease.
