Medicine is in many ways synonymous with progress. Whether through pure quackery or well-considered therapies, physicians throughout the centuries have sought to apply the best of contemporary medical knowledge to develop therapeutics with what was within reach.  While many, many medical theories have been disproven and discredited, their existence points to the never-quenching thirst that humanity has to move forward, to change things for the better, to improve the status quo. 

This spirit of innovation, baked into the human spirit, has turned many diseases once deemed fearsome and incurable into something that can be readily treated today. For example, leprosy, a vague skin disease mentioned in the Bible, was once considered so infectious and incurable that lepers had to live by themselves, separate from society, in a leper’s colony. Today, leprosy in its various forms are easily treatable. How does such a miracle of a change occur? Through the relentless spirit of medicine, always striving ahead, steeped in self-belief, never deterred.

Read more about DLBCL etiology 

Some clinicians hence see fit to chart the evolution of therapies for a particular disease to better appreciate how far we have come. This was the case with Rojek and Smith, who published a study in the Blood Cancer Journal detailing the evolution of treatment for limited-stage diffuse large B-cell lymphoma (DLBCL) in the past few decades. 

Before the availability of 19th-century diagnostic tools, DLBCL was practically undiagnosable, especially in ancient times. Its signs and symptoms may become evident over time, but physicians from antiquity had no way of putting a name to the disorder. DLBCL as a component of non-Hodgkin lymphoma was only identified in the 1800s. 

“The modern approach to the treatment of limited-stage DLBCL was influenced by SWOG 8736,” Rojek and Smith wrote. “This phase 3 trial, conducted in the prerituximab era (1988–1995), established combined modality therapy as a standard of care in the prerituximab era.” 

This landmark study demonstrated that 3 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) with radiation therapy was a combination that was noninferior to 8 cycles of CHOP without radiation therapy. This led to the incorporation of radiation therapy for patients with limited-stage disease, a practice that continues to this day. 

Treatment Down the Ages 

Before we enter into discussions on how limited-stage DLBCL is treated today, it is worth appraising how DLBCL was treated in the prechemoimmunotherapy and prepositron emission tomography (PET) era. 

During this time, physicians were most concerned about evaluating the difference between modality therapy vs chemotherapy alone. Some studies in the early 1900s demonstrated that chemotherapy alone was sufficient for resulting in excellent outcomes. Nonetheless, there was debate about the optimal dosage of chemotherapy regimens. 

When chemoimmunotherapy was introduced into the picture (namely rituximab), scientists observed an increase in survival across all stages of DLBCL. This led to the incorporation of rituximab into 3 cycles of CHOP with radiotherapy. Because PET imaging was not yet available for staging, physicians had different methods to assess treatment response, including the presence of bulky disease. 

With the availability of rituximab, there was considerable debate about whether radiotherapy was still needed. Studies yielded conflicting results, but evidence overwhelmingly supported the exclusion of radiotherapy in nonbulky disease if rituximab is prescribed, mainly because radiotherapy had no impact on prognosis then. 

Read more about DLBCL treatment 

When PET imaging became available, it quickly became the gold standard for tracking disease progression and for making management decisions in DLBCL. Like a window into the human body, PET imaging was heavily used in 3 clinical areas: the staging of the disease, end-of-treatment assessments for prognosis, and investigations into treatment response. 

“This PET-adapted approach successfully reduced the number of chemoimmunotherapy cycles and the need for radiation with equivalent and excellent outcomes,” Rojek and Smith wrote. 

With the choice of drugs expanding and the availability of the PET scan as an important clinical tool dictating management, clinicians had in their possession the building blocks for what constitutes modern DLBCL care today. 

Limited-Stage DLBCL Care Today 

R-CHOP (rituximab + CHOP) can cure more than 80% of patients with limited-stage DLBCL, making it one of the most potent therapeutic options for this disorder. Rituximab-era evidence, as alluded to earlier, gave birth to 4 key strategies: combined modality treatment (R-CHOP + radiotherapy), 6 cycles of standard R-CHOP, 4 cycles of R-CHOP with 2 additional rituximab doses, and PET-directed therapy, which normally translates to 3 to 4 cycles of R-CHOP, followed by radiotherapy or further R-CHOP for PET-positive patients. 

“Limiting the number of cycles of chemotherapy may be desirable in patients with comorbidities and poor tolerance to systemic therapy or in patients with favorable prognostic features in whom extended chemotherapy may be unnecessary, whereas avoiding [radiotherapy] may be desirable depending on the location and extent of disease and concern for acute and long-term risk,” Hawkes and colleagues wrote in Blood. 

Notice that many of the treatment regimens of today were refined during the period when rituximab was first introduced, followed by PET imaging. Today, scientists are looking to use PET imaging to further refine treatment strategies by assessing risk and predicting treatment results. 

“Refining PET-adapted approaches . . . may improve both prognostic assessment accuracy and adaptive management strategies, yielding better outcomes in the future,” the study authors concluded. 


Rojek AE, Smith SM. Evolution of therapy for limited stage diffuse large B-cell lymphomaBlood Cancer J. Published online February 24, 2022. doi:10.1038/s41408-021-00596-z

Hawkes EA, Barraclough A, Sehn LH. Limited-stage diffuse large B-cell lymphomaBlood. Published online February 10, 2022. doi:10.1182/blood.2021013998